CN112939848B - Preparation method of bupivacaine and intermediate (S) -2-piperidinecarboxylic acid thereof - Google Patents
Preparation method of bupivacaine and intermediate (S) -2-piperidinecarboxylic acid thereof Download PDFInfo
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- CN112939848B CN112939848B CN202110214588.0A CN202110214588A CN112939848B CN 112939848 B CN112939848 B CN 112939848B CN 202110214588 A CN202110214588 A CN 202110214588A CN 112939848 B CN112939848 B CN 112939848B
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- piperidinecarboxylic acid
- bupivacaine
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- HXEACLLIILLPRG-YFKPBYRVSA-N L-pipecolic acid Chemical compound [O-]C(=O)[C@@H]1CCCC[NH2+]1 HXEACLLIILLPRG-YFKPBYRVSA-N 0.000 title claims abstract description 37
- HXEACLLIILLPRG-RXMQYKEDSA-N l-pipecolic acid Natural products OC(=O)[C@H]1CCCCN1 HXEACLLIILLPRG-RXMQYKEDSA-N 0.000 title claims abstract description 37
- LEBVLXFERQHONN-UHFFFAOYSA-N 1-butyl-N-(2,6-dimethylphenyl)piperidine-2-carboxamide Chemical compound CCCCN1CCCCC1C(=O)NC1=C(C)C=CC=C1C LEBVLXFERQHONN-UHFFFAOYSA-N 0.000 title claims abstract description 16
- 229960003150 bupivacaine Drugs 0.000 title claims abstract description 15
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 51
- LEBVLXFERQHONN-INIZCTEOSA-N levobupivacaine Chemical compound CCCCN1CCCC[C@H]1C(=O)NC1=C(C)C=CC=C1C LEBVLXFERQHONN-INIZCTEOSA-N 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 13
- OJOFMLDBXPDXLQ-SECBINFHSA-N (4r)-4-benzyl-1,3-oxazolidin-2-one Chemical compound C1OC(=O)N[C@@H]1CC1=CC=CC=C1 OJOFMLDBXPDXLQ-SECBINFHSA-N 0.000 claims abstract description 11
- 238000007112 amidation reaction Methods 0.000 claims abstract description 8
- 238000005804 alkylation reaction Methods 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 50
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 21
- 239000003513 alkali Substances 0.000 claims description 15
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 14
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 238000006482 condensation reaction Methods 0.000 claims description 9
- UFFBMTHBGFGIHF-UHFFFAOYSA-N 2,6-dimethylaniline Chemical compound CC1=CC=CC(C)=C1N UFFBMTHBGFGIHF-UHFFFAOYSA-N 0.000 claims description 8
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 230000009471 action Effects 0.000 claims description 7
- 239000002585 base Substances 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 238000005660 chlorination reaction Methods 0.000 claims description 6
- 238000006467 substitution reaction Methods 0.000 claims description 6
- MPPPKRYCTPRNTB-UHFFFAOYSA-N 1-bromobutane Chemical compound CCCCBr MPPPKRYCTPRNTB-UHFFFAOYSA-N 0.000 claims description 5
- 125000002252 acyl group Chemical group 0.000 claims description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 238000006555 catalytic reaction Methods 0.000 claims description 4
- 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 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 claims description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical group [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 3
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 239000012312 sodium hydride Substances 0.000 claims description 3
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 2
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims description 2
- 239000000920 calcium hydroxide Substances 0.000 claims description 2
- 229910001861 calcium hydroxide Inorganic materials 0.000 claims description 2
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- CGRKYEALWSRNJS-UHFFFAOYSA-N sodium;2-methylbutan-2-olate Chemical compound [Na+].CCC(C)(C)[O-] CGRKYEALWSRNJS-UHFFFAOYSA-N 0.000 claims description 2
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical class CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 claims 1
- 239000000126 substance Substances 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 10
- 230000029936 alkylation Effects 0.000 abstract description 4
- 230000009435 amidation Effects 0.000 abstract description 4
- 239000003589 local anesthetic agent Substances 0.000 abstract description 4
- 230000007062 hydrolysis Effects 0.000 abstract description 3
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 3
- 239000012752 auxiliary agent Substances 0.000 abstract description 2
- 238000007363 ring formation reaction Methods 0.000 abstract description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 28
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 14
- 239000000243 solution Substances 0.000 description 13
- 239000012074 organic phase Substances 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 9
- 239000012071 phase Substances 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- 238000001514 detection method Methods 0.000 description 8
- 239000003480 eluent Substances 0.000 description 8
- 239000003960 organic solvent Substances 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 6
- 239000003208 petroleum Substances 0.000 description 6
- 238000010791 quenching Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 239000011259 mixed solution Substances 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 230000003287 optical effect Effects 0.000 description 5
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 239000012362 glacial acetic acid Substances 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 238000010606 normalization Methods 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 230000002194 synthesizing effect Effects 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 206010002091 Anaesthesia Diseases 0.000 description 3
