CN104926712B - Synthesize intermediate of VX-960 and preparation method thereof - Google Patents
Synthesize intermediate of VX-960 and preparation method thereof Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 35
- 238000006243 chemical reaction Methods 0.000 claims abstract description 17
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000002904 solvent Substances 0.000 claims abstract description 14
- 150000001298 alcohols Chemical class 0.000 claims abstract description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000000126 substance Substances 0.000 claims abstract description 9
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims abstract description 8
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims abstract description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims abstract description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims abstract description 6
- 229910000564 Raney nickel Inorganic materials 0.000 claims abstract description 5
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims 1
- 125000001589 carboacyl group Chemical group 0.000 claims 1
- 229910052760 oxygen Inorganic materials 0.000 claims 1
- 239000001301 oxygen Substances 0.000 claims 1
- 229940125904 compound 1 Drugs 0.000 abstract description 10
- 238000000034 method Methods 0.000 abstract description 7
- NNHOUIKFCCIVCI-UHFFFAOYSA-N cyclopenta[c]pyrrole Chemical class N1=CC2=CC=CC2=C1 NNHOUIKFCCIVCI-UHFFFAOYSA-N 0.000 abstract description 5
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 abstract description 4
- 125000002252 acyl group Chemical group 0.000 abstract description 4
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 239000003795 chemical substances by application Substances 0.000 abstract description 4
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 abstract description 4
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 abstract description 4
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 3
- 231100001261 hazardous Toxicity 0.000 abstract description 3
- 231100000614 poison Toxicity 0.000 abstract description 3
- 230000007096 poisonous effect Effects 0.000 abstract description 3
- QGJOPFRUJISHPQ-NJFSPNSNSA-N carbon disulfide-14c Chemical compound S=[14C]=S QGJOPFRUJISHPQ-NJFSPNSNSA-N 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 abstract description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 102000006992 Interferon-alpha Human genes 0.000 description 3
- 108010047761 Interferon-alpha Proteins 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical class C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- OHDXDNUPVVYWOV-UHFFFAOYSA-N n-methyl-1-(2-naphthalen-1-ylsulfanylphenyl)methanamine Chemical compound CNCC1=CC=CC=C1SC1=CC=CC2=CC=CC=C12 OHDXDNUPVVYWOV-UHFFFAOYSA-N 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 150000003233 pyrroles Chemical class 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 208000030507 AIDS Diseases 0.000 description 2
- 0 CC(CC1)(C(CCCC2*3)O)[C@]23[C@@](*O)N1C1OC1*C*1=CC=CCC=*1 Chemical compound CC(CC1)(C(CCCC2*3)O)[C@]23[C@@](*O)N1C1OC1*C*1=CC=CCC=*1 0.000 description 2
- 206010008909 Chronic Hepatitis Diseases 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 208000005176 Hepatitis C Diseases 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
- 102000012479 Serine Proteases Human genes 0.000 description 2
- 108010022999 Serine Proteases Proteins 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 230000000840 anti-viral effect Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- ZSWFCLXCOIISFI-UHFFFAOYSA-N cyclopentadiene Chemical compound C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- 208000006454 hepatitis Diseases 0.000 description 2
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- KWRNCAUXSJOYQO-ACZMJKKPSA-N (3s,3as,6ar)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrol-2-ium-3-carboxylate Chemical compound C1CC[C@@H]2[C@@H](C(=O)O)NC[C@@H]21 KWRNCAUXSJOYQO-ACZMJKKPSA-N 0.000 description 1
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 241000711549 Hepacivirus C Species 0.000 description 1
- 206010073069 Hepatic cancer Diseases 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
