CN114031542B - Preparation method of azabicyclo medicine intermediate - Google Patents
Preparation method of azabicyclo medicine intermediate Download PDFInfo
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- CN114031542B CN114031542B CN202111504898.2A CN202111504898A CN114031542B CN 114031542 B CN114031542 B CN 114031542B CN 202111504898 A CN202111504898 A CN 202111504898A CN 114031542 B CN114031542 B CN 114031542B
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- 238000002360 preparation method Methods 0.000 title claims description 13
- 239000003814 drug Substances 0.000 title abstract description 14
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 20
- 238000006722 reduction reaction Methods 0.000 claims abstract description 15
- 238000005576 amination reaction Methods 0.000 claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims description 56
- 238000000034 method Methods 0.000 claims description 31
- 238000006243 chemical reaction Methods 0.000 claims description 30
- 125000000217 alkyl group Chemical group 0.000 claims description 27
- 125000003118 aryl group Chemical group 0.000 claims description 21
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 18
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 16
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 15
- 229910052751 metal Inorganic materials 0.000 claims description 15
- 239000002184 metal Substances 0.000 claims description 15
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 14
- 125000004185 ester group Chemical group 0.000 claims description 13
- 125000005843 halogen group Chemical group 0.000 claims description 13
- 230000008569 process Effects 0.000 claims description 11
- 125000001188 haloalkyl group Chemical group 0.000 claims description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 9
- 239000013110 organic ligand Substances 0.000 claims description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 8
- 239000012450 pharmaceutical intermediate Substances 0.000 claims description 7
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 6
- 229910052802 copper Inorganic materials 0.000 claims description 6
- 239000010949 copper Substances 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 5
- 229910052703 rhodium Inorganic materials 0.000 claims description 5
- 239000010948 rhodium Substances 0.000 claims description 5
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims description 5
- 229910017052 cobalt Inorganic materials 0.000 claims description 4
- 239000010941 cobalt Substances 0.000 claims description 4
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 claims description 4
- 229910052763 palladium Inorganic materials 0.000 claims description 4
- -1 hetero-atom bicyclic compound Chemical class 0.000 abstract description 23
- BGOMFPZIMJCRDV-UHFFFAOYSA-N 6,6-dimethyl-3-azabicyclo[3.1.0]hexane Chemical compound C1NCC2C(C)(C)C21 BGOMFPZIMJCRDV-UHFFFAOYSA-N 0.000 abstract description 19
- 238000001308 synthesis method Methods 0.000 abstract description 11
- 125000000664 diazo group Chemical group [N-]=[N+]=[*] 0.000 abstract description 5
- 125000001424 substituent group Chemical group 0.000 description 33
- 239000000543 intermediate Substances 0.000 description 23
- 239000000047 product Substances 0.000 description 19
- 239000002904 solvent Substances 0.000 description 13
- 239000003446 ligand Substances 0.000 description 12
- 239000002994 raw material Substances 0.000 description 11
- 125000004432 carbon atom Chemical group C* 0.000 description 10
- 229940079593 drug Drugs 0.000 description 10
- QKAHKEDLPBJLFD-UHFFFAOYSA-N 6,6-dimethyl-3-oxabicyclo[3.1.0]hexane-2,4-dione Chemical compound O=C1OC(=O)C2C1C2(C)C QKAHKEDLPBJLFD-UHFFFAOYSA-N 0.000 description 9
- 238000004519 manufacturing process Methods 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 8
- 239000012280 lithium aluminium hydride Substances 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- 125000002947 alkylene group Chemical group 0.000 description 7
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 7
- MSPJNHHBNOLHOC-UHFFFAOYSA-N 3,3-dimethylcyclopropane-1,2-dicarboxylic acid Chemical compound CC1(C)C(C(O)=O)C1C(O)=O MSPJNHHBNOLHOC-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 6
- 239000003638 chemical reducing agent Substances 0.000 description 6
- 208000005176 Hepatitis C Diseases 0.000 description 5
- 125000003545 alkoxy group Chemical group 0.000 description 5
- 150000002894 organic compounds Chemical class 0.000 description 5
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 4
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 4
- 241000711573 Coronaviridae Species 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 125000000732 arylene group Chemical group 0.000 description 4
- 125000004104 aryloxy group Chemical group 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
- 150000001879 copper Chemical class 0.000 description 4
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 4
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 4
- 229940045803 cuprous chloride Drugs 0.000 description 4
- 125000002993 cycloalkylene group Chemical group 0.000 description 4
- 238000004821 distillation Methods 0.000 description 4
- 125000005549 heteroarylene group Chemical group 0.000 description 4
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 4
- 125000005647 linker group Chemical group 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 230000003647 oxidation Effects 0.000 description 4
- 238000007254 oxidation reaction Methods 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 4
- 239000002699 waste material Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- 208000025721 COVID-19 Diseases 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 3
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 3
- 150000008064 anhydrides Chemical class 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000005265 energy consumption Methods 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 239000002351 wastewater Substances 0.000 description 3
- 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 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical class ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 2
