WO2004101504A1 - Stereoselective method of preparing gamma-amino vinyl sulphones - Google Patents
Stereoselective method of preparing gamma-amino vinyl sulphones Download PDFInfo
- Publication number
- WO2004101504A1 WO2004101504A1 PCT/ES2004/000218 ES2004000218W WO2004101504A1 WO 2004101504 A1 WO2004101504 A1 WO 2004101504A1 ES 2004000218 W ES2004000218 W ES 2004000218W WO 2004101504 A1 WO2004101504 A1 WO 2004101504A1
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- WO
- WIPO (PCT)
- Prior art keywords
- group
- phenyl
- naphthyl
- alkyl
- preparation process
- Prior art date
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- 230000000707 stereoselective effect Effects 0.000 title claims abstract description 28
- 238000000034 method Methods 0.000 title abstract description 20
- -1 peptidyl vinyl sulphones Chemical class 0.000 claims abstract description 100
- 238000002360 preparation method Methods 0.000 claims abstract description 69
- 238000006243 chemical reaction Methods 0.000 claims abstract description 9
- 238000006297 dehydration reaction Methods 0.000 claims abstract description 8
- 230000018044 dehydration Effects 0.000 claims abstract description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 68
- 150000001875 compounds Chemical class 0.000 claims description 49
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 39
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 26
- 125000006242 amine protecting group Chemical group 0.000 claims description 24
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 20
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 18
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 claims description 15
- 125000006239 protecting group Chemical group 0.000 claims description 14
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 13
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 12
- 125000003277 amino group Chemical group 0.000 claims description 11
- 125000005544 phthalimido group Chemical group 0.000 claims description 10
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 8
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 8
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 8
- 238000006467 substitution reaction Methods 0.000 claims description 8
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 6
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 6
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 6
- RMBAVIFYHOYIFM-UHFFFAOYSA-M sodium methanethiolate Chemical group [Na+].[S-]C RMBAVIFYHOYIFM-UHFFFAOYSA-M 0.000 claims description 6
- 150000003573 thiols Chemical class 0.000 claims description 6
- 229910052783 alkali metal Inorganic materials 0.000 claims description 5
- 239000002585 base Substances 0.000 claims description 5
- 150000001718 carbodiimides Chemical class 0.000 claims description 5
- 125000001624 naphthyl group Chemical group 0.000 claims description 5
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 4
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- 150000001408 amides Chemical class 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 4
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 4
- 150000004657 carbamic acid derivatives Chemical class 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 239000007800 oxidant agent Substances 0.000 claims description 4
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 4
- 229940124530 sulfonamide Drugs 0.000 claims description 4
- 150000003456 sulfonamides Chemical class 0.000 claims description 4
- RFCQDOVPMUSZMN-UHFFFAOYSA-N 2-Naphthalenethiol Chemical compound C1=CC=CC2=CC(S)=CC=C21 RFCQDOVPMUSZMN-UHFFFAOYSA-N 0.000 claims description 3
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical group OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 3
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims description 3
- 150000001413 amino acids Chemical class 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 230000003197 catalytic effect Effects 0.000 claims description 3
- 239000012442 inert solvent Substances 0.000 claims description 3
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical group CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 3
- JRIDTVOTHRSTJZ-UHFFFAOYSA-N n'-cyclohexyl-n-(2-morpholin-4-ylethyl)methanediimine;4-methylbenzenesulfonic acid Chemical group CC1=CC=C(S(O)(=O)=O)C=C1.C1CCCCC1N=C=NCCN1CCOCC1 JRIDTVOTHRSTJZ-UHFFFAOYSA-N 0.000 claims description 3
- 230000009466 transformation Effects 0.000 claims description 3
- 229910021592 Copper(II) chloride Inorganic materials 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 238000010511 deprotection reaction Methods 0.000 claims description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 1
- 125000003545 alkoxy group Chemical group 0.000 claims 1
- 125000000217 alkyl group Chemical group 0.000 claims 1
- 238000005859 coupling reaction Methods 0.000 claims 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 abstract description 6
- 239000000543 intermediate Substances 0.000 abstract description 5
- 239000003814 drug Substances 0.000 abstract description 3
- 230000003287 optical effect Effects 0.000 abstract description 3
- 125000003396 thiol group Chemical class [H]S* 0.000 abstract description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 abstract 1
- 239000005864 Sulphur Substances 0.000 abstract 1
- 150000002118 epoxides Chemical class 0.000 abstract 1
- 239000002184 metal Substances 0.000 abstract 1
- 230000003647 oxidation Effects 0.000 abstract 1
- 238000007254 oxidation reaction Methods 0.000 abstract 1
- 150000003839 salts Chemical class 0.000 abstract 1
- 125000001174 sulfone group Chemical group 0.000 abstract 1
- 238000011097 chromatography purification Methods 0.000 description 32
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 15
- 239000007787 solid Substances 0.000 description 15
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 14
- 239000002904 solvent Substances 0.000 description 13
- 238000010992 reflux Methods 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 150000003457 sulfones Chemical class 0.000 description 11
- 239000000203 mixture Substances 0.000 description 10
- 230000008569 process Effects 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 7
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 description 7
- 101150065749 Churc1 gene Proteins 0.000 description 7
- 102100038239 Protein Churchill Human genes 0.000 description 7
- 239000000377 silicon dioxide Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 230000008034 disappearance Effects 0.000 description 6
- 239000003480 eluent Substances 0.000 description 6
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 6
- 150000002924 oxiranes Chemical class 0.000 description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 5
- 125000006633 tert-butoxycarbonylamino group Chemical group 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 108091005804 Peptidases Proteins 0.000 description 4
- 102000035195 Peptidases Human genes 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000012230 colorless oil Substances 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 239000004365 Protease Substances 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000004305 biphenyl Substances 0.000 description 3
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 3
- 239000012024 dehydrating agents Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 3
- 239000012047 saturated solution Substances 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 0 *N(*)[C@@](C=CS(*)(=O)=O)I Chemical compound *N(*)[C@@](C=CS(*)(=O)=O)I 0.000 description 2
- UQRONKZLYKUEMO-UHFFFAOYSA-N 4-methyl-1-(2,4,6-trimethylphenyl)pent-4-en-2-one Chemical group CC(=C)CC(=O)Cc1c(C)cc(C)cc1C UQRONKZLYKUEMO-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 235000008206 alpha-amino acids Nutrition 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 201000004792 malaria Diseases 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- ATUOYWHBWRKTHZ-SDTNDFKLSA-N 1,2-dideuteriopropane Chemical compound [2H]CC([2H])C ATUOYWHBWRKTHZ-SDTNDFKLSA-N 0.000 description 1
- JECYNCQXXKQDJN-UHFFFAOYSA-N 2-(2-methylhexan-2-yloxymethyl)oxirane Chemical compound CCCCC(C)(C)OCC1CO1 JECYNCQXXKQDJN-UHFFFAOYSA-N 0.000 description 1
- BTANRVKWQNVYAZ-UHFFFAOYSA-N 2-butanol Substances CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 1
- JYVLIDXNZAXMDK-UHFFFAOYSA-N 2-pentanol Substances CCCC(C)O JYVLIDXNZAXMDK-UHFFFAOYSA-N 0.000 description 1
- 206010001935 American trypanosomiasis Diseases 0.000 description 1
- KLSJWNVTNUYHDU-UHFFFAOYSA-N Amitrole Chemical compound NC1=NC=NN1 KLSJWNVTNUYHDU-UHFFFAOYSA-N 0.000 description 1
- UPGXPULPQHMSPV-JJJPLKNQSA-N CC(C)(C)OC(=O)N[C@@H](\C=C\S(=O)(=O)c1ccccc1)c1ccccc1 Chemical compound CC(C)(C)OC(=O)N[C@@H](\C=C\S(=O)(=O)c1ccccc1)c1ccccc1 UPGXPULPQHMSPV-JJJPLKNQSA-N 0.000 description 1
- 208000024699 Chagas disease Diseases 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 239000004593 Epoxy Substances 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 241000430519 Human rhinovirus sp. Species 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 208000004554 Leishmaniasis Diseases 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 229940079156 Proteasome inhibitor Drugs 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- 241000223109 Trypanosoma cruzi Species 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 150000004808 allyl alcohols Chemical class 0.000 description 1
- 150000001370 alpha-amino acid derivatives Chemical class 0.000 description 1
- 150000001371 alpha-amino acids Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229960003280 cupric chloride Drugs 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 238000006735 epoxidation reaction Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 108010007459 falcipain Proteins 0.000 description 1
- 230000008570 general process Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000003328 mesylation reaction Methods 0.000 description 1
- 201000009240 nasopharyngitis Diseases 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 244000045947 parasite Species 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 150000003138 primary alcohols Chemical class 0.000 description 1
- 239000003207 proteasome inhibitor Substances 0.000 description 1
- 229940024999 proteolytic enzymes for treatment of wounds and ulcers Drugs 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 150000003333 secondary alcohols Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/02—Preparation of sulfones; Preparation of sulfoxides by formation of sulfone or sulfoxide groups by oxidation of sulfides, or by formation of sulfone groups by oxidation of sulfoxides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/06—Separation; Purification; Stabilisation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C317/28—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to acyclic carbon atoms of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/06—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents
- C07K1/061—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents using protecting groups
- C07K1/063—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents using protecting groups for alpha-amino functions
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Definitions
- This invention relates to a stereoselective process for the preparation of ⁇ -amino vinyl sulfones, whose enantiomers are useful as intermediates for the preparation of peptidyl vinyl sulfones, as well as to new intermediates useful in said preparation process.
- Cysteinyl proteases are a subclass of proteolytic enzymes that can be found in viruses, bacteria, protozoa, fungi, plants and mammals. The spectrum of biological activity of these enzymes is very wide: they are involved in the cellular turnover of mammals and in apoptosis, in the process of replication of the human rhinovirus and in the life cycle of many parasites. The inhibition of cysteinyl proteases is therefore an important strategy for the development of new drugs for the treatment of tumors, inflammatory diseases, viral infections (for example, the common cold) and for infections by protozoa and bacteria (for example, malaria, Chagas disease or leishmaniasis).
- peptidyl vinyl sulfones are useful as proteasome inhibitors and their bacterial counterpart HsIVU.
- the following compounds are representative examples of inhibitors of the peptidyl vinyl sulfone type.
- a stereoselective process for the manufacture of a substantially pure enantiomer of a ⁇ -amino vinyl sulfone of formula (I), alternatively (I 1 ), which comprises a dehydration step of a ⁇ -hydroxy - ⁇ -amino sulfone of formula (II), alternatively (II 1 ),
- Ri is a radical selected from the group consisting of: (C ⁇ -C 6 ) -alkyl, (C 3 -C 6 ) -cycloalkyl, [(C ⁇ -C 6 ) -alkyl ⁇ phenylsilyloxy] - (C ⁇ -C 6 ) - I rent,
- R 2 is a radical selected from the same group as Ri, also including phenylcarbonyl;
- n is an integer selected from 1 to 10; and GP represents an amine protecting group; GP 'represents a hydrogen atom or an amine protecting group equal to or different from GP; or alternatively, GP and GP 'taken together form a phthalimido group.
- the compounds of formula (II), alternatively (II 1 ), are those where the protective group GP is selected from the group consisting of carbamates, amides and sulfonamides, and GP 'is a hydrogen atom or an amine protecting group selected from the same group as GP, further including an allyl, a benzyl and a mono or disubstituted benzyl.
- the GP protecting group is selected from the group consisting of t-butoxycarbonyl.
- BOC 9-fluorenylmethoxycarbonyl
- Cbz benzyloxycarbonyl
- GP ' is a hydrogen atom or an amine protecting group selected from the group consisting of t-butoxycarbonyl (BOC), 9-fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), allyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl and N-benzylamine.
- the amine protecting group GP is t-butoxycarbonyl (BOC) and GP 'is a hydrogen atom.
- GP and GP 'taken together form a phthalimido group.
- the compounds of formula (II), alternatively (II '), are those in which Ri and R 2 are independently selected from the group consisting of methyl, isobutyl, phenyl, phenylmethyl, 2- phenylethyl, 1-naphthyl, 2-naphthyl, 2,4,6-trimethylphenyl, 4-phenylphenyl, t-butyldiphenylsilyloxypropyl and t-butyldimethylsilyloxypropyl.
- the compounds of formula (II), alternatively (II 1 ), are those where Ri is selected from methyl, isobutyl, phenyl, phenylmethyl, 2-phenylethyl, 1-naphthyl, 2-naphthyl, 2,4 , 6-trimethylphenyl, 4-phenylphenyl, t-butyldiphenylsilyloxypropyl and t-butyldimethylsilyloxypropyl, and R 2 is selected from methyl, phenyl and 2-naphthyl.
- wavy lines mean any of the two possible configurations of the chiral carbon to which they are attached.
- substantially pure enantiomer means a compound with sufficient enantiomeric excess for its preparation on an industrial scale, which depends on each specific case as the person skilled in the art will decide. In most cases, an enantiomeric excess greater than 95% is sufficient.
- Dehydration can be carried out using a carbodiimide as a dehydrating agent in the presence of a catalytic amount of anhydrous copper (II) chloride.
- carbodiimide is 1-cyclohexyl-3- (2-morpholinoethyl) -carbodiimide p-toluenesulfonate.
- dehydration is carried out by reaction with an alkylsulfonyl chloride and an amine, except when Ri is phenyl, substituted phenyl or naphthyl.
- the alkylsulfonyl chloride is mesyl chloride and the amine is 4- (dimethylamino) pyrdine.
- Dehydration reactions are carried out in a solvent suitable for the reagents and materials used and suitable for the transformation to occur.
- a suitable solvent is acetonitrile and the reaction is carried out at a temperature between 20 ° C and 70 ° C.
- suitable organic solvents include chlorinated hydrocarbons such as dichloromethane, ethers such as tetrahydrofuran, and aromatic hydrocarbons such as toluene.
- the reactions are carried out at a temperature between 0 ° C and 40 ° C.
- the compound of formula (II), alternatively (II '), is prepared by reacting the compound of formula (III), alternatively (III 1 ), with an oxidizing agent.
- the oxidizing agent is m-chloroperbenzoic acid, which is generally used in excess and in an appropriate solvent, such as chlorinated hydrocarbons such as dichloromethane or ethers such as tetrahydrofuran. Generally, the reaction is carried out at a temperature between 0 ° C and room temperature.
- the compound of formula (III), alternatively (III 1 ), can be prepared by treating the compound of formula (IV), alternatively (IV), with a thiol of formula R 2 -SH in the presence of a base, and in a inert solvent, R 2 having the same meaning as defined above.
- the reaction is carried out with an equivalent of thiol.
- the base may be a tertiary amine such as triethylamine or an inorganic base such as an alkali metal hydroxide, preferably the alkali metal being sodium or potassium.
- the thiol is selected from thiophenyl and 2-naphthylthiol, and the base is triethylamine.
- the thiol group may also be conveniently introduced by treating a compound of formula (IV), alternatively (IV), with an alkali metal salt of the thiol, usually used in excess and in an appropriate solvent, for example alcohols lower having 1 to 4 carbon atoms and mixtures with water.
- an appropriate solvent for example alcohols lower having 1 to 4 carbon atoms and mixtures with water.
- the solvent is methanol, optionally mixed with water.
- the temperature is not a critical parameter and is generally between the ambient temperature and the reflux temperature of the solvent used.
- the alkali metal salt is sodium methanethiolate.
- the epoxide as a starting material, of formula (IV), alternatively (IV), can be prepared according to a known procedure summarized in the Scheme 1 (cf. eg P. Castejón et al., Tetrahedron letters 1995. vol. 36, pp.
- the 3-amino-1, 2-diol of formula (V), alternatively (V) is subjected to the Mitsunobu delation conditions comprising the reaction with triphenylphosphine and diethyl or diisopropyl azodicarboxylate to obtain, after chromatographic purification, the corresponding 7 / -protected (7-aminoalkyl) epoxide ⁇ / -protected.
- the 3- amino-1,2-diol of formula (V), alternatively (V) can be converted into the corresponding s / 7- (1-aminoalkyl) ⁇ / -protected epoxide, through a simple three-step process comprising: a) selective protection of the primary alcohol of the compound (V), alternatively (V); b) mesylation of secondary alcohol; and c) deprotection / cyclization carried out by successive treatment of the obtained mesylate, with tetrabutylammonium fluoride and sodium methoxide.
- the compound of formula (V), alternatively (V), can be obtained, in a very enantioselective manner, by a method that includes the catalytic asymmetric epoxidation of Sharpless of allylic alcohols that are easily accessible, followed by a regal and stereoselective opening of the ring of oxirane, with an equivalent of ammonia ( ⁇ azida or benzidrilamina) (cf. eg, M. Canas et al., Tetrahedron Lett. 1991, vol. 32, pp. 6931-6934; M. Pastó et al., Tetrahedron Assimmetrv 1996, vol. 7, pp. 243-262; M.
- the compound of formula (I), alternatively (I '), prepared according to the process of the present invention is useful as an intermediate for the preparation of peptidyl vinyl sulfones. Therefore, another aspect of the present invention is the use of a compound of formula (I), alternatively (Y), prepared according to the present invention, for the preparation of said peptidyl vinyl sulfones.
- the compound of formula (I), alternatively (I 1 ), can be treated using known techniques that allow the amine protecting group to be removed and then the free amine group, can be coupled with a carboxyl terminal group of a natural amino acid or of a peptide to obtain a peptidyl vinyl sulfone of formula (VI), alternatively (VI '), wherein PG, Ri and R 2 have the above meaning; R 3 represents a side chain radical or a terminal chain radical of a natural amino acid or a peptide; m is an integer equal to or greater than one and, when m is greater than one, R 3 can be the same or different (cfr. eg J. Kong et al. J. Med. Chem. 1998, vol. 41, pp. 2579 -2587; HS Overkleeft. Et al. Tetrahedron Letters 2000. vol. 41, pp. 6005-6009).
- Another aspect of the present invention is to provide a new stereoisomeric compound selected from the two enantiomeric formulas (II), alternatively (II '), where:
- R 2 is a radical selected from the same group as Ri, also including phenylcarbonyl;
- n is an integer selected from 1 to 10; and GP represents an amine protecting group; GP 'represents a hydrogen atom or an amine protecting group equal to or different from GP; or alternatively, GP and GP 'taken together form a phthalimido group; with the proviso that Ri is not isobutyl
- the GP protecting group is selected from t-butoxycarbonyl (BOC), 9-fluorenylmethoxycarbonyl (Fmoc) and benzyloxycarbonyl (Cbz) and, GP 'is an atom of hydrogen or an amine protecting group equal to or different from GP, selected from the group consisting of t-butoxycarbonyl (BOC), 9-fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), allyl, 4- methoxybenzyl, 2,4-dimethoxybenzyl and N-benzylamine and, those where the protective group GP and GP 'taken together form a phthalimido group.
- the GP protecting group is t-butoxycarbonyl (BOC) and GP 'is a hydrogen atom.
- Ri and R 2 are independently selected from the group consisting of: methyl, phenyl, phenylmethyl, 2-phenylethyl, 1-naphthyl, 2-naphthyl, 2 , 4,6-trimethylphenyl, 4-phenylphenyl, t-butyldiphenylsilyloxypropyl and t-butyldimethylsilyloxypropyl.
- Ri is selected from the group consisting of methyl, phenyl, phenylmethyl, 2-phenylethyl, 1-naphthyl, 2-naphthyl, 2,4,6-timethylphenyl , 4-phenylphenyl, t-butyldiphenylsilyloxypropyl and t-butyldimethylsilyloxypropyl, and R 2 is selected from the group consisting of methyl, phenyl and 2-naphthyl.
- R ⁇ is selected from the group consisting of phenyl, 1- naphthyl, 2-naphthyl, 2,4,6-trimethylphenyl, 4-phenylphenyl, t- butyldiphenylsilyloxypropyl, t- butyldimethylsilyloxypropyl; and R 2 is selected from the group consisting of methyl, phenyl and 2-naphthyl.
- R ⁇ is selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, 2,4,6-trimethylphenyl, 4-phenylphenyl, t-butyldiphenylsilyloxypropyl and t-butyldimethylsilyloxypropyl; and R 2 is phenyl.
- An advantage of the present invention lies in the fact that this stereoselective process of preparing ⁇ -amino vinyl sulfones does not depend on the availability of a suitable ⁇ -amino acid. Another advantage of the present invention lies in the fact that the stereoselective process of preparing ⁇ -amino vinyl sulfones can provide both enantiomers of a given ⁇ -amino vinyl sulfone with equal ease. Furthermore, the present invention provides a short and efficient stereoselective process for preparing ⁇ -amino vinyl sulfones, with high yields and high optical purity.
