CN108358780B - 合成高非对映选择性的α-酰氧化环酮类化合物的方法 - Google Patents
合成高非对映选择性的α-酰氧化环酮类化合物的方法 Download PDFInfo
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- -1 cyclic ketone compound Chemical class 0.000 title claims abstract description 29
- 238000000034 method Methods 0.000 title claims abstract description 19
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 28
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 19
- 230000003647 oxidation Effects 0.000 claims abstract description 14
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 14
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims abstract description 11
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 11
- 239000011630 iodine Substances 0.000 claims abstract description 11
- 239000002841 Lewis acid Substances 0.000 claims abstract description 9
- 150000007517 lewis acids Chemical class 0.000 claims abstract description 9
- 125000002252 acyl group Chemical group 0.000 claims abstract description 8
- 239000007810 chemical reaction solvent Substances 0.000 claims abstract description 7
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 30
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 claims description 10
- XEFCWBLINXJUIV-UHFFFAOYSA-N acetic acid;iodobenzene Chemical group CC(O)=O.CC(O)=O.IC1=CC=CC=C1 XEFCWBLINXJUIV-UHFFFAOYSA-N 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical group CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 claims description 5
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims description 4
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims description 3
- 229910015900 BF3 Inorganic materials 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims 2
- 239000007800 oxidant agent Substances 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 5
- 238000001308 synthesis method Methods 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 239000012847 fine chemical Substances 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 36
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 27
- 239000012043 crude product Substances 0.000 description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