- 230000037005 anaesthesia Effects 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- QKGYJVXSKCDGOK-UHFFFAOYSA-N hexane;propan-2-ol Chemical compound CC(C)O.CCCCCC QKGYJVXSKCDGOK-UHFFFAOYSA-N 0.000 description 3
- 238000009776 industrial production Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 238000005580 one pot reaction Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 230000000171 quenching effect Effects 0.000 description 3
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical class [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 2
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical group CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 230000036592 analgesia Effects 0.000 description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 239000007789 gas Substances 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
- 239000005457 ice water Substances 0.000 description 2
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 2
- 210000003141 lower extremity Anatomy 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 150000003053 piperidines Chemical class 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- WZDUMISBAHEPLN-UHFFFAOYSA-N tert-butyl 2-methoxypiperidine-1-carboxylate Chemical compound COC1CCCCN1C(=O)OC(C)(C)C WZDUMISBAHEPLN-UHFFFAOYSA-N 0.000 description 2
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 2
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 2
- ULTHEAFYOOPTTB-UHFFFAOYSA-N 1,4-dibromobutane Chemical compound BrCCCCBr ULTHEAFYOOPTTB-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical group CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 238000007295 Wittig olefination reaction Methods 0.000 description 1
- QQIRAVWVGBTHMJ-UHFFFAOYSA-N [dimethyl-(trimethylsilylamino)silyl]methane;lithium Chemical compound [Li].C[Si](C)(C)N[Si](C)(C)C QQIRAVWVGBTHMJ-UHFFFAOYSA-N 0.000 description 1
- FYJKEHKQUPSJDH-UHFFFAOYSA-N [dimethyl-(trimethylsilylamino)silyl]methane;potassium Chemical compound [K].C[Si](C)(C)N[Si](C)(C)C FYJKEHKQUPSJDH-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 150000004808 allyl alcohols Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000006208 butylation Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 238000006735 epoxidation reaction Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- BTUGXUCMSBBWSI-UHFFFAOYSA-N hexane;2-methylpropan-1-ol Chemical compound CC(C)CO.CCCCCC BTUGXUCMSBBWSI-UHFFFAOYSA-N 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- VLECDMDGMKPUSK-UHFFFAOYSA-N hydron;piperidin-3-ol;chloride Chemical compound Cl.OC1CCCNC1 VLECDMDGMKPUSK-UHFFFAOYSA-N 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 229960004288 levobupivacaine Drugs 0.000 description 1
- SIEYLFHKZGLBNX-NTISSMGPSA-N levobupivacaine hydrochloride (anhydrous) Chemical compound [Cl-].CCCC[NH+]1CCCC[C@H]1C(=O)NC1=C(C)C=CC=C1C SIEYLFHKZGLBNX-NTISSMGPSA-N 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- NIXOIRLDFIPNLJ-UHFFFAOYSA-M magnesium;benzene;bromide Chemical compound [Mg+2].[Br-].C1=CC=[C-]C=C1 NIXOIRLDFIPNLJ-UHFFFAOYSA-M 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 230000000399 orthopedic effect Effects 0.000 description 1
- 230000032696 parturition Effects 0.000 description 1
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a bupivacaine and a preparation method of an intermediate (S) -2-piperidinecarboxylic acid thereof, wherein the intermediate (S) -2-piperidinecarboxylic acid is prepared by taking (R) -4-benzyl-2-oxazolidinone shown as a formula (I) as a chiral auxiliary agent through amidation, asymmetric alkylation, hydrolysis, cyclization and removal of auxiliary groups; the prepared (S) -2-piperidinecarboxylic acid is used as a raw material to prepare the local anesthetic drug (S) -bupivacaine. The method utilizes cheap and easily-obtained organic raw materials, and has the advantages of simple and convenient operation, mild reaction conditions, good stereoselectivity, high yield and the like.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemical synthesis, in particular to a method for preparing bupivacaine and an intermediate (S) -2-piperidinecarboxylic acid thereof.
Background
Bupivacaine was first approved in swedish in 1999 and clinical trials have been completed in the us, europe, australia and new zealand and have been approved by the FDA in the united states. Bupivacaine is a long-acting local anesthetic, has dual effects of analgesia and anesthesia, is mainly used for surgical anesthesia and epidural block anesthesia, and can be used for various operations including lower limb and lower limb operations of orthopedics, gynecology, urology and the like; can also be used for acute analgesia after operation or parturition, has low toxicity to heart, high safety and better clinical application range. Currently, the main methods for synthesizing bupivacaine are as follows: (1) synthesizing bupivacaine by a triphosgene method, taking 2-piperidinecarboxylic acid as a raw material, synthesizing the raw material through acyl chlorination, amidation, butylation and salification, and obtaining levobupivacaine through optical resolution; (2) the (S) -bupivacaine hydrochloride is obtained by using (S) -2-piperidinecarboxylic acid as a raw material, performing triphosgene chlorination, performing amidation with 2, 6-dimethylaniline, performing butyl bromination and salt formation. The synthesis method of bupivacaine reported in the literature has the defects of low yield, large environmental pollution, high cost and the like.
