CN116199613A - Preparation method of perindopril intermediate (2S, 3aS,7 aS) -octahydroindole-2-carboxylic acid - Google Patents
Preparation method of perindopril intermediate (2S, 3aS,7 aS) -octahydroindole-2-carboxylic acid Download PDFInfo
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- CN116199613A CN116199613A CN202111445347.3A CN202111445347A CN116199613A CN 116199613 A CN116199613 A CN 116199613A CN 202111445347 A CN202111445347 A CN 202111445347A CN 116199613 A CN116199613 A CN 116199613A
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- CQYBNXGHMBNGCG-FXQIFTODSA-N (2s,3as,7as)-2,3,3a,4,5,6,7,7a-octahydro-1h-indol-1-ium-2-carboxylate Chemical compound C1CCC[C@@H]2[NH2+][C@H](C(=O)[O-])C[C@@H]21 CQYBNXGHMBNGCG-FXQIFTODSA-N 0.000 title claims abstract description 17
- 238000002360 preparation method Methods 0.000 title abstract description 15
- IPVQLZZIHOAWMC-QXKUPLGCSA-N perindopril Chemical compound C1CCC[C@H]2C[C@@H](C(O)=O)N(C(=O)[C@H](C)N[C@@H](CCC)C(=O)OCC)[C@H]21 IPVQLZZIHOAWMC-QXKUPLGCSA-N 0.000 title abstract description 7
- 229960002582 perindopril Drugs 0.000 title abstract description 7
- 238000000034 method Methods 0.000 claims abstract description 30
- -1 1-cyclohexenyl Chemical group 0.000 claims abstract description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 21
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000003054 catalyst Substances 0.000 claims abstract description 13
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 10
- 230000003197 catalytic effect Effects 0.000 claims abstract description 8
- 239000003446 ligand Substances 0.000 claims abstract description 8
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims abstract description 8
- 150000001412 amines Chemical class 0.000 claims abstract description 6
- 229910052723 transition metal Inorganic materials 0.000 claims abstract description 6
- 150000001413 amino acids Chemical class 0.000 claims abstract description 5
- 150000003624 transition metals Chemical class 0.000 claims abstract description 5
- 239000000543 intermediate Substances 0.000 claims description 87
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 33
- 238000006243 chemical reaction Methods 0.000 claims description 27
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 23
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- 229910015892 BF 4 Inorganic materials 0.000 claims description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- 239000000243 solution Substances 0.000 claims description 11
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 10
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 238000001308 synthesis method Methods 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 claims description 6
- 150000002081 enamines Chemical class 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 5
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 5
- VYXHVRARDIDEHS-UHFFFAOYSA-N 1,5-cyclooctadiene Chemical compound C1CC=CCCC=C1 VYXHVRARDIDEHS-UHFFFAOYSA-N 0.000 claims description 4
- 239000004912 1,5-cyclooctadiene Substances 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 4
- SJHPCNCNNSSLPL-CSKARUKUSA-N (4e)-4-(ethoxymethylidene)-2-phenyl-1,3-oxazol-5-one Chemical compound O1C(=O)C(=C/OCC)\N=C1C1=CC=CC=C1 SJHPCNCNNSSLPL-CSKARUKUSA-N 0.000 claims description 3
- HCBRTCFUVLYSKU-UHFFFAOYSA-N 2-tert-butyl-1-(2-tert-butyl-1,3-dihydroisophosphindol-1-yl)-1,3-dihydroisophosphindole Chemical compound CC(C)(C)P1CC2=CC=CC=C2C1C1C2=CC=CC=C2CP1C(C)(C)C HCBRTCFUVLYSKU-UHFFFAOYSA-N 0.000 claims description 3
- 230000003301 hydrolyzing effect Effects 0.000 claims description 3
- 238000007069 methylation reaction Methods 0.000 claims description 3
- 229910052763 palladium Inorganic materials 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 125000006239 protecting group Chemical group 0.000 claims description 3
- 239000012429 reaction media Substances 0.000 claims description 3
- 239000004215 Carbon black (E152) Substances 0.000 claims description 2