- 230000001476 alcoholic effect Effects 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 2
- 229910000366 copper(II) sulfate Inorganic materials 0.000 description 2
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 229960003280 cupric chloride Drugs 0.000 description 2
- 238000005888 cyclopropanation reaction Methods 0.000 description 2
- 238000003912 environmental pollution Methods 0.000 description 2
- 239000004210 ether based solvent Substances 0.000 description 2
- VIMXTGUGWLAOFZ-UHFFFAOYSA-N ethyl 2,2-dimethyl-3-(2-methylprop-1-enyl)cyclopropane-1-carboxylate Chemical compound CCOC(=O)C1C(C=C(C)C)C1(C)C VIMXTGUGWLAOFZ-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 150000002739 metals Chemical class 0.000 description 2
- MUTCAPXLKRYEPR-ITWZMISCSA-N methyl (e,3r,5s)-7-[4-bromo-2,3-bis(4-fluorophenyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyhept-6-enoate Chemical compound COC(=O)C[C@H](O)C[C@H](O)\C=C\N1C(C(C)C)=C(Br)C(C=2C=CC(F)=CC=2)=C1C1=CC=C(F)C=C1 MUTCAPXLKRYEPR-ITWZMISCSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 150000003457 sulfones Chemical class 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- ROBSGBGTWRRYSK-SNVBAGLBSA-N (2r)-2-[4-(4-cyano-2-fluorophenoxy)phenoxy]propanoic acid Chemical compound C1=CC(O[C@H](C)C(O)=O)=CC=C1OC1=CC=C(C#N)C=C1F ROBSGBGTWRRYSK-SNVBAGLBSA-N 0.000 description 1
- 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 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 1
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 1
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Natural products NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 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
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 150000004645 aluminates Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- XKMRRTOUMJRJIA-UHFFFAOYSA-N ammonia nh3 Chemical compound N.N XKMRRTOUMJRJIA-UHFFFAOYSA-N 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 239000003849 aromatic solvent Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
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- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000008859 change Effects 0.000 description 1
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- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
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- 150000004292 cyclic ethers Chemical class 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
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- IJGRMHOSHXDMSA-UHFFFAOYSA-O diazynium Chemical group [NH+]#N IJGRMHOSHXDMSA-UHFFFAOYSA-O 0.000 description 1
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- YVPJCJLMRRTDMQ-UHFFFAOYSA-N ethyl diazoacetate Chemical compound CCOC(=O)C=[N+]=[N-] YVPJCJLMRRTDMQ-UHFFFAOYSA-N 0.000 description 1
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- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- DOTMOQHOJINYBL-UHFFFAOYSA-N molecular nitrogen;molecular oxygen Chemical compound N#N.O=O DOTMOQHOJINYBL-UHFFFAOYSA-N 0.000 description 1
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- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
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- 239000012071 phase Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
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- ASUAYTHWZCLXAN-UHFFFAOYSA-N prenol Chemical compound CC(C)=CCO ASUAYTHWZCLXAN-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 241000894007 species Species 0.000 description 1
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- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
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Abstract
The invention relates to an azabicyclo medicament intermediate, in particular to a synthesis method of 6,6-dimethyl-3-azabicyclo [3.1.0] hexane or derivatives thereof, which is characterized in that a hetero-atom bicyclic compound is constructed through intramolecular diazo group and alkene bond cyclization, and a target product is finally obtained through (amination reaction and reduction reaction).
Description
Technical Field
The invention belongs to the field of pharmaceutical chemical industry, in particular to a preparation method of a pharmaceutical intermediate, and particularly relates to a preparation method of a pharmaceutical intermediate 6,6-dimethyl-3-azabicyclo [3.1.0] hexane or derivatives thereof
Background
Pharmaceutical intermediate compounds are an important supply chain link in the pharmaceutical industry, and the stability of the yield and quality of this supply chain is becoming increasingly important to the industry as a whole, especially during periods of increasing drug demand due to the prevalence of infectious diseases.
It is known that 6,6-Dimethyl-3-azabicyclo [3.1.0] hexane (6, 6-Dimethyl-3-azabicyclo [3.1.0] hexane; CAS number 943516-54-9) is an important pharmaceutical intermediate, which is an important raw material used in the synthesis of many drugs such as the hepatitis C protease inhibitor, bosaprevir, and the oral drug for the treatment of novel coronaviruses (PF-07321332).
They have the formula:
the common synthetic route of 6,6-dimethyl-3-azabicyclo [3.1.0] hexane mainly takes ethyl chrysanthemate, kungfu acid or hydroxyl protected isopentenol as raw materials, firstly synthesizes intermediate calonic anhydride, and then prepares the 6,6-dimethyl-3-azabicyclo [3.1.0] hexane through amination and reduction reaction.
Document 1 has developed a method for preparing caronic acid from hydroxyl-protected prenyl alcohol and ethyl diazoacetate, which comprises the following main steps:
the method takes isopentenol ester as a raw material, and obtains the caronic acid through cyclization reaction, hydrolysis and oxidation of diazo groups. However, the method has long reaction steps and low atom economy, and a large amount of oxidizing agent is needed to oxidize the carena aldehyde acid or carena aldehyde lactone to Cheng Kalong acid, so that the yield of cis-form products is low, and a large amount of waste water and waste salt are generated, thereby causing serious environmental pollution.