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 241000701076 Macacine alphaherpesvirus 1 Species 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 description 1
- 208000034189 Sclerosis Diseases 0.000 description 1
- 108050000761 Serpin Proteins 0.000 description 1
- 102000008847 Serpin Human genes 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 238000010170 biological method Methods 0.000 description 1
- FAOSYNUKPVJLNZ-UHFFFAOYSA-N butylstannane Chemical compound CCCC[SnH3] FAOSYNUKPVJLNZ-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- ZOOODBUHSVUZEM-UHFFFAOYSA-N ethoxymethanedithioic acid Chemical compound CCOC(S)=S ZOOODBUHSVUZEM-UHFFFAOYSA-N 0.000 description 1
- YWKVMGDEOUPQGN-UHFFFAOYSA-N ethyl 2-[4-[2-(3-hydroxy-1-azabicyclo[2.2.2]octan-3-yl)ethynyl]phenyl]acetate Chemical compound C1=CC(CC(=O)OCC)=CC=C1C#CC1(O)C(CC2)CCN2C1 YWKVMGDEOUPQGN-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 208000002672 hepatitis B Diseases 0.000 description 1
- 208000010710 hepatitis C virus infection Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- GSYSFVSGPABNNL-UHFFFAOYSA-N methyl 2-dimethoxyphosphoryl-2-(phenylmethoxycarbonylamino)acetate Chemical group COC(=O)C(P(=O)(OC)OC)NC(=O)OCC1=CC=CC=C1 GSYSFVSGPABNNL-UHFFFAOYSA-N 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- WRHZVMBBRYBTKZ-UHFFFAOYSA-N pyrrole-2-carboxylic acid Chemical compound OC(=O)C1=CC=CN1 WRHZVMBBRYBTKZ-UHFFFAOYSA-N 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229960000329 ribavirin Drugs 0.000 description 1
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 1
- 239000003001 serine protease inhibitor Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000010183 spectrum analysis Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 229960002935 telaprevir Drugs 0.000 description 1
- BBAWEDCPNXPBQM-GDEBMMAJSA-N telaprevir Chemical compound N([C@H](C(=O)N[C@H](C(=O)N1C[C@@H]2CCC[C@@H]2[C@H]1C(=O)N[C@@H](CCC)C(=O)C(=O)NC1CC1)C(C)(C)C)C1CCCCC1)C(=O)C1=CN=CC=N1 BBAWEDCPNXPBQM-GDEBMMAJSA-N 0.000 description 1
- 108010017101 telaprevir Proteins 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 239000012991 xanthate Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
It is used to synthesize (1S the invention provides one, 3aR, 6aS) the midbody compound c of the carboxylic acid of octahydro cyclopenta [c] pyrroles 1 preparation method, including compound b is reduced in alcohols solvent and in the presence of Raney's nickel and obtains compound c；Reaction condition is：Reaction temperature is 70 90 DEG C, one or more of the alcohols solvent in methanol, ethanol, propyl alcohol, n-butanol, isopropanol, the tert-butyl alcohol；See route VI；R wherein in chemical formula1Selected from benzyloxy carbonyl acyl group or tertbutyloxycarbonyl, R2Alkyl selected from C1 C4.Pass through novel compound of present invention b, avoided in the subsequently method of synthesis compound 1 using hazardous agents sodium hydrogen, poisonous reagent carbon disulfide, iodomethane etc., raw material is cheap and easy to get, simple to operate, and the yield of prepare compound 1 is suitable with the method that former patent document WO02/18369 is reported.
Description
Technical field
The invention belongs to medical synthesis field, and in particular to synthesize intermediate of VX-960 and preparation method thereof.
Background technology
HCV (hepatitis C virus, referred to as HCV) causes chronic hepatitis and and then to develop into liver hard
Change one of main pathogens with hepatocellular carcinoma, hepatitis C virus infection rate is 0.1%~10% in human population worldwide.In China
HCV infection rate is 3.2%, i.e. about 38,000,000 population HCV carrier.In recent years, Chinese hepatitis C is examined
Disconnected rate also continues to increase in continuous improvement and hepatitis C latest report case；After HCV infection, state of an illness concealment, and 50%~80%
Chronic hepatitis can be transformed into, if do not taken rational therapy, wherein 10%~30% patient most probably developed into after 10~20 years
Hepatic sclerosis, and 1%~3% can develop into primary carcinoma of liver, so as to seriously endanger patient health or even life.