- 229930195733 hydrocarbon Natural products 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- 230000011987 methylation Effects 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 230000007704 transition Effects 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 claims 3
- FSYKKLYZXJSNPZ-UHFFFAOYSA-N sarcosine Chemical compound C[NH2+]CC([O-])=O FSYKKLYZXJSNPZ-UHFFFAOYSA-N 0.000 claims 2
- AJNZWRKTWQLAJK-UHFFFAOYSA-N 1-[2-(2,5-dimethylphospholan-1-yl)phenyl]-2,5-dimethylphospholane Chemical compound CC1CCC(C)P1C1=CC=CC=C1P1C(C)CCC1C AJNZWRKTWQLAJK-UHFFFAOYSA-N 0.000 claims 1
- NPKSPKHJBVJUKB-UHFFFAOYSA-N N-phenylglycine Chemical compound OC(=O)CNC1=CC=CC=C1 NPKSPKHJBVJUKB-UHFFFAOYSA-N 0.000 claims 1
- 108010077895 Sarcosine Proteins 0.000 claims 1
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical class C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 claims 1
- 230000008569 process Effects 0.000 abstract description 10
- 239000002994 raw material Substances 0.000 abstract description 6
- 230000007613 environmental effect Effects 0.000 abstract description 3
- 238000006136 alcoholysis reaction Methods 0.000 abstract description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- 239000000047 product Substances 0.000 description 6
- QIAFMBKCNZACKA-UHFFFAOYSA-N N-benzoylglycine Chemical compound OC(=O)CNC(=O)C1=CC=CC=C1 QIAFMBKCNZACKA-UHFFFAOYSA-N 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 229910052786 argon Inorganic materials 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 229910052741 iridium Inorganic materials 0.000 description 3
- 125000002757 morpholinyl group Chemical group 0.000 description 3
- SJYNFBVQFBRSIB-UHFFFAOYSA-N norbornadiene Chemical compound C1=CC2C=CC1C2 SJYNFBVQFBRSIB-UHFFFAOYSA-N 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 229910052703 rhodium Inorganic materials 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 239000002699 waste material Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- OKJIRPAQVSHGFK-UHFFFAOYSA-N N-acetylglycine Chemical compound CC(=O)NCC(O)=O OKJIRPAQVSHGFK-UHFFFAOYSA-N 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 2
- 238000005265 energy consumption Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000012265 solid product Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- AJNZWRKTWQLAJK-KLHDSHLOSA-N (2r,5r)-1-[2-[(2r,5r)-2,5-dimethylphospholan-1-yl]phenyl]-2,5-dimethylphospholane Chemical compound C[C@@H]1CC[C@@H](C)P1C1=CC=CC=C1P1[C@H](C)CC[C@H]1C AJNZWRKTWQLAJK-KLHDSHLOSA-N 0.000 description 1
- DYWSVUBJGFTOQC-QMMMGPOBSA-N (2s)-2-ethylheptanoic acid Chemical compound CCCCC[C@H](CC)C(O)=O DYWSVUBJGFTOQC-QMMMGPOBSA-N 0.000 description 1
- KPVMGWQGPJULFL-UHFFFAOYSA-N 1-(cyclohexen-1-yl)piperidine Chemical compound C1CCCCN1C1=CCCCC1 KPVMGWQGPJULFL-UHFFFAOYSA-N 0.000 description 1
- VAPOFMGACKUWCI-UHFFFAOYSA-N 4-(cyclopenten-1-yl)morpholine Chemical group C1CCC=C1N1CCOCC1 VAPOFMGACKUWCI-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 239000005541 ACE inhibitor Substances 0.000 description 1
- 101710129690 Angiotensin-converting enzyme inhibitor Proteins 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical group [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- 101710086378 Bradykinin-potentiating and C-type natriuretic peptides Proteins 0.000 description 1
- SKVVLPFEDFQEPS-UHFFFAOYSA-N Cl.Cl.Cl.[PH3]=O Chemical compound Cl.Cl.Cl.[PH3]=O SKVVLPFEDFQEPS-UHFFFAOYSA-N 0.000 description 1
- 229910020366 ClO 4 Inorganic materials 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
- 206010019280 Heart failures Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- 229910021115 PF 6 Inorganic materials 0.000 description 1
- 229910018286 SbF 6 Inorganic materials 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 description 1
- NISGSNTVMOOSJQ-UHFFFAOYSA-N cyclopentanamine Chemical compound NC1CCCC1 NISGSNTVMOOSJQ-UHFFFAOYSA-N 0.000 description 1
- 125000006312 cyclopentyl amino group Chemical group [H]N(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000001207 fluorophenyl group Chemical group 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- HDACQVRGBOVJII-JBDAPHQKSA-N ramipril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](C[C@@H]2CCC[C@@H]21)C(O)=O)CC1=CC=CC=C1 HDACQVRGBOVJII-JBDAPHQKSA-N 0.000 description 1