It is worth noting that (S) -2-piperidinecarboxylic acid is a key intermediate of local anesthetic bupivacaine, and the synthesis method mainly comprises the following steps:
in The literature (The Journal of organic chemistry, 2010, 75 (6): 2077-2080), chiral amide is used as a raw material, chiral N-iminopyridine salt is synthesized under The activation of trifluoromethanesulfonic anhydride, then phenyl is introduced under The action of Grignard reagent PhMgBr. LiBr, and (S) -2-piperidinecarboxylic acid is obtained through hydrogenation reduction, chiral auxiliary group removal, amino protection by trifluoroacetyl, phenyl oxidation and hydrolysis. The product of the synthetic route has good stereoselectivity, but the reaction steps are more complicated, so the synthetic route is not suitable for industrial production.
The literature (Organic Letters, 2000, 2 (2): 155-158) uses 3-hydroxypiperidine hydrochloride as raw material, and obtains N-Boc-piperidyl methyl ether through three-step reaction, and the N-Boc-piperidyl methyl ether is converted into unsaturated piperidine derivative under the catalysis of catalyst S-BuLi/TMEDA, and then is subjected to (S) -BINAP-RuCl2Under the action of the catalyst, asymmetric catalytic hydrogenation reaction is carried out to obtain (S) -N-Boc-piperidine formic acid, and the target product is obtained by deprotection. This route requires the use of expensive chiral ligands and is costly.
The literature (Tetrahedron letters, 2002, 43 (5): 779-782) uses allyl alcohol derivative as raw material, and obtains unsaturated piperidine derivative through asymmetric epoxidation, ring opening and RCM reaction, and then obtains the target product (S) -N-Boc-piperidinecarboxylic acid through catalytic hydrogenation and oxidation. The route has high stereoselectivity, but the catalyst is expensive and has high production cost, so the route is not suitable for industrial production.
In the literature (Tetrahedron: Asymmetry, 2005, 16 (23): 3858-. The process has complex steps, harsh reaction conditions and low reaction yield.
The literature (Tetrahedron: Asymmetry, 2014, 25 (16-17): 1246-4Oxidizing, Wittig olefination, debenzylating, cyclizing to obtain piperidone, and finally amide reducing, KMnO4Oxidizing to obtain the (S) -2-piperidinecarboxylic acid. The method has more steps, fussy operation and low yield, and is difficult to realize large-scale industrial production.
In conclusion, the literature reports that the synthetic method of (S) -2-piperidinecarboxylic acid has the defects of difficult obtainment of starting materials, need of using expensive noble metal catalysts, complicated steps, low yield, high production cost and the like. Therefore, the development of a novel method for synthesizing (S) -2-piperidinecarboxylic acid, which is simple and convenient to operate, mild in reaction conditions, good in stereoselectivity and high in yield, has important research value and good application prospect.
Disclosure of Invention
The invention provides a bupivacaine and a preparation method of an intermediate (S) -2-piperidinecarboxylic acid thereof, wherein the (S) -2-piperidinecarboxylic acid is prepared by taking (R) -4-benzyl-2-oxazolidinone as a chiral auxiliary agent and performing amidation, asymmetric alkylation, hydrolysis, cyclization and chiral auxiliary group removal, and the prepared (S) -2-piperidinecarboxylic acid is used as a raw material to further prepare the local anesthetic (S) -bupivacaine.
The technical scheme provided by the invention for solving the technical problem is as follows:
a preparation method of (S) -2-piperidinecarboxylic acid specifically comprises the following steps:
step A: under the catalysis of alkali, (R) -4-benzyl-2-oxazolidinone shown in the formula (I) and a compound (II) are subjected to condensation reaction to generate a compound (III);
and B: carrying out asymmetric alkylation on the compound (III) and 1, 4-dihalobutane under the action of alkali to prepare a compound (IV);
and C: hydrolyzing, cyclizing and removing chiral auxiliary group from the compound (IV) to obtain (S) -2-piperidinecarboxylic acid shown in the formula (V);
wherein, X is respectively and independently Cl, Br or I.