Infect the patient of HIV (HIV, or be AIDS AIDS viruses) and hepatitis type B virus (HBV)
Still there is efabirenz to be treated, and for HCV, still lack effective prevention vaccine at present, and nearly 20
The treatment method in year is mainly interferon (IFN-α) or polyethyleneglycol modified long-acting IFN-α and broad-spectrum antiviral medicament profit bar
Wei Lin's is used in combination, and the therapy is more notable for gene II type and Ш type patient's curative effects, but only 40% or so I type is suffered from
Person is effective, and the serious adverse reaction such as fash also have impact on its use in addition.It is anti-to find the specific targeting antiviral therapy medicines of HCV
The important directions of HCV researchs, with the inhibitor VX-960 using serine protease HCV NS3/4A as target
(Telaprevir) with the use in conjunction of IFN-α and Ribavirin clinically, HCV NS3/4A serpins
Increasingly become study hotspot.
Patent WO02/18369 disclose for treat HCV infection protease inhibitors, particularly serine protease
The series compound of inhibitor and the intermediate for synthesizing these compounds, wherein, (1S, aR, 6aS)-octahydro cyclopenta
[c] pyrroles -1- carboxylic acids [(1S, 3aR, 6aS)-octahydrocyclopenta [c] pyrrole-carboxylic acid, are changed
Compound 1] be synthesize VX-960 with and the like a key intermediate, disclosed in this patent preparation method exist it is more
Individual deficiency：It is cumbersome and hazardous agents explosive substance sodium hydrogen (NaH), poisonous reagent curing have been used in crucial preparation process
Carbon and iodomethane；With reference to route II.The compound 11 obtained in route II is by sloughing N- benzyloxycarbonyl groups and carboxylate water
The key intermediate 1 of VX-960 can be prepared in solution two-step reaction.
Initial feed racemic-octahydro cyclopenta for prepare compound 1 is reported in patent WO07/109023
[c] pyrroles (compound 2) is synthesized by biological method, therefore is prepared expensive.
For (1S, aR, 6aS)-octahydro cyclopenta [c] pyrroles -1- carboxylic acids (compound 1), it is as the special drawing of synthesis
Wei with and the like a key intermediate, still urgently wish to obtain the symbol of safer, high yield and low cost
Close the preparation method of industrialized production.
Document J.Org.Chem, Vol.59, the syntheti c route of racemic compound 6 is provided in 2773-2778 pages, with thiophene
Zole derivatives 9 are used as initiation material, and compound 6 can be prepared by three-step reaction.
The content of the invention
The present invention is intended to provide a kind of be used to synthesize (the change of (1S, aR, 6aS)-octahydro cyclopenta [c] pyrroles -1- carboxylic acids
Compound 1) intermediate-compound c and preparation method thereof, can relatively easily synthesize to obtain compound 1 by the intermediate,
Referring to route IV.
Compound d (R are prepared in the method that compound a may be referred to route III2=Et, it is compound 6), by changing
N-protected on compound d, compound a can be prepared, referring to route V.
The invention provides a kind of prepare compound c method, including by compound b in alcohols solvent and in thunder Buddhist nun
Reduction obtains compound c in the presence of nickel；Reaction condition is：Reaction temperature is 70-90 DEG C, and the alcohols solvent is selected from methanol, second
One or more in alcohol, propyl alcohol, n-butanol, isopropanol, the tert-butyl alcohol；See route VI；Wherein R in chemical formula1Selected from benzyloxy carbonyl
Acyl group or tertbutyloxycarbonyl, R2Alkyl selected from C1-C4.
The R in above-mentioned reaction equation (route VI), chemical formula1It is preferred that benzyloxy carbonyl acyl group.