- 229960003401 ramipril Drugs 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- SUBJHSREKVAVAR-UHFFFAOYSA-N sodium;methanol;methanolate Chemical compound [Na+].OC.[O-]C SUBJHSREKVAVAR-UHFFFAOYSA-N 0.000 description 1
- 230000002194 synthesizing effect Effects 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
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to a process for the preparation of perindopril as the main intermediate of formula I (2S, 3aS,7 aS) -octahydroindole-2-carboxylic acid. Taking N-acyl glycine derivatives as raw materials, and obtaining a 4- (alkoxymethylene) -2-alkyl oxazolone intermediate formula II through one step or multiple steps; reacting the intermediate formula II with various N- (1-cyclohexenyl) amine at room temperature to obtain an intermediate formula III; alcoholysis of the intermediate formula III under the condition of catalytic amount of alkyl alkoxide to generate an unsaturated amino acid intermediate formula IV; intermediate formula IV generates enantiomer enriched intermediate formula V (including formula Va and formula Vb) under the condition of transition metal rhodium-chiral phosphine ligand complex catalyst; intermediate vb yields (2S, 3aS,7 aS) -octahydroindole-2-carboxylic acid of formula I under hydrochloric acid and catalytic amounts of palladium on carbon. The process has the characteristics of higher yield, simple process, environmental friendliness and the like, and has good industrialized application prospect.
Description
Technical Field
The present invention relates to a process for the preparation of perindopril (formula IX) as the main intermediate (2S, 3aS,7 aS) -octahydroindole-2-carboxylic acid (formula I). The process has the characteristics of higher yield, simple process, environmental friendliness and the like, and has good industrialized application prospect.
Background
Perindopril (Perindopril) is a third generation long acting angiotensin converting enzyme inhibitor developed by french pharmaceutical industry Shi Weiya for the treatment of various hypertension and heart failure. The main intermediate is (2S, 3aS,7 aS) -octahydroindole-2-carboxylic acid, and the method used for synthesizing the intermediate in the prior art is chemical resolution [ e.g. DE 3345355,EP 115345] or biological conversion [ e.g. US 2009/0017509], however, the methods waste nearly half of precursor raw materials, and the energy consumption and resource waste are serious.
Disclosure of Invention
The invention solves the problems of serious energy consumption and resource waste caused by the traditional chemical resolution. The process has the characteristics of higher yield, simple process, environmental friendliness and the like, has better industrialized application prospect, and has the same advantages in raw material utilization.
The invention provides a preparation method of a main intermediate (2S, 3aS,7 aS) -octahydroindole-2-carboxylic acid of ramipril. The invention takes N-acyl glycine derivative as raw material, and obtains the intermediate formula II of 4- (alkoxymethylene) -2-alkyl oxazolone through one step or multiple steps; reacting the intermediate formula II with various N- (1-cyclohexenyl) amine at room temperature to obtain an intermediate formula III; alcoholysis of the intermediate formula III under the condition of catalytic amount of sodium methoxide or sodium ethoxide to generate unsaturated amino acid intermediate formula IV; intermediate formula IV generates enantiomer enriched intermediate formula V (including formula Va and formula Vb) under the condition of transition metal rhodium-chiral phosphine ligand complex catalyst; intermediate vb yields (2S, 3aS,7 aS) -octahydroindole-2-carboxylic acid of formula I under aqueous hydrochloric acid and catalytic amounts of palladium on carbon.
Firstly, the invention provides a method for preparing a 4- (alkoxymethylene) -2-alkyl oxazolone intermediate as shown in a formula II by taking an N-acyl glycine derivative as a raw material through one or more steps.