- 125000000217 alkyl group Chemical group 0.000 description 13
- 239000000047 product Substances 0.000 description 13
- 125000004432 carbon atom Chemical group C* 0.000 description 12
- 150000001875 compounds Chemical class 0.000 description 12
- 125000003118 aryl group Chemical group 0.000 description 10
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
- 238000012512 characterization method Methods 0.000 description 9
- 125000001072 heteroaryl group Chemical group 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- 238000010898 silica gel chromatography Methods 0.000 description 9
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 9
- 235000019345 sodium thiosulphate Nutrition 0.000 description 9
- 125000001424 substituent group Chemical group 0.000 description 9
- 150000003997 cyclic ketones Chemical class 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 125000003107 substituted aryl group Chemical group 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 239000004215 Carbon black (E152) Substances 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- 239000007795 chemical reaction product Substances 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 229930195733 hydrocarbon Natural products 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 3
- YKAYMASDSHFOGI-UHFFFAOYSA-N 4-phenylcyclohexan-1-one Chemical compound C1CC(=O)CCC1C1=CC=CC=C1 YKAYMASDSHFOGI-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 150000008064 anhydrides Chemical class 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 150000001717 carbocyclic compounds Chemical class 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 125000000547 substituted alkyl group Chemical group 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000010276 construction Methods 0.000 description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 150000002497 iodine compounds Chemical class 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 150000003413 spiro compounds Chemical class 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- LGVJRKCQQHOWAU-IUCAKERBSA-N (4as,8as)-3,4,4a,5,6,7,8,8a-octahydro-1h-naphthalen-2-one Chemical compound C1CCC[C@H]2CC(=O)CC[C@@H]21 LGVJRKCQQHOWAU-IUCAKERBSA-N 0.000 description 1