Said
Is composed of
The invention also provides a preparation method of bupivacaine, which comprises the following steps of firstly, preparing (S) -2-piperidinecarboxylic acid shown in a formula (V) according to the preparation method of (S) -2-piperidinecarboxylic acid; then, through step (D): reacting (S) -2-piperidinecarboxylic acid shown in a formula (V) with acid in a solvent D to form salt, and performing amidation reaction with 2, 6-dimethylaniline after the acyl chlorination reaction to obtain a compound (VI); finally, the step (E): the compound (VI) and 1-bromobutane are subjected to substitution reaction under the action of alkali to prepare (S) -bupivacaine (VII);
in the step A, the alkali is sodium hydride, potassium tert-butoxide, sodium tert-amylate, n-butyllithium, lithium diisopropylamide, potassium hexamethyldisilazane, sodium hexamethyldisilazane or lithium hexamethyldisilazane; n-butyllithium is preferred.
In the step A, the mass ratio of the (R) -4-benzyl-2-oxazolidinone, the compound (II) and the alkali is 1.0: 1.0-1.5, preferably 1.0: 1.0-1.2: 1.1-1.3, and more preferably 1.0: 1.1: 1.2.
The solvent A of the condensation reaction is tetrahydrofuran, 2-methyltetrahydrofuran or diethyl ether; the volume consumption of the solvent A in the condensation reaction is 6-15 mL/g based on the mass of the compound (II).
The condensation reaction is carried out under the reaction condition of-85 to-70 ℃ for 15 to 30 minutes, and then the temperature is increased to 15 to 40 ℃ for 2 to 8 hours. The reaction is carried out at 15-40 ℃ for 2-8 hours, and preferably at 20-30 ℃ for 3-5 hours.
The step A: under the catalysis of alkali, carrying out condensation reaction on (R) -4-benzyl-2-oxazolidinone shown in a formula (I) and a compound (II) to generate a compound (III), which specifically comprises the following steps: dissolving (R) -4-benzyl-2-oxazolidinone shown in a formula (I) in a solvent A, adding alkali under the protection of nitrogen, cooling the mixed solution to-85 to-70 ℃, dissolving a compound (II) in the solvent A, then dropwise adding the compound (II) into the mixed solution, reacting for 15-30 minutes at-85 to-70 ℃, naturally raising the temperature to 15-40 ℃, reacting for 2-8 hours, and after the reaction is finished, performing post-treatment to obtain a compound (III).
The post-treatment method of the condensation reaction comprises the following steps: after the condensation reaction is finished, quenching the reaction by glacial acetic acid, adding water, extracting by an organic solvent, combining organic phases, washing by water, concentrating the organic phase, separating by column chromatography, collecting eluent containing the target compound by taking a mixed solution of petroleum ether and ethyl acetate as an eluent, and evaporating the organic solvent to obtain a compound (III); the organic solvent includes, but is not limited to, dichloromethane.
In the step B, the base is n-butyllithium, tert-butyllithium, lithium diisopropylamide, potassium hexamethyldisilazide, sodium hexamethyldisilazide or lithium hexamethyldisilazide; lithium hexamethyldisilazide is preferred.
The amount ratio of the compound (III), 1, 4-dihalobutane and alkali is 1.0:1.0 to 1.5, preferably 1.0: 1.1 to 1.3, and more preferably 1.0: 1.2.
The solvent B for the one-pot reaction is tetrahydrofuran, 2-methyltetrahydrofuran or diethyl ether.
The volume consumption of the solvent B for the one-pot reaction is 5-10 mL/g based on the mass of the compound (III).
The reaction conditions of the one-pot reaction are that the reaction is carried out for 30-60 minutes at-85 to-70 ℃, and then the temperature is increased to 15-40 ℃ for reaction for 2-8 hours; the reaction is carried out at 15-40 ℃ for 1-6 hours, and preferably at 20-30 ℃ for 3-4 hours.
The step B: the compound (III) and 1, 4-dihalobutane are subjected to asymmetric alkylation under the action of alkali to prepare a compound (IV), which specifically comprises the following steps: dissolving a compound (III) in a solvent B, adding alkali under the protection of inert gas, cooling to-85 to-70 ℃, adding 1, 4-dihalobutane, continuing to react for 30-60 minutes at-85 to-70 ℃, then heating to 15-40, reacting for 1-6 hours, and after the reaction is finished, carrying out post-treatment to obtain a compound (IV).
The post-treatment comprises the following steps: after the reaction is finished, quenching the reaction liquid by glacial acetic acid, adding water, extracting a water phase by an organic solvent, combining organic phases, concentrating, carrying out column chromatography separation, collecting eluent containing a target compound by taking a mixed solution of petroleum ether and ethyl acetate as an eluent, and evaporating the organic solvent to obtain a compound (IV); the organic solvent includes, but is not limited to, ethyl acetate.