The R in above-mentioned reaction equation (route VI), chemical formula2It is preferred that Me, Et or Pr；More preferably Et.
In a preferred embodiment, the alcohols solvent is the tert-butyl alcohol.It is highly preferred that the amount that solvent uses is 1gization
Compound b uses 50-100mL solvents, preferably 90-100mL.
In a preferred embodiment, the appropriate mass ratio of compound b/ Raney's nickels dosage is 1:100-1:150, preferably
1:120。
In a preferred embodiment, reaction temperature is 70-90 DEG C, preferably 75-80 DEG C.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition can be combined, of the invention each so as to obtain
Preferable embodiment.
The positive progress of the present invention is to synthesize compound c by a kind of novel compounds b, and such compound c can be with
For prepare as VX-960 key intermediate (1S, aR, 6aS)-octahydro cyclopenta [c] pyrroles -1- carboxylic acids (1S,
3aR, 6aS)-octa hydrocyclopenta [c] pyrrole-carboxylic acid (compound 1).Using obtaining chemical combination
Thing c is avoided in the subsequently method of synthesis compound 1 using hazardous agents sodium hydrogen, poisonous reagent carbon disulfide, iodomethane etc., former
Expect it is cheap and easy to get, it is simple to operate, and the yield of prepare compound 1 is suitable with the method that former patent document WO02/18369 is reported.
Term
Unless otherwise indicated, it is used herein to abbreviation min refer to minute, h refers to hour, and MS refers to mass spectral analysis,
NMR refers to that nuclear magnetic spectrum is analyzed.
By the following examples so that the present invention is furture elucidated；It should be pointed out that the ordinary skill people for the art
Member, without departing from the inventive concept of the premise, can also make some improvements and modifications, these improvements and modifications also should be regarded as
In protection scope of the present invention.
Embodiment
The experimental method of unreceipted actual conditions in the following example, conventionally and condition, or said according to commodity
Bright book selection.The commercially available acquisition of agents useful for same and raw material of the present invention.
Embodiment 1
4g (13.4mmol) racemics -2- (benzyloxy carbonyl acyl group) -4- (carbonyl) octahydro cyclopenta is added in four-hole bottle
[c] pyrroles -1- carboxylic acid, ethyl esters, 1.36g (14.7mmol) 1,2- dithioglycols, 3.8g (26.8mmol) BFEE,
40ml dichloromethane, 30min is stirred at room temperature and stops reaction, is washed 2 times (40ml*2) with saturated sodium bicarbonate solution, washing 1
Secondary (40ml*1), anhydrous magnesium sulfate dry organic phase, filter, are spin-dried for, obtain target compound 4g (yield 96%)；MS(m/z)：
407.12[M+H]+；1HNMR(CDCl3.400MHz)δ：1.1-1.2(t,3H),1.65-1.68(m,1H),2.0-2.21(m,
2H),2.21-2.34(m,2H),2.85-2.852(m,1H),3.0-3.05(m,1H),3.27-3.276(m,4H),3.5-3.8
(m,2H),4.0-4.2(m,2H),5.0-5.1(m,2H),7.2-7.4(m,5H)。
Embodiment 2
7.62g (18.7mmol) compound 12,76.2g (10 times of mass fractions) Raney's nickel, uncle 700mL are added in four-hole bottle
Butanol, lead to nitrogen protection, back flow reaction 8h stops reaction, filters, is spin-dried for obtaining 3.8g target compounds (yield 65%), MS (m/
z)：317.16[M+H]+。
Embodiment 3
10.4g is added in four-hole bottle（35mmol）Racemic -2-（Tert-butoxycarbonyl）-4-（Carbonyl）Octahydro cyclopentadiene
And [c] pyrroles -1- carboxylic acid, ethyl esters, 3.5g (38.5mmol) 1,2- dithioglycols, 10g (70mmol) BFEE, 100mL
Dichloromethane, 30min is stirred at room temperature and stops reaction, is washed 2 times with saturated sodium bicarbonate solution（100ml*2）, wash 1 time
（100ml*1）, anhydrous magnesium sulfate drying organic phase, it is spin-dried for.Obtain target compound 9.1g (yield 95%) MS (m/z)：274.09
[M+H]+；1HNMR(CDCl3.400MHz)δ：1.1-1.2(t,3H),1.65-1.68(m,1H),2.0-2.21(m,2H),2.21-
2.34(m,2H),2.85-2.852(m,1H),3.0-3.05(m,1H),3.27-3.276(m,4H),3.5-3.8(m,2H),
4.0-4.2(m,2H),8.1-8.12(s,1H,D2O, which is exchanged, to disappear).
