CN114539125A - 一种帕西洛韦中间体的合成方法 - Google Patents
一种帕西洛韦中间体的合成方法 Download PDFInfo
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- CN114539125A CN114539125A CN202210215353.8A CN202210215353A CN114539125A CN 114539125 A CN114539125 A CN 114539125A CN 202210215353 A CN202210215353 A CN 202210215353A CN 114539125 A CN114539125 A CN 114539125A
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- butoxide
- sodium
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- 238000010189 synthetic method Methods 0.000 title abstract description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 28
- 238000000034 method Methods 0.000 claims abstract description 27
- -1 S-substituted sulfinamide Chemical class 0.000 claims abstract description 18
- 230000009471 action Effects 0.000 claims abstract description 11
- 239000003513 alkali Substances 0.000 claims abstract description 11
- 230000006698 induction Effects 0.000 claims abstract description 8
- 150000001242 acetic acid derivatives Chemical class 0.000 claims abstract description 6
- 238000006722 reduction reaction Methods 0.000 claims abstract description 5
- 230000007704 transition Effects 0.000 claims abstract description 4
- 125000006239 protecting group Chemical group 0.000 claims abstract description 3
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 13
- SSKYNJZREFFALT-ZLUOBGJFSA-N (1r,2s,5s)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid Chemical compound C1N[C@H](C(O)=O)[C@H]2C(C)(C)[C@H]21 SSKYNJZREFFALT-ZLUOBGJFSA-N 0.000 claims description 8
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 8
- JMXKSZRRTHPKDL-UHFFFAOYSA-N titanium ethoxide Chemical compound [Ti+4].CC[O-].CC[O-].CC[O-].CC[O-] JMXKSZRRTHPKDL-UHFFFAOYSA-N 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- 239000003638 chemical reducing agent Substances 0.000 claims description 6
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 4
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims description 4
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 4
- JILPJDVXYVTZDQ-UHFFFAOYSA-N lithium methoxide Chemical compound [Li+].[O-]C JILPJDVXYVTZDQ-UHFFFAOYSA-N 0.000 claims description 4
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 claims description 4
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 claims description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 4
- 239000012279 sodium borohydride Substances 0.000 claims description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 4
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 4