- PGZVFRAEAAXREB-UHFFFAOYSA-N 2,2-dimethylpropanoyl 2,2-dimethylpropanoate Chemical compound CC(C)(C)C(=O)OC(=O)C(C)(C)C PGZVFRAEAAXREB-UHFFFAOYSA-N 0.000 description 1
- 125000004398 2-methyl-2-butyl group Chemical group CC(C)(CC)* 0.000 description 1
- 125000004918 2-methyl-2-pentyl group Chemical group CC(C)(CCC)* 0.000 description 1
- 125000004922 2-methyl-3-pentyl group Chemical group CC(C)C(CC)* 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000004917 3-methyl-2-butyl group Chemical group CC(C(C)*)C 0.000 description 1
- 125000004919 3-methyl-2-pentyl group Chemical group CC(C(C)*)CC 0.000 description 1
- 125000004921 3-methyl-3-pentyl group Chemical group CC(CC)(CC)* 0.000 description 1
- CJAUDSQXFVZPTO-UHFFFAOYSA-N 3-phenylcyclohexan-1-one Chemical compound C1C(=O)CCCC1C1=CC=CC=C1 CJAUDSQXFVZPTO-UHFFFAOYSA-N 0.000 description 1
- YJZOKOQSQKNYLW-UHFFFAOYSA-N 3-tert-butylcyclohexan-1-one Chemical compound CC(C)(C)C1CCCC(=O)C1 YJZOKOQSQKNYLW-UHFFFAOYSA-N 0.000 description 1
- LSVOBJIOONAGLU-UHFFFAOYSA-N 4-hydroxy-3,5-bis(3-methylbut-2-enyl)benzoic acid Chemical compound CC(C)=CCC1=CC(C(O)=O)=CC(CC=C(C)C)=C1O LSVOBJIOONAGLU-UHFFFAOYSA-N 0.000 description 1
- 125000004920 4-methyl-2-pentyl group Chemical group CC(CC(C)*)C 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- GXGJIOMUZAGVEH-UHFFFAOYSA-N Chamazulene Chemical group CCC1=CC=C(C)C2=CC=C(C)C2=C1 GXGJIOMUZAGVEH-UHFFFAOYSA-N 0.000 description 1
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 125000004104 aryloxy group Chemical group 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
- 150000001244 carboxylic acid anhydrides Chemical class 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- YKFKEYKJGVSEIX-UHFFFAOYSA-N cyclohexanone, 4-(1,1-dimethylethyl)- Chemical compound CC(C)(C)C1CCC(=O)CC1 YKFKEYKJGVSEIX-UHFFFAOYSA-N 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- VGGRCVDNFAQIKO-UHFFFAOYSA-N formic anhydride Chemical compound O=COC=O VGGRCVDNFAQIKO-UHFFFAOYSA-N 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- LSACYLWPPQLVSM-UHFFFAOYSA-N isobutyric acid anhydride Chemical compound CC(C)C(=O)OC(=O)C(C)C LSACYLWPPQLVSM-UHFFFAOYSA-N 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000012263 liquid product Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 1