The method comprises the following steps: the N-acyl glycine derivative and triethyl orthoformate or trimethyl orthoformate are reacted in acetic anhydride solvent at 100-130 deg.c to produce intermediate II;
the second method is as follows: the N-acylglycine derivatives can be obtained in a plurality of steps as intermediates of formula II, first in POCl 3 Reaction under DMF condition to produce intermediateAnd (3) hydrolyzing the intermediate in the presence of NaOH aqueous solution/organic solvent at room temperature to obtain an intermediate formula VII, and carrying out methylation reaction on the intermediate formula VII and dimethyl sulfate under the action of alkali to obtain an intermediate formula II.
Wherein R is 1 Is alkyl, R 2 Is aryl or alkyl; r is R 1 Preferably C 1 ～C 6 Alkyl, R 2 Aryl or C of less than 12C 1 ～C 6 Alkyl, R 1 Further preferred are methyl, ethyl, propyl or butyl, R 2 Further preferred is phenyl or methyl. Wherein the aryl or phenyl group may have a substituent, and the substituent is C 1 ～C 6 Alkyl, C 1 ～C 6 Alkoxy, halogen, trifluoromethyl, hydroxy, nitro or cyano, preferably methyl, ethyl, methoxy, ethoxy, F, cl, br, trifluoromethyl, hydroxy, nitro or cyano.
Next, the present invention provides the reaction of 4- (alkoxymethylene) -2-alkyl oxazolone intermediate of formula II with N- (1-cyclohexenyl) amine at room temperature to produce intermediate of formula III.
Wherein R is 2 As described above, R is independently selected from C 1 ～C 6 Alkyl, or R is linked with N and another R to form a five-membered or six-membered ring, which may contain O. Further, the five-membered ring may be piperidinyl, morpholinyl, cyclopentylamino or cyclohexylamino.
Furthermore, the invention provides an unsaturated amino acid intermediate formula IV which is obtained by ring opening of oxazolone parent nucleus under the condition of catalytic amount of alkyl alkoxide.
Wherein R, R 2 As described above, R 3 Is alkyl, preferably C 1 ～C 6 Alkyl, R 3 Preferably methyl, ethyl, propyl or butyl.
Most importantly, the present invention provides for the formation of enantiomerically enriched intermediate formula V (including formulas Va and Vb) of intermediate formula IV in the presence of a transition metal rhodium-chiral phosphine ligand complex catalyst
Wherein R, R 2 ，R 3 As described above, the transition metal-chiral phosphine ligand complex catalyst has the structure: m (L) (P) X, wherein M is Rh, ru and Ir; l=1, 5-cyclooctadiene or 2, 5-norbornadiene; the reaction medium is dichloromethane, methanol, tetrahydrofuran, acetonitrile, ethyl acetate, toluene or a mixed solvent; the P is chiral monodentate or bidentate ligand, and X is tetrahalogenated borate. In this reaction according to the invention P is R-BINAP, S-BINAP, scRp-DuanPhos, rcSp-DuanPhos, SSRR-tangPhos, RRSS-TangPhos, duPhos, or BPE.
Preferably, in [ Rh (cod) (2R, 5R-Me-Duphos)]BF 4 Or [ Rh (cod) (2S, 5S-Me-Duphos)]BF 4 Or [ Rh (cod) (2R, 5R-Et-Duphos)]BF 4 Or [ Rh (cod) (2R, 5R-Et-Duphos)]BF 4 In the presence of an asymmetric hydrogenation reaction.
Finally, the invention provides that intermediate formula vb is first stripped of the N-acyl protecting group under heating of hydrochloric acid solution and enamine is hydrolyzed to form intermediate formula VIII, after which palladium hydro-hydrogen is heated under pressure to form (2S, 3aS,7 aS) -octahydroindole-2-carboxylic acid of formula I.
Wherein R, R 2 ，R 3 As described above.
The intermediate formula V is generated into (2S, 3aS,7 aS) -octahydroindole-2-carboxylic acid, and the selected condition is that the intermediate formula V is refluxed in hydrochloric acid aqueous solution to generate intermediate formula VIII, and the intermediate formula VIII is added with catalytic amount of palladium carbon in acidic aqueous solution to perform hydrogenation, heating and pressurizing reaction to generate (2S, 3aS,7 aS) -octahydroindole-2-carboxylic acid.