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 claims description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- RWFNAAZDBOSSIY-YCLXABBFSA-N (1r,2s,5s)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid;hydrochloride Chemical compound Cl.C1N[C@H](C(O)=O)[C@H]2C(C)(C)[C@H]21 RWFNAAZDBOSSIY-YCLXABBFSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 229910000085 borane Inorganic materials 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- YHWCPXVTRSHPNY-UHFFFAOYSA-N butan-1-olate;titanium(4+) Chemical compound [Ti+4].CCCC[O-].CCCC[O-].CCCC[O-].CCCC[O-] YHWCPXVTRSHPNY-UHFFFAOYSA-N 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 229910000365 copper sulfate Inorganic materials 0.000 claims description 2
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims description 2
- 238000010511 deprotection reaction Methods 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- ITNVWQNWHXEMNS-UHFFFAOYSA-N methanolate;titanium(4+) Chemical compound [Ti+4].[O-]C.[O-]C.[O-]C.[O-]C ITNVWQNWHXEMNS-UHFFFAOYSA-N 0.000 claims description 2
- 125000003107 substituted aryl group Chemical group 0.000 claims description 2
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 claims description 2
- 235000005074 zinc chloride Nutrition 0.000 claims description 2
- 239000011592 zinc chloride Substances 0.000 claims description 2
- 239000000543 intermediate Substances 0.000 abstract description 25
- 238000002360 preparation method Methods 0.000 abstract description 10
- 238000005265 energy consumption Methods 0.000 abstract description 4
- LIENCHBZNNMNKG-OJFNHCPVSA-N nirmatrelvir Chemical compound CC1([C@@H]2[C@H]1[C@H](N(C2)C(=O)[C@H](C(C)(C)C)NC(=O)C(F)(F)F)C(=O)N[C@@H](C[C@@H]3CCNC3=O)C#N)C LIENCHBZNNMNKG-OJFNHCPVSA-N 0.000 abstract description 3
- 229940125675 paxlovid Drugs 0.000 abstract description 3
- OIUKJBJURCIFTN-UHFFFAOYSA-N 3,3-dimethyl-4-oxobutanoic acid Chemical compound O=CC(C)(C)CC(O)=O OIUKJBJURCIFTN-UHFFFAOYSA-N 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 238000001308 synthesis method Methods 0.000 description 4
- 230000002194 synthesizing effect Effects 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- FKVUDBWXNAFSPB-MKXDVQRUSA-N methyl (1r,2s,5s)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate;hydrochloride Chemical compound Cl.COC(=O)[C@H]1NC[C@@H]2C(C)(C)[C@H]12 FKVUDBWXNAFSPB-MKXDVQRUSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- JZHLPJFZVKRSHW-UHFFFAOYSA-N ethyl 3,3-dimethyl-4-oxobutanoate Chemical compound CCOC(=O)CC(C)(C)C=O