- (2S, 3S) - ⁇ / -Boc-3-amino-5-phenylpentan-1,2-diol (0.10 g, 0.34 mmol) and triphenylphosphine (95 mg, 0.36 mmol) in anhydrous chloroform (2 mi)
- a solution of diisopropyl azodicarboxylate (71 ⁇ l, 0.36 mmol) in 1 ml of anhydrous chloroform was added.
- the reaction mixture was diluted with dichloromethane (3 mL), and washed sequentially with a cold solution (0 ° C) of 10% HCI (10 mL) and with a saturated solution of sodium bicarbonate (2x5 mL).
- the organic phase was dried with anhydrous magnesium sulfate and the solvent was removed under reduced pressure.
- the residue was purified by column chromatography (silica previously treated with triethylamine, 2.5% v / v) with hexane-ethyl acetate mixtures as eluents and 76 mg (94% yield) of the title compound was obtained as a colorless solid.
- CDCI 3 CDCI 3 ) ⁇ : 1.39 (s, 9H), 4.88 (br, 1H), 6.24 (br, 1H), 6.64 (dd, 1H), 7.26-7.64
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Abstract
The invention relates to a stereoselective method of preparing η-amino vinyl sulphones. The inventive method comprises: the reaction of the corresponding N-protected (1-aminoalkyl) epoxide with a thiol, or an alkaline metal salt thereof; oxidation of the sulphur obtained to form sulphone; and subsequent dehydration in order to obtain, separately, either of the two enantiomers of the η-amino vinyl sulphone having formula (I). The method can also be used equally simply to obtain both enantiomers of a determined η-amino vinyl sulphone in high yields and with good optical purity. The invention also relates to novel intermediates which are used in the aforementioned preparation method and some substantially-pure novel enantiomers of said η-amino vinyl sulphones. Moreover, the enantiomers of the η-amino vinyl sulphones can be used as intermediates in the preparation of pharmaceuticals based on peptidyl vinyl sulphones. R1-CH[N(GP)(GP')]-CH=CH-SO2-R2 (I)
Description
Procedimiento estereoselectivo de preparación de γ-amino vinil sulfonasStereoselective procedure for preparing γ-amino vinyl sulfones
Esta invención se refiere a un procedimiento estereoselectivo para la preparación de γ-amino vinil sulfonas, cuyos enantiómeros son útiles como intermedios para la preparación de peptidil vinil sulfonas, así como a nuevos intermedios útiles en dicho procedimiento de preparación.This invention relates to a stereoselective process for the preparation of γ-amino vinyl sulfones, whose enantiomers are useful as intermediates for the preparation of peptidyl vinyl sulfones, as well as to new intermediates useful in said preparation process.
ESTADO DE LA TÉCNICA ANTERIORSTATE OF THE PREVIOUS TECHNIQUE
Las cisteinil proteasas son una subclase de enzimas proteolíticos que pueden encontrarse en virus, bacterias, protozoos, hongos, plantas y mamíferos. El espectro de actividad biológica de estos enzimas es muy amplio: están implicados en el recambio celular de los mamíferos y en la apoptosis, en el proceso de replicación del rinovirus humano y en el ciclo vital de muchos parásitos. La inhibición de las cisteinil proteasas constituye por tanto una estrategia importante para el desarrollo de nuevos fármacos para el tratamiento de tumores, de enfermedades inflamatorias, de infecciones víricas (por ejemplo, el resfriado común) y de infecciones por protozoos y bacterias (por ejemplo, la malaria, la enfermedad de Chagas o la leishmaniasis). En 1995, investigadores de "Khepri Pharmaceuticals" describieron por primera vez la utilización de determinadas peptidil vinil sulfonas como inhibidores potentes y selectivos de las cisteinil proteasas (cfr. e.g. J.T. Palmer et al., J. Med. Chem. 1995, vol 38, pp. 3193-3196; D. Brómme et al, Biochem. J. 1996, vol. 315, pp. 85-89). Investigaciones posteriores condujeron al desarrollo de una peptidil vinil sulfona inhibidora de la falcipaína cuya evaluación in vivo demostró que retrasaba claramente la progresión de la malaria en múridos (cfr. e.g. J.E. Olson et al., Bioorq. Med. Chem. 1999, vol. 7, pp. 633-638; K.A Scheidt et al., Bioorq. Med. Chem. 1998, vol. 6, pp. 2477-2494). Se ha establecido también que las peptidil vinil sulfonas son útiles como inhibidores de proteasoma y de su homólogo bacteriano HsIVU. Los siguientes compuestos son ejemplos representativos de inhibidores del tipo peptidil vinil sulfona.
Cysteinyl proteases are a subclass of proteolytic enzymes that can be found in viruses, bacteria, protozoa, fungi, plants and mammals. The spectrum of biological activity of these enzymes is very wide: they are involved in the cellular turnover of mammals and in apoptosis, in the process of replication of the human rhinovirus and in the life cycle of many parasites. The inhibition of cysteinyl proteases is therefore an important strategy for the development of new drugs for the treatment of tumors, inflammatory diseases, viral infections (for example, the common cold) and for infections by protozoa and bacteria (for example, malaria, Chagas disease or leishmaniasis). In 1995, researchers at "Khepri Pharmaceuticals" described for the first time the use of certain peptidyl vinyl sulfones as potent and selective inhibitors of cysteinyl proteases (cf. eg JT Palmer et al., J. Med. Chem. 1995, vol 38, pp. 3193-3196; D. Brómme et al, Biochem. J. 1996, vol. 315, pp. 85-89). Further research led to the development of a peptidyl vinyl sulfone inhibitor of falcipain whose in vivo evaluation showed that it clearly delayed the progression of malaria in murides (cfr. Eg JE Olson et al., Bioorq. Med. Chem. 1999, vol. 7 , pp. 633-638; KA Scheidt et al., Bioorq. Med. Chem. 1998, vol. 6, pp. 2477-2494). It has also been established that peptidyl vinyl sulfones are useful as proteasome inhibitors and their bacterial counterpart HsIVU. The following compounds are representative examples of inhibitors of the peptidyl vinyl sulfone type.
PhPh
A pesar de su relevancia biomédica, los procedimientos de preparación de las necesarias γ-amino vinil sulfonas en forma enantioméricamente pura son muy limitados, y se basan sin excepción en transformaciones estereoespecíficas de α-amino ácidos quirales no racémicos (cfr. e.g. J.T. Palmer et al., J. Med. Chem. 1995, vol 38, pp. 3193-3196; S. Sengupta et al., Tetrahedron Asvmmetry 1998, vol. 9, pp. 2311-2316). En concreto, estos procedimientos implican la preparación bien de α-amino aldehidos (un tipo de compuestos que generalmente racemiza con facilidad) o bien de α-amino diazocetonas (cuya manipulación a escala industrial es difícil). Por todo ello, los procedimientos de preparación de γ-amino vinil sulfonas conocidos en el estado de la técnica son difíciles de escalar y están seriamente limitados en lo que respecta a la estructura de los productos finales. Por tanto, la aportación de un procedimiento alternativo para la preparación de γ-amino vinil sulfonas en forma N-protegida, que sea corto y eficiente (es decir, que tenga lugar con rendimientos elevados y que conduzca a productos de elevada pureza óptica), es interesante de cara a la fabricación industrial de fármacos basados en peptidil vinil sulfonas.
DESCRIPCIÓN DE LA INVENCIÓNDespite their biomedical relevance, the procedures for preparing the necessary γ-amino vinyl sulfones in enantiomerically pure form are very limited, and are based without exception on stereospecific transformations of non-racemic chiral α-amino acids (cf. eg JT Palmer et al., J. Med. Chem. 1995, vol 38, pp. 3193-3196; S. Sengupta et al., Tetrahedron Asvmmetry 1998, vol. 9, pp. 2311-2316). Specifically, these procedures involve the preparation of either α-amino aldehydes (a type of compounds that generally readily racemize) or of α-amino diazoketones (whose industrial scale handling is difficult). Therefore, the processes for preparing γ-amino vinyl sulfones known in the state of the art are difficult to scale and are seriously limited in terms of the structure of the final products. Therefore, the contribution of an alternative process for the preparation of γ-amino vinyl sulfones in N-protected form, which is short and efficient (i.e., which takes place with high yields and which leads to products of high optical purity), It is interesting for the industrial manufacture of drugs based on peptidyl vinyl sulfones. DESCRIPTION OF THE INVENTION
Según un aspecto de la presente invención, se proporciona un procedimiento estereoselectivo para la fabricación de un enantiómero sustancialmente puro de una γ-amino vinilsulfona de fórmula (I), alternativamente (I1), que comprende un paso de deshidratación de una β-hidroxi-γ-amino sulfona de fórmula (II), alternativamente (II1),According to one aspect of the present invention, a stereoselective process is provided for the manufacture of a substantially pure enantiomer of a γ-amino vinyl sulfone of formula (I), alternatively (I 1 ), which comprises a dehydration step of a β-hydroxy -γ-amino sulfone of formula (II), alternatively (II 1 ),
(I) (!')(I) (! ')
donde:where:
en las fórmulas (II) y (II1), las líneas onduladas significan cualquiera de las dos posibles configuraciones del carbono quiral al que están unidas;in formulas (II) and (II 1 ), wavy lines mean any of the two possible configurations of the chiral carbon to which they are attached;
Ri es un radical seleccionado entre el grupo formado por: (Cι-C6)-alquilo, (C3-C6)-cicloalquilo, [(Cι-C6)-alquild¡fenilsililoxi]-(Cι-C6)-alquilo,Ri is a radical selected from the group consisting of: (Cι-C 6 ) -alkyl, (C 3 -C 6 ) -cycloalkyl, [(Cι-C 6 ) -alkyl¡phenylsilyloxy] - (Cι-C 6 ) - I rent,
[(CrCeHrialquilsililoxil-ÍCrCeí-alquilo,
GP-O-(CH2)n-,1- naftilo, 2-naftilo, fenilo, Ph-(CH2)n-, R-COO-(CH2)n- con R = (C CβJ-alquilo o fenilo, y un radical derivado de los anteriormente mencionados con anillos bencénicos a través de una mono-, una di- o una tri-sustitución en sus anillos
bencénicos, siendo los sustituyentes un radical independientemente seleccionado entre el grupo formado por: halógeno, (CrC4)-alquilo, (Cι-C )- alcoxilo, trifluorometilo, fenilo, un grupo amino protegido y un hidroxilo protegido;[(CrCeHrialquilsililoxil-ÍCrCeí-alkyl, GP-O- (CH 2 ) n-, 1- naphthyl, 2-naphthyl, phenyl, Ph- (CH 2 ) n -, R-COO- (CH 2 ) n - with R = (C CβJ-alkyl or phenyl , and a radical derived from the aforementioned with benzene rings through a mono-, a di- or a tri-substitution in their rings benzene, the substituents being a radical independently selected from the group consisting of: halogen, (CrC 4 ) -alkyl, (Cι-C) -alkoxy, trifluoromethyl, phenyl, a protected amino group and a protected hydroxyl;
R2 es un radical seleccionado entre el mismo grupo que Ri, incluyendo además el fenilcarbonilo;R 2 is a radical selected from the same group as Ri, also including phenylcarbonyl;
n es un entero seleccionado entre 1 y 10; y GP representa un grupo protector de aminas; GP' representa un átomo de hidrógeno o un grupo protector de aminas igual o diferente a GP; o alternativamente, GP y GP' tomados conjuntamente forman un grupo ftalimido.n is an integer selected from 1 to 10; and GP represents an amine protecting group; GP 'represents a hydrogen atom or an amine protecting group equal to or different from GP; or alternatively, GP and GP 'taken together form a phthalimido group.
En una realización preferida de la invención, los compuestos de fórmula (II), alternativamente (II1), son aquéllos donde el grupo protector GP se selecciona entre el grupo formado por carbamatos, amidas y sulfonamidas, y GP' es un átomo de hidrógeno o un grupo protector de aminas seleccionado del mismo grupo que GP, incluyendo además un alilo, un bencilo y un bencilo mono o disustituido. En una realización más preferida de la invención, el grupo protector GP se selecciona entre el grupo formado por t-butoxicarboniloIn a preferred embodiment of the invention, the compounds of formula (II), alternatively (II 1 ), are those where the protective group GP is selected from the group consisting of carbamates, amides and sulfonamides, and GP 'is a hydrogen atom or an amine protecting group selected from the same group as GP, further including an allyl, a benzyl and a mono or disubstituted benzyl. In a more preferred embodiment of the invention, the GP protecting group is selected from the group consisting of t-butoxycarbonyl.
(BOC), 9-fluorenilmetoxicarbonilo (Fmoc) y benciloxicarbonilo (Cbz), y GP' es un átomo de hidrógeno o un grupo protector de aminas seleccionado entre el grupo formado por t-butoxicarbonilo (BOC), 9-fluorenilmetoxicarbonilo (Fmoc), benciloxicarbonilo (Cbz), alilo, 4-metoxibencilo, 2,4-dimetoxibencilo y N-bencilamina. Todavía es más preferida la realización en la que el grupo protector de aminas GP es el t-butoxicarbonilo (BOC) y GP' es un átomo de hidrógeno. En otra realización preferida de la invención, GP y GP' tomados conjuntamente forman un grupo ftalimido.(BOC), 9-fluorenylmethoxycarbonyl (Fmoc) and benzyloxycarbonyl (Cbz), and GP 'is a hydrogen atom or an amine protecting group selected from the group consisting of t-butoxycarbonyl (BOC), 9-fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), allyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl and N-benzylamine. Even more preferred is the embodiment in which the amine protecting group GP is t-butoxycarbonyl (BOC) and GP 'is a hydrogen atom. In another preferred embodiment of the invention, GP and GP 'taken together form a phthalimido group.
En una realización también preferida de la invención, los compuestos de fórmula (II), alternativamente (II'), son aquéllos en los que R-i y R2son independientemente seleccionados entre el grupo formado por metilo, isobutilo, fenilo, fenilmetilo, 2-feniletilo, 1-naftilo, 2-naftilo, 2,4,6-trimetilfenilo, 4-fenilfenilo, t-butildifenilsililoxipropilo y t-butildimetilsililoxipropilo. En una realización más preferida, los compuestos de fórmula (II), alternativamente (II1), son aquéllos donde Ri se selecciona entre metilo, isobutilo, fenilo, fenilmetilo, 2-feniletilo, 1-naftilo, 2-naftilo, 2,4,6-trimetilfenilo, 4-fenilfenilo,
t-butildifenilsililoxipropilo y t-butildimetilsililoxipropilo, y R2 se selecciona entre metilo, fenilo y 2-naftilo.In a also preferred embodiment of the invention, the compounds of formula (II), alternatively (II '), are those in which Ri and R 2 are independently selected from the group consisting of methyl, isobutyl, phenyl, phenylmethyl, 2- phenylethyl, 1-naphthyl, 2-naphthyl, 2,4,6-trimethylphenyl, 4-phenylphenyl, t-butyldiphenylsilyloxypropyl and t-butyldimethylsilyloxypropyl. In a more preferred embodiment, the compounds of formula (II), alternatively (II 1 ), are those where Ri is selected from methyl, isobutyl, phenyl, phenylmethyl, 2-phenylethyl, 1-naphthyl, 2-naphthyl, 2,4 , 6-trimethylphenyl, 4-phenylphenyl, t-butyldiphenylsilyloxypropyl and t-butyldimethylsilyloxypropyl, and R 2 is selected from methyl, phenyl and 2-naphthyl.
En las fórmulas (II) y (II'), las líneas onduladas significan cualquiera de las dos configuraciones posibles del carbono quiral al que están unidas. En el contexto de esta invención, el término "enantiómero sustancialmente puro" significa un compuesto con suficiente exceso enantiómerico para su preparación a escala industrial, lo cual depende de cada caso concreto como decidirá el experto en la materia. En la mayoría de los casos, un exceso enantiomérico superior al 95% es suficiente.In formulas (II) and (II '), wavy lines mean any of the two possible configurations of the chiral carbon to which they are attached. In the context of this invention, the term "substantially pure enantiomer" means a compound with sufficient enantiomeric excess for its preparation on an industrial scale, which depends on each specific case as the person skilled in the art will decide. In most cases, an enantiomeric excess greater than 95% is sufficient.
La deshidratación puede llevarse a cabo usando una carbodiimida como agente deshidratante en presencia de una cantidad catalítica de cloruro de cobre (II) anhidro. Preferiblemente la carbodiimida es el p-toluensulfonato de 1-ciclohexil-3-(2-morfolinoetil)-carbodiimida. Alternativamente, la deshidratación se lleva a cabo por reacción con un cloruro de alquilsulfonilo y una amina, excepto cuando Ri es fenilo, fenilo sustituido o naftilo. En una realización preferida el cloruro de alquilsulfonilo es el cloruro de mesilo y la amina es la 4-(dimetilamino)pir¡dina. Las reacciones de deshidratación se llevan a cabo en un solvente apropiado para los reactivos y materiales empleados y adecuado para que la transformación se produzca. Cuando el agente deshidratante es una carbodiimida, un ejemplo de solvente adecuado es acetonitrilo y la reacción se realiza a una temperatura comprendida entre 20 °C y 70 °C. Cuando el agente deshidratante es un cloruro de alquilsulfonilo, ejemplos de solventes orgánicos adecuados incluyen hidrocarburos clorados tal como el diclorometano, éteres tal como el tetrahidrofurano, y hidrocarburos aromáticos tal como el tolueno. Generalmente, las reacciones se llevan a cabo a una temperatura comprendida entre 0 °C y 40 °C.Dehydration can be carried out using a carbodiimide as a dehydrating agent in the presence of a catalytic amount of anhydrous copper (II) chloride. Preferably carbodiimide is 1-cyclohexyl-3- (2-morpholinoethyl) -carbodiimide p-toluenesulfonate. Alternatively, dehydration is carried out by reaction with an alkylsulfonyl chloride and an amine, except when Ri is phenyl, substituted phenyl or naphthyl. In a preferred embodiment the alkylsulfonyl chloride is mesyl chloride and the amine is 4- (dimethylamino) pyrdine. Dehydration reactions are carried out in a solvent suitable for the reagents and materials used and suitable for the transformation to occur. When the dehydrating agent is a carbodiimide, an example of a suitable solvent is acetonitrile and the reaction is carried out at a temperature between 20 ° C and 70 ° C. When the dehydrating agent is an alkylsulfonyl chloride, examples of suitable organic solvents include chlorinated hydrocarbons such as dichloromethane, ethers such as tetrahydrofuran, and aromatic hydrocarbons such as toluene. Generally, the reactions are carried out at a temperature between 0 ° C and 40 ° C.
El compuesto de fórmula (II), alternativamente (II'), se prepara por reacción del compuesto de fórmula (III), alternativamente (III1), con un agente oxidante. Preferiblemente el agente oxidante es el ácido m-cloroperbenzoico, que por lo general se usa en exceso y en un solvente apropiado, como por ejemplo hidrocarburos clorados tal como el diclorometano o éteres tal como el tetrahidrofurano. Generalmente, la reacción se lleva a cabo a una temperatura comprendida entre 0 °C y la temperatura ambiente.
The compound of formula (II), alternatively (II '), is prepared by reacting the compound of formula (III), alternatively (III 1 ), with an oxidizing agent. Preferably the oxidizing agent is m-chloroperbenzoic acid, which is generally used in excess and in an appropriate solvent, such as chlorinated hydrocarbons such as dichloromethane or ethers such as tetrahydrofuran. Generally, the reaction is carried out at a temperature between 0 ° C and room temperature.