The intermediate formula V generates an intermediate formula VIII reaction, and the selected condition is hydrochloric acid aqueous solution, and the temperature is 60-100 ℃.
This step may be carried out in a polar solvent, such as one or more of water, methanol, ethanol and acetic acid, under a hydrogen pressure of 5 to 15bar and a reaction temperature of 20 to 80 ℃. The reaction is preferably carried out in acetic acid at 40 ℃.
Detailed Description
The invention provides a preparation method of an indoline main intermediate (2S, 3aS,7 aS) -octahydroindole-2-carboxylic acid, which is prepared according to the following synthetic route.
The synthesis method of the (2S, 3aS,7 aS) -octahydroindole-2-carboxylic acid comprises the following steps:
(1) In a specific example, the process of formula II is carried out in one or more steps starting from N-acylglycine derivatives to give 4- (alkoxymethylene) -2-alkyl oxazolone intermediates.
The method comprises the following steps: the N-acyl glycine derivative and triethyl orthoformate or trimethyl orthoformate are reacted in acetic anhydride solvent at 100-130 deg.c to produce intermediate II;
R 1 ＝Me，Et，R 2 ＝Me，Ph
wherein the N-acyl glycine derivative is preferably N-acetyl glycine or N-benzoyl glycine, and the molar ratio of the N-acyl glycine derivative, triethyl orthoformate or trimethyl orthoformate to acetic anhydride is 1.0:1.0 to 2.0:1.0 to 3.0.
The second method is as follows: the N-acyl glycine is obtained as an intermediate of formula II in a plurality of steps, firstly in POCl 3 Reacting under DMF condition to obtain intermediate VI, hydrolyzing under 2N NaOH/ethanol condition at room temperature to obtain intermediate VII, and methylation reacting intermediate VII with dimethyl sulfate to obtain intermediate II.
R 2 ＝Me，Ph
Wherein the N-acyl glycine derivative and POCl 3 DMF molar ratio of 1.0:2.0 to 3.0:2.0 to 3.0; the molar ratio of the intermediate formula VI to NaOH is 1.0:1.0 to 1.5; intermediate formula VII, dimethyl sulfate and alkali mole ratio of 1.0:1.0 to 3.0:1.0 to 3.0, wherein the alkali can be sodium hydroxide, potassium hydroxide, triethylamine, potassium carbonate and sodium carbonate.
(2) The 4- (alkoxymethylene) -2-alkyl oxazolone intermediate of formula II reacts with N- (1-cyclopentenyl) amine at room temperature to produce intermediate of formula III.
R (R) N- =morpholinyl, cyclopentylamino, cyclohexylamino
R 1 ＝Me，Et
R 2 ＝Me，Ph
In particular embodiments, the N- (1-cyclopentenyl) amine is N- (1-cyclopentenyl) morpholine, N- (1-cyclopentenyl) cyclopentylamine, N- (1-cyclopentenyl) cyclohexylamine, and the molar ratio of intermediate II to enamine is 1.0:1.0 to 1.5, and the solvent can be selected from dichloromethane, tetrahydrofuran, acetonitrile, ethyl acetate, methanol and ethanol.
(3) Under the condition of catalytic amount of alkyl alkoxide, the oxazolone mother nucleus is ring-opened to generate unsaturated amino acid intermediate as shown in the formula IV.
R (R) N- =morpholinyl, cyclopentylamino, cyclohexylamino
R 2 ＝Me，Ph
R 3 ＝Me，Et
In a specific embodiment the alkyl alkoxide is sodium methoxide, sodium ethoxide, under conditions selected to be 5 to 20 mole% sodium methoxide or sodium ethoxide, methanol or ethanol reflux, preferably 10 mole% sodium methoxide or sodium ethoxide, methanol or ethanol reflux.
(4) In the presence of hydrogen, the intermediate formula IV is prepared into an enantiomerically enriched intermediate formula V by using a transition metal rhodium-chiral phosphine ligand complex catalyst.