JZHLPJFZVKRSHW-UHFFFAOYSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- VKJVXYWGRYQADR-UHFFFAOYSA-N s-tert-butylthiohydroxylamine Chemical group CC(C)(C)SN VKJVXYWGRYQADR-UHFFFAOYSA-N 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- CESUXLKAADQNTB-UHFFFAOYSA-N tert-butanesulfinamide Chemical group CC(C)(C)S(N)=O CESUXLKAADQNTB-UHFFFAOYSA-N 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- LMSDLVWKLIICSU-MTICXXPYSA-N (2S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide hydrochloride Chemical compound CCCC([C@@H](C(=O)NC1CC1)O)N.Cl LMSDLVWKLIICSU-MTICXXPYSA-N 0.000 description 1
- HEMYJVAMSVISRT-UHFFFAOYSA-N 6,6-dimethyl-3-azabicyclo[3.1.0]hexane;hydrochloride Chemical compound Cl.C1NCC2C(C)(C)C21 HEMYJVAMSVISRT-UHFFFAOYSA-N 0.000 description 1
- 101710134784 Agnoprotein Proteins 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 1
- 208000005176 Hepatitis C Diseases 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229960000517 boceprevir Drugs 0.000 description 1
- LHHCSNFAOIFYRV-DOVBMPENSA-N boceprevir Chemical compound O=C([C@@H]1[C@@H]2[C@@H](C2(C)C)CN1C(=O)[C@@H](NC(=O)NC(C)(C)C)C(C)(C)C)NC(C(=O)C(N)=O)CC1CCC1 LHHCSNFAOIFYRV-DOVBMPENSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000011217 control strategy Methods 0.000 description 1
- 238000005888 cyclopropanation reaction Methods 0.000 description 1
- VEUUMBGHMNQHGO-UHFFFAOYSA-N ethyl chloroacetate Chemical compound CCOC(=O)CCl VEUUMBGHMNQHGO-UHFFFAOYSA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- BYRPTKZOXNFFDB-UHFFFAOYSA-N lithium;bis(trimethylsilyl)azanide;oxolane Chemical compound [Li+].C1CCOC1.C[Si](C)(C)[N-][Si](C)(C)C BYRPTKZOXNFFDB-UHFFFAOYSA-N 0.000 description 1
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- USHAGKDGDHPEEY-UHFFFAOYSA-L potassium persulfate Chemical compound [K+].[K+].[O-]S(=O)(=O)OOS([O-])(=O)=O USHAGKDGDHPEEY-UHFFFAOYSA-L 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 238000003756 stirring 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
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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C313/00—Sulfinic acids; Sulfenic acids; Halides, esters or anhydrides thereof; Amides of sulfinic or sulfenic acids, i.e. compounds having singly-bound oxygen atoms of sulfinic or sulfenic groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C313/02—Sulfinic acids; Derivatives thereof
- C07C313/06—Sulfinamides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D203/00—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom
- C07D203/04—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D203/06—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D203/22—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
- C07D203/24—Sulfur atoms
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Indole Compounds (AREA)
Abstract
本发明公开了一种帕西洛韦(Paxlovid)中间体的合成方法，涉及化学药物中间体技术领域。包括如下步骤：3,3‑二甲基‑4‑氧代丁酸酯与S‑取代亚磺酰胺反应生成化合物C‑1；化合物C‑1和单卤素取代乙酸酯在强碱作用下反应，利用S‑取代亚磺酰胺手性诱导，得到化合物C‑2；化合物C‑2在强碱作用下形成过渡态中间体化合物C‑3，进一步在强碱作用下和S‑取代亚磺酰手性诱导下，生成化合物C‑4；化合物C‑4脱保护基得化合物C‑5；化合物C‑5经还原反应得帕西洛韦中间体。本发明的方法原料低价易得、能耗低、制备简单、安全性高且降低了因手性拆分导致的损失。
Description
技术领域
本发明涉及化学药物中间体技术领域，具体涉及一种帕西洛韦(Paxlovid)中间体的合成方法。
背景技术
化合物(1R,2S,5S)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2-羧酸甲酯盐酸盐用式(A)表示，是合成新冠抗病毒口服药帕西洛韦(Paxlovid)和丙型肝炎蛋白酶抑制剂波普瑞韦重要的中间体，由(1R,2S,5S)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2-羧酸甲酯盐酸盐合成帕西洛韦，具有操作简单、利于工业化生产等特点。该中间体结构式如下：
PCT国际专利申请WO2004/113295公开了一种(1R,2S,5S)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2-羧酸甲酯盐酸盐的合成方法，其具体合成路线如下：
其中，R2为氢或乙烷。虽然该方法合成了帕西洛韦中间体(S)-3-氨基-N-环丙基-2-羟基己酰胺盐酸盐，但是该合成过程中使用昂贵的钯碳催化剂和比较危险的氢化铝锂还原剂，在工业化生产中安全性是很大的挑战，而且反应需要使用特殊设备，导致生产成本较高，能耗和设备的占用率高。此外，该合成方法的步骤极其繁琐，反应时间较长，不仅增大了生产成本和后处理成本，还严重影响最终产物的收率和纯度。
PCT国际专利申请WO2007/075790公开了一种(1R,2S,5S)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2-羧酸甲酯盐酸盐的合成方法，其具体合成路线如下：
虽然该方法合成过程中同样使用了昂贵的催化剂钯碳、箔碳和AgNO3，和采用了强氧化剂过硫酸钾和危险的氢化铝锂还原剂。反应时对设备需要有特殊要求，此外该合成方法的步骤繁琐，反应时间较长，如最后一步就需要在烘干箱中处理3天左右，该方法对化合物的手性无法控制，需要手性拆分，增加操作步骤，还严重影响产品的收率和生产成本。
中国专利公开号CN103435532B公开了一种(1R,2S,5S)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2-羧酸甲酯盐酸盐的合成方法，其具体合成路线如下：
该方法采用6,6-二甲基-3-氮杂双环[3.1.0]己烷盐酸盐为原料，难以获得，价格高。反应中使用了极易燃的仲丁基锂，危险性较高。最后一步使用了腐蚀性较大的二氯亚砜，对设备有较高的防腐要求。该路线并无手性控制的策略，通过手性拆分，增加操作步骤，还严重影响产品的收率和生产成本。
因此，针对现有技术中存在的上述问题，本发明提供一种原料低价易得、能耗低、制备简单、安全性高且降低因手性拆分导致的损失的制备方法。
发明内容
本发明的目的是提供(1R,2S,5S)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2-羧酸酯的制备方法，以3,3-二甲基-4-氧代丁酸乙酯为起始原料，引入S-叔丁基亚磺酰胺基团，在合成桥环结构的过程中，S-叔丁基亚磺酰胺基团能够诱导作用，选择性合成所需的对映异构体，避免了现有合成方法中因手性拆分导致的损失。
为实现上述发明目的，本发明的技术方案如下：
一种(1R,2S,5S)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2-羧酸酯的制备方法，包括如下步骤：
(1)3,3-二甲基-4-氧代丁酸酯与S-取代亚磺酰胺反应生成化合物C-1；
(2)化合物C-1和单卤素取代乙酸酯在强碱作用下反应，利用S-取代亚磺酰胺手性诱导，得到化合物C-2；
(3)化合物C-2在强碱作用下形成过渡态中间体化合物C-3，进一步在强碱作用下和S-取代亚磺酰手性诱导下，生成化合物C-4；
(4)化合物C-4脱保护基得化合物C-5；
(5)化合物C-5经还原反应得(1R,2S,5S)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2-羧酸酯，
优选地，R1、R3各自独立的选自脂肪烃或芳香烃；进一步优选为烷基，最优选为乙基。
优选地，R2选自烷基、芳基、取代芳基中的任一种；进一步优选为C2-6烷基、苯基、取代苯基中的任一种；更进一步优选为丁基，最优选为叔丁基。
优选地，步骤(1)中，需要加入催化剂，所述催化剂选自硫酸铜，四氯化钛，钛酸四甲酯，钛酸四乙酯，钛酸四异丙酯，钛酸四丁酯，氯化锌，氯化铝中的一种或几种；最优选为钛酸四乙酯。
优选地，步骤(2)中，所述单卤素取代乙酸酯中的卤素为氯或溴，进一步优选为氯。