The step C: the compound (IV) is hydrolyzed, cyclized and chiral auxiliary group is removed to prepare the (S) -2-piperidinecarboxylic acid shown in the formula (V), which specifically comprises the following steps: dissolving the compound (IV) in a solvent C, adding hydrogen peroxide and lithium hydroxide, reacting at 20-40 ℃ for 2-3 h, and after the reaction is finished, performing post-treatment to obtain the (S) -2-piperidinecarboxylic acid shown in the formula (V).
The compound (IV): hydrogen peroxide: the mass ratio of the lithium hydroxide is 1.0: 2.0-5.0, preferably 1.0: 2.5-3.5: 3.5-4.5; further preferably 1.0: 3.0: 4.0.
The hydrogen peroxide is added in the form of 30% hydrogen peroxide.
The post-treatment in the step C comprises the following specific steps: after the reaction is finished, adding a saturated sodium sulfite aqueous solution, concentrating to remove the solvent C, adjusting the pH of an aqueous layer to 1.5-2.5 with hydrochloric acid, extracting an aqueous phase with an organic solvent, adjusting the pH of the aqueous phase to 6-7, precipitating a solid, filtering, and drying to obtain the (S) -2-piperidinecarboxylic acid represented by the formula (V).
The reaction condition of the acyl chlorination reaction is 40-80 ℃ for 1-5 h, preferably 50-60 ℃ for 1-5 h.
The reaction condition of the amidation reaction is 50-60 ℃ for 1-6 h.
The reaction condition of the substitution reaction is 50-100 ℃ for 2-6 h.
The alkali in the substitution reaction is selected from sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide, potassium carbonate or sodium carbonate; potassium carbonate is preferred.
The following steps: compound (VI): 1-bromobutane: the ratio of the amount of the alkali is 1.0:1.0 to 1.2: 1.0 to 1.5, preferably 1.0: 1.05 to 1.15: 1.1 to 1.3, and more preferably 1.0: 1.1: 1.2.
And the solvent E in the step E is tetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, acetone, acetonitrile or dimethyl sulfoxide.
And the volume dosage of the solvent E in the step E is 3-5 mL/g based on the mass of the compound (VI).
The post-processing method of the step E comprises the following steps: after the reaction is finished, pouring the reaction liquid into ice water, stirring to generate white solid, and performing suction filtration to obtain (S) -bupivacaine.
Compared with the prior art, the invention has the beneficial effects that:
the preparation method of the (S) -2-piperidinecarboxylic acid can obtain the (S) -2-piperidinecarboxylic acid which is the key chiral intermediate of the (S) -bupivacaine only by three steps, greatly improves the synthesis efficiency, and has the advantages of cheap and easily-obtained raw materials, short route, high yield, good stereoselectivity and the like.
The preparation method of (S) -bupivacaine provided by the invention is efficient, simple and convenient, good in atomic economy, low in production cost and good in market application prospect.
Detailed Description
The technical scheme of the invention is further specifically explained by the specific embodiment; however, the present invention is not limited to these examples.
Example 1 Synthesis of Compound (III)
Dissolving (R) -4-benzyl-2-oxazolidinone I (1.62g, 16mmol) in tetrahydrofuran (20mL), adding n-hexane solution of n-butyllithium (7.7mL, 19.2mmol, 2.5mol/L) at-78 ℃ under the protection of nitrogen, stirring at-78 ℃ for 30 minutes, adding tetrahydrofuran solution (25mL) of compound II (3.92g, 17.6mmol), continuing the reaction at the temperature for 30 minutes, and naturally raising the temperature to room temperature for reaction for 3 hours. After the reaction is finished, 2mL of glacial acetic acid is dripped to quench the reaction, 30mL of water is added to stir, dichloromethane is used for extraction (2X 100mL), an organic phase is collected, the organic phase is dried and concentrated, a crude product is purified by silica gel column chromatography, an eluent is petroleum ether and ethyl acetate (the volume ratio is 5: 1-3: 1), 5.3g of a light yellow oily liquid compound III is obtained after concentration, and the yield is 91%.
1H NMR(500MHz，Chloroform-d)δ7.92-7.74(m，4H)，7.36-7.19(m，5H)，5.13-5.00(m，2H)，4.70-4.66(m，1H)，4.42-4.21(m，2H)，3.25(dd，J＝13.6，3.2Hz，1H)，2.88(dd，J＝13.5，9.2Hz，1H)ppm.13C NMR(125MHz，Chloroform-d)δ167.73，166.62，153.53，134.71，134.26，132.11，129.45，129.06，127.48，123.64，67.25，55.10，41.72，37.50ppm。
Example 2 Synthesis of Compound (III)
Dissolving (R) -4-benzyl-2-oxazolidinone I (1g, 10mmol) in tetrahydrofuran (10mL), adding sodium hydride (480mg, 12mmol, content 60%) at-5 ℃ under nitrogen protection, stirring at 0 ℃ for 1h, adding a tetrahydrofuran solution (15mL) of compound II (2.45g, 11mmol), and naturally heating to room temperature for reaction for 5 h. After the reaction is finished, 1mL of glacial acetic acid is added dropwise to quench the reaction, 20mL of water is added, the mixture is stirred, dichloromethane is used for extraction (2X 80mL), an organic phase is collected, the organic phase is dried and concentrated, a crude product is purified by silica gel column chromatography, and an eluent is petroleum ether: ethyl acetate (volume ratio 5: 1-3: 1) was concentrated to give 3.13g of a pale yellow oily liquid compound III, 86% yield.