Further, document 2 discloses a synthetic route for preparing 6,6-dimethyl-3-azabicyclo [3.1.0] hexane from caronic anhydride as a starting material, as follows:
the method needs to use a large amount of expensive lithium aluminum hydride reducing agent to reduce the caronic anhydride to obtain the 6,6-dimethyl-3-azabicyclo [3.1.0] hexane, and has high production cost.
Of course, other researchers have studied the synthetic route of 6,6-dimethyl-3-azabicyclo [3.1.0] hexane and its precursor Carlongic acid (anhydride), but in view of the rapid demands of current and future hepatitis C and new coronaries, how to obtain a new method for preparing azabicyclo derivatives with environmental protection and high atom economy is a problem to be solved at present.
Citation literature:
document 1: CN104163759B
Document 2: CN101384551B
Disclosure of Invention
Problems to be solved by the invention
As previously mentioned, the prior art, while providing some synthetic routes for the preparation of 6,6-dimethyl-3-azabicyclo [3.1.0] hexane and its precursor, caronic acid (anhydride), has also found the following problems in long-term industrial synthetic practice:
in the document 1, isovalerenol or its derivative is used as a raw material, and caronic acid and caronic anhydride are prepared first and then reduced by the caronic anhydride to obtain 6,6-dimethyl-3-azabicyclo [3.1.0] hexane. The method has long reaction steps and low atom economy. A large amount of oxidizing agent is needed in the preparation of the caronic acid, a large amount of waste water and waste salt are generated, and the environmental pollution is serious; the prepared caronic acid is a cis-trans mixture, and trans-caronic anhydride needs to be isomerized into cis-caronic anhydride at high temperature, so that the steps are increased and the energy consumption is huge. In addition, two carbonyl groups of the caronic anhydride are required to be reduced, so that the consumption of the expensive lithium aluminum hydride reducing agent is greatly increased, and the production cost is high.
The use of caronic anhydride as a starting material in document 2 advantageously affords 6,6-dimethyl-3-azabicyclo [3.1.0] hexane. However, in the method, the caronic anhydride takes ethyl chrysanthemate or cyhalofop acid as raw materials, the raw materials are difficult to prepare, the production manufacturers have few and limited scales, and the synthesized caronic anhydride has high cost and cannot meet the increasing dosage requirement.
Based on the defects existing in the prior art, the invention provides a novel synthesis method of 6,6-dimethyl-3-azabicyclo [3.1.0] hexane and functional derivatives thereof. In the method, in the presence of a ligand, a high cis-selective hetero-atom bicyclic compound is obtained by utilizing intramolecular cyclization reaction, and then the target product is finally obtained through (amination reaction and reduction reaction), so that an oxidation step is omitted, and the discharge of waste water and waste salt is greatly reduced; the high cis-selectivity avoids the energy consumption of the high-temperature isomerism process of the trans-isomer; the oxidation and re-reduction process is bypassed and the amount of reducing agent is greatly reduced. The method is green, mild and high in atomic economy, is suitable for industrial mass production, and provides raw material assurance for synthesizing downstream products such as hepatitis C protease inhibitor drug compounds or drugs for treating novel coronavirus (COVID-19) and the like.
Solution for solving the problem
Through long-term and intensive researches of the inventor team, the technical problems can be solved through implementation of the following technical scheme:
[1] the invention firstly provides a synthesis method of 6,6-dimethyl-3-azabicyclo [3.1.0] hexane or a derivative thereof, wherein the method comprises the following steps:
a cyclization reaction step of subjecting the compound represented by the general formula (1) to a cyclization reaction to obtain a cyclized product represented by the compound of the general formula (2),
wherein,,
the X represents an oxygen atom or an-NH-group;
r represents a hydrogen atom or a polar group.
[2] The process according to [1], wherein the step of cyclizing reaction is carried out in the presence of a metal (salt) comprising one or more of rhodium, palladium, cobalt, copper and salts thereof and an organic ligand comprising one or more of nitrogen oxide, nitrogen polydentate ligand
[3] The method of [2], wherein the organic ligand is selected from one or more of the following general formulae La, lb, lc, ld or Le:
in the formula La, R 1 Can represent a hydrogen atom, a halogen atom, a cyano group, a nitro group, a haloalkyl group, an ester group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted aryl groupSubstituted or unsubstituted cycloalkyl; r is R 2 Represents a hydrogen atom, an alkyl group or an aryl group;
in formula Lb, Q 1 May represent a divalent linking group or a direct bond, preferably a carbonyl group, a substituted or unsubstituted alkylene group, a substituted or unsubstituted arylalkylene group, a substituted or unsubstituted arylene group, a substituted or unsubstituted cycloalkylene group, or a substituted or unsubstituted heteroarylene group;
in formula Lc, R 3 、R 4 、R 5 、R 10 Which may be the same or different, represent a hydrogen atom, a halogen atom, a cyano group, a nitro group, a haloalkyl group, an ester group, an alkoxy group having a substituent or unsubstituted, an aryloxy group having a substituent or unsubstituted, an alkyl group having a substituent or unsubstituted, an aralkyl group having a substituent or unsubstituted, an aryl group having a substituent or an cycloalkyl group having a substituent or unsubstituted;
in formula Ld, R 6 、R 7 Which may be the same or different, represent a hydrogen atom, a halogen atom, a cyano group, a nitro group, a haloalkyl group, an ester group, an alkoxy group having a substituent or unsubstituted, an aryloxy group having a substituent or unsubstituted, an alkyl group having a substituent or unsubstituted, an aralkyl group having a substituent or unsubstituted, an aryl group having a substituent or an cycloalkyl group having a substituent or unsubstituted;
in Le, R 8 、R 9 Which may be the same or different, represent a hydrogen atom, a halogen atom, a cyano group, a nitro group, a haloalkyl group, an ester group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted cycloalkyl group; q (Q) 2 May represent a divalent linking group or a direct bond, preferably a carbonyl group, a substituted or unsubstituted alkylene group, a substituted or unsubstituted arylalkylene group, a substituted or unsubstituted arylene group, a substituted or unsubstituted cycloalkylene group, or a substituted or unsubstituted heteroarylene group.