- OFMQCKGSKVARCL-CMDGGOBGSA-N tert-butyl (e)-3-(4-formylphenyl)prop-2-enoate Chemical compound CC(C)(C)OC(=O)\C=C\C1=CC=C(C=O)C=C1 OFMQCKGSKVARCL-CMDGGOBGSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/0825—Preparations of compounds not comprising Si-Si or Si-cyano linkages
- C07F7/083—Syntheses without formation of a Si-C bond
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/14—All rings being cycloaliphatic
- C07C2602/26—All rings being cycloaliphatic the ring system containing ten carbon atoms
- C07C2602/28—Hydrogenated naphthalenes
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本申请属于合成化学技术领域,具体涉及合成高非对映选择性的α‑酰氧化环酮类化合物的方法。本发明所提供的合成方法包括:在高价碘试剂的氧化催化作用下,环酮类化合物、路易斯酸和酰氧化试剂在反应溶剂中进行反应。该方法反应条件温和可控、操作简单优化,产物单一,非对映选择性高,适用于多种环酮类化合物。与现有技术相比,本发明的优点在于,通过上述方法制备得到的产物,其非对映异构体选择性高达12:1,适用于实验室和工厂制备特定立体构型的α‑酰氧化环酮类药物中间体和精细化学品。
Description
技术领域
本发明属于合成化学技术领域,具体涉及合成高非对映选择性的α-酰氧化环酮类化合物的方法。
背景技术
环酮的α-酰氧化,尤其是构建具有不同构象的α取代环酮类化合物,在新化合物和药物中间体的构建方面具有非常重要的作用。对于有机化学来讲,研究具有好的立体选择性的合成方法来构建这些化合物是一个非常重要的课题和任务。
传统的α-酰氧化环酮类化合物的合成通常是利用亲电试剂来进攻稀醇或稀醇化合物中间体而得到,这些方法通常需要较高的还原性和碱性的条件。传统的合成方法步骤较为复杂,必须先合成稀醇中间体,加大了合成这类化合物的成本。近年来,随着有机界对高碘化合物研究的深入,高碘化合物开始被应用于环酮的α-酰氧化的研究,研究发现不论是高碘还是原位都能很好的从环酮底物合成到环酮的α-酰氧化产物。但是,这些研究也只仅限于环酮的α-酰氧化的研究,并未涉及其立体选择性的研究。
因此,寻找一种非对映选择性高、反应产物可控、副反应少、合成步骤简单的用于合成具有高非对映选择性的α-酰氧化环酮类化合物的方法,是本领域技术人员亟待解决的技术问题。
发明内容
为了解决上述技术问题,本发明的目的在于提供一种高非对映选择性的α-酰氧化环酮类化合物的合成方法,其具体技术方案如下:
合成高非对映选择性的α-酰氧化环酮类化合物的方法,包括:在高价碘试剂的氧化催化作用下,环酮类化合物、路易斯酸和酰氧化试剂在反应溶剂中进行反应。
优选的,所述环酮类化合物、高价碘试剂、路易斯酸和酰氧化试剂的反应摩尔比为1:(1~10):(0.3~20):(1~50)。
优选的,所述反应为在室温下反应2~48h。
优选的,所述酰氧化试剂选自乙酸、特戊酸、异丁酸、甲酸或苯甲酸,或其酸酐或酯。
优选的,所述路易斯酸选自三氟化硼、三氟乙酸、氯化铝、氯化铁、氯化锂和三氟甲磺酸盐中的一种或多种。
优选的,所述反应溶剂为有机溶剂;所述有机溶剂选自乙酸、甲酸、异丁酸、特戊酸、乙酸酐、甲酸酐、异丁酸酐、特戊酸酐、乙腈、甲醇、乙醇、二氯甲烷、氯仿、苯、甲苯、四氢呋喃、乙醚、二甲基甲酰胺、二甲基乙酰胺、二甲基亚或乙酸乙酯。
本发明还提供了由上述合成方法得到的α-酰氧化环酮类化合物,其化学结构如通式(I)所示:
其中,其非对映异构体比例大于4.6;
R1的个数至少为1个;
R1和R2各自独立地选自芳基、取代芳基、杂芳基、取代杂芳基、烷基、取代烷基或硅烷基;
n选自0、1、2、3或4;
其中,上述取代芳基、取代杂芳基和取代烷基为各自独立地被卤素、烷基、卤代烷基、烷氧基、硝基、氰基、羟基、酯基、羰基和酰胺基中的一个或多个基团任选取代的取代芳基、取代杂芳基或取代烷;
所述碳环化合物优选为桥环化合物或螺环化合物,所述桥环化合物优选为二环烃。
优选的,所述α-酰氧化环酮类化合物为:
综上所述,本发明提供了合成高非对映选择性的α-酰氧化环酮类化合物的方法,通过将环酮类化合物、酰氧化试剂和高价碘试剂在反应溶剂中混合,再加入路易斯酸进行反应得到α-酰氧化环酮类化合物。
本发明采用三价碘试剂作为催化剂,可避免因金属催化而产生的金属残留和毒性,绿色环保;采用常见的羧酸或羧酸酐作为酰氧化试剂,简便高效,反应产物可控,易于分离纯化,适合工业化生产。因此,本发明所提供的合成方法具有反应条件温和、反应产物可控、产物单一易于纯化、化学选择性高、合成步骤简单、安全可靠和绿色环保的优点,同时适用于多种环酮类化合物,包括四、五、六、七、八元环酮及其衍生物。
与现有技术相比,本发明的优点在于,通过上述方法制备得到的产物,其非对映异构体选择性高达12:1,适用于实验室和工厂制备特定立体构型的α-酰氧化环酮类药物中间体和精细化学品。
具体实施方式
为了更有效可控的合成具有高非对映选择性的α-酰氧化环酮类化合物,本发明提供了一种反应条件温和、反应产物可控、操作简单的合成方法,通过将环酮类化合物、酰氧化试剂和高价碘试剂在反应溶剂中混合,再加入路易斯酸进行反应得到具有高非对映选择性的α-酰氧化环酮类化合物。
本发明所使用的术语“各自独立地”,表示具有并列关系的两个基团其上的取代基互不影响,各自独立。也就是R1为取代芳基时,R2可以为与之相同的取代芳基,也可以为与之不同的取代芳基或者烷基等其他官能团。
本发明所使用的术语“取代”,表示所给结构中的一个或多个氢原子被具体取代基所取代。本发明所使用的术语“任选取代”,表示所给结构可以有一个取代基在基团各个可取代的位置进行取代。当所给出的结构式中不只一个位置能被选自具体基团的一个或多个取代基所取代,那么取代基可以相同或不同地在各个位置取代。其中所述的取代基可以是,但并不限于,羟基,氨基,卤素,氰基,芳基,杂芳基,烷氧基,烷基,烯基,炔基,杂环基,巯基,硝基,芳氧基等等。
本发明使用的术语“烷基”,表示含1-20个碳原子的饱和直链、环状或支链一价碳氢化合物原子团。其中所述烷基基团可以独立任选地被一个或多个取代基所取代。除非另外详细说明,烷基基团含有1-20个碳原子,其中一些实施例是,烷基基团含有1-10个碳原子,另外一些实施例是,烷基基团含有1-8个碳原子,另外一些实施例是,烷基基团含有1-6个碳原子,另外一些实施例是,烷基基团含有1-4个碳原子,另外一些实施例是,烷基基团含有1-3个碳原子。
烷基基团的实例包含,但并不限于,甲基(Me,-CH3),乙基(Et,-CH2CH3),正丙基(n-Pr,-CH2CH2CH3),异丙基(i-Pr,-CH(CH3)2),正丁基(n-Bu,-CH2CH2CH2CH3),异丁基(i-Bu,-CH2CH(CH3)2),仲丁基(s-Bu,-CH(CH3)CH2CH3),叔丁基(t-Bu,-C(CH3)3),正戊基(-CH2CH2CH2CH2CH3),2-戊基(-CH(CH3)CH2CH2CH3),3-戊基(-CH(CH2CH3)2),2-甲基-2-丁基(-C(CH3)2CH2CH3),3-甲基-2-丁基(-CH(CH3)CH(CH3)2),3-甲基-1-丁基(-CH2CH2CH(CH3)2),2-甲基-1-丁基(-CH2CH(CH3)CH2CH3),正己基(-CH2CH2CH2CH2CH2CH3),2-己基(-CH(CH3)CH2CH2CH2CH3),3-己基(-CH(CH2CH3)(CH2CH2CH3)),2-甲基-2-戊基(-C(CH3)2CH2CH2CH3),3-甲基-2-戊基(-CH(CH3)CH(CH3)CH2CH3),4-甲基-2-戊基(-CH(CH3)CH2CH(CH3)2),3-甲基-3-戊基(-C(CH3)(CH2CH3)2),2-甲基-3-戊基(-CH(CH2CH3)CH(CH3)2),2,3-二甲基-2-丁基(-C(CH3)2CH(CH3)2),3,3-二甲基-2-丁基(-CH(CH3)C(CH3)3),正庚基,正辛基,等等。
本发明使用的术语“芳基”,表示含1-20个碳原子的不饱和共轭碳氢化合物原子团。其中所述芳基可以独立任选地被一个或多个取代基所取代。除非另外详细说明,芳基含有1-20个碳原子,其中一些实施例是,芳基含有1-14个碳原子,另外一些实施例是,芳基含有1-10个碳原子,另外一些实施例是,芳基基团含有1-6个碳原子。芳基的实例包含,但并不限于,苯基,取代苯基,萘基,取代萘基,蒽基,取代蒽基,等等。
本发明使用的术语“杂芳基”,表示包含氮、硫和氧中的一个原子或多个原子组合成的含5-12个原子的芳环,或者为饱和环与杂芳环的衍生环状取代基。其中,所述杂芳基可以独立任选地被一个或多个取代基所取代。优选的,所述杂芳基为吡啶基或噻吩基。
本发明使用的术语“碳环化合物”,表示不含氮、硫和氧中的一个原子或多个原子组合成的环烃,优选为桥环化合物或螺环化合物,更优选为桥环化合物,桥环化合物优选为二环烃。
本发明使用的术语“或其酸酐或酯”,表示酰氧化试剂不仅可以为乙酸、特戊酸、异丁酸、甲酸或苯甲酸,还可以为以上列举物质的酸酐产物或其酯化产物。
下面将结合本发明的实施例,对本发明的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