R=morpholine, cyclopentylamine, cyclohexylamine
R 2 ＝Me，Ph
R 3 ＝Me，Et
Intermediate formula V includes formulas Va and Vb
The preferred chiral phosphine-transition metal catalyst has the general formula [ M (L) (P ]]X, wherein M is Rh, ru or Ir; l is 1, 5-cyclooctadiene or 2, 5-norbornadiene; p (P) * Is a chiral phosphine compound, e.g. ScRp-DuanPhos, rcSp-DuanPhos, SSRR-Tangphos, RRSS-TangPhos, (R) -BINAP, (S) -BINAP, duPhos, BPE; x is BF 4 ,ClO 4 ,SbF 6 ,PF 6 ,CF 3 SO 3 RCOO or mixtures thereof, B (Ar) 4 Wherein Ar is fluorophenyl or 3, 5-di-trifluoromethyl-1-phenyl.
In a preferred embodiment, M is Rh, ru or Ir; l is 1, 5-cyclooctadiene or 2, 5-norbornadiene; p is (2R, 5R) -Me-Duphos, (2S, 5S) -Me-Duphos, (2R, 5R) -Et-Duphos, (2S, 5S) -Et-Duphos, X is BF 4 。
In at least one embodiment of this step, the hydrogen pressure may be between 10 and 50bar,
the converted reaction medium is selected from one or more of dichloromethane, methanol, tetrahydrofuran, toluene and ethyl acetate; preferably dichloromethane, methanol or tetrahydrofuran; further preferred is dichloromethane. Suitable reaction temperatures for intermediate IV to intermediate V are from 10 to 50℃and preferably from 20 to 30 ℃.
The present invention provides two enantiomers of intermediate formula V (including formulas Va and Vb) by use of different chiral catalysts. In a specific embodiment of this aspect, [ Rh (COD) (2S, 5S-Me-DuPhos)]BF 4 Or [ Rh (COD) (2S, 5S-Et-DuPhos)]BF 4 As a catalyst, R-configuration intermediate formula Va was obtained using [ Rh (COD) (2R, 5R-Me-DuPhos)]BF 4 Or [ Rh (COD) (2R, 5R-Et-DuPhos)]BF 4 And (3) preparing an S-configuration intermediate formula Vb by using the catalyst.
(5) The intermediate formula vb is firstly subjected to N-acyl protecting group removal and enamine hydrolysis under the heating condition of a hydrochloric acid solution to generate an intermediate formula VIII, and then palladium hydro-carbon is subjected to heating and pressurizing conditions to generate the azabicyclo [3, 0] octane-3 (S) -carboxylic acid of the formula I.
In a specific embodiment the hydrochloric acid solution is a 6N hydrochloric acid solution, and this step may be carried out in a polar solvent, such as one or more of water, methanol, ethanol and acetic acid, at a hydrogen pressure of 5 to 15bar and a reaction temperature of 20 to 80 ℃. The reaction is preferably carried out in acetic acid at 40 ℃.
Example 1: preparation of 4- (alkoxymethylene) -2-alkyl oxazolone intermediate formula II
The method comprises the following steps: preparation of 4- (ethoxymethylene) -2-phenyloxazolone
To a 100mL three-necked flask equipped with a stirrer, a thermometer and a reflux tube were added 25g of hippuric acid under argon atmosphere, 24mL of triethyl orthoformate and 26mL of acetic anhydride were added at room temperature, and the mixture was refluxed at 130℃for 30 minutes. After the reaction was completed, the reaction solution was cooled to room temperature. Under ice bath condition, saturated NaHCO is added 3 Until no bubbles are generated. The reaction solution was extracted three times with 50mL of diethyl ether (50 mL. Times.3), the organic phases were combined, washed with saturated brine once, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure to give a thick solid, which was recrystallized from 100mL of isopropyl alcohol to give 15g of pale red solid in 49% yield.