[4] The method according to any one of [1] to [3], wherein the cyclization reaction is carried out in an organic solvent; the cyclization reaction is carried out at a temperature of-10 to 120 ℃, preferably 60 to 80 ℃, for a reaction time of 2 to 64 hours, preferably 2 to 15 hours, and more preferably 2 to 6 hours.
[5] The method according to any one of [1] to [4], wherein the X is an oxygen atom, and the cyclized product is a compound represented by the general formula (2-1), and further comprising:
i) Subjecting the compound of the general formula (2-1) to an amination reaction to obtain a compound of the general formula (3); and
ii) subjecting the compound of the general formula (3) to a reduction reaction to obtain a compound of the general formula (4),
wherein R is as defined in claim 1.
[6] The method according to any one of [1] to [4], wherein the X is an-NH-group, the cyclized product is a compound represented by the general formula (3), and further comprising:
subjecting the compound of the general formula (3) to a reduction reaction to obtain a compound of the general formula (4),
wherein the definitions of the general formula (3), the general formula (4) and R are the same as defined in claim 5.
[7] The method according to any one of [1] to [6], wherein R is a hydrogen atom, a carboxylic acid (salt) group, an ester group, a halogen atom or a cyano group.
[8] Further, the invention also provides a preparation method of the drug intermediate, wherein the method comprises the synthesis method of the azabicyclo medicine intermediate according to any one of the above [1] to [7].
[9] Furthermore, the present invention also provides a process for producing a pharmaceutical compound, wherein the process comprises the process according to the above [8].
[10] The method according to [9], wherein the pharmaceutical compound comprises a hepatitis C protease inhibitor-type pharmaceutical compound or a pharmaceutical compound for treating novel coronavirus (COVID-19).
ADVANTAGEOUS EFFECTS OF INVENTION
Through implementation of the technical scheme, the invention can obtain the following technical effects:
1) The preparation method avoids the steps of hydrolysis and oxidation for preparing the caronic anhydride, greatly shortens the preparation route, reduces the mass production of industrial wastewater and waste salt, has high reaction yield, is particularly beneficial to industrialized mass production, and can meet the huge requirement of terminal drug production.
2) The intramolecular cyclization reaction catalyst adopts rhodium, palladium, cobalt, copper or copper salt and the like and ligand combination, the yield reaches 98.5 percent, and the cis-trans ratio is more than 100:1, omitting high temperature isomerization step, greatly reducing production energy consumption and simultaneously ensuring high yield of azabicyclo products.
3) The preparation method of the invention greatly reduces the dosage of the expensive catalyst in the reduction reaction process and obviously improves the economy.
4) The synthesis method provided by the invention can flexibly obtain the drug intermediates with various structures, thereby meeting different drug synthesis requirements.
Drawings
Fig. 1: synthetic reaction schemes in some embodiments of the invention.
Detailed Description
The following describes the present invention in detail. The following description of the technical features is based on the representative embodiments and specific examples of the present invention, but the present invention is not limited to these embodiments and specific examples. It should be noted that:
in the present specification, the numerical range indicated by the term "numerical value a to numerical value B" means a range including the end point numerical value A, B.
In the present specification, a numerical range indicated by "above" or "below" is a numerical range including the present number.
In the present specification, the meaning of "can" includes both the meaning of performing a certain process and the meaning of not performing a certain process.
In the present specification, the use of "optional" or "optional" means that some substances, components, steps of execution, conditions of application, and the like may or may not be used, and the manner of use is not limited.
In the present specification, unit names used are international standard unit names, and "%" used represent weight or mass% unless otherwise specified.
Reference throughout this specification to "some specific/preferred embodiments," "other specific/preferred embodiments," "an embodiment," and so forth, means that a particular element (e.g., feature, structure, property, and/or characteristic) described in connection with the embodiment is included in at least one embodiment described herein, and may or may not be present in other embodiments. In addition, it is to be understood that the elements may be combined in any suitable manner in the various embodiments.
Further, in the present specification, the following structures or substituents are to be interpreted as defined below, unless otherwise specified:
the term "alkyl" refers to an aliphatic hydrocarbon group, which may be straight or branched and includes from 1 to 20 carbon atoms in the chain. Preferred alkyl groups include 1 to 12 carbon atoms in the chain. More preferred alkyl groups include 1 to 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups, such as methyl, ethyl or propyl, are attached to a straight alkyl chain. "lower alkyl" refers to a group having 1 to 6 carbon atoms in the chain, which may be straight or branched.