(III) (iir)(III) (iir)
El compuesto de fórmula (III), alternativamente (III1), puede ser preparado por tratamiento del compuesto de fórmula (IV), alternativamente (IV), con un tiol de fórmula R2-SH en presencia de una base, y en un solvente inerte, teniendo R2 el mismo significado que se ha definido anteriormente. Por lo general, la reacción se lleva a cabo con un equivalente del tiol. La base puede ser una amina terciaria como la trietilamina o una base inorgánica tal como un hidróxido de metal alcalino, siendo preferiblemente el metal alcalino sodio o potasio. En una realización preferida el tiol se selecciona entre el tiofenol y el 2-naftiltiol, y la base es la trietilamina. Alternativamente, el grupo tiol también puede ser convenientemente introducido por tratamiento de un compuesto de fórmula (IV), alternativamente (IV), con una sal de metal alcalino del tiol, por lo general utilizada en exceso y en un solvente apropiado, por ejemplo alcoholes inferiores teniendo de 1 a 4 átomos de carbono y sus mezclas con agua. Preferiblemente, el solvente es el metanol, opcionalmente mezclado con agua. La temperatura no es un parámetro critico y, generalmente, está comprendida entre la temperatura ambiente y la temperatura de reflujo del solvente empleado. En una realización preferida la sal de metal alcalino es el metanotiolato sódico.The compound of formula (III), alternatively (III 1 ), can be prepared by treating the compound of formula (IV), alternatively (IV), with a thiol of formula R 2 -SH in the presence of a base, and in a inert solvent, R 2 having the same meaning as defined above. Usually, the reaction is carried out with an equivalent of thiol. The base may be a tertiary amine such as triethylamine or an inorganic base such as an alkali metal hydroxide, preferably the alkali metal being sodium or potassium. In a preferred embodiment, the thiol is selected from thiophenyl and 2-naphthylthiol, and the base is triethylamine. Alternatively, the thiol group may also be conveniently introduced by treating a compound of formula (IV), alternatively (IV), with an alkali metal salt of the thiol, usually used in excess and in an appropriate solvent, for example alcohols lower having 1 to 4 carbon atoms and mixtures with water. Preferably, the solvent is methanol, optionally mixed with water. The temperature is not a critical parameter and is generally between the ambient temperature and the reflux temperature of the solvent used. In a preferred embodiment the alkali metal salt is sodium methanethiolate.
El epóxido como material de partida, de fórmula (IV), alternativamente (IV), puede ser preparado según un procedimiento conocido resumido en el
Esquema 1 (cfr. e.g. P. Castejón et al., Tetrahedron letters 1995. vol. 36, pp. 3019-3022), Esencialmente, el 3-amino-1 ,2-diol de fórmula (V), alternativamente (V), se somete a las condiciones de delación de Mitsunobu que comprenden la reacción con trifenilfosfina y el azodicarboxilato de dietilo o de diisopropilo para obtener, después de una purificación cromatográfica, el at7í/-(1-aminoalquil) epóxido Λ/-protegido correspondiente. Por otro lado, el 3- amino-1 ,2-diol de fórmula (V), alternativamente (V), puede ser convertido en el s//7-(1-aminoalquil) epóxido Λ/-protegido correspondiente, a través de un procedimiento simple de tres pasos que comprende: a) protección selectiva del alcohol primario del compuesto (V), alternativamente (V); b) mesilación del alcohol secundario; y c) desprotección/ciclación llevada a cabo por tratamiento sucesivo del mesilato obtenido, con fluoruro de tetrabutilamonio y metóxido sódico.The epoxide as a starting material, of formula (IV), alternatively (IV), can be prepared according to a known procedure summarized in the Scheme 1 (cf. eg P. Castejón et al., Tetrahedron letters 1995. vol. 36, pp. 3019-3022), Essentially, the 3-amino-1, 2-diol of formula (V), alternatively (V) , it is subjected to the Mitsunobu delation conditions comprising the reaction with triphenylphosphine and diethyl or diisopropyl azodicarboxylate to obtain, after chromatographic purification, the corresponding 7 / -protected (7-aminoalkyl) epoxide Λ / -protected. On the other hand, the 3- amino-1,2-diol of formula (V), alternatively (V), can be converted into the corresponding s / 7- (1-aminoalkyl) Λ / -protected epoxide, through a simple three-step process comprising: a) selective protection of the primary alcohol of the compound (V), alternatively (V); b) mesylation of secondary alcohol; and c) deprotection / cyclization carried out by successive treatment of the obtained mesylate, with tetrabutylammonium fluoride and sodium methoxide.
El compuesto de fórmula (V), alternativamente (V), puede obtenerse, de modo muy enantioselectivo, mediante un procedimiento que incluye la epoxidación asimétrica catalítica de Sharpless de alcoholes alílicos que son fácilmente accesibles, seguido de una apertura regio y estereoselectiva del anillo de oxirano, con un equivalente de amoníaco (¡on azida o benzidrilamina) (cfr. e.g, M. Canas et al., Tetrahedron Lett. 1991 , vol. 32, pp. 6931-6934; M. Pastó et al., Tetrahedron Assimmetrv 1996, vol. 7, pp. 243- 262; M. Alcón et al., Tetrahedron Assimmetrv 1997, vol. 8, pp. 2967-2974; P. Castejón et al., Tetrahedron Lett. 1995, vol. 17, pp. 3019-3022).The compound of formula (V), alternatively (V), can be obtained, in a very enantioselective manner, by a method that includes the catalytic asymmetric epoxidation of Sharpless of allylic alcohols that are easily accessible, followed by a regal and stereoselective opening of the ring of oxirane, with an equivalent of ammonia (¡azida or benzidrilamina) (cf. eg, M. Canas et al., Tetrahedron Lett. 1991, vol. 32, pp. 6931-6934; M. Pastó et al., Tetrahedron Assimmetrv 1996, vol. 7, pp. 243-262; M. Alcón et al., Tetrahedron Assimmetrv 1997, vol. 8, pp. 2967-2974; P. Castejón et al., Tetrahedron Lett. 1995, vol. 17, pp. 3019-3022).
Esquema 1: Proceso general de preparación de compuestos de fórmula (IV), a allttee»rrnnía»1ti\v/aammιe=>nntt<e=» ( (\I\VT\)
Scheme 1: General process of preparation of compounds of formula (IV), at allttee »rnnía» 1ti \ v / aammιe => nntt <e = »((\ I \ VT \)
Como se ha comentado anteriormente, el compuesto de fórmula (I), alternativamente (I'), preparado según el procedimiento de la presente invención, es útil como intermedio para la preparación de peptidil vinil sulfonas. Por lo tanto, otro aspecto de la presente invención es el uso de un compuesto de fórmula (I), alternativamente (Y), preparado según la presente invención, para la preparación de dichas peptidil vinil sulfonas. El compuesto de fórmula (I), alternativamente (I1), puede ser tratado utilizando técnicas conocidas que permiten eliminar el grupo protector de la amina y, seguidamente el grupo amina libre, puede acoplarse con un grupo carboxilo terminal de un aminoácido natural o de un péptido para obtener una peptidil vinil sulfona de fórmula (VI), alternativamente (VI'), donde GP, R-i y R2 tienen el significado anteriormente mencionado; R3 representa un radical de cadena lateral o un radical de cadena terminal de un aminoácido natural o un péptido; m es un entero igual o mayor que uno y, cuando m es mayor que uno, R3 puede ser igual o diferente (cfr. e.g. J. Kong et al. J. Med. Chem. 1998, vol. 41, pp. 2579-2587; H.S. Overkleeft. et al.. Tetrahedron Letters 2000. vol. 41, pp. 6005-6009).
As mentioned above, the compound of formula (I), alternatively (I '), prepared according to the process of the present invention, is useful as an intermediate for the preparation of peptidyl vinyl sulfones. Therefore, another aspect of the present invention is the use of a compound of formula (I), alternatively (Y), prepared according to the present invention, for the preparation of said peptidyl vinyl sulfones. The compound of formula (I), alternatively (I 1 ), can be treated using known techniques that allow the amine protecting group to be removed and then the free amine group, can be coupled with a carboxyl terminal group of a natural amino acid or of a peptide to obtain a peptidyl vinyl sulfone of formula (VI), alternatively (VI '), wherein PG, Ri and R 2 have the above meaning; R 3 represents a side chain radical or a terminal chain radical of a natural amino acid or a peptide; m is an integer equal to or greater than one and, when m is greater than one, R 3 can be the same or different (cfr. eg J. Kong et al. J. Med. Chem. 1998, vol. 41, pp. 2579 -2587; HS Overkleeft. Et al. Tetrahedron Letters 2000. vol. 41, pp. 6005-6009).
(VI')(SAW')
Otro aspecto de la presente invención es proporcionar un nuevo compuesto estereoisomérico seleccionado de las dos fórmulas enantioméricas (II), alternativamente (II'), donde:Another aspect of the present invention is to provide a new stereoisomeric compound selected from the two enantiomeric formulas (II), alternatively (II '), where:
Ri es un radical seleccionado entre el grupo formado por: (Cι-C6)-alquilo, (C3- C6)-cicloalquilo, [(Ci-CβJ-alquildifenilsililoxiHCrCeJ-alquilo, [(C-ι-C6)- trialquilsililoxiHCrCeJ-alquilo, (Cι-C4)-alcoxilo, GP-O-(CH2)n-, 1-naftilo, 2- naftilo, fenilo, Ph-(CH2)n-, R-COO-(CH2)n- con R = (Cι-C6)-alquilo o fenilo, y un radical derivado de los anteriomente mencionados con anillos bencénicos a través de una mono-, una di- o una tri-sustitución en sus anillos bencénicos, siendo los sustituyentes un radical independientemente seleccionado entre el grupo formado por halógeno, (d^J-alquilo, (Cι-C4)-alcoxilo, trifluorometilo, fenilo, un grupo amino protegido y un hidroxilo protegido;Ri is a radical selected from the group consisting of: (Cι-C 6 ) -alkyl, (C 3 -C 6 ) -cycloalkyl, [(Ci-CβJ-alkyldiphenylsilyloxyHCrCeJ-alkyl, [(C-ι-C 6 ) - trialkylsilyloxy HCrCeJ-alkyl, (Cι-C 4 ) -alkoxy, GP-O- (CH 2 ) n -, 1-naphthyl, 2- naphthyl, phenyl, Ph- (CH 2 ) n -, R-COO- (CH 2 ) n - with R = (Cι-C 6 ) -alkyl or phenyl, and a radical derived from the aforementioned with benzene rings through a mono-, a di- or a tri-substitution in their benzene rings, the substituents a radical independently selected from the group consisting of halogen, (d ^ J-alkyl, (Cι-C 4 ) -alkoxy, trifluoromethyl, phenyl, a protected amino group and a protected hydroxyl;
R2 es un radical seleccionado del mismo grupo que Ri, incluyendo además el fenilcarbonilo;R 2 is a radical selected from the same group as Ri, also including phenylcarbonyl;
n es un entero seleccionado entre 1 y 10; y GP representa un grupo protector de aminas; GP' representa un átomo de hidrógeno o un grupo protector de aminas igual o diferente a GP; o alternativamente, GP y GP' tomados conjuntamente forman un grupo ftalimido; con la condición de que Ri no sea
isobutilo.n is an integer selected from 1 to 10; and GP represents an amine protecting group; GP 'represents a hydrogen atom or an amine protecting group equal to or different from GP; or alternatively, GP and GP 'taken together form a phthalimido group; with the proviso that Ri is not isobutyl
(II) (II')(II) (II ')
Especialmente preferidos son los compuestos de fórmula (II), alternativamente (II1), donde el grupo protector de aminas GP se selecciona entre el grupo formado por carbamatos, amidas y sulfonamidas, y GP' es un átomo de hidrógeno o un grupo protector seleccionado del mismo grupo que GP, incluyendo además un alilo, un bencilo y un bencilo mono o di-sustituido. Aún más preferidos son los compuestos de fórmula (II), alternativamente (IP), donde el grupo protector GP se selecciona de t-butoxicarbonilo (BOC), 9- fluorenilmetoxicarbonilo (Fmoc) y benciloxicarbonilo (Cbz) y, GP' es un átomo de hidrógeno o un grupo protector de aminas igual o diferente a GP, seleccionado entre el grupo formado por t-butoxicarbonilo (BOC), 9- fluorenilmetoxicarbonilo (Fmoc), benciloxicarbonilo (Cbz), alilo, 4- metoxibencilo, 2,4-dimetoxibencilo y N-bencilamina y, aquéllos donde el grupo protector GP y GP' tomados conjuntamente forman un grupo ftalimido. Los más preferidos son aquéllos donde el grupo protector GP es t- butoxicarbonilo (BOC) y GP' es un átomo de hidrógeno.Especially preferred are the compounds of formula (II), alternatively (II 1 ), wherein the GP amine protecting group is selected from the group consisting of carbamates, amides and sulfonamides, and GP 'is a hydrogen atom or a selected protecting group from the same group as GP, also including an allyl, a benzyl and a mono or di-substituted benzyl. Even more preferred are the compounds of formula (II), alternatively (IP), where the GP protecting group is selected from t-butoxycarbonyl (BOC), 9-fluorenylmethoxycarbonyl (Fmoc) and benzyloxycarbonyl (Cbz) and, GP 'is an atom of hydrogen or an amine protecting group equal to or different from GP, selected from the group consisting of t-butoxycarbonyl (BOC), 9-fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), allyl, 4- methoxybenzyl, 2,4-dimethoxybenzyl and N-benzylamine and, those where the protective group GP and GP 'taken together form a phthalimido group. Most preferred are those where the GP protecting group is t-butoxycarbonyl (BOC) and GP 'is a hydrogen atom.
Compuestos también preferidos de fórmula (II), alternativamente (IP), son aquéllos donde: Ri y R2se seleccionan independientemente entre el grupo formado por: metilo, fenilo, fenilmetilo, 2-feniletilo, 1-naftilo, 2-naftilo, 2,4,6- trimetilfenilo, 4-fenilfenilo, t-butildifenilsililoxipropilo y t-butildimetilsililoxipropilo. Más preferidos son aquéllos compuestos de fórmula (II), alternativamente (IP), donde Ri se selecciona entre el grupo formado por metilo, fenilo, fenilmetilo, 2-feniletilo, 1-naftilo, 2-naftilo, 2,4,6-timetilfenilo, 4-fenilfenilo, t- butildifenilsililoxipropilo y t-butildimetilsililoxipropilo, y R2 se selecciona entre el grupo formado por metilo, fenilo y 2-naftilo.
Esta invención proporciona también nuevos compuestos estereoisoméricos seleccionados entre aquéllos de fórmula (I), alternativamente (P), donde Ri se selecciona entre el grupo formado (C3-C6)-cicloalquilo, [(Cι-C6)- alquildifenilsililoxi]-(Cι-C6)-alquilo, [(Ci-CeMrialquilsililoxiHC CβJ-alquilo, 1- naftilo, 2-naftilo, fenilo, R-COO-(CH2)n- con R = (Cι-C6)-alquilo o fenilo, y un radical derivado de los mencionados anteriormente con anillos bencénicos a través de una mono-, una di- o una tri-sustitución en sus anillos bencénicos, siendo los sustituyentes un radical independientemente seleccionado entre el grupo formado por halógeno, (d^J-alquilo, (Cι-C4)-alcoxilo, trifluorometilo, fenilo, un grupo amino protegido y un hidroxilo protegido; R2 se selecciona entre el grupo formado por (Cι-C6)-alquilo, (C3-C6)-cicloalquilo, [(Ci-Cβ)- alquildifenilsililoxi]-(CrC6)-alquilo, [(Cι-C6)-trialquilsililoxi]-(Cι-C6)-alquilo, (C-r C4)-alcoxilo, GP-O-(CH2)n-, 1 -naftilo, 2-naftilo, fenilo, Ph-(CH2)n-, R-COO- (CH2)n- con R = (C CβJ-alquilo o fenilo, y un radical derivado de los anteriormente mencionados con anillos bencénicos a través de una mono-, una di- o una tri-sustitución en sus anillos bencénicos, siendo los sustituyentes un radical independientemente seleccionado entre el grupo formado por: halógeno, (Cι-C4)-alquilo, (Cι-C4)-alcoxilo, trifluorometilo, fenilo, un grupo amino protegido y un hidroxilo protegido; y GP representa un grupo protector de aminas; GP' representa un átomo de hidrógeno o un grupo protector de aminas igual o diferente a GP; o alternativamente GP y GP1 tomados conjuntamente forman un grupo ftalimido. Especialmente preferidos son los compuestos de formula (I), alternativamente (P), donde el grupo protector de aminas es un t-butoxicarbonilo (BOC) y GP' es un átomo de hidrógeno.Also preferred compounds of formula (II), alternatively (IP), are those where: Ri and R 2 are independently selected from the group consisting of: methyl, phenyl, phenylmethyl, 2-phenylethyl, 1-naphthyl, 2-naphthyl, 2 , 4,6-trimethylphenyl, 4-phenylphenyl, t-butyldiphenylsilyloxypropyl and t-butyldimethylsilyloxypropyl. More preferred are those compounds of formula (II), alternatively (IP), where Ri is selected from the group consisting of methyl, phenyl, phenylmethyl, 2-phenylethyl, 1-naphthyl, 2-naphthyl, 2,4,6-timethylphenyl , 4-phenylphenyl, t-butyldiphenylsilyloxypropyl and t-butyldimethylsilyloxypropyl, and R 2 is selected from the group consisting of methyl, phenyl and 2-naphthyl. This invention also provides new stereoisomeric compounds selected from those of formula (I), alternatively (P), where Ri is selected from the group formed (C 3 -C 6 ) -cycloalkyl, [(Cι-C 6 ) -alkyldiphenylsilyloxy] - (Cι-C 6 ) -alkyl, [(Ci-CeMrialkylsilyloxyHC CβJ-alkyl, 1- naphthyl, 2-naphthyl, phenyl, R-COO- (CH 2 ) n - with R = (Cι-C 6 ) -alkyl or phenyl, and a radical derived from those mentioned above with benzene rings through a mono-, a di- or a tri-substitution in their benzene rings, the substituents being a radical independently selected from the group consisting of halogen, (d ^ J-alkyl, (Cι-C 4 ) -alkoxy, trifluoromethyl, phenyl, a protected amino group and a protected hydroxyl; R 2 is selected from the group consisting of (Cι-C 6 ) -alkyl, (C3-C6) - cycloalkyl, [(Ci-Cβ) - alkyldiphenylsilyloxy] - (CrC 6 ) -alkyl, [(Cι-C 6 ) -trialkylsilyloxy] - (Cι-C 6 ) -alkyl, (Cr C 4 ) -alkoxy, GP-O - (CH 2 ) n -, 1 -naphthyl, 2-naphthyl, phenyl, Ph- (CH 2 ) n -, R-COO- (CH 2 ) n - with R = (C CβJ-alkyl or phenyl, and a radical derived from the above mentioned with benzene rings through a mono-, a di- or a tri-substitution in their benzene rings, the substituents being a radical independently selected from the group consisting of: halogen, (Cι-C 4 ) -alkyl, (Cι -C 4 ) -alkoxy, trifluoromethyl, phenyl, a protected amino group and a protected hydroxyl; and GP represents an amine protecting group; GP 'represents a hydrogen atom or an amine protecting group equal to or different from GP; or alternatively GP and GP 1 taken together form a phthalimido group. Especially preferred are the compounds of formula (I), alternatively (P), where the amine protecting group is a t-butoxycarbonyl (BOC) and GP 'is a hydrogen atom.
(I) (!')(I) (! ')
También especialmente preferidos son aquéllos compuestos de fórmula (I), alternativamente (P), donde R^ se selecciona del grupo formado por fenilo, 1- naftilo, 2-naftilo, 2,4,6-trimetilfenilo, 4-fenilfenilo, t-butildifenilsililoxipropilo, t-
butildimetilsililoxipropilo; y R2 se selecciona entre el grupo formado por metilo, fenilo y 2-naftilo. Aún más preferidos son aquéllos compuestos donde R^ se selecciona entre el grupo formado por fenilo, 1-naftilo, 2-naftilo, 2,4,6- trimetilfenilo, 4-fenilfenilo, t-butildifenilsililoxipropilo y t- butildimetillsililoxipropilo; y R2 es fenilo.Also especially preferred are those compounds of formula (I), alternatively (P), where R ^ is selected from the group consisting of phenyl, 1- naphthyl, 2-naphthyl, 2,4,6-trimethylphenyl, 4-phenylphenyl, t- butyldiphenylsilyloxypropyl, t- butyldimethylsilyloxypropyl; and R 2 is selected from the group consisting of methyl, phenyl and 2-naphthyl. Even more preferred are those compounds where R ^ is selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, 2,4,6-trimethylphenyl, 4-phenylphenyl, t-butyldiphenylsilyloxypropyl and t-butyldimethylsilyloxypropyl; and R 2 is phenyl.
Una ventaja de la presente invención radica en el hecho de que este procedimiento estereoselectivo de preparación de γ-amino vinil sulfonas no depende de la disponibilidad de un α-aminoácido adecuado. Otra ventaja de la presente invención radica en el hecho de que el procedimiento estereoselectivo de preparación de γ-amino vinil sulfonas puede proporcionar con igual facilidad ambos enantiómeros de una γ-amino vinil sulfona dada. Además la presente invención proporciona un procedimiento estereoselectivo corto y eficiente de preparación de γ-amino vinil sulfonas, con altos rendimientos y elevada pureza óptica.An advantage of the present invention lies in the fact that this stereoselective process of preparing γ-amino vinyl sulfones does not depend on the availability of a suitable α-amino acid. Another advantage of the present invention lies in the fact that the stereoselective process of preparing γ-amino vinyl sulfones can provide both enantiomers of a given γ-amino vinyl sulfone with equal ease. Furthermore, the present invention provides a short and efficient stereoselective process for preparing γ-amino vinyl sulfones, with high yields and high optical purity.