Example 3 Synthesis of Compound (III)
Dissolving (R) -4-benzyl-2-oxazolidinone I (1g, 10mmol) in tetrahydrofuran (10mL), adding potassium tert-butoxide (1.35g, 12mmol) at 0 ℃ under nitrogen protection, stirring at this temperature for 1h, adding a solution of compound II (2.45g, 11mmol) in tetrahydrofuran (15mL), and naturally warming to room temperature for 5 hours. After the reaction is finished, 20mL of water is added for quenching reaction, dichloromethane is used for extraction (2X 80mL), an organic phase is collected, the organic phase is dried and concentrated, a crude product is purified by silica gel column chromatography, an eluent is petroleum ether and ethyl acetate (the volume ratio is 5: 1-3: 1), and a light yellow oily liquid compound III3g is obtained after concentration, wherein the yield is 82%.
EXAMPLE 4 Synthesis of Compound (IV)
Compound III (1.82g, 5mmol) was dissolved in tetrahydrofuran (10mL), a solution of n-butyllithium in n-hexane (2.4mL, 6mmol, 2.5mol/L) was added at-78 deg.C under nitrogen, a solution of 1, 4-dibromobutane (1.2g, 5.5mmol) in tetrahydrofuran (5mL) was added after stirring at-78 deg.C for 30 minutes, and the reaction was continued at this temperature for 4 hours. After the reaction is finished, 10mL of water is added dropwise to quench the reaction, dichloromethane is used for extraction (3X 50mL), an organic phase is collected, the organic phase is dried and concentrated, a crude product is purified by silica gel column chromatography, and an eluent is petroleum ether: ethyl acetate (volume ratio 3: 1-1: 1) was concentrated to give 2.0g of compound IV as a yellow oil in 80% yield.
1H NMR(400MHz，D2O)δ1.22-1.28(m，2H)，1.81-1.95(m，4H)，3.00(dd，J＝13.6，3.2Hz，1H)，2.68(dd，J＝13.5，9.2Hz，1H)，3.52(t，J＝7.2Hz，2H)，4.16-4.24(m，1H)，4.41-4.48(m，1H)，4.70-4.81(m，2H)，7.21-7.28(m，5H)，7.81-7.91(m，4H)ppm。
The purity was 98% by HPLC area normalization method [ chromatographic conditions: chromatographic column Kromasil C18Column (4.6 mm. times.250 mm, 5 μm), mobile phase acetonitrile-water (volume ratio 30: 70), detection wavelength: 254nm, column temperature: 25 ℃, flow rate: 1.0 mL/min-1]。
Optical purity 98% [ chromatographic conditions: chiral column CHIRALPAK AD-H (250 mm. times.4.6 mm, 5 μm); mobile phase: n-hexane-isopropanol (volume ratio: 85: 15); detection wavelength: 254 nm; column temperature: 25 ℃; flow rate: 0.8 mL/min-1]。
Example 5 Synthesis of (S) -2-Piperidinecarboxylic acid represented by the formula (V)
The crude compound IV (2.7g) obtained in example 4 was dissolved in a mixed solution of tetrahydrofuran (12mL) and water (1.2mL), and 30% hydrogen peroxide solution (1.8g, 15mmol) and lithium hydroxide (0.5g, 20mmol) were added, respectively, and stirred at room temperature overnight, TLC showed complete reaction of the starting material, saturated aqueous sodium sulfite solution was added, the tetrahydrofuran was concentrated to remove the tetrahydrofuran, the pH of the aqueous layer was adjusted to 2 with 1mol/L hydrochloric acid, the aqueous phase was extracted with ethyl acetate (2 × 20mL), and then the pH of the aqueous phase was adjusted to 6-7 with saturated aqueous sodium bicarbonate solution, and a solid precipitated, filtered and dried to give V483 mg of (S) -2-piperidinecarboxylic acid as a white solid in 75% yield.