The term "aryl" refers to an aromatic monocyclic or polycyclic ring system comprising 6 to 14 carbon atoms, preferably 6 to 10 carbon atoms. Non-limiting examples of suitable aryl groups include phenyl and naphthyl.
The term "aralkyl" refers to an aryl-alkyl-group, wherein aryl and alkyl are as previously described. Preferred aralkyl groups include lower alkyl groups. Non-limiting examples of suitable aralkyl groups include benzyl, 2-phenethyl, and naphthylmethyl. The bond to the parent moiety is through the alkyl group. "arylalkylene" refers to an alkylene group having an aryl substitution, preferably, the arylalkylene group comprises a lower alkylene group. And "lower alkyl" refers to an alkylene group having 1 to 6 carbon atoms in the chain, which may be straight or branched.
The term "cycloalkyl" refers to a non-aromatic mono-or polycyclic ring system comprising 3 to 10 carbon atoms, preferably 5 to 10 carbon atoms. Preferred cycloalkyl rings include 5 to 7 carbon atoms. Non-limiting examples of suitable monocyclic cycloalkyl groups include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. Non-limiting examples of suitable polycyclic cycloalkyl groups include 1-decalin, norbornyl (norbornyl), adamantyl, and the like.
The term "halogen atom" refers to fluorine, chlorine, bromine or iodine. Preferred are fluorine, chlorine or bromine, and more preferred are bromine and chlorine.
The term "substituted" means that the subject group being described may be substituted with one or more substituents, which may be the same or different, each substituent being independently selected from the group consisting of halogen atom, alkyl group, aryl group, cycloalkyl group, cyano group, hydroxy group, alkoxy group, alkylthio group, amino group, -NH (alkyl group), -NH (cycloalkyl group), -N (alkyl group) 2 Carboxyl and-C (O) O-alkyl. Also, for substitution of aryl or heteroaryl, the aryl group as a substituent may be present in a parallel ring manner. Non-limiting examples of "alkyl" groups indicated in this paragraph as substituents include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, heptyl, nonyl, decyl and cyclopropylmethyl.
The invention provides a synthesis method of 6,6-dimethyl-3-azabicyclo [3.1.0] hexane or a derivative thereof, which is characterized in that a hetero-atom bicyclic compound is constructed by cyclizing a diazo group in a molecule and an alkene bond, and a target product is finally obtained through (amination reaction and reduction reaction). Among them, 6-dimethyl-3-azabicyclo [3.1.0] hexane or a derivative thereof can be used as an intermediate in pharmaceutical synthesis.
In the present invention, the derivative of 6,6-dimethyl-3-azabicyclo [3.1.0] hexane refers to a case where the substituent R is changed as described below and the substituent R is changed to another substituent through a chemical reaction.
In particular, the synthetic method of the present invention comprises, in a first aspect, a step of cyclisation, and the cyclisation is essentially a cyclopropanation of a diazo group with an olefinic bond. The cyclopropanation reaction is typically a bond between a carbon attached to a diazo group and two carbons of an olefinic bond to form a three-carbon ring structure having a cyclopropane shape.
In the present invention, the cyclizing reaction is carried out on a compound represented by the general formula (1) as a starting material to obtain a cyclized product represented by the compound of the general formula (2),
wherein X represents an oxygen atom or an-NH-group. R represents a hydrogen atom or a polar group, and the polar group is preferably selected from a carboxylic acid (salt) group, an ester group, a halogen atom or a cyano group. And, more preferably, the R is a hydrogen atom, a formic acid (salt) group or an ester group of formic acid with an alkyl group, a substituted alkyl group, an aryl group, a substituted aryl group, an aralkyl group or a substituted aralkyl group, a cycloalkyl group or a substituted cycloalkyl group.
In some preferred embodiments of the present invention, the compound of formula (1) has the structure of the formula:
further, the compounds of the respective structures described above can be obtained commercially or synthesized in the laboratory, and for example, the respective compounds described above can be obtained by diazotization reaction (nitrite, acidic condition) using (primary) glycine ester having a double bond in the ester moiety.
Further, in some specific embodiments, the cyclization reaction of the present invention is carried out in the presence of a catalyst and a solvent; in other specific embodiments, the cyclization reaction of the present invention may be carried out under microwave irradiation conditions.
In some specific embodiments, the catalyst comprises rhodium, palladium, cobalt, copper, and like metals (salts) and organic ligands.
For the metal (salt), it includes one or more of a metal, an inorganic acid salt of a metal, an organic acid salt of a metal, and a halide of a metal. In some embodiments of the invention, at least copper or copper salts are included. Further, the copper salt of the present invention is selected from one or more of cuprous chloride, cuprous bromide, cuprous iodide, cuprous triflate, cupric sulfate, cupric acetate, cupric triflate and cupric chloride, preferably, the copper salt is selected from one or more of cuprous chloride, cuprous triflate, cupric sulfate, cupric triflate and cupric chloride. In addition, the metal (salt) may include other metals or metal salts, such as rhodium, ruthenium, and the like, in addition to the copper (salt) component described above.
For organic ligands, the organic ligands described herein include one or more of nitroxide, nitroxide polydentate ligands.