Para los expertos en la materia, otros objetos, ventajas y características de la invención se desprenderán en parte de la descripción y en parte de la práctica de la invención. A lo largo de la descripción y las reivindicaciones la palabra "comprende" y sus variantes no pretenden excluir otras características técnicas, aditivos, componentes o pasos. Las descripciones en el resumen de esta solicitud, y en la solicitud que se reivindica como prioritaria, se incorporan aquí como referencia. Los siguientes ejemplos se proporcionan a modo de ilustración, y no se pretende que sean limitativos de la presente invención.For those skilled in the art, other objects, advantages and features of the invention will be derived partly from the description and partly from the practice of the invention. Throughout the description and the claims the word "comprises" and its variants are not intended to exclude other technical characteristics, additives, components or steps. The descriptions in the summary of this application, and in the application claimed as a priority, are incorporated herein by reference. The following examples are provided by way of illustration, and are not intended to be limiting of the present invention.
EJEMPLOSEXAMPLES
Los siguientes ejemplos no limitantes ilustran la invención para una determinada configuración estereoisomérica. Cuando se requiere otra configuración de los estereoisómeros, la invención puede llevarse a cabo de manera similar partiendo de compuestos de configuración adecuada, como sería obvio para la persona experta en la materia.The following non-limiting examples illustrate the invention for a certain stereoisomeric configuration. When another configuration of stereoisomers is required, the invention can be carried out in a similar manner starting from compounds of suitable configuration, as would be obvious to the person skilled in the art.
Ejemplo 1 : Preparación de (SH(S)-1-íferc-butoxicarbonílamino)-3- fenilpropilloxirano (IV. Rι= Ph(CH?W)
A una solución de (2S,3S)-Λ/-Boc-3-amino-5-fenilpentan-1 ,2-diol (0.10 g, 0.34 mmol) y de trifenilfosfina (95 mg, 0.36 mmol) en cloroformo anhidro (2 mi) se le añadió una solución de azodicarboxilato de diisopropilo (71 μl, 0.36 mmol) en 1 mi de cloroformo anhidro. La mezcla de reacción se calentó a reflujo durante 20 h, tiempo en el que el análisis por CCF mostró la desaparición del producto de partida. Se evaporó el disolvente, se purificó el residuo por cromatografía en columna de sílice con mezclas de hexano-acetato de etilo como eluyentes y se obtuvieron 86 mg (92% de rendimiento) del producto del título en forma de un sólido incoloro. P.f.: 68-70°C. [α]D23= -8.5 (c = 1.02, CHCI3). IR (NaCI film, v max, cm"1): 2979, 1696, 1522, 1427, 1366, 1248, 1171. MS (CI-NH3, m/e): 295 (M+18, 45%), 278 ( +1 , 46%), 240 (M-37, 100%).Example 1: Preparation of (SH (S) -1-íferc-butoxycarbonylamino) -3-phenylpropilloxyran (IV. Rι = Ph (CH? W) To a solution of (2S, 3S) -Λ / -Boc-3-amino-5-phenylpentan-1,2-diol (0.10 g, 0.34 mmol) and triphenylphosphine (95 mg, 0.36 mmol) in anhydrous chloroform (2 mi) a solution of diisopropyl azodicarboxylate (71 μl, 0.36 mmol) in 1 ml of anhydrous chloroform was added. The reaction mixture was heated at reflux for 20 h, at which time the analysis by TLC showed the disappearance of the starting product. The solvent was evaporated, the residue was purified by silica column chromatography with hexane-ethyl acetate mixtures as eluents and 86 mg (92% yield) of the title product was obtained as a colorless solid. Mp: 68-70 ° C. [α] D 23 = -8.5 (c = 1.02, CHCI3). IR (NaCI film, v max , cm "1 ): 2979, 1696, 1522, 1427, 1366, 1248, 1171. MS (CI-NH3, m / e): 295 (M + 18, 45%), 278 ( +1, 46%), 240 (M-37, 100%).
Ejemplo 2: Preparación de (S)-í(S)-1-(terc-butoxicarbonilamino)-4-(ferc- butildimetilsililoxi)but¡noxirano (IV. Rι= TBDMSOfCHgW)Example 2: Preparation of (S) -i (S) -1- (tert-butoxycarbonylamino) -4- (ferc- butyldimethylsilyloxy) butynoxyran (IV. Rι = TBDMSOfCHgW)
De manera similar se obtuvo el producto del título con un 81% de rendimiento, después de su purificación cromatográfica, a partir de N-Boc-3- amino-3-(ferc-butildimetils¡liloxi)propan-1 ,2-d¡ol (0.29 g, 0.80 mmol), azodicarboxilato de diisopropilo (0.17 mi, 0.86 mmol) y trifenilfosfina (0.22 g, 0.86 mmol) en cloroformo a reflujo (4 mi, 7 h) en forma de un aceite incoloro. [α]D23= -5.15 (c = 1.04, CHCI3). IR (NaCI film, v max, cm"1): 2930, 2859, 1702, 1522, 1254, 1173, 1100, 836. MS (FAB+, NBA, m/e): 346 (M+1 , 100%), 468 (M+23, 61%).Similarly, the title product was obtained in 81% yield, after chromatographic purification, from N-Boc-3- amino-3- (ferc-butyldimethylsiloxy) propan-1,2-d¡ ol (0.29 g, 0.80 mmol), diisopropyl azodicarboxylate (0.17 mi, 0.86 mmol) and triphenylphosphine (0.22 g, 0.86 mmol) in reflux chloroform (4 mi, 7 h) as a colorless oil. [α] D 23 = -5.15 (c = 1.04, CHCI3). IR (NaCI film, v max , cm "1 ): 2930, 2859, 1702, 1522, 1254, 1173, 1100, 836. MS (FAB +, NBA, m / e): 346 (M + 1, 100%), 468 (M + 23, 61%).
Ejemplo 3: Preparación de (2S,3S)-3-(ferc-butoxicarbonilamíno)-3-fenil-1- feniltio-2-propanol (III. R-ι= Ph. Rz= Ph)Example 3: Preparation of (2S, 3S) -3- (ferc-butoxycarbonylamine) -3-phenyl-1- phenylthio-2-propanol (III. R-ι = Ph. R z = Ph)
A una solución de (S)-[(S)-1-(ferc-butoxicarbonilamino)-3-fenilmetil]oxirano (0.10 g, 0.40 mmol) en metanol anhidro (4 mi), se le añadieron secuencialmente trietilamina (57 μl, 0.40 mmol) y tiofenol (41 μl, 0.40 mmol). La mezcla resultante se calentó a reflujo hasta que el análisis mediante CCF mostró la desaparición del producto de partida (1 h). Se eliminó el disolvente, se purificó el residuo por cromatografía en columna (sílice previamente tratada con trietilamina, 2.5% v/v) con mezclas de hexano-acetato de etilo como eluyentes, y se obtuvieron 143 mg (100% de rendimiento) del
compuesto del título en forma de un sólido incoloro. P. f. 119-120 °C. [α]D23= +6.4 (c = 1.02, CHCI3). IR (NaCI film, v max, cm"1): 1684, 1497, 1457, 1368, 1167. MS (CI-NH3, m/e): 360 (M+1, 22%), 359 (M, 100%), 321 (M-38, 56%), 304 (M-55, 43%).To a solution of (S) - [(S) -1- (ferc-butoxycarbonylamino) -3-phenylmethyl] oxirane (0.10 g, 0.40 mmol) in anhydrous methanol (4 ml), triethylamine (57 μl, was added sequentially 0.40 mmol) and thiophenol (41 μl, 0.40 mmol). The resulting mixture was heated to reflux until analysis by TLC showed the disappearance of the starting product (1 h). The solvent was removed, the residue was purified by column chromatography (silica previously treated with triethylamine, 2.5% v / v) with hexane-ethyl acetate mixtures as eluents, and 143 mg (100% yield) of the title compound in the form of a colorless solid. P. f. 119-120 ° C. [α] D 23 = +6.4 (c = 1.02, CHCI3). IR (NaCI film, v max , cm "1 ): 1684, 1497, 1457, 1368, 1167. MS (CI-NH3, m / e): 360 (M + 1, 22%), 359 (M, 100% ), 321 (M-38, 56%), 304 (M-55, 43%).
Ejemplo 4: Preparación de (2S,3S)-3-(ferc-butoxicarbonilamino)-4-fenil-1- feniltio-2-butanol (III. Rι= PhCH?. R?= Ph)Example 4: Preparation of (2S, 3S) -3- (ferc-butoxycarbonylamino) -4-phenyl-1- phenylthio-2-butanol (III. Rι = PhCH ?. R? = Ph)
De manera similar, se obtuvo el producto del título con un 100% de rendimiento (0.8 mmol). P. f. 148-149 °C. [α]D = -26.6 (c = 1.0, CHCI3). IR (NaCI film, v max, cm"1): 3747, 3359, 1686, 1654, 1559, 1522, 1457, 1173, 741.Similarly, the title product was obtained in 100% yield (0.8 mmol). P. f. 148-149 ° C. [α] D = -26.6 (c = 1.0, CHCI3). IR (NaCI film, v max, cm "1 ): 3747, 3359, 1686, 1654, 1559, 1522, 1457, 1173, 741.
Ejemplo 5: Preparación de (2S,3S)-3-(ferc-butoxicarbonilamíno)-5-fenil-1-
Example 5: Preparation of (2S, 3S) -3- (ferc-butoxycarbonylamine) -5-phenyl-1-
De manera similar, se obtuvo el producto del título con un 78% de rendimiento, después de su purificación cromatográfica, a partir de (S)-[(S)-1- (íerc-butoxicarbonilamino)-3-fenilpropil]oxirano (0.50 g, 1.8 mmol), tiofenol (184 μl, 1.8 mmol) y trietilamina (255 μl, 1.8 mmol) en metanol a reflujo (18 mi, 4 h). P. f. 118-119 °C. [α]D23= - 1.6 (c = 0.7, CHCI3). IR (NaCI film, v max, cm"1): 3347, 1681, 1528, 1299, 1248, 1169, 1017. MS (CI-NH3, m/e): 388 (M+1 , 100%), 349 (M-38, 55%), 332 (M-55, 34%).Similarly, the title product was obtained in a 78% yield, after chromatographic purification, from (S) - [(S) -1- (íerc-butoxycarbonylamino) -3-phenylpropyl] oxirane (0.50 g, 1.8 mmol), thiophenol (184 µl, 1.8 mmol) and triethylamine (255 µl, 1.8 mmol) in methanol at reflux (18 mL, 4 h). P. f. 118-119 ° C. [α] D 23 = - 1.6 (c = 0.7, CHCI3). IR (NaCI film, vm ax , cm "1 ): 3347, 1681, 1528, 1299, 1248, 1169, 1017. MS (CI-NH3, m / e): 388 (M + 1, 100%), 349 ( M-38, 55%), 332 (M-55, 34%).
Ejemplo 6: Preparación de (2S,3S)-3-(ferc-butoxicarbonilamino)-5-metil-1- feniltio-2-hexanol (III. Rι= (CHa CHCH?, R2= Ph)Example 6: Preparation of (2S, 3S) -3- (ferc-butoxycarbonylamino) -5-methyl-1- phenylthio-2-hexanol (III. Rι = (CHa CHCH ?, R 2 = Ph)
De manera similar, se obtuvo el producto del título con un 84% de rendimiento, después de su purificación cromatográfica, a partir del epóxido IV, R,= (CH3)2CHCH2 (0.30 g, 1.3 mmol), tiofenol (135 μl, 1.3 mmol) y trietilamina (185 μl, 1.3 mmol) en metanol a reflujo (10 mi, 1 h). P. f. 83-85 °C. [α]D23= -25.3 (c = 1.02, CHCI3). IR (NaCI film, v max, cm"1): 1684, 1654, 1559, 1507, 1368, 1167, 737, 668. MS (CI-NH3, m/e): 340 (M+1, 6%), 339 (M, 32%), 284 (M-55, 100%).Similarly, the title product was obtained in 84% yield, after chromatographic purification, from epoxy IV, R, = (CH 3 ) 2 CHCH 2 (0.30 g, 1.3 mmol), thiophenol (135 μl, 1.3 mmol) and triethylamine (185 μl, 1.3 mmol) in methanol at reflux (10 ml, 1 h). P. f. 83-85 ° C. [α] D 23 = -25.3 (c = 1.02, CHCI3). IR (NaCI film, v max , cm "1 ): 1684, 1654, 1559, 1507, 1368, 1167, 737, 668. MS (CI-NH3, m / e): 340 (M + 1, 6%), 339 (M, 32%), 284 (M-55, 100%).
Ejemplo 7: Preparación de (2S,3S)-3-(ferc-butoxicarbon¡lamino)-6-(ferc- but¡ldimetils¡loxi)-1-fen¡ltio-2-hexanol (III. Rι= TBDMSO(CH? R?= Ph)
De manera similar^ se obtuvo el producto del título con un 89% de rendimiento, después de su purificación cromatográfica, a partir de (S)-[(S)-1- (terc-butoxicarbonilamino)-4-(terc-but¡ldimetilsililoxi)butil]oxirano (0.17 g, 0.50 mmol), tiofenol (51 μl, 0.50 mmol) y trietilamina (71 μl, 0.51 mmol) en metanol a reflujo (5 mi, 1.5 h) en forma de un aceite incoloro. [α]D = -10.0 (c = 1.1 , CHCI3). IR (NaCI film, v max, cm"1): 2931 , 1696, 1654, 1507, 1252, 1169, 1100, 836. MS (FAB+, NBA, m/e): 456 (M+1 , 100%), 478 (M+23, 39%).Example 7: Preparation of (2S, 3S) -3- (ferc-butoxycarbonylamino) -6- (ferc- butyldimethylsloxy) -1-phenylthio-2-hexanol (III. Rι = TBDMSO (CH ? R? = Ph) Similarly, the title product was obtained in 89% yield, after chromatographic purification, from (S) - [(S) -1- (tert-butoxycarbonylamino) -4- (tert-but¡ ldimethylsilyloxy) butyl] oxirane (0.17 g, 0.50 mmol), thiophenol (51 μl, 0.50 mmol) and triethylamine (71 μl, 0.51 mmol) in methanol at reflux (5 ml, 1.5 h) in the form of a colorless oil. [α] D = -10.0 (c = 1.1, CHCI3). IR (NaCI film, v max , cm "1 ): 2931, 1696, 1654, 1507, 1252, 1169, 1100, 836. MS (FAB +, NBA, m / e): 456 (M + 1, 100%), 478 (M + 23, 39%).
Ejemplo 8: Preparación de (2S.3S)-3-(ferc-butoxicarbonilam¡no)-5-fen¡l-2- naftiltio-2-pentanol mi. R_ι= Ph (CH?)?. R?= naftilo)Example 8: Preparation of (2S.3S) -3- (ferc-butoxycarbonylamine) -5-phenol-2-naphthylthio-2-pentanol mi. R_ι = Ph (CH?) ?. R? = Naphthyl)
A una solución de (S)-[(S)-1-(íerc-butoxicarbonilamino)-3-fenilpropil]oxirano (0.50 g, 1.80 mmol) en metanol anhidro (18 mi), se le añadieron secuencialmente trietilamina (255 μl, 1.82 mmol) y 2-naftiltiol (0.29 g, 1.80 mmol). La mezcla resultante se calentó a reflujo durante 4 h, tiempo en el que el análisis por CCF mostró la desaparición del epóxido de partida. Se eliminó el disolvente y se purificó el residuo por cromatografía en columna (sílice previamente tratada con trietilamina, 2.5% v/v) con mezclas de hexano- acetato de etilo como eluyentes, y se obtuvieron 143 mg (87% de rendimiento) del compuesto del título en forma de un sólido incoloro. P.f. 125- 127 °C. [α]D23= -23.0 (c = 1.01 , CHCI3). IR (NaCI filmv maX, cm"1): 3357, 1683, 1524, 1297, 1248, 1173, 1021. MS (CI-NH3) m/e: 455 (M+18, 69%), 438 (M+1 , 36%), 437 (M, 100%).To a solution of (S) - [(S) -1- (íerc-butoxycarbonylamino) -3-phenylpropyl] oxirane (0.50 g, 1.80 mmol) in anhydrous methanol (18 ml), triethylamine (255 μl, was added sequentially 1.82 mmol) and 2-naphthylthiol (0.29 g, 1.80 mmol). The resulting mixture was heated at reflux for 4 h, at which time the analysis by TLC showed the disappearance of the starting epoxide. The solvent was removed and the residue was purified by column chromatography (silica previously treated with triethylamine, 2.5% v / v) with hexane-ethyl acetate mixtures as eluents, and 143 mg (87% yield) of the compound were obtained. of the title in the form of a colorless solid. Mp 125-127 ° C. [α] D 23 = -23.0 (c = 1.01, CHCI3). IR (NaCI filmv ma X , cm "1 ): 3357, 1683, 1524, 1297, 1248, 1173, 1021. MS (CI-NH3) m / e: 455 (M + 18, 69%), 438 (M + 1, 36%), 437 (M, 100%).
Ejemplo 9: Preparación de (2S,3S)-3-(ferc-butoxicarbonilamino)-3-fenil-1- metiltio-2-propanol (III. Rι= Ph. R?= CH3)Example 9: Preparation of (2S, 3S) -3- (ferc-butoxycarbonylamino) -3-phenyl-1- methylthio-2-propanol (III. Rι = Ph. R? = CH 3 )
Se calentó a reflujo una solución de (S)-[(S)-1-(íerc-butoxicarbonilamino)-3- fenilmetiljoxirano (0.10 g, 0.40 mmol) y de metanotiolato de sodio (34 mg,A solution of (S) - [(S) -1- (íerc-butoxycarbonylamino) -3-phenylmethyljoxyran (0.10 g, 0.40 mmol) and sodium methanethiolate (34 mg, was heated to reflux
0.50 mmol) en metanol anhidro (5 ml) hasta que el análisis por CCF mostró la desaparición del epóxido de partida (4 h). Se eliminó el disolvente, se purificó el residuo por cromatografía en columna (sílice previamente tratada con trietilamina, 2.5% v/v) con mezclas de hexano-acetato de etilo como eluyentes y se obtuvieron 100 mg (84% de rendimiento) del compuesto del título en forma de un sólido incoloro. P. f. 129-130 °C. [α]o23
= +29.2 (c = 1.05, CHCI3). IR (NaCI film, v max, cm"1): 3377, 1684, 1654, 1522, 1457, 1246, 1171 , 1015. MS (CI-NH3, m/e): 315 (M+18, 9%), 298 (M+1 , 100%), 259 (M-38, 75%), 242 (M-55, 23%).0.50 mmol) in anhydrous methanol (5 ml) until the analysis by TLC showed the disappearance of the starting epoxide (4 h). The solvent was removed, the residue was purified by column chromatography (silica previously treated with triethylamine, 2.5% v / v) with hexane-ethyl acetate mixtures as eluents and 100 mg (yield 84%) of the compound was obtained. title in the form of a colorless solid. P. f. 129-130 ° C. [α] or 23 = +29.2 (c = 1.05, CHCI3). IR (NaCI film, vm ax , cm "1 ): 3377, 1684, 1654, 1522, 1457, 1246, 1171, 1015. MS (CI-NH3, m / e): 315 (M + 18, 9%), 298 (M + 1, 100%), 259 (M-38, 75%), 242 (M-55, 23%).
Ejemplo 10: Preparación de (2S,3S)-3-(ferc-butoxicarbonilam¡no)-4-fenil-1- metiltio-2-butanol (III. Rι= PhCH?. R?= CH3)Example 10: Preparation of (2S, 3S) -3- (ferc-butoxycarbonylamine) -4-phenyl-1- methylthio-2-butanol (III. Rι = PhCH ?. R? = CH3)
De manera similar, se obtuvo el producto del título con un 92% de rendimiento, después de su purificación cromatográfica, a partir de (S)-[(S)-1- (ferc-butoxicarbonilamino)-3-feniletil]oxirano (0.20 g, 0.76 mmol) y metanotiolato de sodio (60 mg, 0.84 mmol) en metanol a reflujo (10 mi, 0.5 h).Similarly, the title product was obtained in 92% yield, after chromatographic purification, from (S) - [(S) -1- (ferc-butoxycarbonylamino) -3-phenylethyl] oxirane (0.20 g, 0.76 mmol) and sodium methanethiolate (60 mg, 0.84 mmol) in reflux methanol (10 mL, 0.5 h).