1 HNMR(500MHz,CDCl 3 )：δ8.12–8.04(m,1H),7.60–7.52(m,1H),7.51–7.45(m,1H),7.35(s,1H),4.44(q,J＝7.1Hz,1H),1.50(t,J＝7.1Hz,2H)。
The second method is as follows: preparation of 4- (methoxymethylene) -2-phenyloxazolone
9g of hippuric acid is added into a two-port bottle with 100mL of stirrer, 10mL of LDMF and argon are added for protection, 12mL of phosphine oxide trichloride (more than 1 h) is slowly added through a syringe under the ice bath condition, the reaction is continued for 30min after the dripping is finished, and the reaction is carried out at room temperature for 2h. After the reaction is finished, saturated NaHCO is added under the ice bath condition 3 The solution was left until no bubbles were generated. The reaction mixture was extracted three times with 50mL of methylene chloride (50 mL. Times.3), washed with saturated brine once, and the solvent was removed under reduced pressure to give 10.6g of yellow product VI, which was used in the next step without purification in 90% yield. Adding the product of the previous step into 50mL of ethanolNitrile and 35mL 2N NaOH were reacted overnight at room temperature. After the reaction was completed, the solvent was removed under reduced pressure, filtered, and rinsed with a small amount of acetonitrile to obtain 9.8g of a white solid product VII, which was used in the next step without purification. 50mL of the above-mentioned 9.8-product VII was added, 9.8g of potassium carbonate was added under the protection of argon, 8.5mL of dimethyl sulfate was added, and the mixture was reacted at 60℃for 5 hours. After completion of the reaction, water was added thereto, and the reaction mixture was extracted three times with 50mL of methylene chloride (50 mL. Times.3), washed once with saturated brine, and the solvent was removed under reduced pressure to obtain 7.8g of a product. The total yield was 76%.
Example 2: preparation of intermediate III
To a 50mL two-necked flask equipped with a stirrer was added 3.0g of 4- (ethoxymethylene) -2-phenyloxazolone under argon protection, 20mL of anhydrous methylene chloride was added, and 2.3. 2.3g N- (1-cyclohexenyl) piperidine (85% purity) was added at room temperature to react for three hours at room temperature. After the reaction was completed, the organic solvent was removed under reduced pressure to give a yellow solid product, which was used directly in the next step without purification.
Example 3: preparation of intermediate formula IV
The intermediate II obtained in example 2 was put into a 50mL two-necked flask equipped with a stirrer, and was purged with argon, and 30mL of an anhydrous methanol solution and 1.5mL of a sodium methoxide methanol solution (1 mol/L) were added at room temperature, followed by refluxing for 1 hour. The reaction solution was cooled to room temperature and filtered to give 3.5g of a yellow solid with a yield of 75% in two steps.
1 H NMR(500MHz,CDCl 3 )：δ8.44(s,1H),7.82(d,J＝7.1Hz,2H),7.51(t,J＝7.3Hz,1H),7.44(t,J＝7.5Hz,2H),7.21(s,1H),3.80(s,3H),2.97(s,4H),2.26(t,J＝5.7Hz,2H),2.13(t,J＝5.8Hz,2H),1.67-1.63(m,2H),1.60-1.58(m,4H),1.56–1.48(m,4H)。
Example 4: preparation of intermediate Va
To the autoclave, 360mg (1 mmol) of intermediate IV, 15mL of methylene chloride and 1mol% [ Rh (COD) (2R, 5R-Me-DuPhos) were charged]BF 4 The autoclave was hydrogenated to 2Obar and stirred at room temperature for 6h. After the reaction was completed, the organic solvent was directly removed under reduced pressure to obtain 150mg of oily product Va.
Example 5: preparation of (2S, 3aS,7 aS) -octahydroindole-2-carboxylic acid
To 150mg of the oil obtained in example 4 was added 1mL of 6N HC1, and the mixture was refluxed overnight. Cooled to room temperature, and the reaction was extracted twice with MTBE (2X 3 mL). The aqueous phase was concentrated to dryness under reduced pressure to give a solid which was used directly in the next step without further purification. The reaction mixture was charged into a high-pressure autoclave by adjusting p H to 1-2 with hydrochloric acid, 3mg l of 0% palladium on carbon was then added, and the mixture was pressurized to l0bar with hydrogen and reacted at 80C overnight. The reaction system was cooled and then hydrogen was slowly released. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. Concentrating, drying, and recrystallizing with acetone to obtain the hydrochloride of the target product.
The invention describes a preparation method of perindopril main intermediate (2S, 3aS,7 aS) -octahydroindole-2-carboxylic acid in detail, and the preparation method has the characteristics of easily available raw materials, simple process, convenient operation, higher yield, low cost and the like, has potential industrialization value, and accords with the development direction of green chemistry.