the purity was 98% by HPLC area normalization method [ chromatographic conditions: chromatographic column Kromasil C18Column (4.6mm × 250mm, 5 μm), mobile phase: acetonitrile-water (volume ratio 70: 30), detection wavelength: 220nm, column temperature: 25 ℃, flow rate: 1.0 mL/min-1]。
Optical purity 98% [ chromatographic conditions: chiral column CHIRALPAK AD-H (250 mm. times.4.6 mm, 5 μm); mobile phase: n-hexane-isopropanol (volume ratio: 75: 25); detection wavelength: 220 nm; column temperature: 25 ℃; flow rate: 1.0 mL/min-1]。
Example 6 Synthesis of Compound (VI)
(S) -2-Piperidinecarboxylic acid (3.25g, 25mmol) and toluene (100mL) were mixed, and dry hydrogen chloride gas was introduced at room temperature until the solution was strongly acidic, to give a white solid. The reaction was then heated to 55 deg.C, N-dimethylformamide (1mL) was added dropwise, thionyl chloride (2.7mL, 37mmol) was added slowly dropwise, and stirring was continued at this temperature for 3 h. Cooling the reaction solution to room temperature, and introducing N2Removing residual thionyl chloride and hydrogen chloride gas, heating the reaction solution to 55 ℃, slowly adding 2, 6-dimethylaniline (16mL, 125mmol) in toluene (6mL) dropwise, and adding dropwiseAfter the reaction is finished, the reaction is continued for 3 hours. Filtering, dissolving the filter cake in water (70mL), adjusting the pH to 4.0-5.0 by using 20% sodium hydroxide solution by mass fraction, extracting with toluene, separating out an aqueous phase, adjusting the pH of the aqueous phase to 11-12 by using 20% sodium hydroxide solution by mass fraction, extracting with ethyl acetate (3X 50mL), combining organic phases, drying, filtering, and concentrating under reduced pressure to obtain 5.2g (22.2mmol) of a white solid compound VI with the yield of 88%.
Melting point: 128-129 ℃ of the temperature,1H NMR(500MHz，CDCl3)δ8.26(s，1H)，7.08(d，J＝2.2Hz，3H)，3.41(m，1H)，3.19-3.07(m，1H)，2.84-2.71(m，1H)，2.23(s，6H)，2.07(m，1H)，1.91-1.78(m，2H)，1.73-1.58(m，2H)，1.57-1.43(m，2H)ppm.13C NMR(125MHz，CDCl3)δ172.3，135.0，133.6，128.0，126.9，60.6，45.7，30.3，25.9，23.9，18.4ppm。
the purity was 98% by HPLC area normalization method [ chromatographic conditions: chromatographic column Kromasil C18Column (4.6mm × 250mm, 5 μm), mobile phase: acetonitrile-water (volume ratio 40: 60), detection wavelength: 254nm, column temperature: 25 ℃, flow rate: 1.0 mL/min-1]。
Optical purity 98% [ chromatographic conditions: column CHIRALPAK AD-H (250 mm. times.4.6 mm, 5 μm); mobile phase: n-hexane-isopropanol (volume ratio: 80: 20); detection wavelength: 254 nm; column temperature: 25 ℃; flow rate: 1.0 mL/min-1]。
Example 7 Synthesis of Compound (S) -bupivacaine (1-N-butyl-N- (2, 6-dimethylphenyl) -2-piperidinecarboxamide) represented by the formula (VII)
Dissolving compound VI (3g, 12.9mmol) in N, N-dimethylformamide (10mL), adding 1-bromobutane (1.93g, 14.2mmol), potassium carbonate (2.14g, 15.5mmol), and reacting at 80 deg.C for 3 h; after completion of the reaction, the reaction mixture was poured into ice water and stirred to give a white solid, which was filtered under suction to give (S) -bupivacaine (3.53g) in yield: 95 percent.
the purity was 98% by HPLC area normalization method [ chromatographic conditions: chromatographic column Kromasil C18Column (4.6mm × 250mm, 5 μm), mobile phase: acetonitrile-water (volume ratio 60: 40), detection wavelength: 254nm, column temperature: 25 ℃, flow rate: 1.0 mL/min-1]。
Optical purity 98% [ chromatographic conditions: chiral column CHIRALPAK AD-H (250 mm. times.4.6 mm, 5 μm); mobile phase: n-hexane-isobutanol (volume ratio: 90: 10); detection wavelength: 254 nm; column temperature: 25 ℃; flow rate: 0.8 mL/min-1]。
Claims (8)
1. A preparation method of (S) -2-piperidinecarboxylic acid is characterized by comprising the following steps:
step A: under the catalysis of alkali, (R) -4-benzyl-2-oxazolidinone shown in the formula (I) and a compound (II) are subjected to condensation reaction to generate a compound (III);
and B: carrying out asymmetric alkylation reaction on the compound (III) and 1, 4-dihalogenated butane under the action of alkali to prepare a compound (IV);
step C: the compound (IV) is hydrolyzed, cyclized and chiral auxiliary group is removed to prepare the (S) -2-piperidinecarboxylic acid shown in the formula (V), which specifically comprises the following steps: dissolving the compound (IV) in a solvent C, adding hydrogen peroxide and lithium hydroxide, reacting at 20-40 ℃ for 2-3 h, and after the reaction is finished, performing post-treatment to obtain (S) -2-piperidinecarboxylic acid shown in a formula (V); the compound (IV): hydrogen peroxide: the mass ratio of lithium hydroxide is 1.0: 2.0-5.0: 2.0 to 5.0;
wherein, X is respectively and independently Cl, Br or I.