P. f. 134.5-135.5 °C. [α]D23= -7.0 (c = 1.0, CHCI3). IR (NaCI film, v max, cm" P. f. 134.5-135.5 ° C. [α] D 23 = -7.0 (c = 1.0, CHCI3). IR (NaCI film, v max , cm "
1): 3357, 1685, 1527, 1316, 1250, 1171, 1015, 702 cm"1. MS (CI-NH3, m/e): 1 ): 3357, 1685, 1527, 1316, 1250, 1171, 1015, 702 cm "1. MS (CI-NH3, m / e):
312 (M+1, 76%), 273 (M-38, 100%), 256 (M-55, 99%).312 (M + 1, 76%), 273 (M-38, 100%), 256 (M-55, 99%).
Ejemplo 11 : Preparación de (2S.3S)-3-(ferc-butoxicarbonilamino)-5-fenil-1- metiltio-2-pentanol (III. Rι= Ph(CH?)?. R?= CH )Example 11: Preparation of (2S.3S) -3- (ferc-butoxycarbonylamino) -5-phenyl-1- methylthio-2-pentanol (III. Rι = Ph (CH?) ?. R? = CH)
De manera similar, se obtuvo el producto del título con un 78% de rendimiento, después de su purificación cromatográfica, a partir de (S)-[(S)-1- (íerc-butoxicarbonilamino)-3-fenilpropil]oxirano (0.50 g, 1.8 mmol) y metanotiolato de sodio (150 mg, 2.2 mmol) en metanol a reflujo (20 mi, 4 h). P. f. 108-109 °C. [α]D23= -7.6 (c = 1.02, CHCI3). IR (NaCI film, v max, cm"1): 3357, 1685, 1522, 1248, 1173, 1019, 699. MS (CI-NH3, m/e): 343 (M+18, 100%), 326 (M+1 , 15%), 325 (M, 83%), 287 (M-38, 32%).Similarly, the title product was obtained in a 78% yield, after chromatographic purification, from (S) - [(S) -1- (íerc-butoxycarbonylamino) -3-phenylpropyl] oxirane (0.50 g, 1.8 mmol) and sodium methanethiolate (150 mg, 2.2 mmol) in reflux methanol (20 mL, 4 h). P. f. 108-109 ° C. [α] D 23 = -7.6 (c = 1.02, CHCI3). IR (NaCI film, vm ax , cm "1 ): 3357, 1685, 1522, 1248, 1173, 1019, 699. MS (CI-NH3, m / e): 343 (M + 18, 100%), 326 ( M + 1, 15%), 325 (M, 83%), 287 (M-38, 32%).
E¡emplo 12: Preparación de (2S.3S)-3-(ferc-butoxicarbonilam¡no)-5-metil-1- metiltio-2-hexanol (III. Rι= (CH3)?CHCH?, R?= CHa)Example 12: Preparation of (2S.3S) -3- (ferc-butoxycarbonylamine) -5-methyl-1- methylthio-2-hexanol (III. Rι = (CH 3 )? CHCH ?, R? = CHa)
De manera similar, se obtuvo el producto del título con un 86% de rendimiento, después de su purificación cromatográfica, a partir del epóxido (IV, (CH3)2CHCH2), (0.30 g, 1.31 mmol) y metanotiolato de sodio (101 mg, 1.44 mmol) en metanol a reflujo (20 mi, 1 h). P. f. 109-110 °C. [α]D23= - 24.4 (c = 1.0, CHCI3). IR (NaCI film, v maX> crrf1): 3359, 2952, 1679, 1530, 1329, 1254, 1171. MS (CI-NH3, m/e): 295 (M+18, 8%), 278 (M+1 , 100%), 239 (M-38, 23%), 223 (M-54, 58%).
Ejemplo 13: Preparación de (2S.3S)-3-(feΛC-butoxicarbonilamino)-3-fenil-1- fenilsulfonil-2-propanol (II. Rι= Ph. R?= Ph)Similarly, the title product was obtained in 86% yield, after chromatographic purification, from epoxide (IV, (CH 3 ) 2 CHCH 2 ), (0.30 g, 1.31 mmol) and sodium methanethiolate (101 mg, 1.44 mmol) in methanol at reflux (20 ml, 1 h). P. f. 109-110 ° C. [α] D 23 = - 24.4 (c = 1.0, CHCI3). IR (NaCI film, v ma X> crrf 1 ): 3359, 2952, 1679, 1530, 1329, 1254, 1171. MS (CI-NH3, m / e): 295 (M + 18, 8%), 278 ( M + 1, 100%), 239 (M-38, 23%), 223 (M-54, 58%). Example 13: Preparation of (2S.3S) -3- (feΛC-butoxycarbonylamino) -3-phenyl-1- phenylsulfonyl-2-propanol (II. Rι = Ph. R? = Ph)
A una solución del sulfuro preparado en el Ejemplo 3 (0.107 g, 0.30 mmol) en diclorometano anhidro (6 mi), se le añadió, gota a gota, una solución de ácido m-cloroperbenzoico (0.130 g, 0.75 mmol) en diclorometano anhidro (6 mi). La mezcla de reacción se agitó a temperatura ambiente (t.a.) hasta que el análisis por CCF mostró la desaparición del producto de partida (3 h); se enfrió a 0 °C y se trató con una solución de sulfito de sodio al 10% (4 mi). Después de 15 min de agitación, se separó la fase acuosa. La fase orgánica se lavó con una solución saturada de bicarbonato de sodio (5 mi) y con una solución saturada de cloruro de sodio (5 mi), y se secó con sulfato de magnesio anhidro. Se eliminó el disolvente, se purificó el residuo por cromatografía en columna (sílice previamente tratada con trietilamina, 2.5% v/v) con mezclas de hexano-acetato de etilo como eluyentes y se obtuvieron 115 mg (100% de rendimiento) del compuesto del título en forma de un sólido incoloro. P. f. 158-160 °C. [α]o23= +3.2 (c = 1.1, CHCI3). IR (NaCI film, v max, cm"1): 3504, 1702, 1497, 1366, 1308, 1153. MS (CI-NH3, m/e): 409 (M+18, 100%), 354 (M-37, 74%), 335 (M-55, 82%).To a solution of the sulfide prepared in Example 3 (0.107 g, 0.30 mmol) in anhydrous dichloromethane (6 ml), a solution of m-chloroperbenzoic acid (0.130 g, 0.75 mmol) in anhydrous dichloromethane was added dropwise (6 mi). The reaction mixture was stirred at room temperature (ta) until the analysis by TLC showed the disappearance of the starting product (3 h); it was cooled to 0 ° C and treated with a 10% sodium sulphite solution (4 ml). After 15 min of stirring, the aqueous phase was separated. The organic phase was washed with a saturated solution of sodium bicarbonate (5 ml) and with a saturated solution of sodium chloride (5 ml), and dried with anhydrous magnesium sulfate. The solvent was removed, the residue was purified by column chromatography (silica previously treated with triethylamine, 2.5% v / v) with hexane-ethyl acetate mixtures as eluents and 115 mg (100% yield) of the compound was obtained. title in the form of a colorless solid. P. f. 158-160 ° C. [α] or 23 = +3.2 (c = 1.1, CHCI3). IR (NaCI film, v max, cm "1 ): 3504, 1702, 1497, 1366, 1308, 1153. MS (CI-NH3, m / e): 409 (M + 18, 100%), 354 (M- 37, 74%), 335 (M-55, 82%).
Ejemplo 14: Preparación de (2S,3S)-3-(ferc-butoxicarbonilamino)-3-fenil-1- metilsulfonil-2-propanol (II. Rj= Ph. R?= CH3)Example 14: Preparation of (2S, 3S) -3- (ferc-butoxycarbonylamino) -3-phenyl-1- methylsulfonyl-2-propanol (II. R j = Ph. R? = CH 3 )
De manera similar, se obtuvo el producto del título con un 100% de rendimiento, después de su purificación cromatográfica, a partir del sulfuro preparado en el Ejemplo 9 (55 mg, 0.3 mmol). IR (NaCI film, v max, cnrf '): 1719, 1685, 1507, 1366, 1283, 1121 , 1071. MS (CI-NH3, m/e): 347 (M+18, 9%), 330 (M+1 , 88%), 291 (M-38, 18%), 274 (M-55, 100%).Similarly, the title product was obtained in 100% yield, after chromatographic purification, from the sulfide prepared in Example 9 (55 mg, 0.3 mmol). IR (NaCI film, vm a x, cnrf '): 1719, 1685, 1507, 1366, 1283, 1121, 1071. MS (CI-NH3, m / e): 347 (M + 18, 9%), 330 ( M + 1, 88%), 291 (M-38, 18%), 274 (M-55, 100%).
Ejemplo 15: Preparación de (2S.3S -3-(ferc-butoxicarbonilamino)-4-fenil-1- fenilsulfonil-2-butanol (II. Rι= PhCH?. R?= Ph)Example 15: Preparation of (2S.3S -3- (ferc-butoxycarbonylamino) -4-phenyl-1- phenylsulfonyl-2-butanol (II. Rι = PhCH ?. R? = Ph)
De manera similar, se obtuvo el producto del título con un 81 % de rendimiento, después de su purificación cromatográfica, a partir del sulfuro preparado en el Ejemplo 4 (0.20 g, 0.55 mmol). P. f. 154-155 °C. [α]D23= +3.0 (c = 1.04, CHCI3). IR (NaCI film, , v max. cm"1): 3355, 1692, 1526, 1316,
1148, 1013, 739. MS (CI-NH3, m/e): 423 (M+18, 7%), 406 (M+1 , 5%), 405 (M, 19.%), 366 (M-39, 100%), 349 (M-56, 41%).Similarly, the title product was obtained in 81% yield, after chromatographic purification, from the sulfide prepared in Example 4 (0.20 g, 0.55 mmol). P. f. 154-155 ° C. [α] D 23 = +3.0 (c = 1.04, CHCI3). IR (NaCI film,, vm to x. Cm "1 ): 3355, 1692, 1526, 1316, 1148, 1013, 739. MS (CI-NH3, m / e): 423 (M + 18, 7%), 406 (M + 1, 5%), 405 (M, 19.%), 366 (M- 39, 100%), 349 (M-56, 41%).
Ejemplo 16: Preparación de (2S.3S)-3-(feΛC-butoxicarbonilamino)-4-fen¡l-1- metilsulfonil-2-butanol (II. Rι= PhCH?. R?= CHg)Example 16: Preparation of (2S.3S) -3- (feΛC-butoxycarbonylamino) -4-phenyl-1-methylsulfonyl-2-butanol (II. Rι = PhCH ?. R? = CHg)
De manera similar, se obtuvo el producto del título con un 80% de rendimiento, después de su purificación cromatográfica, a partir del sulfuro preparado en el Ejemplo 10 (0.20 g, 0.64 mmol). P. f. 155-156 °C. [α]D = - 23.1 (c = 0.9, CHCI3). IR (NaCI film, v max, cm"1): 3359, 1686, 1521 , 1301 , 1254, 1169, 1129, 1013. MS (CI-NH3) m/e: 344 (M+1 , 2%), 343 (M, 11%), 305 (M-38, 100%), 288 (M-55, 19%).Similarly, the title product was obtained in 80% yield, after chromatographic purification, from the sulfide prepared in Example 10 (0.20 g, 0.64 mmol). P. f. 155-156 ° C. [α] D = - 23.1 (c = 0.9, CHCI3). IR (NaCI film, v max, cm "1 ): 3359, 1686, 1521, 1301, 1254, 1169, 1129, 1013. MS (CI-NH3) m / e: 344 (M + 1, 2%), 343 (M, 11%), 305 (M-38, 100%), 288 (M-55, 19%).
Ejemplo 17: Preparación de (2S,3S)-3-(ferc-butoxicarbonilamino)-5-fenil-1- fenilsulfonil-2-pentanol (II. Rι= Ph(CH?)?. R?= Ph)Example 17: Preparation of (2S, 3S) -3- (ferc-butoxycarbonylamino) -5-phenyl-1- phenylsulfonyl-2-pentanol (II. Rι = Ph (CH?)? R? = Ph)
De manera similar, se obtuvo el producto del título con un 100% de rendimiento, después de su purificación cromatográfica, a partir del sulfuro preparado en el Ejemplo 5 (0.155 g, 0.40 mmol). P. f. 129-130°C. [α]D23= - 13.5 (c = 1.0, CHCl3). IR (NaCI film, v max, cm"1): 2362, 2341 , 1717, 1507, 1289, 1144 . MS (CI-NH3, m/e): AZI (M+18, 16%), 420 (M+1 , 15%), 381 (M- 38, 22%), 380 (M-39, 100%).Similarly, the title product was obtained in 100% yield, after chromatographic purification, from the sulfide prepared in Example 5 (0.155 g, 0.40 mmol). P. f. 129-130 ° C. [α] D 23 = - 13.5 (c = 1.0, CHCl3). IR (NaCI film, vm to x, cm "1 ): 2362, 2341, 1717, 1507, 1289, 1144. MS (CI-NH3, m / e): AZI (M + 18, 16%), 420 (M +1, 15%), 381 (M- 38, 22%), 380 (M-39, 100%).
Ejemplo 18: Preparación de (2S.3S)-3-(ferc-butoxicarbon¡lam¡no)-5-fenil-1- metilsulfonil-2-pentanol (II. Rι= Ph(CH?)?. R?= CH3)Example 18: Preparation of (2S.3S) -3- (ferc-butoxycarbonyllamine) -5-phenyl-1- methylsulfonyl-2-pentanol (II. Rι = Ph (CH?)? R? = CH 3 )
De manera similar, se obtuvo el producto del título con un 80% de rendimiento, después de su purificación cromatográfica, a partir del sulfuro preparado en el Ejemplo 11 (0.20 g, 0.62 mmol). P. f. 125-127 °C. [α]D23= - 11.6 (c = 1.0, CHCI3). IR (NaCI film v max, cm"1): 1685, 1522, 1457, 1299, 1129, 473. MS (CI-NH3, m/e): 374 (M+18, 100%).Similarly, the title product was obtained in 80% yield, after chromatographic purification, from the sulfide prepared in Example 11 (0.20 g, 0.62 mmol). P. f. 125-127 ° C. [α] D 23 = - 11.6 (c = 1.0, CHCI3). IR (NaCI film v max , cm "1 ): 1685, 1522, 1457, 1299, 1129, 473. MS (CI-NH3, m / e): 374 (M + 18, 100%).
Ejemplo 19: Preparación de (2S,3S)-3-(ferc-butoxicarbon¡lamino)-5-fenil-1-(2- naftilsulfonil)-2-pentanol (II. Rι= Ph(CH?)?. R?= naftilo)Example 19: Preparation of (2S, 3S) -3- (ferc-butoxycarbonyllamino) -5-phenyl-1- (2- naphthylsulfonyl) -2-pentanol (II. Rι = Ph (CH?)? R? = naphthyl)
De manera similar, se obtuvo el producto del título con un 87% de rendimiento, después de su purificación cromatográfica, a partir del sulfuro
preparado en el Ejemplo 8 (0.30 g, 0.69 mmol). P. f. 158-159 °C. [α]D23= -Similarly, the title product was obtained in 87% yield, after chromatographic purification, from the sulfide prepared in Example 8 (0.30 g, 0.69 mmol). P. f. 158-159 ° C. [α] D 23 = -
17.7 (c = 1.03, CHCI3). IR (NaCl film, v max, cm"1): 1696, 1507, 1368, 1304 1246, 1144, 1127, 1019, 749. MS (CI-NH3, m/e): 487 (M+18, 100%), 431 (M- 38, 5%).17.7 (c = 1.03, CHCI3). IR (NaCl film, v max , cm "1 ): 1696, 1507, 1368, 1304 1246, 1144, 1127, 1019, 749. MS (CI-NH3, m / e): 487 (M + 18, 100%) , 431 (M- 38.5%).
Ejemplo 20: Preparación de (2S,3S)-3-(ferc-butoxicarbonilam¡no)-5-metil-1- fenilsulfonil-2-hexanol (II. Rι= (CH3)?CHCH?, R?= Ph)Example 20: Preparation of (2S, 3S) -3- (ferc-butoxycarbonylamine) -5-methyl-1- phenylsulfonyl-2-hexanol (II. Rι = (CH 3 )? CHCH ?, R? = Ph)
De manera similar, se obtuvo el producto del título con un 97% de rendimiento, después de su purificación cromatográfica, a partir del sulfuro preparado en el Ejemplo 6 (0.20 g, 0.60 mmol). P. f. 106-107 °C
-Similarly, the title product was obtained in 97% yield, after chromatographic purification, from the sulfide prepared in Example 6 (0.20 g, 0.60 mmol). P. f. 106-107 ° C -
16.2 (c = 1.03, CHCI3). IR (NaCI film, v max, cm"1): 2960, 1962, 1521 , 1449,16.2 (c = 1.03, CHCI3). IR (NaCI film, v max, cm "1 ): 2960, 1962, 1521, 1449,
1368, 1304, 1144.. MS (CI-NH3, m/e): 372 (M+1 , 18%), 371 (M, 86%), 3161368, 1304, 1144 .. MS (CI-NH3, m / e): 372 (M + 1, 18%), 371 (M, 86%), 316
(M-55, 100%).(M-55, 100%).
Ejemplo 21: Preparación de (2S.3S)-3-(ferc-butoxicarbonilamino)-5-metil-1-
Example 21: Preparation of (2S.3S) -3- (ferc-butoxycarbonylamino) -5-methyl-1-
De manera similar, se obtuvo el producto del título con un 86% de rendimiento, después de su purificación cromatográfica, a partir del sulfuro preparado en el Ejemplo 12 (0.10 g, 0.36 mmol). P. f. 137-138 °C. [α]D23= -Similarly, the title product was obtained in 86% yield, after chromatographic purification, from the sulfide prepared in Example 12 (0.10 g, 0.36 mmol). P. f. 137-138 ° C. [α] D 23 = -
22.8 (c = 1.0, CHCI3). IR (NaCI film, v max, cm"1): 2960, 1686, 1522, 1393, 1368, 1295, 1167, 1133. MS (CI-NH3, m/e): 327 (M+18, 29%), 310 (M+1 , 23%), 271 (M-38, 100%), 254 (M-55, 15%).22.8 (c = 1.0, CHCI3). IR (NaCI film, v max, cm "1 ): 2960, 1686, 1522, 1393, 1368, 1295, 1167, 1133. MS (CI-NH3, m / e): 327 (M + 18, 29%), 310 (M + 1, 23%), 271 (M-38, 100%), 254 (M-55, 15%).
Ejemplo 22: Preparación de (2S.3S)-3-(ferc-butoxicarbonilamino)-6-(ferc- butildimetilsililoxi)-1-fen¡lsulfonil-2-hexanol (II, Rι= TBDMSO(CH? R?= Ph)Example 22: Preparation of (2S.3S) -3- (ferc-butoxycarbonylamino) -6- (ferc- butyldimethylsilyloxy) -1-phenylsulfonyl-2-hexanol (II, Rι = TBDMSO (CH? R? = Ph)
De manera similar, se obtuvo el producto del título con un 85% de rendimiento, después de su purificación cromatográfica, a partir del sulfuro preparado en el Ejemplo 7 (80 mg, 0.18 mmol) en forma de un aceite incoloro. [α]D23= -4.1 (c = 1.7, CHCI3). IR (NaCI film, v maχ, cm"1): 2931 , 1685, 1507, 1366, 1306, 1252, 1146, 1086, 836. MS (FAB+, NBA, m/e): 488 (M+1 , 47%), 510 (M+23, 100%).Similarly, the title product was obtained in 85% yield, after chromatographic purification, from the sulfide prepared in Example 7 (80 mg, 0.18 mmol) as a colorless oil. [α] D 23 = -4.1 (c = 1.7, CHCI3). IR (NaCI film, v ma χ, cm "1 ): 2931, 1685, 1507, 1366, 1306, 1252, 1146, 1086, 836. MS (FAB +, NBA, m / e): 488 (M + 1, 47 %), 510 (M + 23, 100%).