优选地，步骤(2)中，所述强碱选自叔丁醇钠，叔丁醇钾，乙醇钠，乙醇钾，甲醇钠，甲醇钾，LDA，正丁基锂，甲醇锂，叔丁醇锂，LiHMDS中的一种；最优选为LiHMDS。
在步骤(2)中，利用强碱拔去单卤素取代的乙酸酯上的氢，加成到中间体C-1的碳氮双键上，形成氮杂三元环，并利用S-取代亚磺酰胺手性诱导三元环上两个叔碳的手性。
优选地，步骤(3)中，所述强碱选自叔丁醇钠，叔丁醇钾，乙醇钠，乙醇钾，甲醇钠，甲醇钾，LDA，正丁基锂，甲醇锂，叔丁醇锂，LiHMDS中的一种；最优选为叔丁醇钠。
在步骤(3)中，中间体C-2在强碱拔氢作用下，氮杂三元环打开，环丙烷化形成过渡态中间体C-3，进一步在强碱作用下关上五元环，并利用S-取代亚磺酰手性诱导作用，控制五元环上的立体构型。
优选地，步骤(4)中，所述脱保护基通过加酸实现，进一步优选的，所述酸选自硫酸，盐酸，磷酸，三氟乙酸，甲磺酸，对甲苯磺酸中的一种或几种；最优选为盐酸。
优选地，步骤(5)中，所述还原反应需要加入还原剂，所述还原剂选自氢化锂铝，硼烷，硼氢化钠中的一种；最优选为硼氢化钠。
优选地，步骤(5)中，(1R,2S,5S)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2-羧酸酯再经盐酸成盐步骤得到(1R,2S,5S)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2-羧酸酯盐酸盐。
本发明的有益效果为：
(1)所用原料为3,3-二甲基-4-氧代丁酸酯，原料廉价，合成简单易操作；所用的试剂均为常规试剂，并未使用昂贵的以及需要特殊设备的试剂，能耗低，生产成本低；
(2)利用S-取代亚磺酰手性诱导作用，实现手性控制，在合成桥环结构的过程中，S-叔丁基亚磺酰胺基团能够诱导作用，选择性合成所需的对映异构体。避免了现有合成方法中因手性拆分导致的损失；
(3)该方法制备的(1R,2S,5S)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2-羧酸酯立体选择性高、收率好。
具体实施方式
为了使本发明实现的技术手段、创作特征、达成目的与功效易于明白了解，下面结合具体实施例，进一步阐明本发明，但下述实施例仅为本发明的优选实施例，并非全部。基于实施方式中的实施例，本领域技术人员在没有做出创造性劳动的前提下所获得其它实施例，都属于本发明的保护范围。下述实施例中，若无特殊说明，所用的操作方法均为常规操作方法，所用设备均为常规设备，各个实施例所用设备材料均相同。
下述实施例中，所用原料3,3-二甲基-4-氧代丁酸乙酯由文献(Reissig H U,ReicheltI,Kunz T.Methoxycarbonylmethylation of Aldehydes viaSiloxycyclopropanes:Methyl 3,3-Dimethyl-4-Oxobutanoate[M].John Wiley&Sons,Inc.2003.)所述方法合成。
本发明制备路径如下：
实施例1中间体C-1的制备
将3,3-二甲基-4-氧代丁酸乙酯(10.3g，65mmol)溶于100mL二氯甲烷中，加入叔丁基亚磺酰胺(15.6g，129mmol)，滴加钛酸四乙酯(17.6g，77mmol)，25℃搅拌反应，TLC监测反应进程。反应结束后，向反应瓶内加入100mL水淬灭反应。过滤，滤液分层，弃水相。有机相浓缩，硅胶柱层析纯化得15.47g中间体C-1，纯度95.3％，收率91.1％。
1H-NMR(CDCl3，400MHz)：δ4.11(q,J＝7.2Hz,2H),2.62-2.50(m,2H),1.34(s,3H),1.32(s,3H),1.29(t,J＝7.2Hz,3H),1.25(s,9H)ppm.
实施例2中间体C-2的制备
向100ml三口瓶中加入氯乙酸乙酯(1.5g，12.5mmol)，氮气置换三次，加入干燥的四氢呋喃40mL，冷却至-78℃。缓慢滴加1M双三甲基硅基胺基锂四氢呋喃溶液(12.5mL，12.5mmol)，-78℃搅拌十分钟。中间体C-1(1.3g，5mmol)溶解于3mL四氢呋喃中，缓慢注射至反应液中。加料完毕后-78℃搅拌2小时。向反应液加水淬灭，乙酸乙酯萃取，干燥、浓缩有机相，硅胶柱层析纯化得到1.55g浅黄色油状物C-2，纯度91.2％，收率89.3％。
1H-NMR(CDCl3，400MHz)：δ4.30-4.11(m,4H),2.90-2.82(m,2H),2.37-2.23(m,2H),1.40(s,9H),1.36(s,3H),1.32(s,3H),1.31-1.22(m,6H)ppm.
实施例3中间体C-4的制备
向100ml单口瓶中加入30ml四氢呋喃，中间体C-2(1.7g，5mmol)和叔丁醇钠(960mg，10mmol)室温搅拌3小时。向反应液加水淬灭，乙酸乙酯萃取，干燥、浓缩有机相，硅胶柱层析纯化得到1.1g浅黄色油状物C-4，纯度92.4％，收率73.3％。
1H-NMR(CDCl3，400MHz)：δ4.16(q,J＝7.2Hz,2H),3.13-3.06(m,1H),2.21-2.12(m,1H),1.62-1.54(m,1H),1.36(s,9H),1.32(t,J＝7.2Hz,3H),1.25(s,3H),1.23(s,3H)ppm.
实施例4中间体C-5的制备
将中间体C-4(0.3g，1mmol)溶解于3mL 1,4-二氧六环中，加入1M氯化氢的1,4-二氧六环溶液(2mL，2mmol)，室温搅拌3小时。加入碳酸氢钠溶液中和，乙酸乙酯萃取。干燥、浓缩有机相，硅胶柱层析纯化得到177mg中间体C-5，纯度94.9％，收率89.8％。
1H-NMR(CDCl3，400MHz)：δ4.11(q,J＝7.2Hz,2H),3.22-3.11(m,1H),2.23-2.15(m,1H),1.66-1.59(m,1H),1.34(t,J＝7.2Hz,3H),1.26(s,3H),1.23(s,3H)ppm.