实施例1
将87.1mg(0.50mmol)对苯基环己酮和241.6mg(0.75mmol)碘苯二乙酸溶解于1.0mL乙酸中,然后将185.1μL(3.00mmol)三氟化硼乙醚滴加到反应体系中,在室温条件下反应24h后,用20mL饱和碳酸氢钠和5mL硫代硫酸钠(0.1g/mL)猝灭反应,再用二氯甲烷萃取三次,合并有机相后减压浓缩得到粗产物1。将粗产物1进行硅胶柱层析(丙酮:正己烷=1:30)分离纯化,得到白色固体产物1,产率为67%,dr=11.8:1。
其表征数据如下:
顺式异构体,熔点:90.1-95.1℃;
1H NMR(400MHz,CDCl3):δ=7.35-7.23(m,5H),5.38(dd,J=12.8Hz,J=6.4Hz,1H),3.23(t,J=12.4Hz,1H),2.62-2.59(m,2H),2.49-2.44(m,1H),2.27-2.24(m,1H),2.17(s,3H),2.08(q,J=12.4Hz,1H),1.96-1.85(m,1H);
13C NMR(100MHz,CDCl3):δ=204.0,170.1,143.2,128.9,127.1,126.8,75.8,42.1,40.0,39.9,34.5,20.8;
IR(KBr):3081,3021,2938,2875,2854,1757,1718,1641,1492,1445,1423,1385,1370,1324,1287,1263,1245,1150,1120,1072,1061,982,935,911,852,756,743,695,610,517,466cm-1;
HRMS(ESI+):m/z[M+Na]+calcd for C14H16O3:255.0997;found:255.0987。
实施例2
将87.1mg(0.50mmol)间苯基环己酮和241.6mg(0.75mmol)碘苯二乙酸溶解于1.0mL乙酸中,然后将185.1μL(3.00mmol)三氟化硼乙醚滴加到反应体系中,在室温条件下反应48h后,用20mL饱和碳酸氢钠和5mL硫代硫酸钠(0.1g/mL)猝灭反应,再用二氯甲烷萃取三次,合并有机相后减压浓缩得到粗产物2。将粗产物2进行硅胶柱层析(丙酮:正己烷=1:30)分离纯化,得到白色固体产物2,产率为47%,dr=6.1:1。
其表征数据如下:
反式异构体,熔点:71.9-74.8℃;
1H NMR(400MHz,CDCl3):δ=7.35-7.31(m,2H),7.25-7.20(m,3H),5.29(dd,J=6.4Hz,J=12.8Hz,1H),3.02-2.94(m,1H),2.70-2.62(m,2H),2.40-2.35(m,1H),2.18(s,3H),2.14(m,1H),2.09-1.98(m,1H),1.95-1.84(m,1H);
13C NMR(100MHz,CDCl3):δ=203.4,170.3,143.2,129.0,127.2,126.6,76.3,47.9,45.4,31.8,31.7,20.9;
IR(KBr):3033,2959,2941,2908,1745,1721,1602,1501,1458,1432,1376,1319,1281,1233,1174,1081,1046,897,763,703,665,599,531,501cm-1;
HRMS(ESI+):m/z[M+Na]+calcd for C9H14O3:255.0997;found:255.0986。
实施例3
将77.1mg(0.50mmol)对叔丁基环己酮和241.6mg(0.75mmol)碘苯二乙酸溶解于1.0mL乙酸中,然后将185.1μL(3.00mmol)三氟化硼乙醚滴加到反应体系中,在室温条件下反应24h后,用20mL饱和碳酸氢钠和5mL硫代硫酸钠(0.1g/mL)猝灭反应,再用二氯甲烷萃取三次,合并有机相后减压浓缩得到粗产物3。将粗产物3进行硅胶柱层析(丙酮:正己烷=1:30)分离纯化,得到无色透明液体产物3,产率为57%,dr=11.1:1。
其表征数据如下:
顺式异构体;
1H NMR(400MHz,CDCl3):δ=5.23-5.18(m,1H),2.52-2.47(m,1H),2.43-2.34(m,1H),2.33-2.27(m,1H),2.15(s,3H),2.13-2.07(m,1H),1.74-1.66(m,1H),1.57(q,J=12.4Hz,1H),1.48-1.37(m,1H),0.93(s,9H);
13C NMR(100MHz,CDCl3):δ=205.0,170.2,76.3,46.0,39.7,34.4,32.6,28.2,27.7,20.9。
实施例4
将84.0μL(0.50mmol)间叔丁基环己酮和241.6mg(0.75mmol)碘苯二乙酸溶解于1.0mL乙酸中,然后将185.1μL(3.00mmol)三氟化硼乙醚滴加到反应体系中,在室温条件下反应24h后,用20mL饱和碳酸氢钠和5mL硫代硫酸钠(0.1g/mL)猝灭反应,再用二氯甲烷萃取三次,合并有机相后减压浓缩得到粗产物4。将粗产物4进行硅胶柱层析(丙酮:正己烷=1:30)分离纯化,得到淡黄色液体产物4,产率为36%,dr=12.3:1。