Ejemplo 23: Preparación de (2S.3S)-3-(ferc-butox¡carbonilamino)-3-(1'-naftil)- 1-fenilsulfonilpropan-2-ol (II, Rι= 1'-naftilo. R?= fenilo)
De manera similar, se obtuvo el producto del título con un 62% de rendimiento, después de su purificación cromatográfica, a partir del sulfuro correspondiente (1.22 g, 2.98 mmol) como un sólido incoloro. P.f. 162-164 °C. [α]D23= +6.6 (c= 1.2, CHCI3). 1H-NMR (200 MHz, CDCI3) δ: 1.37 (s, 9H), 3.07-3.38 (m, 2H), 3.51 (d, 1 H), 4.69 (m, 1 H), 5.28 (d, 1H), 5.53 (t, 1 H), 7.47- 8.10 (m, 12H) ppm. 13C- NMR (50 MHz, CDCI3) δ: 28.2, 53.2, 59.5, 68.6, 80.3, 122.6, 124.6, 125.2, 125.8, 126.7, 128.7, 128.9, 129.2, 131.2, 131.8, 133.8, 133.9, 138.9, 155.0 ppm. MS (CI-NH3, m/e): 442 (M+1, 100%), 459 (M+18, 26%).Example 23: Preparation of (2S.3S) -3- (ferc-butoxycarbonylamino) -3- (1'-naphthyl) -1-phenylsulfonylpropan-2-ol (II, Rι = 1'-naphthyl. R? = phenyl) Similarly, the title product was obtained in 62% yield, after chromatographic purification, from the corresponding sulfide (1.22 g, 2.98 mmol) as a colorless solid. Mp 162-164 ° C. [α] D 23 = +6.6 (c = 1.2, CHCI 3 ). 1 H-NMR (200 MHz, CDCI3) δ: 1.37 (s, 9H), 3.07-3.38 (m, 2H), 3.51 (d, 1 H), 4.69 (m, 1 H), 5.28 (d, 1H) , 5.53 (t, 1 H), 7.47-8.10 (m, 12H) ppm. 13 C-NMR (50 MHz, CDCI 3 ) δ: 28.2, 53.2, 59.5, 68.6, 80.3, 122.6, 124.6, 125.2, 125.8, 126.7, 128.7, 128.9, 129.2, 131.2, 131.8, 133.8, 133.9, 138.9, 155.0 ppm. MS (CI-NH 3 , m / e): 442 (M + 1, 100%), 459 (M + 18, 26%).
Ejemplo 24: Preparación de (2S,3S)-3-(terc-butoxicarbonilamino)-3-(2'- naftílo)-1-fenilsulfonilpropan-2-ol (II, Rι= 2'-naftilo. R?= fenilo)Example 24: Preparation of (2S, 3S) -3- (tert-butoxycarbonylamino) -3- (2'-naphtyl) -1-phenylsulfonylpropan-2-ol (II, Rι = 2'-naphthyl. R? = Phenyl)
De manera similar, se obtuvo el producto del título con un 70% de rendimiento, después de su purificación cromatográfica, a partir del sulfuro correspondiente (1.60 g, 3.92 mmol) como un sólido incoloro. P.f. 153-156 °C. [α]D23= +8.2 (c= 0.4, CHCI3). 1H-NMR (200 MHz, CDCI3) δ: 1.37 (s, 9H), 2.86-3.27 (m, 2H), 3.51 (s, 1 H), 4.55-4.73 (m, 2H), 5.60 (d, 1H), 7.41-7.89 (m, 12H) ppm. 13C- NMR (50 MHz, CDCI3) δ: 28.3, 59.8, 68.3, 80.2, 125.4, 126.2,Similarly, the title product was obtained in 70% yield, after chromatographic purification, from the corresponding sulfide (1.60 g, 3.92 mmol) as a colorless solid. Mp 153-156 ° C. [α] D 23 = +8.2 (c = 0.4, CHCI 3 ). 1 H-NMR (200 MHz, CDCI3) δ: 1.37 (s, 9H), 2.86-3.27 (m, 2H), 3.51 (s, 1 H), 4.55-4.73 (m, 2H), 5.60 (d, 1H ), 7.41-7.89 (m, 12H) ppm. 13 C-NMR (50 MHz, CDCI 3 ) δ: 28.3, 59.8, 68.3, 80.2, 125.4, 126.2,
126.3, 127.1 , 127.5, 127.8, 128.5, 129.4, 132.9, 134.1 , 138.9 ppm. MS (Cl- NH3, m/e): 442 (M+1, 10%), 386 (M-55, 40%).126.3, 127.1, 127.5, 127.8, 128.5, 129.4, 132.9, 134.1, 138.9 ppm. MS (Cl-NH 3 , m / e): 442 (M + 1, 10%), 386 (M-55, 40%).
Ejemplo 25: Preparación de (2S,3S)-3-(ferc-butoxicarbon¡lam¡no)-3-(4'- bifeniD-1-fenilsulfonilpropan-2-ol (II. Rι= 4'-bifenilo. R?= fenilo)Example 25: Preparation of (2S, 3S) -3- (ferc-butoxycarbonyllamine) -3- (4'- biphenylD-1-phenylsulfonylpropan-2-ol (II. Rι = 4'-biphenyl. R? = phenyl)
De manera similar, se obtuvo el producto del título con un 88% de rendimiento, después de su purificación cromatográfica, a partir del sulfuro correspondiente (805 mg, 1.85 mmol) como un sólido incoloro. P.f. 168-169 °C. [α]D23= -7.6 (c= 0.8, CHCI3). 1H-NMR (200 MHz, CDCI3) δ: 1.39 (s, 9H), 2.98 (m, 2H), 3.49 (d, 1 H), 4.47-4.59 (m, 2H), 5.49 (d, 1H), 7.25-7.90 (m, 14H) ppm. 13C- NMR (50 MHz, CDCI3) δ: 28.1 , 58.2, 59.8, 68.2, 80.0, 126.9, 127.3,Similarly, the title product was obtained in 88% yield, after chromatographic purification, from the corresponding sulfide (805 mg, 1.85 mmol) as a colorless solid. Mp 168-169 ° C. [α] D 23 = -7.6 (c = 0.8, CHCI3). 1 H-NMR (200 MHz, CDCI 3 ) δ: 1.39 (s, 9H), 2.98 (m, 2H), 3.49 (d, 1 H), 4.47-4.59 (m, 2H), 5.49 (d, 1H) , 7.25-7.90 (m, 14H) ppm. 13 C-NMR (50 MHz, CDCI3) δ: 28.1, 58.2, 59.8, 68.2, 80.0, 126.9, 127.3,
127.4, 127.9, 128.3, 128.7, 129.4, 134.1, 137.0, 129.0, 140.0, 141.0, 155.0 ppm. MS (FAB+, NBA, m/e): 468 (M+1 , 48%), 490 (M+23, 39%).
Ejemplo 26: Preparación de (2S,3S)-3-(ferc-butoxicarbonilamino)-3-(mesitil)- 1-fenilsulfonilpropan-2-ol (II. Rι= mesitilo. R?= fenilo)127.4, 127.9, 128.3, 128.7, 129.4, 134.1, 137.0, 129.0, 140.0, 141.0, 155.0 ppm. MS (FAB +, NBA, m / e): 468 (M + 1, 48%), 490 (M + 23, 39%). Example 26: Preparation of (2S, 3S) -3- (ferc-butoxycarbonylamino) -3- (mesityl) -1-phenylsulfonylpropan-2-ol (II. Rι = mesityl. R? = Phenyl)
De manera similar, se obtuvo el producto del título con un 71 de rendimiento, después de su purificación cromatográfica, a partir del sulfuro correspondiente (1.89 g, 4.71 mmol) como un sólido incoloro. P.f. 60-63 °C. [ ]D23= +20.1 (c= 1.5, CHCI3). 1H-NMR (200 MHz, CDCI3) δ: 1.38 (s, 9H), 2.23 (s, 3H), 2.36 (s, 6H), 3.30-3.60 (m, 2H), 4.55-4.64 (m, 1H), 5.00-5.20 (m, 2H), 6.84 (s, 2H), 7.50-7.95 (m, 5H) ppm. 13C- NMR (50 MHz, CDCI3) δ: 20.7, 21.3, 28.3, 54.0, 60.4, 68.4, 127.9, 129.3, 130.3, 131.4, 133.9, 137.5, 155.0 ppm. MS (DEP-CI-NH3> m/e): 434 (M+1 , 35%), 395 (M-38, 100%), 378 (M-55, 61%).Similarly, the title product was obtained in 71 yield, after chromatographic purification, from the corresponding sulfide (1.89 g, 4.71 mmol) as a colorless solid. Mp 60-63 ° C. [] D 23 = +20.1 (c = 1.5, CHCI 3 ). 1 H-NMR (200 MHz, CDCI 3 ) δ: 1.38 (s, 9H), 2.23 (s, 3H), 2.36 (s, 6H), 3.30-3.60 (m, 2H), 4.55-4.64 (m, 1H ), 5.00-5.20 (m, 2H), 6.84 (s, 2H), 7.50-7.95 (m, 5H) ppm. 13 C-NMR (50 MHz, CDCI 3 ) δ: 20.7, 21.3, 28.3, 54.0, 60.4, 68.4, 127.9, 129.3, 130.3, 131.4, 133.9, 137.5, 155.0 ppm. MS (DEP-CI-NH 3> m / e): 434 (M + 1, 35%), 395 (M-38, 100%), 378 (M-55, 61%).
Ejemplo 27: Preparación de (3S,E)-3-(ferc-butoxicarbonilamino)-4-fenil-1- fenilsulfonil-1-buteno (I. Rι= PhCH?, R?= Ph)Example 27: Preparation of (3S, E) -3- (ferc-butoxycarbonylamino) -4-phenyl-1- phenylsulfonyl-1-butene (I. Rι = PhCH ?, R? = Ph)
A una solución fría (0°C) de la 2-hidroxi sulfona preparada en el Ejemplo 15 (85 mg, 0.21 mmol) y de 4-(Λ ,/V-dimetilamino)piridina (105 mg, 0.86 mmol) en diclorometano anhidro (2 mi), se le añadió una solución de cloruro de mesilo (33 mi, 0.43 mmol) en diclorometano anhidro (1 mi). La mezcla de reacción se agitó a temperatura ambiente durante 30 min, tiempo en el que el análisis por CCF mostró la desaparición del producto de partida. La mezcla de reacción se diluyó con diclorometano (3 mi), y se lavó secuencialmente con una solución fría (0°C) de HCI al 10% (10 mi) y con una solución saturada de bicarbonato de sodio (2x5 mi). Se secó la fase orgánica con sulfato de magnesio anhidro y se eliminó el disolvente a presión reducida. Se purificó el residuo por cromatografía en columna (sílice previamente tratada con trietilamina, 2.5% v/v) con mezclas de hexano-acetato de etilo como eluyentes y se obtuvieron 76 mg (94% de rendimiento) del compuesto del título en forma de un sólido incoloro. P. f. 139.0-140.5 °C. [α]D23= +3.2 (c = 1.05, CHCI3). IR (NaCI film, v maχ, cm'1 ): 1702, 1507, 1447, 1368, 1308, 1148, 1086, 753. MS (CI-NH3, m/e): 405 (M+18, 100%), 348 (M-39, 30%).To a cold solution (0 ° C) of the 2-hydroxy sulfone prepared in Example 15 (85 mg, 0.21 mmol) and 4- (Λ, / V-dimethylamino) pyridine (105 mg, 0.86 mmol) in anhydrous dichloromethane (2 ml), a solution of mesyl chloride (33 ml, 0.43 mmol) in anhydrous dichloromethane (1 ml) was added. The reaction mixture was stirred at room temperature for 30 min, at which time the analysis by TLC showed the disappearance of the starting product. The reaction mixture was diluted with dichloromethane (3 mL), and washed sequentially with a cold solution (0 ° C) of 10% HCI (10 mL) and with a saturated solution of sodium bicarbonate (2x5 mL). The organic phase was dried with anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The residue was purified by column chromatography (silica previously treated with triethylamine, 2.5% v / v) with hexane-ethyl acetate mixtures as eluents and 76 mg (94% yield) of the title compound was obtained as a colorless solid. P. f. 139.0-140.5 ° C. [α] D 23 = +3.2 (c = 1.05, CHCI3). IR (NaCI film, v ma χ, cm '1 ): 1702, 1507, 1447, 1368, 1308, 1148, 1086, 753. MS (CI-NH3, m / e): 405 (M + 18, 100%) , 348 (M-39, 30%).
Ejemplo 28: Preparación de (3S,E)-3-(terc-butoxicarbonilaminoV4-fenil-1- metilsulfonil-1-buteno (I, Rι= PhCH?, R?= CHg)
De manera similar, se obtuvo el producto del título con un 100% de rendimiento, después de su purificación cromatográfica, a partir de la sulfona preparada en el Ejemplo 16 (18 mg, 0.052 mmol). P. f. 145-146 °C. [α]D23= +8.4 (c = 0.83, CHCI3). Se determinó un ee del 95% por HPLC (Chiralpak columna AS, 80 : 20 hexano: alcohol isopropílico; tR(R) = 25.3 min, tR(S) = 29.2 min).Example 28: Preparation of (3S, E) -3- (tert-butoxycarbonylamino V4-phenyl-1- methylsulfonyl-1-butene (I, Rι = PhCH ?, R? = CHg) Similarly, the title product was obtained in 100% yield, after chromatographic purification, from the sulfone prepared in Example 16 (18 mg, 0.052 mmol). P. f. 145-146 ° C. [α] D 23 = +8.4 (c = 0.83, CHCI3). A 95% ee was determined by HPLC (Chiralpak column AS, 80: 20 hexane: isopropyl alcohol; t R (R) = 25.3 min, t R (S) = 29.2 min).
Ejemplo 29: Preparación de (3S,E)-3-(ferc-butoxicarbonilamino)-5-fenil-1- fenilsulfonil-1-penteno (I, Rι= Ph(CH?)?. R?= Ph)Example 29: Preparation of (3S, E) -3- (ferc-butoxycarbonylamino) -5-phenyl-1- phenylsulfonyl-1-pentene (I, Rι = Ph (CH?)? R? = Ph)
De manera similar, se obtuvo el producto del título con un 100% de rendimiento, después de su purificación cromatográfica, a partir de la sulfona preparada en el Ejemplo 17 (100 mg, 0.24 mmol), P. f. 78-80 °C. [α]D23= -1.3 (c = 0.9, CHCI3). IR (NaCI film v maχ, cm"1) : 1702, 1517, 1368, 1308, 1250, 1148, 1086. MS (CI-NH3, m/e): 419 (M+18, 100%), 363 (M-38, 33%), 345 (M- 56, 19%).Similarly, the title product was obtained in 100% yield, after chromatographic purification, from the sulfone prepared in Example 17 (100 mg, 0.24 mmol), P. f. 78-80 ° C. [α] D 23 = -1.3 (c = 0.9, CHCI3). IR (NaCI film v ma χ, cm "1 ): 1702, 1517, 1368, 1308, 1250, 1148, 1086. MS (CI-NH3, m / e): 419 (M + 18, 100%), 363 ( M-38, 33%), 345 (M-56, 19%).
Ejemplo 30: Preparación de (3S,E)-3-(ferc-butoxicarbon¡lam¡no)-5-fenil-1- metilsulfonil-1-penteno (I. Rι= Ph(CH?)?, R?= CHa)Example 30: Preparation of (3S, E) -3- (ferc-butoxycarbonyllamine) -5-phenyl-1- methylsulfonyl-1-pentene (I. Rι = Ph (CH?) ?, R? = CHa )
De manera similar, se obtuvo el producto del título con un 100% de rendimiento, después de su purificación cromatográfica, a partir de la sulfona preparada en el Ejemplo 18 (100 mg, 0.28 mmol). P. f. 118-120 °C. [α]D23= +5.6 (c = 1.04, CHCI3). IR (NaCI film, v max, cm'1): 1700, 1521 , 1310, 1248, 1167, 1135, 1048, 967, 668. MS (CI-NH3, m/e): 357 (M+18, 100%), 301 (M- 38, 9%).Similarly, the title product was obtained in 100% yield, after chromatographic purification, from the sulfone prepared in Example 18 (100 mg, 0.28 mmol). P. f. 118-120 ° C. [α] D 23 = +5.6 (c = 1.04, CHCI3). IR (NaCI film, v max, cm '1 ): 1700, 1521, 1310, 1248, 1167, 1135, 1048, 967, 668. MS (CI-NH3, m / e): 357 (M + 18, 100% ), 301 (M- 38, 9%).
Ejemplo 31: Preparación de (3S,E)-3-(terc-butoxicarbonilam¡no)-5-fenil-1-(2- naft¡lsulfon¡l)-1-penteno (I. Rj= Ph(CH?)?, R?= naftil)Example 31: Preparation of (3S, E) -3- (tert-butoxycarbonylamine) -5-phenyl-1- (2- naphthlsulfonyl) -1-pentene (I. R j = Ph (CH? ) ?, R? = Naphthyl)
De manera similar, se obtuvo el producto del título con un 100% de rendimiento, después de su purificación cromatográfica, a partir de la sulfona preparada en el Ejemplo 19 (100 mg, 0.28 mmol). P. f. 123-126 °C (descomp.). [α]D23= +0.6 (c = 1.02, CHCI3). IR (NaCI film, v maχ, cm"1): 3855, 1702, 1654, 1559, 1507, 1457, 1148, 1127, 668. MS (CI-NH3, m/e): 469 (M+18, 100%).
Ejemplo 32: Preparación de (3S,θ-3-(feΛC-butoxicarbonilamino)-5-metil-1- fenilsulfonil-1-hexeno (l, Rι= (CH3)?CHCH?, R?= Ph)Similarly, the title product was obtained in 100% yield, after chromatographic purification, from the sulfone prepared in Example 19 (100 mg, 0.28 mmol). P. f. 123-126 ° C (decomp.). [α] D 23 = +0.6 (c = 1.02, CHCI3). IR (NaCI film, v ma χ, cm "1 ): 3855, 1702, 1654, 1559, 1507, 1457, 1148, 1127, 668. MS (CI-NH3, m / e): 469 (M + 18, 100 %). Example 32: Preparation of (3S, θ-3- (feΛC-butoxycarbonylamino) -5-methyl-1- phenylsulfonyl-1-hexene (l, Rι = (CH 3 )? CHCH ?, R? = Ph)
De manera similar, se obtuvo el producto del título con un 94% de rendimiento, después de su purificación cromatográfica, a partir de la sulfona preparada en el Ejemplo 20 (100 mg, 0.28 mmol). P. f. 74-75 °C. [α]D23= -6.0 (c = 1.0, CHCI3). IR (NaCI film, v max, cm"1): 3363, 2959, 1702, 1517, 1368, 1308, 1148, 1086. MS (CI-NH3, m/e): 371 (M+18, 100%), 315 (M-38, 33%).Similarly, the title product was obtained in 94% yield, after chromatographic purification, from the sulfone prepared in Example 20 (100 mg, 0.28 mmol). P. f. 74-75 ° C. [α] D 23 = -6.0 (c = 1.0, CHCI3). IR (NaCI film, v max , cm "1 ): 3363, 2959, 1702, 1517, 1368, 1308, 1148, 1086. MS (CI-NH3, m / e): 371 (M + 18, 100%), 315 (M-38, 33%).
Ejemplo 33: Preparación de (3S,E)-3-(ferc-butoxicarbonilamino)-5-met¡l-1- metilsulfonil-1-hexeno (I, Rι= (CHj)?CHCH?, R?= CH3)Example 33: Preparation of (3S, E) -3- (ferc-butoxycarbonylamino) -5-methyl-1-methylsulfonyl-1-hexene (I, Rι = (CHj)? CHCH ?, R? = CH 3 )
De manera similar se obtuvo el producto del título con un 88% de rendimiento, después de su purificación cromatográfica, a partir de la sulfona preparada en el Ejemplo 21 (50 mg, 0.16 mmol). P. f. 69-70 °C. [α]D 3= -20.3 (c = 1.0, CHCI3). IR (NaCI film, v max, cm"1): 3357, 2960, 1702, 1521 , 1393, 1368, 1310, 1252, 1169, 1136 . MS (CI-NH3, m/e) 309 (M+18, 100%), 253 (M-38, 97%).Similarly, the title product was obtained in 88% yield, after chromatographic purification, from the sulfone prepared in Example 21 (50 mg, 0.16 mmol). P. f. 69-70 ° C. [α] D 3 = -20.3 (c = 1.0, CHCI3). IR (NaCI film, v max , cm "1 ): 3357, 2960, 1702, 1521, 1393, 1368, 1310, 1252, 1169, 1136. MS (CI-NH3, m / e) 309 (M + 18, 100 %), 253 (M-38, 97%).