实施例5中间体C-6的制备
将中间体C-5(2g，10mmol)溶解于30mL乙醇中，加入硼氢化钠(450mg，12mmol)，加热回流搅拌7小时。稀盐酸调节至中性，乙酸乙酯萃取，有机相浓缩干。浓缩物溶解于1mL30％氯化氢乙醇溶液，加入10mLMTBE，室温搅拌2小时，析出大量固体。过滤、干燥得到1.9g白色固体，收率88.3％，纯度99.1％，ee值大于97％。
1H-NMR(CD3OD，400MHz)：δ4.31(d,J＝1.6Hz,1H),4.20(t,J＝7.2Hz,2H),3.77-3.74(m,1H),3.31-3.28(m,1H),2.00-1.94(m,1H),1.84-1.79(m,1H),1.33(t,J＝7.2Hz,3H),1.21(s,3H),1.18(s,3H)ppm.
实施例6
与实施例2不同的是，将实施例2中的双三甲基硅基胺基锂替换为相同用量的叔丁醇钠，其余皆相同，纯度88.4％，收率42.3％。
实施例7
与实施例3不同的是，将实施例3中的叔丁醇钠替换为相同用量的双三甲基硅基胺基锂，其余皆相同，纯度90.2％，收率22.5％。
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (10)
1.一种(1R,2S,5S)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2-羧酸酯的制备方法，其特征在于，包括如下步骤：
(1)3,3-二甲基-4-氧代丁酸酯与S-取代亚磺酰胺反应生成化合物C-1；
(2)化合物C-1和单卤素取代乙酸酯在强碱作用下反应，利用S-取代亚磺酰胺手性诱导，得到化合物C-2；
(3)化合物C-2在强碱作用下形成过渡态中间体化合物C-3，进一步在强碱作用下和S-取代亚磺酰手性诱导下，生成化合物C-4；
(4)化合物C-4脱保护基得化合物C-5；
(5)化合物C-5经还原反应得(1R,2S,5S)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2-羧酸酯，
其中，R1、R3各自独立的选自脂肪烃或芳香烃；R2选自烷基、芳基、取代芳基中的任一种。
2.根据权利要求1所述的制备方法，其特征在于，R1、R3选自烷基，R2选自C2-6烷基、苯基、取代苯基中的任一种。
3.根据权利要求2所述的制备方法，其特征在于，R1、R3选自乙基，R2选自丁基。
4.根据权利要求1所述的制备方法，其特征在于，步骤(1)中，需要加入催化剂，所述催化剂选自硫酸铜，四氯化钛，钛酸四甲酯，钛酸四乙酯，钛酸四异丙酯，钛酸四丁酯，氯化锌，氯化铝中的一种或几种。
5.根据权利要求1所述的制备方法，其特征在于，步骤(2)中，所述单卤素取代乙酸酯中的卤素为氯或溴。
6.根据权利要求1所述的制备方法，其特征在于，步骤(2)中，所述强碱选自叔丁醇钠，叔丁醇钾，乙醇钠，乙醇钾，甲醇钠，甲醇钾，LDA，正丁基锂，甲醇锂，叔丁醇锂，LiHMDS中的一种。
7.根据权利要求1所述的制备方法，其特征在于，步骤(3)中，所述强碱选自叔丁醇钠，叔丁醇钾，乙醇钠，乙醇钾，甲醇钠，甲醇钾，LDA，正丁基锂，甲醇锂，叔丁醇锂，LiHMDS中的一种。
8.根据权利要求1所述的制备方法，其特征在于，步骤(4)中，所述脱保护基通过加酸实现，所述酸选自硫酸，盐酸，磷酸，三氟乙酸，甲磺酸，对甲苯磺酸中的一种或几种。
9.根据权利要求1所述的制备方法，其特征在于，步骤(5)中，所述还原反应需要加入还原剂，所述还原剂选自氢化锂铝，硼烷，硼氢化钠中的一种。
10.根据权利要求1所述的制备方法，其特征在于，步骤(5)中，(1R,2S,5S)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2-羧酸酯再经盐酸成盐步骤，得到(1R,2S,5S)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2-羧酸酯盐酸盐。
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1805931A (zh) * | 2003-06-17 | 2006-07-19 | 先灵公司 | 制备(1r,2s,5s)－6,6－二甲基－3－氮杂双环[3,1,0]己烷－2－羧酸酯或其盐的方法和中间体 |
| CN103435532A (zh) * | 2013-09-02 | 2013-12-11 | 苏州永健生物医药有限公司 | 波普瑞韦中间体的合成方法 |
| WO2013190509A2 (en) * | 2012-06-22 | 2013-12-27 | Dr.Reddys Laboratories Limited | Preparation of intermediates of boceprevir |
| CN109776364A (zh) * | 2017-11-10 | 2019-05-21 | 和鼎（南京）医药技术有限公司 | 一种氟苯尼考中间体v的制备方法及利用该中间体v的氟苯尼考制备方法 |