For nitrogen-oxygen, nitrogen-nitrogen polydentate ligands, coordination to the metal is typically achieved through nitrogen and/or oxygen in the aromatic heterocycle. The organic ligand is selected from one or more of the following general formulas La, lb, lc, ld or Le:
in the formula La, R 1 Can represent a hydrogen atom, a halogen atom, a cyano group, a nitro group, a haloalkyl group, an ester group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted cycloalkyl group; r is R 2 Represents a hydrogen atom, an alkyl group or an aryl group;
in formula Lb, Q 1 May represent a divalent linking group or a direct bond, preferably a carbonyl group, a substituted or unsubstituted alkylene group, a substituted or unsubstituted arylalkylene group, a substituted or unsubstituted arylene group, a substituted or unsubstituted cycloalkylene group, or a substituted or unsubstituted heteroarylene group;
in formula Lc, R 3 、R 4 、R 5 、R 10 Which may be the same or different, represent a hydrogen atom, a halogen atom, a cyano group, a nitro group, a haloalkyl group, an ester group, an alkoxy group having a substituent or unsubstituted, an aryloxy group having a substituent or unsubstituted, an alkyl group having a substituent or unsubstituted, an aralkyl group having a substituent or unsubstituted, an aryl group having a substituent or an cycloalkyl group having a substituent or unsubstituted;
in formula Ld, R 6 、R 7 Which may be the same or different, represent a hydrogen atom, a halogen atom, a cyano group, a nitro group, a haloalkyl group, an ester group, an alkoxy group having a substituent or unsubstituted, an aryloxy group having a substituent or unsubstituted, an alkyl group having a substituent or unsubstituted, an aralkyl group having a substituent or unsubstituted, an aryl group having a substituent or an cycloalkyl group having a substituent or unsubstituted;
in Le, R 8 、R 9 Which may be the same or different, represent a hydrogen atom, a halogen atom, a cyano group, a nitro group, a haloalkyl group, an ester group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted cycloalkyl group; q (Q) 2 May represent a divalent linking group or a direct bond, preferably a carbonyl group, a substituted or unsubstituted alkylene group, a substituted or unsubstituted arylalkylene group, a substituted or unsubstituted arylene group, a substituted or unsubstituted cycloalkylene group, or a substituted or unsubstituted heteroarylene group.
In some specific embodiments of the invention, for ligands of the general formula La, organic compounds of the following structure may be employed:
for the ligand of the general formula Lb, an organic compound of the following structure may be employed:
for the ligand of the general formula Lc, organic compounds of the following structure may be employed:
for the ligand of the general formula Ld, an organic compound of the following structure may be employed:
for ligands of the general formula Le, organic compounds of the following structure can be employed:
further, from the viewpoint of increasing the yield of the cyclized product and increasing the cis-to-trans ratio of the cyclized product, the preferable organic ligand may be any one or more of the following L1 to L3:
the ratio of organic ligand to metal (salt) used in the catalyst may be in some embodiments (molar ratio) 1 to 5:1, preferably 2 to 3:1. The ratio of the metal (salt) to the compound of formula (1) may be 0.1:1 or less, preferably 0.01 to 0.09:1, and more preferably 0.02 to 0.08:1.
Further, the cyclization reaction is carried out in the presence of an organic solvent, and the kind of the organic solvent is not particularly limited in principle, as long as it is an organic solvent that does not significantly affect the stability of the diazonium structure. In some preferred embodiments, the organic solvent is selected from one or more of aromatic solvents, halogenated hydrocarbon solvents, sulfone solvents, amide solvents, acetonitrile, and the like; more preferably, one or more selected from Toluene (tolene), dichloroethane (DCE), dimethyl sulfoxide (DMSO), dimethylformamide (DMF), acetonitrile may be used.
For the cyclization reaction conditions, in some specific embodiments of the present invention, after the catalyst is dissolved using a solvent in the cyclization reaction, the compound of formula (1) is added, preferably, the compound of formula (1) is added dropwise or a solution in which the compound of formula (1) is dissolved is added to ensure the safety and yield of the reaction. The cyclization reaction of the present invention may be preferably carried out under the protection of an inert gas, which may be nitrogen, argon or a mixture thereof. For reaction temperatures and reaction times, in some specific embodiments, the cyclization reaction temperature is from-10 to 120 ℃, preferably from 60 to 80 ℃, and the reaction time is from 2 to 64 hours, preferably from 2 to 15 hours, more preferably from 2 to 6 hours.
Further, other control conditions for the cyclization reaction are not particularly limited, but it is preferable to perform auxiliary measures such as mechanical stirring or magnetic stirring at the same time as the reaction.
In the present invention, the compound having the structure of the above general formula (2) can be obtained by the cyclization reaction. In some preferred embodiments, the yield of the cyclization reaction of the present invention may be 75% or more, preferably 80% or more, more preferably 90% or more. And the cis-to-trans ratio (dr value) of the compound of the general formula (2) is more than 100:1, and the selectivity is high.
In addition, for the purification of the cyclization reaction product, the product is typically separated and purified by means of distillation under reduced pressure or the like.
After obtaining the compound of formula (2), the specific species of the intermediate X atom according to formula (2) is subjected to the subsequent synthesis steps.