其表征数据如下:
反式异构体;
1H NMR(400MHz,CDCl3):δ=5.15(dd,J=6.8Hz,J=12.8Hz,1H),2.56-2.53(m,1H),2.33-2.27(m,1H),2.22-2.13(m,1H),2.16(s,3H),2.03-2.00(m,1H),1.73-1.63(m,1H),1.56-1.51(m,2H),0.91(s,9H);
13C NMR(150MHz,CDCl3):δ=205.3,170.3,76.6,50.0,42.4,32.9,31.7,27.4,25.0,20.9。
实施例5
将87.1mg(0.50mmol)对苯基环己酮和241.6mg(0.75mmol)碘苯二乙酸溶解于1.0mL特戊酸中,然后将185.1μL(3.00mmol)三氟化硼乙醚滴加到反应体系中,在50℃条件下反应24小时后,用20mL饱和碳酸氢钠和5mL硫代硫酸钠(0.1g/mL)猝灭反应,再用二氯甲烷萃取三次,合并有机相后减压浓缩得到粗产物5。将粗产物5进行硅胶柱层析(丙酮:正己烷=1:30)分离纯化,得到淡黄色固体产物5,产率为25%,dr=4.6:1。
其表征数据如下:
顺式异构体,熔点:85.4-88.7℃;
1H NMR(400MHz,CDCl3):δ=7.35-7.32(m,2H),7.26-7.24(m,3H),5.35(dd,J=6.4Hz,J=12.8Hz,1H),3.23(t,J=12.8Hz,1H),2.67-2.59(m,2H),2.44(m,1H),2.26-2.23(m,1H),2.10(q,J=12.8Hz,1H),1.98-1.87(m,1H),1.26(s,9H);
13C NMR(150MHz,CDCl3):δ=204.1,177.8,143.4,128.9,127.1,126.8,75.4,42.1,40.0,39.9,38.9,34.4,27.3;
IR(KBr):3087,3030,2974,2956,2932,2863,1742,1721,1635,1605,1483,1456,1426,1394,1364,1328,1290,1171,1144,1069,980,900,858,766,701,546,513,423cm-1;
HRMS(ESI+):m/z[M+Na]+calcd for C17H22O3:297.1467;found:297.1461。
实施例6
将87.1mg(0.50mmol)对苯基环己酮和241.6mg(0.75mmol)碘苯二乙酸溶解于1.0mL异丁酸中,然后将185.1μL(3.00mmol)三氟化硼乙醚滴加到反应体系中,在室温条件下反应24小时后,用20mL饱和碳酸氢钠和5mL硫代硫酸钠(0.1g/mL)猝灭反应,再用二氯甲烷萃取三次,合并有机相后减压浓缩得到粗产物6。将粗产物6进行硅胶柱层析(丙酮:正己烷=1:30)分离纯化,得到淡黄色固体产物6,产率为50%,dr=10.2:1。
其表征数据如下:
顺式异构体,熔点:62.8-65.4℃;
1H NMR(400MHz,CDCl3):δ=7.38-7.34(m,2H),7.29-7.26(m,3H),5.41(dd,J=6.0Hz,J=12.8Hz,1H),3.26(t,1H,J=12.8Hz),2.71-2.62(m,3H),2.51-2.46(m,1H),2.30-2.26(m,1H),2.11(q,J=12.8,1H),2.00-1.89(m,1H);1.28(d,J=6.8Hz,3H),1.23(d,J=6.8Hz,3H);
13C NMR(100MHz,CDCl3):δ=204.1,176.4,143.3,128.9,127.1,126.8,75.4,42.1,40.0,39.9,34.5,34.0,19.2,19.1;
IR(KBr):3030,2977,2929,2866,1751,1727,1632,1605,1498,1462,1429,1385,1349,1293,1260,1200,1165,1147,1117,1069,977,918,843,763,739,701,596,540,507cm-1;
HRMS(ESI+):m/z[M+Na]+calcd for C16H20O3:283.1310;found:283.1299。
实施例7
将77.7μL(0.50mmol)的(4aS,8aS)-八氢-2-(1H)萘酮和241.6mg(0.75mmol)碘苯二乙酸溶解于1.0mL乙酸中,然后将185.1μL(3.00mmol)三氟化硼乙醚滴加到反应体系中,在室温条件下反应24h后,用20mL饱和碳酸氢钠和5mL硫代硫酸钠(0.1g/mL)猝灭反应,再用二氯甲烷萃取三次,合并有机相后减压浓缩得到粗产物7。将粗产物7进行硅胶柱层析(丙酮:正己烷=1:30)分离纯化,得到淡黄色固体产物7,产率为50.5%,dr=9.9:1。
其表征数据如下:
1H NMR(400MHz,CDCl3):δ=5.19(dd,J=6.8Hz,J=12.0Hz,1H),2.41-2.37(m,1H),2.20-2.10(m,2H),2.13(s,3H),1.78-1.68(m,4H),1.56-1.46(m,2H),1.36-0.99(m,5H);
13C NMR(100MHz,CDCl3):δ=204.0,170.2,76.1,47.2,43.8,40.5,39.4,33.7,32.5,25.8,25.5,20.8。
实施例8
将69.1μL(0.50mmol)的(3S,4R)-3,4-二甲基环己酮和241.6mg(0.75mmol)的碘苯二乙酸溶解于1.0mL乙酸中,然后将61.7μL(3.00mmol)三氟化硼乙醚滴加到反应体系中,在室温条件下反应3小时后,用20mL饱和碳酸氢钠和5mL硫代硫酸钠(0.1g/mL)猝灭反应,再用二氯甲烷萃取三次,合并有机相后减压浓缩得到粗产物8。将粗产物8进行硅胶柱层析(丙酮:正己烷=1:30)分离纯化,得到淡黄色液体产物8,产率为40.5%,dr>20:1。
其表征数据如下:
1H NMR(400MHz,CDCl3):δ=5.19(dd,J=6.8Hz,J=12.4Hz,1H),2.67-2.62(m,1H),2.35-2.21(m,3H),2.14(s,3H),2.07-2.03(m,1H),1.74(q,J=12.8Hz,1H),1.01(d,J=6.8Hz,3H),0.83(d,J=6.8Hz,3H);
13C NMR(100MHz,CDCl3,ppm):δ=204.6,170.1,75.6,47.3,36.5,34.9,33.2,20.8,18.5,12.1;
IR(KBr):2959,2928,2891,2871,1749,1721,1470,1455,1431,1380,1370,1243,1175,1102,1087,1075,1036,975,941,885,790,715,651,609,549,510,482,436cm-1;
HRMS(ESI+):m/z[M+Na]+calcd for C10H16O3:207.0997;found:207.0988。
实施例9
将118.6μL(0.50mmol)的4-(二甲基(苯基)硅烷基)环己酮和241.6mg(0.75mmol)碘苯二乙酸溶解于1.0mL乙酸中,然后将185.1μL(3.00mmol)三氟化硼乙醚滴加到反应体系中,在室温条件下反应0.5h后,用20mL饱和碳酸氢钠和5mL硫代硫酸钠(0.1g/mL)猝灭反应,再用二氯甲烷萃取三次,合并有机相后减压浓缩得到粗产物9。将粗产物9进行硅胶柱层析(丙酮:正己烷=1:30)分离纯化,得到白色固体产物9,产率为36%,dr=6.8:1。
其表征数据如下:
顺式异构体,熔点:120.5-124.5℃;
1H NMR(400MHz,CDCl3):δ=7.49-7.37(m,5H),5.15(dd,J=12.4Hz,J=6.4Hz,1H),2.53-2.50(m,1H),2.43-2.35(m,1H),2.27-2.23(m,1H),2.13(s,3H),2.09-2.04(m,1H),1.61(q,J=12.8Hz,1H),1.53-1.42(m,1H),1.38-1.32(m,1H),0.33(s,6H);
13C NMR(100MHz,CDCl3):δ=204.9,170.2,136.5,133.9,129.9,129.6,128.1,77.7,42.5,34.7,28.9,24.1,20.9,-4.9,-5.0;
IR(KBr):3071,3012,2949,2935,2865,2841,1748,1721,1427,1407,1376,1342,1321,1257,1233,1173,1143,1112,1102,1082,1050,968,912,885,850,834,821,776,763,742,728,704,661,643,605,570,482,451,436cm-1;
HRMS(ESI+):m/z[M+Na]+calcd for C16H22O3Si:313.1236;found:313.1227。
Claims (3)
1.合成高非对映选择性的α-酰氧化环酮类化合物的方法,其特征在于,包括:在高价碘试剂的氧化催化作用下,环酮类化合物、路易斯酸和酰氧化试剂在反应溶剂中进行反应;
所述合成高非对映选择性的α-酰氧化环酮类化合物的方法的步骤包括:
1)将所述环酮类化合物、所述酰氧化试剂和所述高价碘试剂与所述反应溶剂混合得到第一混合物;
2)在所述第一混合物中滴加所述路易斯酸;
所述高价碘试剂为碘苯二乙酸;
所述路易斯酸为三氟化硼;
所述酰氧化试剂选自乙酸、特戊酸或异丁酸;
所述反应溶剂为乙醚。
2.根据权利要求1所述的方法,其特征在于,所述环酮类化合物、高价碘试剂、路易斯酸和酰氧化试剂的反应摩尔比为1:(1~10):(0.3~20):(1~50)。
3.根据权利要求1所述的方法,其特征在于,所述反应为在室温下反应2~48h。
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