Comparative example
Embodiment 6
12.18g (36.6mmol) compound 13,120mL ethanol are added in four-hole bottle, stirring makes its dissolving, and ice salt bath makes
Temperature drops to 0 DEG C, and 1.44g sodium borohydrides are added portionwise, adds and is slowly increased to room temperature, continues to stir 30min, adds 4.5ml vinegar
Sour terminating reaction, ethanol is spin-dried for, and adds 350ml ethyl acetate, molten with saturated ammonium chloride solution and saturated sodium bicarbonate respectively
Liquid washs, and dries, is spin-dried for.Obtain 11.5g compounds 14 (yield 95%), MS (m/z)：333.14[M+H]+。
Embodiment 7
4.8 (14.4mmol) compounds 14 are added in four-hole bottle, 120ml tetrahydrofurans, -5 DEG C is cooled to, is slowly added to
1.17g (28.8mmol) 60% sodium hydrogen, adds, is slowly increased to room temperature, continues to stir 12h, adds 29.7g (388.8mmol) two
Nitric sulfid, 13.2ml (17.3mmol) iodomethane, is stirred overnight at room temperature.Tetrahydrofuran is spin-dried for, adds 120ml methyl- tert fourths
Base ether, with twice of saturated common salt water washing, organic phase is dried, is spin-dried for, obtained xanthate compound 12 is directly cast one
Step reaction.
Embodiment 8
Obtained crude product in embodiment 4,0.237g (1.44mmol) azodiisobutyronitrile, 5.8ml are added in four-hole bottle
(21.6mmol) three n-butyltin hydride, 120mL toluene, lead to nitrogen protection, be heated to 90 DEG C of reaction 3h, toluene is spin-dried for obtaining
The crude product of 2.17g compounds 11, crude yield 60%, MS (m/z)：317.16[M+H]+。
Claims (7)
1. compound c preparation method, including by compound b in alcohols solvent and in the presence of Raney's nickel reductionization
Compound c；Reaction condition is:Reaction temperature be 70-90 DEG C, wherein not include 80 DEG C, the alcohols solvent be selected from methanol, ethanol,
One or more in propyl alcohol, n-butanol, isopropanol, the tert-butyl alcohol；See route VI；R wherein in chemical formula1Selected from benzyloxy carboxylic acyl
Base or tertiary fourth oxygen carboxyl, R2Alkyl selected from C1-C4, the appropriate mass ratio of the compound b/ Raney's nickel dosages is 1:100-1:
150, the amount that the alcohols solvent uses is that 1g compounds b uses 60-100mL solvents,
2. R in preparation method according to claim 1, wherein chemical formula1Selected from benzyloxy carboxylic acyl group.
3. the R in preparation method according to claim 1, wherein chemical formula2Selected from Me, Et or Pr.
4. according to the preparation method described in claim 1-3 any one, wherein, the alcohols solvent is the tert-butyl alcohol.
5. preparation method according to claim 1, wherein, the amount that the alcohols solvent uses is that 1g compounds b uses 90-
100mL solvents.
6. preparation method according to claim 1, wherein, the appropriate mass ratio of the compound b/ Raney's nickel dosages is 1:
120。
7. preparation method according to claim 1, wherein, the reaction temperature is 75-80 DEG C, wherein not including 80 DEG C.
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