In some specific embodiments of the present invention, formula (2) has the structure of formula (2-1),
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furthermore, the synthesis method of the invention further comprises the following steps:
i) Amination of the compound of formula (2-1) to give a compound of formula (3); and
ii) subjecting the compound of the general formula (3) to a reduction reaction to obtain a compound of the general formula (4),
wherein R is as defined in the general formula (1).
In step i, specific conditions for the amination reaction are not particularly limited, and those conventionally used in the art can be employed.
In some specific embodiments of the present invention, the amination reaction is carried out with an alcoholic solvent of ammonia gas, and methanol is preferred for the alcoholic solvent from the viewpoint of convenience.
Typically, the compound of the general formula (2-1) may be dissolved in an alcohol solvent, and an ammonia-alcohol reagent may be added thereto, and the reaction may be carried out at a temperature of not higher than 10 ℃, preferably-10 to 5 ℃, more preferably-5 to 0 ℃, for a period of time not particularly limited, and may be 1 to 3 hours.
Further, after the reaction in step i is completed, the product of the structure of the general formula (3) can be separated by means of reduced pressure distillation.
In step ii, the carbonyl structure of formula (3) is reduced. For the reduction reaction, it is possible to carry out with the aid of a solvent and a reducing agent. As the solvent, an aprotic solvent such as one or more of an ester-based solvent, an amide-based solvent, an ether-based solvent, a cyclic ether-based solvent, a ketone-based solvent, a sulfone-based solvent, an aromatic hydrocarbon-based solvent, and the like; preferably, one or more of tetrahydrofuran, 1, 4-dioxane, diethyl ether, benzene, toluene, ethylene glycol dimethyl ether may be used. As the reducing agent, at least one selected from lithium aluminum hydride, sodium borohydride/boron trifluoride diethyl ether, borane, sodium 2-hydrobis (dimethoxyethoxy) aluminate, and more preferably, the reducing agent is lithium aluminum hydride or sodium borohydride/boron trifluoride diethyl ether. In some specific embodiments of the present invention, lithium aluminum hydride may be used as a catalyst. The other reaction conditions in step ii are not particularly limited, and those commonly used in the art for reduction reactions can be employed. In a typical manner, for example, the molar ratio of lithium aluminum hydride to the compound of formula (3) in the reduction reaction is from 1 to 4:1, the reaction time is 2-3 hours, and the reaction temperature is-5-10 ℃. After the reaction is finished, the final product represented by the general formula (4) can be obtained by split-phase extraction and reduced pressure distillation.
In addition, in the case where R is a polar group, the step ii of the present invention is particularly preferably carried out in such a manner that R is a hydrogen atom, and if necessary, R may be temporarily protected with an optional protecting group or the carbonyl group may be reduced by another reducing means.
In some specific embodiments, the overall yield of steps i and ii may be above 90%.
In other specific embodiments of the present invention, the general formula (2) as a cyclized product has the structure of the general formula (3), and then in the subsequent reaction after the cyclizing reaction, the above-mentioned step ii may be directly performed to obtain the final product represented by the final general formula (4).
Further, a typical synthetic route of the present invention is illustrated in FIG. 1:
taking diazoacetic acid (2-methyl-2-butene) ester as a raw material, preparing an intermediate formula a through intramolecular cyclization reaction, and obtaining a product 6,6-dimethyl-3-azabicyclo [3.1.0] hexane through amination and reduction reaction of the intermediate formula a;
or, taking diazo (2-methyl-2-butene) acetamide as a raw material, preparing an intermediate b through intramolecular cyclization reaction, and obtaining a product 6,6-dimethyl-3-azabicyclo [3.1.0] hexane through one-step acylation reduction reaction of the intermediate b.
Further, by adjusting the substituents of R in the general formula (1) as starting materials according to the present invention, the present invention can yield various pharmaceutical intermediates, typically:
when R is hydrogenWhen the compound represented by the following formula (A) is obtained; when R is an ester group, a compound of the following formula (B) can be obtained. And, it goes without saying that when R is changed to another polar group (for example-CN, as in the compound of formula (C)). R can also be changed to the desired other radicals R by subsequent arbitrary chemical processes 1 (R 1 May be a pharmaceutically active group), the kind and manner of change of which are not particularly limited, for example, the compound of formula B may also be obtained by subsequent treatment of the-CN group in the compound of formula C.
Further, based on the novel synthesis method provided by the invention, the production of related drug intermediates can be provided with high efficiency, and the method can be used as an intermediate synthesis step in drug synthesis.
Meanwhile, the synthesis method of the invention can also provide improved environment protection and synthesis flexibility, and is particularly suitable for providing stable and high-yield raw material supply in the pharmaceutical synthesis industry.
In addition, the pharmaceutical intermediates provided by the synthesis method of the invention can be used for preparing pharmaceutical compounds including hepatitis C protease inhibitor or pharmaceutical compounds for treating novel coronavirus (COVID-19).
Examples
Hereinafter, the present invention will be further described by way of specific examples.