Ejemplo 34: Preparación de (3S.E)-3-(ferc-butoxicarbonilamino)-6-(ferc- butildimetilsililoxn-1-fenilsulfonil-1-hexeno (I. R1=TBDMSO(CH?)3| R?= Ph)Example 34: Preparation of (3S.E) -3- (ferc-butoxycarbonylamino) -6- (ferc- butyldimethylsilyloxy-1-phenylsulfonyl-1-hexene (I. R 1 = TBDMSO (CH?) 3 | R? = Ph )
De manera similar, se obtuvo el producto del título con un 100% de rendimiento, después de su purificación cromatográfica, a partir de la sulfona preparada en el Ejemplo 22 (67 mg, 0.17 mmol) en forma de un aceite incoloro. [α]D23= -3.0 (c = 1.2, CHCI3). IR (NaCI film v max, cm"1): 2931 , 1702, 1507, 1252, 1148, 1086, 1017, 836. MS (FAB+, NBA) m/e: 492 (M+23, 46%).Similarly, the title product was obtained in 100% yield, after chromatographic purification, from the sulfone prepared in Example 22 (67 mg, 0.17 mmol) as a colorless oil. [α] D 23 = -3.0 (c = 1.2, CHCI3). IR (NaCI film v max , cm "1 ): 2931, 1702, 1507, 1252, 1148, 1086, 1017, 836. MS (FAB +, NBA) m / e: 492 (M + 23, 46%).
Ejemplo 35: Preparación de (3S,E)-3-(terc-butoxicarbonilamino)-3-fen¡l-1- fenilsulfonil-1-propeno (I, Rι= Ph. R?= Ph).Example 35: Preparation of (3S, E) -3- (tert-butoxycarbonylamino) -3-phenyl-1- phenylsulfonyl-1-propene (I, Rι = Ph. R? = Ph).
A una solución de la 2-hidroxi sulfona preparada en el Ejemplo 13 (50 mg, 0.13 mmol) en acetonitrilo anhidro (2 mi), se le añadieron secuencialmente p- toluensulfonato de 1-ciclohexil-3-(2-morfolinoetil)carbodiimida (110 mg, 0.26 mmol) y cloruro cúprico anhidro (2 mg), y la mezcla resultante se calentó a 70 °C durante 1 h. La mezcla de reacción se dejó enfriar a temperatura ambiente y se filtró a través de Celite y sílice lavando con diclorometano. Se eliminó el
disolvente a presión reducida y se obtuvo el compuesto del título (48 mg, 100% rendimiento) en forma de -un sólido incoloro. P. f. 88-89 °C. [α]D = +31.5 (c = 1.04, CHCI3). IR (NaCl film v max, cm"1): 1700, 1507, 1320, 1148, 1086, 753, 689. MS (CI-NH3, m/e): 391 (M+18, 99%), 374 (M+1 , 4%), 335 (M- 38, 100%), 318 (M-55, 9%).To a solution of the 2-hydroxy sulfone prepared in Example 13 (50 mg, 0.13 mmol) in anhydrous acetonitrile (2 ml), 1-cyclohexyl-3- (2-morpholinoethyl) carbodiimide p-toluenesulfonate was added sequentially ( 110 mg, 0.26 mmol) and anhydrous cupric chloride (2 mg), and the resulting mixture was heated at 70 ° C for 1 h. The reaction mixture was allowed to cool to room temperature and filtered through celite and silica by washing with dichloromethane. The solvent under reduced pressure and the title compound (48 mg, 100% yield) was obtained as a colorless solid. P. f. 88-89 ° C. [α] D = +31.5 (c = 1.04, CHCI3). IR (NaCl film vm at x, cm "1 ): 1700, 1507, 1320, 1148, 1086, 753, 689. MS (CI-NH3, m / e): 391 (M + 18, 99%), 374 ( M + 1, 4%), 335 (M- 38, 100%), 318 (M-55, 9%).
Ejemplo 36: Preparación de (3S,E)-3-(ferc-butoxicarbonilamino)-3-fenil-1- metilsulfonil-1-propeno (I, Rι= Ph, R?= CH- .Example 36: Preparation of (3S, E) -3- (ferc-butoxycarbonylamino) -3-phenyl-1- methylsulfonyl-1-propene (I, Rι = Ph, R? = CH-.
De manera similar, se obtuvo el producto del título con un 96% de rendimiento a partir de la 2-hidroxi sulfona preparada en el Ejemplo 14 (45 mg, 0.14 mmol). P. f. 128-130 °C. [α]D23= +50.3 (c = 0.30, CHCI3). IR (NaCI film v max, cm"1): 1702, 1654, 1559, 1507, 1457, 1312, 1165, 1135, 969, 700. MS (CI-NH3) m/e: 329 (M+18, 100%), 274 (M-37, 13%).Similarly, the title product was obtained in 96% yield from the 2-hydroxy sulfone prepared in Example 14 (45 mg, 0.14 mmol). P. f. 128-130 ° C. [α] D 23 = +50.3 (c = 0.30, CHCI3). IR (NaCI film vm a x , cm "1 ): 1702, 1654, 1559, 1507, 1457, 1312, 1165, 1135, 969, 700. MS (CI-NH3) m / e: 329 (M + 18, 100 %), 274 (M-37, 13%).
Ejemplo 37: Preparación de (3S)-3-(terc-butoxicarbonilamino)-3-(1'-naftil -1-
Example 37: Preparation of (3S) -3- (tert-butoxycarbonylamino) -3- (1'-naphthyl -1-
De manera similar, se obtuvo el producto del título con un 100% de rendimiento, después de su purificación cromatográfica, a partir de la sulfona preparada en el Ejemplo 23 (751 mg, 1.70 mmol) como un sólido amarillento.Similarly, the title product was obtained in 100% yield, after chromatographic purification, from the sulfone prepared in Example 23 (751 mg, 1.70 mmol) as a yellowish solid.
P.f. 125.5-128 °C. [α]D23= +38.1 (c= 1.3, acetona). 1H-NMR (200 MHz,Mp 125.5-128 ° C. [α] D 23 = +38.1 (c = 1.3, acetone). 1 H-NMR (200 MHz,
CDCI3) δ: 1.39 (s, 9H), 4.88 (br, 1H), 6.24 (br, 1H), 6.64 (dd, 1H), 7.26-7.64CDCI 3 ) δ: 1.39 (s, 9H), 4.88 (br, 1H), 6.24 (br, 1H), 6.64 (dd, 1H), 7.26-7.64
(m, 8H), 7.83-7.95 (m, 5H) ppm. 13C- NMR (50 MHz, CDCI3) δ: 28.2, 51.6, 80.5, 122.9, 125.1 , 125.4, 126.1 , 126.9, 127.6, 128.9, 129.2, 129.4, 130.5,(m, 8H), 7.83-7.95 (m, 5H) ppm. 13 C-NMR (50 MHz, CDCI 3 ) δ: 28.2, 51.6, 80.5, 122.9, 125.1, 125.4, 126.1, 126.9, 127.6, 128.9, 129.2, 129.4, 130.5,
131.3, 132.2, 133.4, 134.0, 140.1 , 146.0, 154.5 ppm. MS (CI-NH3, m/e): 441131.3, 132.2, 133.4, 134.0, 140.1, 146.0, 154.5 ppm. MS (CI-NH3, m / e): 441
(M+18, 10%).(M + 18, 10%).
Ejemplo 38: Preparación de (3S)-3-(ferc-butoxicarbonilamino)-3-(2'-naft¡l)-1- fenilsulfonil-1-propeno (I. Rι= 2'-naftilo. R?= fenilo)Example 38: Preparation of (3S) -3- (ferc-butoxycarbonylamino) -3- (2'-naphthl) -1-phenylsulfonyl-1-propene (I. Rι = 2'-naphthyl. R? = Phenyl)
De manera similar, se obtuvo el producto del título con un 91% de rendimiento, después de su purificación cromatográflca, a partir de la sulfona preparada en el Ejemplo 24 (400 mg, 0.91 mmol) como un sólido amarillento. P.f.. 149-153 °C. [α]D23= +45.1 (c= 1.4, acetona). 1H-NMR (200 MHz, CDCI3) δ: 1.39 (s, 9H), 4.95 (br, 1H), 5.63 (br, 1H), 6.54 (dd, 1H), 7.21 (dd, 1 H), 7.31 (dd, 1 H), 7.52-7.65 (m, 4H), 7.70-7.80 (m, 2H), 7.82-7.90 (m, 5H) ppm. 13C-
NMR (50 MHz, CDCI3) δ: 28.2, 55.1, 124.6, 126.5, 126.6, 127.6, 127.9, 129.1 , 129.2, 131.3, 132.9, 138.1 , 133.4, 135.2, 140.0, 145.1 , 154.5 ppm. MS (Cl- NH3) m/e): 441 (M+18, 4%), 384 (M-39, 5%).Similarly, the title product was obtained in 91% yield, after chromatographic purification, from the sulfone prepared in Example 24 (400 mg, 0.91 mmol) as a yellowish solid. Mp 149-153 ° C. [α] D 23 = +45.1 (c = 1.4, acetone). 1 H-NMR (200 MHz, CDCI 3 ) δ: 1.39 (s, 9H), 4.95 (br, 1H), 5.63 (br, 1H), 6.54 (dd, 1H), 7.21 (dd, 1 H), 7.31 (dd, 1 H), 7.52-7.65 (m, 4H), 7.70-7.80 (m, 2H), 7.82-7.90 (m, 5H) ppm. 13 C- NMR (50 MHz, CDCI 3 ) δ: 28.2, 55.1, 124.6, 126.5, 126.6, 127.6, 127.9, 129.1, 129.2, 131.3, 132.9, 138.1, 133.4, 135.2, 140.0, 145.1, 154.5 ppm. MS (Cl-NH 3) m / e): 441 (M + 18, 4%), 384 (M-39, 5%).
Ejemplo 39: Preparación de (3S)-3-(ferc-butoxicarbonilamino)-3-(4'-bifenil)-1- fenilsulfonil-1-propeno (I, Rι= 4'-bifenilo, R?= fenilo)Example 39: Preparation of (3S) -3- (ferc-butoxycarbonylamino) -3- (4'-biphenyl) -1-phenylsulfonyl-1-propene (I, Rι = 4'-biphenyl, R? = Phenyl)
De manera similar, se obtuvo el producto del título con un 90% de rendimiento, después de su purificación cromatográfica, a partir de la sulfona preparada en el Ejemplo 25 (712 mg, 1.52 mmol) como un sólido incoloro. P.f. 176-177 °C. [α]D23= +54.9 (c- 15, CHCi3). 1H-NMR (200 MHz, CDCI3) δ: 1.39 (s, 9H), 4.87 (br, 1H), 5.51 (br, 1 H), 6.53 (dd, 1 H), 7.14 (dd, 1H), 7.27- 7.61 (m, 12H), 7.9 (m, 2H) ppm. 13C- NMR (50 MHz, CDCI3) δ: 28.2, 54.7, 80.5, 127.0, 127.5, 127.6, 127.8, 128.8, 129.3, 131.1 , 133.4, 136.1, 140.1 , 141.5, 145.1 ppm. MS (CI-CH4, m/e): 478 (M+29, 7%), 450 (M+1 , 6%), 411 (M-38, 27%), 394 (M-55, 23%).Similarly, the title product was obtained in 90% yield, after chromatographic purification, from the sulfone prepared in Example 25 (712 mg, 1.52 mmol) as a colorless solid. Mp 176-177 ° C. [α] D 23 = +54.9 (c-15, CHCi 3 ). 1 H-NMR (200 MHz, CDCI3) δ: 1.39 (s, 9H), 4.87 (br, 1H), 5.51 (br, 1 H), 6.53 (dd, 1 H), 7.14 (dd, 1H), 7.27 - 7.61 (m, 12H), 7.9 (m, 2H) ppm. 13 C-NMR (50 MHz, CDCI 3 ) δ: 28.2, 54.7, 80.5, 127.0, 127.5, 127.6, 127.8, 128.8, 129.3, 131.1, 133.4, 136.1, 140.1, 141.5, 145.1 ppm. MS (CI-CH 4 , m / e): 478 (M + 29, 7%), 450 (M + 1, 6%), 411 (M-38, 27%), 394 (M-55, 23% ).
Ejemplo 40: Preparación de (3S)-3-(terc-butoxicarbonilamino)-3-(mesitil)-1- fenilsulfonil-1-propeno (I, Rι= mesitilo, R?= fenilo)Example 40: Preparation of (3S) -3- (tert-butoxycarbonylamino) -3- (mesityl) -1-phenylsulfonyl-1-propene (I, Rι = mesityl, R? = Phenyl)
De manera similar, se obtuvo el producto del título con un 99 de rendimiento, después de su purificación cromatográfica, a partir de la sulfona preparada en el Ejemplo 26 (1.00 mg, 2.31 mmol) como un sólido amarillo. P.f. 121-123 °C. [α]D23= +30.9 (c= 1.6, CHCI3). 1H-NMR (200 MHz, CDCI3) δ: 1.40 (s, 9H), 2.25 (s, 9H), 4.95 (br, 1H), 5.93 (br, 1 H), 6.32 (dd, 1H), 6.83 (s, 2H), 7.14 (dd, 1H), 7.53-7.88 (m, 5H) ppm. 13C- NMR (50 MHz, CDCI3) δ: 20.8, 28.2, 50.9, 127.5, 127.8, 129.2, 130.0, 130.1, 133.3, 136.0, 137.9, 140.2, 147.7, 155.0 ppm. MS (CI-NH3, m/e): 433 (M+18, 22%).
Similarly, the title product was obtained in 99 yield, after chromatographic purification, from the sulfone prepared in Example 26 (1.00 mg, 2.31 mmol) as a yellow solid. Mp 121-123 ° C. [α] D 23 = +30.9 (c = 1.6, CHCI3). 1 H-NMR (200 MHz, CDCI3) δ: 1.40 (s, 9H), 2.25 (s, 9H), 4.95 (br, 1H), 5.93 (br, 1 H), 6.32 (dd, 1H), 6.83 ( s, 2H), 7.14 (dd, 1H), 7.53-7.88 (m, 5H) ppm. 13 C-NMR (50 MHz, CDCI 3 ) δ: 20.8, 28.2, 50.9, 127.5, 127.8, 129.2, 130.0, 130.1, 133.3, 136.0, 137.9, 140.2, 147.7, 155.0 ppm. MS (CI-NH 3 , m / e): 433 (M + 18, 22%).
Claims
1. Procedimiento estereoselectivo de preparación de un enantiómero sustancialmente puro de una γ-amino vinilsulfona de fórmula (I), alternativamente (P), que comprende un paso de deshidratación de una β-hidroxi-γ-amino sulfona de fórmula (II), alternativamente (I ):1. Stereoselective process for preparing a substantially pure enantiomer of a γ-amino vinyl sulfone of formula (I), alternatively (P), comprising a dehydration step of a β-hydroxy-γ-amino sulfone of formula (II), alternatively (I):
(i)(i)
00 (ir)00 (go)
donde:where:
en las fórmulas (II) and (IP), la línea ondulada significa cualquiera de las dos posibles configuraciones del carbono quiral al que están unidas;in formulas (II) and (IP), the wavy line means any of the two possible configurations of the chiral carbon to which they are attached;
Ri es un radical seleccionado entre el grupo formado por (Cι-C6)-alquilo, (C3-C6)-cicloalquilo, [(Cι-C6)-alquildifenilsililoxi]-(Cι-C6)-alquilo, [(CrCeí-trialquilsililoxij-ÍCi-CeJ-alquilo, (Cι-C4)-alcoxilo, GP-O-(CH2)n-, 1- naftilo, 2-naftilo, fenilo, Ph-(CH2)n-, R-COO-(CH2)n- con R = (CrCeJ-alquilo o fenilo, y un radical derivado de los anteriormente mencionados con anillos bencénicos a través de una mono-, una di- o una tri-sustitución en sus anillos bencénicos, siendo los sustituyentes un radical independientemente seleccionado entre el grupo formado por: halógeno, (^^y-alquilo, (C1-C4)- alcoxilo, trifluorometilo, fenilo, un grupo amino protegido y un hidroxilo protegido;Ri is a radical selected from the group consisting of (Cι-C 6 ) -alkyl, (C 3 -C 6 ) -cycloalkyl, [(Cι-C 6 ) -alkyl diphenylsilyloxy] - (Cι-C 6 ) -alkyl, [ (CrCeí-trialkylsilyloxij-IC-CeJ-alkyl, (Cι-C 4 ) -alkoxy, GP-O- (CH 2 ) n -, 1- naphthyl, 2-naphthyl, phenyl, Ph- (CH 2 ) n -, R-COO- (CH 2 ) n - with R = (CrCeJ-alkyl or phenyl, and a radical derived from those mentioned above with benzene rings through a mono-, a di- or a tri-substitution in their benzene rings , the substituents being a radical independently selected from the group consisting of: halogen, (^^ and -alkyl, (C 1 -C 4 ) - alkoxy, trifluoromethyl, phenyl, a protected amino group and a protected hydroxyl;
R2 es un radical seleccionado del mismo grupo que Ri, incluyendo además el fenilcarbonilo;R 2 is a radical selected from the same group as Ri, also including phenylcarbonyl;
n es un entero seleccionado entre 1 y 10; y GP representa un grupo protector de aminas; GP' representa un átomo de hidrógeno o un grupo protector de aminas igual o diferente a GP; o alternativamente, GP y GP' tomados conjuntamente forman un grupo ftalimido.n is an integer selected from 1 to 10; and GP represents an amine protecting group; GP 'represents a hydrogen atom or an amine protecting group equal to or different from GP; or alternatively, GP and GP 'taken together form a phthalimido group.
2. Procedimiento estereoselectivo de preparación según la reivindicación 1 , donde el grupo protector GP se selecciona entre el grupo formado por carbamatos, amidas y sulfonamidas, y GP' es un átomo de hidrógeno o un grupo protector de aminas seleccionado del mismo grupo que GP, incluyendo además un alilo, un bencilo y un bencilo mono o di-sustituido.2. Stereoselective preparation process according to claim 1, wherein the GP protecting group is selected from the group consisting of carbamates, amides and sulfonamides, and GP 'is a hydrogen atom or an amine protecting group selected from the same group as GP, also including an allyl, a benzyl and a mono or di-substituted benzyl.
3. Procedimiento estereoselectivo de preparación según la reivindicación 2, donde el grupo protector GP se selecciona entre el grupo formado por t-butoxicarbonilo (BOC), 9-fluorenilmetoxicarbonilo (Fmoc) y benciloxicarbonilo (Cbz), y GP' es un átomo de hidrógeno o un grupo protector de aminas, igual o diferente a GP, seleccionado entre el grupo formado por t-butoxicarbonilo (BOC), 9-fluorenilmetoxicarbonilo (Fmoc), benciloxicarbonilo (Cbz), alilo, 4-metoxibencilo, 2,4-dimetoxibencilo y N- bencilamina.3. Stereoselective preparation process according to claim 2, wherein the GP protecting group is selected from the group consisting of t-butoxycarbonyl (BOC), 9-fluorenylmethoxycarbonyl (Fmoc) and benzyloxycarbonyl (Cbz), and GP 'is a hydrogen atom or an amine protecting group, equal to or different from GP, selected from the group consisting of t-butoxycarbonyl (BOC), 9-fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), allyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl and N-benzylamine.
4. Procedimiento estereoselectivo de preparación según la reivindicación 3, donde el grupo protector GP es el t-butoxicarbonilo (BOC) y GP' es un átomo de hidrógeno.4. Stereoselective preparation process according to claim 3, wherein the GP protecting group is t-butoxycarbonyl (BOC) and GP 'is a hydrogen atom.
5. Procedimiento estereoselectivo de preparación según la reivindicación 1 , donde el grupo protector GP y GP' tomados conjuntamente forman un grupo ftalimido.5. Stereoselective preparation process according to claim 1, wherein the protective group GP and GP 'taken together form a phthalimido group.
6. Procedimiento estereoselectivo de preparación según la reivindicación 1 , donde Ri and R2son independientemente seleccionados entre el grupo formado por metilo, isobutilo, fenilo, fenilmetilo, 2-feniletilo, 1-naftilo, 2-naftilo, 2,4,6-trimetilfenilo, 4-fenilfenilo, t-butildifenilsililoxipropilo y t- butildimetilsililoxipropilo.6. stereoselective preparation process according to claim 1, wherein Ri and R2 are independently selected from the group consisting of methyl, isobutyl, phenyl, phenylmethyl, 2-phenylethyl, 1-naphthyl, 2-naphthyl, 2,4,6-trimethylphenyl, 4-phenylphenyl, t-butyldiphenylsilyloxypropyl and t-butyldimethylsilyloxypropyl.