| CN114057627A (zh) * | 2022-01-18 | 2022-02-18 | 南京桦冠生物技术有限公司 | 一种丙型肝炎及新冠药物中间体及其盐的制备方法 |
| CN114133350A (zh) * | 2021-12-16 | 2022-03-04 | 浙江乐普药业股份有限公司 | 一种抗新冠药物Paxlovid中间体的制备方法 |
| WO2022235866A1 (en) * | 2021-05-05 | 2022-11-10 | Revolution Medicines, Inc. | Covalent ras inhibitors and uses thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1805931A (zh) * | 2003-06-17 | 2006-07-19 | 先灵公司 | 制备(1r,2s,5s)－6,6－二甲基－3－氮杂双环[3,1,0]己烷－2－羧酸酯或其盐的方法和中间体 |
| WO2013190509A2 (en) * | 2012-06-22 | 2013-12-27 | Dr.Reddys Laboratories Limited | Preparation of intermediates of boceprevir |
| CN103435532A (zh) * | 2013-09-02 | 2013-12-11 | 苏州永健生物医药有限公司 | 波普瑞韦中间体的合成方法 |
| CN109776364A (zh) * | 2017-11-10 | 2019-05-21 | 和鼎（南京）医药技术有限公司 | 一种氟苯尼考中间体v的制备方法及利用该中间体v的氟苯尼考制备方法 |
| WO2022235866A1 (en) * | 2021-05-05 | 2022-11-10 | Revolution Medicines, Inc. | Covalent ras inhibitors and uses thereof |
| CN114133350A (zh) * | 2021-12-16 | 2022-03-04 | 浙江乐普药业股份有限公司 | 一种抗新冠药物Paxlovid中间体的制备方法 |
| CN114057627A (zh) * | 2022-01-18 | 2022-02-18 | 南京桦冠生物技术有限公司 | 一种丙型肝炎及新冠药物中间体及其盐的制备方法 |
Non-Patent Citations (4)
| Title |
|---|
| MAKOTO OBA, ET AL.: "Novel stereocontrolled approach to conformationally constrained analogues of L -glutamic acid and L -proline via stereoselective cyclopropanation of 3,4-didehydro- L -pyroglutamic ABO ester", 《TETRAHEDRON》, vol. 61, pages 8456 - 8464 * |
| SRINIVASA REDDY KALLAM, ET AL.: "A diastereoselective synthesis of boceprevir\'s gem-dimethyl bicyclic [3.1.0] proline intermediate from an insecticide ingredient cis- cypermethric acid", 《TETRAHEDRON》, vol. 73, pages 4285 - 4294 * |
| TONI MORAGAS SOLA, ET AL.: "Stereoselective aza-Darzens reactions of tert-butanesulfinimines: convenient access to chiral aziridines", 《ORG. BIOMOL. CHEM.》, vol. 9, pages 5034 - 5035 * |
| TONI MORAGAS, ET AL.: "Asymmetric Synthesis of Trisubstituted Aziridines via Aza-Darzens Reaction of Chiral Sulfinimines", 《ORG. LETT.》, vol. 16, pages 6290 - 6293 * |
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| WO2023168827A1 (zh) | 2023-09-14 |
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