(source of raw materials)
The compound diazoacetic acid (2-methyl-2-butene) ester (self-made):
the compound diazo (2-methyl-2-butene) acetamide (homemade):
(intermediate a configuration):
cis structure
Trans structure
(intermediate b configuration):
cis structure
Trans structure
Example 1 (preparation of intermediate formula a)
Into a 200mL flask was added 196mg of cuprous chloride, 680mg of ligand L1 and 100mL of dichloroethane solution, stirred at room temperature for 1h, warmed to 75℃and slowly added dropwise 15.4g
Compound 3h, after the reaction, the product intermediate formula a is distilled off under reduced pressure, the yield is 93.1%, and the ratio of cis to trans is greater than 100:1.
examples 2 to 14(preparation of intermediate formula a)
The difference from example 1 is that the reaction parameters are controlled differently, and the specific reaction parameters and reaction effects are shown in Table 1.
Example 15
12.6g of intermediate formula a prepared in example 1 was dissolved in methanol, 100mL of 5mol/L methanolic ammonia solution was added, and stirred at 0deg.C for 1h to yield intermediate formula b, and the solution was directly distilled under reduced pressure to obtain 12g of crude product. To the crude product, 150mL of tetrahydrofuran solution was added 7.6g of lithium aluminum hydride at 0deg.C, stirred for 2 hours, after the reaction was completed, 200mL of ethyl acetate was added to quench the reaction, 50mL of water was added, the layers were separated by extraction, and the organic phases were combined, and the organic phase was distilled under reduced pressure to obtain 10.1g of the compound of the formula A as a product, and the total yield of the two steps was 91.0%.
Example 16
Into a 200mL flask was added 196mg of cuprous chloride, 680mg of ligand L1 and 100mL of dichloroethane solution, stirred at room temperature for 1h, warmed to 75℃and slowly added dropwise 15.2g
Compound 3h, after the reaction, the intermediate compound b is distilled off under reduced pressure, the product yield is 92.8%, and the ratio of cis to trans is more than 100:1.
adding 150mL of tetrahydrofuran solution into 12.5g of the intermediate formula b prepared in the previous step; 7.6g of lithium aluminum hydride is added at 0 ℃, stirring is carried out for 2 hours, 200mL of ethyl acetate is added after the reaction is finished, quenching reaction is carried out, 50mL of water is added, the layers are extracted and combined with an organic phase, and 10.3g of the compound of the formula A is obtained by reduced pressure distillation, and the yield is 92.7%.
TABLE 1 reaction parameters (examples 1-14)
It should be noted that, although the technical solution of the present invention is described in specific examples, those skilled in the art can understand that the present disclosure should not be limited thereto.
The foregoing description of the embodiments of the present disclosure has been presented for purposes of illustration and description, and is not intended to be exhaustive or limited to the embodiments disclosed. Many modifications and variations will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the various embodiments described. The terminology used herein was chosen in order to best explain the principles of the embodiments, the practical application, or the improvement of technology in the marketplace, or to enable others of ordinary skill in the art to understand the embodiments disclosed herein.
Industrial applicability
The synthesis method provided by the invention can be used for industrially preparing the medical intermediate compound.
Claims (3)
1. A process for the preparation of an azabicyclo pharmaceutical intermediate, comprising:
a cyclization reaction step of subjecting the compound represented by the general formula (1) to a cyclization reaction to obtain a cyclized product represented by the compound of the general formula (2),
wherein,,
the X represents an oxygen atom or an-NH-group;
r represents a hydrogen atom, and:
(1) in the case where X is an oxygen atom, the cyclized product is a compound represented by the general formula (2-1), and further, the method further comprises:
i) Subjecting the compound of the general formula (2-1) to an amination reaction to obtain a compound of the general formula (3); and
ii) subjecting the compound of the general formula (3) to a reduction reaction to obtain a compound of the general formula (4),
(2) the cyclized product is a compound represented by the general formula (3) under the condition that X is an-NH-group, and further, the method further comprises:
subjecting the compound of formula (3) to a reduction reaction to obtain a compound of formula (4), the step of cyclizing reaction being carried out in the presence of a metal/metal salt comprising one or more of rhodium, palladium, cobalt, copper and salts thereof and an organic ligand
One or more of the general formulae La selected from:
in the formula La, R 1 Represents a hydrogen atom, a halogen atom, a cyano group, a nitro group, a haloalkyl group, an ester group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted cycloalkyl group; r is R 2 Represents a hydrogen atom, an alkyl group or an aryl group.
2. The process according to claim 1, characterized in that the cyclisation reaction is carried out in an organic solvent; the temperature of the cyclization reaction is-10-120 ℃ and the reaction time is 2-64 hours.
3. The process according to claim 1 or 2, wherein the cyclisation reaction is carried out at a temperature of 60 to 80 ℃ for a reaction time of 2 to 15 hours.
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| CN114591217B (en) * | 2022-03-18 | 2024-04-16 | 浙江新和成股份有限公司 | Preparation method of 6, 6-dimethyl-3-azabicyclo- [3.1.0] -hexane and lactone intermediate thereof |
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| CN114605311B (en) * | 2022-05-16 | 2022-07-15 | 南京桦冠生物技术有限公司 | Process for the preparation of intermediates of the drug nitratrelvir useful in the treatment of novel coronaviruses |
| CN115043772B (en) * | 2022-05-27 | 2024-03-15 | 浙江新和成股份有限公司 | Preparation method of 6, 6-dimethyl-3-azabicyclo- [3.1.0] -hexane |
| CN115304537B (en) * | 2022-08-16 | 2024-06-14 | 北京京宇复瑞科技集团有限责任公司 | Method for preparing 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane |
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