7. Procedimiento estereoselectivo de preparación según la reivindicación 6, donde Ri se selecciona del grupo formado por metilo, isobutilo, fenilo, fenilmetilo, 2-feniletilo, 1 -naftilo, 2-naftilo, 2,4,6-trimetilfenilo, 4-fenilfenilo, t-butildifenilsililoxipropilo y t-butildimetillsililoxipropilo y R2 se selecciona del grupo formado por metilo, fenilo y 2-naftilo.7. Stereoselective preparation process according to claim 6, wherein Ri is selected from the group consisting of methyl, isobutyl, phenyl, phenylmethyl, 2-phenylethyl, 1-naphthyl, 2-naphthyl, 2,4,6-trimethylphenyl, 4-phenylphenyl , t-butyldiphenylsilyloxypropyl and t-butyldimethylsilyloxypropyl and R 2 is selected from the group consisting of methyl, phenyl and 2-naphthyl.
8. Procedimiento estereoselectivo de preparación según la reivindicación 1 , donde el paso de deshidratación se lleva a cabo por reacción con una carbodiimida en presencia de una cantidad catalítica de cloruro de cobre (II) anhidro.8. Stereoselective preparation process according to claim 1, wherein the dehydration step is carried out by reaction with a carbodiimide in the presence of a catalytic amount of anhydrous copper (II) chloride.
9. Procedimiento estereoselectivo de preparación según la reivindicación 8, donde la carbodiimida es el p-toluensulfonato de 1 -ciclohexil-3- (2-morfolinoetil)carbodiimida.9. Stereoselective preparation process according to claim 8, wherein carbodiimide is 1-cyclohexyl-3- (2-morpholinoethyl) carbodiimide p-toluenesulfonate.
10. Procedimiento estereoselectivo de preparación según la reivindicación 1 , donde el paso de deshidratación se lleva a cabo por reacción con un cloruro de alquilsulfonilo y una amina, con la condición que Ri no es fenilo, fenilo- sustituido o naftilo.10. Stereoselective preparation process according to claim 1, wherein the dehydration step is carried out by reaction with an alkylsulfonyl chloride and an amine, with the proviso that Ri is not phenyl, phenyl-substituted or naphthyl.
11. Procedimiento estereoselectivo de preparación según la reivindicación 10, donde el cloruro de alquilsulfonilo es el cloruro de mesilo.11. Stereoselective preparation process according to claim 10, wherein the alkylsulfonyl chloride is mesyl chloride.
12. Procedimiento estereoselectivo de preparación según la reivindicación 11 , donde la amina es la 4-(dimetilamino)pir¡dina.12. Stereoselective preparation process according to claim 11, wherein the amine is 4- (dimethylamino) pyrdine.
13. Procedimiento estereoselectivo de preparación según la reivindicación 1 , donde el compuesto de fórmula (II), alternativamente (IP), se prepara por reacción del compuesto de fórmula (III), alternativamente (IIP), con un agente oxidante en un solvente inerte. 
13. Stereoselective preparation process according to claim 1, wherein the compound of formula (II), alternatively (IP), is prepared by reacting the compound of formula (III), alternatively (IIP), with an oxidizing agent in an inert solvent .
(III) (IIP)(III) (IIP)
14. Procedimiento estereoselectivo de preparación según la reivindicación 13, donde el agente oxidante es el ácido m-cloroperbenzoico.14. Stereoselective preparation process according to claim 13, wherein the oxidizing agent is m-chloroperbenzoic acid.
15. Procedimiento estereoselectivo de preparación según la reivindicación 13, donde el compuesto de fórmula (III), alternativamente (IIP), se prepara por reacción del compuesto de fórmula (IV), alternativamente (IV), con un tiol de fórmula R2-SH en presencia de una base, o con una sal de metal alcalino de éste, en un solvente inerte, teniendo R2 tiene el mismo significado que se definió anteriormente.15. Stereoselective preparation process according to claim 13, wherein the compound of formula (III), alternatively (IIP), is prepared by reacting the compound of formula (IV), alternatively (IV), with a thiol of formula R 2 - SH in the presence of a base, or with an alkali metal salt thereof, in an inert solvent, having R 2 has the same meaning as defined above.
16. Procedimiento estereoselectivo de preparación según la reivindicación 15, donde el tiol se selecciona entre tiofenol y 2-naftiltiol.16. Stereoselective preparation process according to claim 15, wherein the thiol is selected from thiophenol and 2-naphthylthiol.
17. Procedimiento estereoselectivo de preparación según la reivindicación 15, donde la base es trietilamina.17. Stereoselective preparation process according to claim 15, wherein the base is triethylamine.
18. Procedimiento estereoselectivo de preparación según la reivindicación 15, donde la sal de metal alcalino es el metanotiolato sódico. 18. Stereoselective preparation process according to claim 15, wherein the alkali metal salt is sodium methanethiolate.
19. Procedimiento de preparación que comprende el paso definido en la reivindicación 1 , y la posterior transformación de un compuesto de fórmula (I), alternativamente (P), en una peptidil vinil sulfona de fórmula (VI), alternativamente (VP), a través de una reacción de desprotección del grupo amino, seguido de una reacción de acoplamiento del grupo amino desprotegido con un grupo carboxilo terminal de un aminoácido N-protegido o de un péptido N-protegido, donde GP, Ri y R2 son como se definieron en la reivindicación 1 ; R3 representa un radical de una cadena lateral o un radical de una cadena terminal de un aminoácido natural o de un péptido ; m es un entero mayor o igual que uno, y cuando m es mayor que uno, R3 puede ser igual o diferente.19. Preparation process comprising the step defined in claim 1, and the subsequent transformation of a compound of formula (I), alternatively (P), into a peptidyl vinyl sulfone of formula (VI), alternatively (VP), to through a deprotection reaction of the amino group followed by a coupling reaction of the deprotected amino group with a terminal carboxyl group of a N-protected or an N-protected, amino acid peptide wherein PG, Ri and R 2 are as defined in claim 1; R 3 represents a radical of a side chain or a radical of a terminal chain of a natural amino acid or a peptide; m is an integer greater than or equal to one, and when m is greater than one, R 3 may be the same or different.
(VI)(SAW)
(VP)(VP)
20. Compuesto estereoisomérico seleccionado entre las dos fórmulas enantioméricas, (II), alternativamente (II1), donde:20. Stereoisomeric compound selected from the two enantiomeric formulas, (II), alternatively (II 1 ), where:
R1 es un radical seleccionado entre el grupo formado por (CrC6)-alquilo, (C3-C6)-cicloalquilo, [(Cι-C6)-alquildifenilsililoxiHCι-C6)-alquilo, [(d-CeHrialquilsililoxij-íd-Ceí-alquilo, 
GP-0-(CH2)n-, 1- naftilo, 2-naftilo, fenilo, Ph-(CH2)n-, R-COO-(CH2)n- con R = (CrCeJ-alquilo o fenilo, y un radical derivado de los anteriormente mencionados con anillos bencénicos a través de una mono-, una di- o una tri-sustitución en sus anillos bencénicos, siendo los sustituyentes un radical independientemente seleccionado entre el grupo formado por halógeno, (Cι-C )-alquilo, (Cι-C )- alcoxilo, trifluorometilo, fenilo, un grupo amino protegido y un hidroxilo protegido;R 1 is a radical selected from the group consisting of (CrC 6 ) -alkyl, (C 3 -C 6 ) -cycloalkyl, [(Cι-C 6 ) -alkyldiphenylsilyloxyHCι-C 6 ) -alkyl, [(d-CeHrialkylsilyloxy-j- id-Cei-alkyl, GP-0- (CH 2 ) n -, 1- naphthyl, 2-naphthyl, phenyl, Ph- (CH 2 ) n-, R-COO- (CH 2 ) n - with R = (CrCeJ-alkyl or phenyl, and a radical derived from the aforementioned with benzene rings through a mono-, a di- or a tri-substitution in their benzene rings, the substituents being a radical independently selected from the group consisting of halogen, (Cι- C) -alkyl, (Cι-C) -alkoxy, trifluoromethyl, phenyl, a protected amino group and a protected hydroxyl;
R2 es un radical seleccionado del mismo grupo que Ri, incluyendo además el fenilcarbonilo;R 2 is a radical selected from the same group as Ri, also including phenylcarbonyl;
n es un entero seleccionado entre 1 y 10; y GP representa un grupo protector de aminas; GP' representa un átomo de hidrógeno o un grupo protector de aminas igual o diferente a GP; o alternativamente, GP y GP' tomados conjuntamente forman un grupo ftalimido; con la condición de que Ri no sea isobutilo.n is an integer selected from 1 to 10; and GP represents an amine protecting group; GP 'represents a hydrogen atom or an amine protecting group equal to or different from GP; or alternatively, GP and GP 'taken together form a phthalimido group; with the proviso that Ri is not isobutyl.
21. Compuesto estereoisomérico según la reivindicación 20, donde el grupo protector GP se selecciona entre el grupo formado por carbamatos, amidas y sulfonamidas y, GP' es un átomo de hidrógeno o un grupo protector de aminas seleccionado del mismo grupo que GP, incluyendo además un alilo, un bencilo y un bencilo mono o di-sustituido.21. Stereoisomeric compound according to claim 20, wherein the GP protecting group is selected from the group consisting of carbamates, amides and sulfonamides and, GP 'is a hydrogen atom or an amine protecting group selected from the same group as GP, further including an allyl, a benzyl and a mono or di-substituted benzyl.
22. Compuesto estereoisomérico según la reivindicación 21 , donde el grupo protector GP se selecciona entre el grupo formado por t-butoxicarbonilo (BOC), 9-fluorenilmetoxicarbonilo (Fmoc) y benciloxicarbonilo (Cbz) y, GP' es un átomo de hidrógeno o un grupo protector de aminas, igual o diferente a GP, seleccionado entre el grupo formado por t-butoxicarbonilo (BOC), 9-fluorenilmetoxicarbonilo (Fmoc), benciloxicarbonilo (Cbz), alilo, 4- metoxibencilo, 2,4-dimetoxibencilo y N-bencilamina.22. Stereoisomeric compound according to claim 21, wherein the GP protecting group is selected from the group consisting of t-butoxycarbonyl (BOC), 9-fluorenylmethoxycarbonyl (Fmoc) and benzyloxycarbonyl (Cbz) and, GP 'is a hydrogen atom or a amine protecting group, equal to or different from GP, selected from the group consisting of t-butoxycarbonyl (BOC), 9-fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), allyl, 4- methoxybenzyl, 2,4-dimethoxybenzyl and N-benzylamine.
23. Compuesto estereoisomérico según la reivindicación 22, donde el grupo protector GP es t-butoxicarbonilo (BOC) y GP' es un átomo de hidrógeno.23. Stereoisomeric compound according to claim 22, wherein the GP protecting group is t-butoxycarbonyl (BOC) and GP 'is a hydrogen atom.
24. Compuesto estereoisomérico según la reivindicación 20, donde el grupo protector GP y GP' tomados conjuntamente forman un grupo ftalimido.24. Stereoisomeric compound according to claim 20, wherein the protective group GP and GP 'taken together form a phthalimido group.
25. Compuesto esteroisomérico según la reivindicación 20, donde Ri y R2 son independientemente seleccionados entre el grupo formado por metilo, fenilo, fenilmetilo, 2-feniletilo, 1 -naftilo, 2-naftilo, 2,4,6-trimetilfenilo, 4-fenilfenilo, t-butildifenilsililoxipropilo y t-butildimetilsililoxipropilo.Esteroisomérico 25. The compound of claim 20 wherein Ri and R2 are independently selected from the group consisting of methyl, phenyl, phenylmethyl, 2-phenylethyl, 1 - naphthyl, 2-naphthyl, 2,4,6-trimethylphenyl, 4- phenylphenyl, t-butyldiphenylsilyloxypropyl and t-butyldimethylsilyloxypropyl.
26. Compuesto esteroisomérico según la reivindicación 25, donde Ri se selecciona entre el grupo formado por metilo, fenilo, fenilmetilo, 2-feniletilo, 1- naftilo, 2-naftilo, 2,4,6-trimetilfenilo, 4-fenilfenilo, t-butildifenilsililoxipropilo y t-butildimetilsililoxipropilo, y R2 se selecciona entre el grupo formado por metilo, fenilo y 2-naftilo.26. Steroisomeric compound according to claim 25, wherein Ri is selected from the group consisting of methyl, phenyl, phenylmethyl, 2-phenylethyl, 1- naphthyl, 2-naphthyl, 2,4,6-trimethylphenyl, 4-phenylphenyl, t- Butyldiphenylsilyloxypropyl and t-butyldimethylsilyloxypropyl, and R 2 is selected from the group consisting of methyl, phenyl and 2-naphthyl.
27. Compuesto estereoisomérico seleccionado entre los de formula (I) , alternativamente (P), donde:27. Stereoisomeric compound selected from those of formula (I), alternatively (P), where:
Ri se selecciona entre el grupo formado por: (C3-C6)-cicloalqu¡lo, [(Cι-C6)- alquildifenilsililoxi]-(Cι-C6)-alqu¡lo, [(Cι-C6)-trialquπsililoxi3-(Cι-C6)-alquilo, 1- naftilo, 2-naftilo, fenilo, R-COO-(CH2)n- con R = (C C6)-alquilo o fenilo, y un radical derivado de los mencionados anteriormente con anillos bencénicos a través de una mono-, una di- o una tri-sustitución en sus anillos bencénicos, siendo los sustituyentes un radical independientemente seleccionado entre el grupo formado por halógeno, (C1-C4)-alquilo, (d^^alcoxilo, trifluorometilo, fenilo, un grupo amino protegido y un hidroxilo protegido;Ri is selected from the group consisting of: (C 3 -C 6 ) -cycloalkyl, [(Cι-C 6 ) - alkyldiphenylsilyloxy] - (Cι-C 6 ) -alkyl, [(Cι-C 6 ) -trialquπsilyloxy3- (Cι-C 6 ) -alkyl, 1- naphthyl, 2-naphthyl, phenyl, R-COO- (CH 2 ) n - with R = (CC 6 ) -alkyl or phenyl, and a radical derived from mentioned above with benzene rings through a mono-, a di- or a tri-substitution in their benzene rings, the substituents being a radical independently selected from the group consisting of halogen, (C 1 -C 4 ) -alkyl, ( d ^^ alkoxy, trifluoromethyl, phenyl, a protected amino group and a protected hydroxyl;
R2 es (Cι-C6)-alquilo, (C3-C6)-cicloalquilo, [(Cι-C6)-alquildifenilsililoxi]-(Cι-C6)- alquilo, [(d-CeHrialquilsililoxij-ÍCrCβ alquilo, (d^-alcoxilo, GP-O-(CH2)n-, 1 -naftilo, 2-naftilo, fenilo, Ph-(CH2)n-, R-COO-(CH2)n- con R = (Cι-C6)-alquilo o fenilo, y un radical derivado de los anteriormente mencionados con anillos bencénicos a través de una mono-, una di- o una tri-sustitución en sus anillos bencénicos, siendo los sustituyentes un radical independientemente seleccionado entre el grupo formado por halógeno, (d-C4)-alquilo, (d-C4)- alcoxilo, trifluorometilo, fenilo, un grupo amino protegido y un hidroxilo protegido;R 2 is (Cι-C 6 ) -alkyl, (C3-C 6 ) -cycloalkyl, [(Cι-C 6 ) -alkyldiphenylsilyloxy] - (Cι-C 6 ) - alkyl, [(d-CeHrialkylsilyloxy-ÍCrCβ alkyl, (d ^ -alkoxy, GP-O- (CH 2 ) n -, 1 -naphthyl, 2-naphthyl, phenyl, Ph- (CH 2 ) n -, R-COO- (CH 2 ) n - with R = ( Cι-C 6 ) -alkyl or phenyl, and a radical derived from the aforementioned with benzene rings through a mono-, a di- or a tri-substitution in their rings benzene, the substituents being a radical independently selected from the group consisting of halogen, (dC 4 ) -alkyl, (dC 4 ) -alkoxy, trifluoromethyl, phenyl, a protected amino group and a protected hydroxyl;
GP representa un grupo protector de aminas; GP' representa un hidrógeno o un grupo protector de aminas igual o diferente a GP; o alternativamente, GP y GP' tomados conjuntamente forman un grupo ftalimido.GP represents an amine protecting group; GP 'represents a hydrogen or an amine protecting group equal to or different from GP; or alternatively, GP and GP 'taken together form a phthalimido group.
28. Compuesto estereoisomérico según la reivindicación 27, donde el grupo protector de aminas es el f-butoxicarbonilo (BOC) y GP' es un átomo de hidrógeno.28. Stereoisomeric compound according to claim 27, wherein the amine protecting group is f-butoxycarbonyl (BOC) and GP 'is a hydrogen atom.
29. Compuesto estereoisomérico según la reivindicación 27, donde Ri se selecciona del grupo formado por fenilo, 1 -naftilo, 2-naftilo, 2,4,6-trimetilfenilo, 4-fenilfenilo, t-butildifenilsililoxipropilo, t-butildimetilsililoxipropilo; y R2 se selecciona entre el grupo formado por metilo, fenilo y 2-naftilo.29. Stereoisomeric compound according to claim 27, wherein Ri is selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, 2,4,6-trimethylphenyl, 4-phenylphenyl, t-butyldiphenylsilyloxypropyl, t-butyldimethylsilyloxypropyl; and R 2 is selected from the group consisting of methyl, phenyl and 2-naphthyl.
30. Compuesto estereoisomérico según la reivindicación 29, donde Ri se selecciona entre el grupo formado por fenilo, 1-naftilo, 2-naftilo, 2,4,6- trimetilfenilo, 4-fenilfenilo, t-butildifenilsililoxipropilo y t- butildimetillsililoxipropilo; y R2es fenilo. 30. Stereoisomeric compound according to claim 29, wherein Ri is selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, 2,4,6-trimethylphenyl, 4-phenylphenyl, t-butyldiphenylsilyloxypropyl and t-butyldimethylsilyloxypropyl; and R 2 is phenyl.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ES200301259A ES2220226A1 (en) | 2003-05-19 | 2003-05-19 | Stereoselective method of preparing gamma-amino vinyl sulphones |
| ESP200301259 | 2003-05-19 |
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| WO2004101504A1 true WO2004101504A1 (en) | 2004-11-25 |
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| PCT/ES2004/000218 WO2004101504A1 (en) | 2003-05-19 | 2004-05-18 | Stereoselective method of preparing gamma-amino vinyl sulphones |
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| WO (1) | WO2004101504A1 (en) |
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| US4826815A (en) * | 1985-05-17 | 1989-05-02 | Abbott Laboratories | Renin inhibiting compounds |
| WO2000078794A1 (en) * | 1999-06-22 | 2000-12-28 | Merck & Co., Inc. | Cysteinyl protease inhibitors |
| US6362166B1 (en) * | 1996-05-14 | 2002-03-26 | Agouron Pharmaceuticals, Inc. | Antipicornaviral compounds and methods for their use and preparation |
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2003
- 2003-05-19 ES ES200301259A patent/ES2220226A1/en not_active Withdrawn
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- 2004-05-18 WO PCT/ES2004/000218 patent/WO2004101504A1/en active Application Filing
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4826815A (en) * | 1985-05-17 | 1989-05-02 | Abbott Laboratories | Renin inhibiting compounds |
| US6362166B1 (en) * | 1996-05-14 | 2002-03-26 | Agouron Pharmaceuticals, Inc. | Antipicornaviral compounds and methods for their use and preparation |
| WO2000078794A1 (en) * | 1999-06-22 | 2000-12-28 | Merck & Co., Inc. | Cysteinyl protease inhibitors |
Non-Patent Citations (3)
| Title |
|---|
| LULY J.R.: "Modified peptides which display potent and specific inhibition of human renin", BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, vol. 143, no. 1, 1987, pages 44 - 51 * |
| PALMER J.T. ET AL.: "Vinyl sulfones as mechanism-based cysteine protease inhibitors", JOURNAL OF MEDICINAL CHEMISTRY, vol. 38, 1995, pages 3193 - 3196 * |
| SENGUPTA S. ET AL: "g-chiral b-ketosulfones in asymetric synthesis:a unified synthetic strategy for enantiopure g-amino and g-hydroxy vinyl sulfones", TETRAHEDRON: ASYMETRY, vol. 9, 1998, pages 2311 - 2316 * |
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| Publication number | Publication date |
|---|---|
| ES2220226A1 (en) | 2004-12-01 |
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