2. The process according to claim 1, wherein in step A, the base is sodium hydride, potassium tert-butoxide, sodium tert-amylate, n-butyllithium, lithium diisopropylamide, potassium hexamethyldisilazide, sodium hexamethyldisilazide or lithium hexamethyldisilazide.
3. The method for producing (S) -2-piperidinecarboxylic acid according to claim 1 or 2, wherein in step A, the amount ratio of the (R) -4-benzyl-2-oxazolidinone, compound (II) and base is 1.0:1.0 to 1.5; the condensation reaction is carried out under the reaction condition of-85 to-70 ℃ for 15 to 30 minutes, and then the temperature is increased to 15 to 40 ℃ for 2 to 8 hours.
4. The process according to claim 1, wherein in step B, the base is n-butyllithium, t-butyllithium, lithium diisopropylamide, potassium hexamethyldisilazide, sodium hexamethyldisilazide or lithium hexamethyldisilazide.
5. The method for producing (S) -2-piperidinecarboxylic acid according to claim 1 or 4, wherein the amount of the compound (III), 1, 4-dihalobutane and base in the step B is 1.0:1.0 to 1.5; the reaction conditions of the reaction are that the reaction is carried out for 30-60 minutes at-85 to-70 ℃, and then the temperature is increased to 15-40 ℃ for reaction for 2-8 hours.
6. A method for producing bupivacaine, characterized by specifically comprising the steps of, first, producing (S) -2-piperidinecarboxylic acid represented by the formula (V) according to the method for producing (S) -2-piperidinecarboxylic acid according to claim 1; then, through step (D): reacting (S) -2-piperidinecarboxylic acid shown in a formula (V) with acid in a solvent D to form salt, and performing amidation reaction with 2, 6-dimethylaniline after the acyl chlorination reaction to obtain a compound (VI); finally, the step (E): the compound (VI) and 1-bromobutane are subjected to substitution reaction under the action of alkali to prepare (S) -bupivacaine (VII);
7. the method for preparing bupivacaine according to claim 6, wherein the reaction conditions of the acyl chlorination reaction are 40-80 ℃ for 1-5 h; the reaction condition of the amidation reaction is 50-60 ℃ for 1-6 h; the reaction condition of the substitution reaction is 50-100 ℃ for 2-6 h.
8. The method for preparing bupivacaine according to claim 6, wherein the base in the substitution reaction is selected from sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide, potassium carbonate or sodium carbonate; the compound (VI): 1-bromobutane: the ratio of the amounts of the substances of the bases is 1.0: 1.0-1.2: 1.0 to 1.5.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU3704995A (en) * | 1994-10-25 | 1996-05-15 | Darwin Discovery Limited | Process for preparing levobupivacaine and analogues thereof |
| CN105418489A (en) * | 2016-01-22 | 2016-03-23 | 江苏宝众宝达药业有限公司 | Synthesis method of bupivacaine |
| CN111995565A (en) * | 2020-07-24 | 2020-11-27 | 浙江工业大学 | Preparation method of (S) -2-piperidinecarboxylic acid |
-
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- 2021-02-25 CN CN202110214588.0A patent/CN112939848B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU3704995A (en) * | 1994-10-25 | 1996-05-15 | Darwin Discovery Limited | Process for preparing levobupivacaine and analogues thereof |
| CN105418489A (en) * | 2016-01-22 | 2016-03-23 | 江苏宝众宝达药业有限公司 | Synthesis method of bupivacaine |
| CN111995565A (en) * | 2020-07-24 | 2020-11-27 | 浙江工业大学 | Preparation method of (S) -2-piperidinecarboxylic acid |
Non-Patent Citations (2)
| Title |
|---|
| "（2R,4S）-4-甲基-2-哌啶甲酸乙酯的合成";刘兵 等;《合成化学》;20131231;第21卷(第5期);第608-610页 * |
| "A new synthetic route to compounds of the AFDX-type with affinity to muscarinic M2-receptor";Ulrike Holzgrabe，et al.;《Tetrahedron》;20031231;第59卷;第781-787页 * |
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