Although the invention has been described with respect to preferred embodiments and methods of use, it should be understood that alternatives, modifications, and variations are possible without departing from the spirit of the invention. Accordingly, all such alternatives, modifications and variations as may be contemplated by those skilled in the art are within the scope of the present invention.
Claims (10)
1. Synthesis method of enantiomerically enriched (2S, 3aS,7 aS) -octahydroindole-2-carboxylic acid shown in formula I
The method is characterized by comprising the following steps of:
(1) The N-acyl glycine derivative is reacted in one step or multiple steps to obtain a 4- (alkoxymethylene) -2-alkyl oxazolone intermediate formula II;
wherein R is 1 Is methyl or ethyl, R 2 Is phenyl or methyl;
(2) Reacting the intermediate formula II with various N- (1-cyclohexenyl) amines to generate an intermediate formula III;
wherein R is 2 As mentioned above, R is independently selected from C 1 ～C 6 Alkyl, or R is connected with N and the other R to form a five-membered or six-membered ring, wherein the five-membered or six-membered ring can contain O;
(3) Under the condition of catalytic amount of alkyl alkoxide, the oxazolone mother nucleus is ring-opened to generate unsaturated amino acid intermediate formula IV;
wherein R, R 2 As described above, R 3 Methyl or ethyl;
(4) Generating an enantiomer enrichment intermediate formula V in the presence of a transition metal rhodium-chiral phosphine ligand complex catalyst, wherein the enantiomer enrichment intermediate formula V comprises a formula Va and a formula Vb;
wherein R, R 2 ，R 3 As described above, formula Va is in the R configuration and Vb is in the S configuration;
(5) The intermediate type vb is firstly subjected to N-acyl protecting group removal and enamine hydrolysis under the heating condition of hydrochloric acid solution, and then palladium hydrocarbon is subjected to heating and pressurizing conditions to generate (2S, 3aS,7 aS) -octahydroindole-2-carboxylic acid of the formula I.
2. The synthesis method according to claim 1, wherein: the synthesis method of the 4- (alkoxymethylene) -2-alkyl oxazolone intermediate in the formula II can be a method I or a method II:
the method comprises the following steps: the N-acyl glycine derivative and triethyl orthoformate or trimethyl orthoformate are reacted in acetic anhydride solvent at 100-130 deg.c to produce intermediate II;
the second method is as follows: the N-acylglycine derivatives can be obtained in a plurality of steps as intermediates of formula II, first in POCl 3 Reacting under DMF condition to obtain intermediate formula VI, hydrolyzing under NaOH aqueous solution/organic solvent condition at room temperature to obtain intermediate formula VII, and methylation reacting intermediate formula VII with dimethyl sulfate under alkali to obtain intermediate formula II
3. The synthesis method according to claim 2, wherein: in the first method, the molar ratio of the N-acyl glycine derivative to the triethyl orthoformate or the trimethyl orthoformate to the acetic anhydride is 1.0:1.0-2.0:1.0-3.0; the N-acylglycine derivative is preferably N-methylglycine or N-phenylglycine.
4. The synthesis method according to claim 2, wherein: in method two, N-acyl glycine derivative and POCl 3 DMF molar ratio of 1.0:2.0 to 3.0:2.0 to 3.0; the molar ratio of the intermediate formula VI to NaOH is 1.0:1.0 to 1.5; intermediate formula VII, dimethyl sulfate and alkali mole ratio of 1.0:1.0 to 3.0:1.0 to 3.0, wherein the alkali can be one or more of sodium hydroxide, potassium hydroxide, triethylamine, potassium carbonate and sodium carbonate.
5. The synthesis method according to claim 1, wherein: reacting the intermediate II with various enamines to obtain an intermediate III, wherein the selected condition is that the molar ratio of the intermediate II to the enamine is 1.0:1.0 to 1.5, and the solvent can be selected from one or more of dichloromethane, tetrahydrofuran, acetonitrile, ethyl acetate, methanol and ethanol.
6. The synthesis method according to claim 1, wherein: intermediate formula III forms an intermediate formula IV reaction, and the selected conditions are 10mol percent sodium methoxide or sodium ethoxide, methanol or ethanol reflux.
7. The synthesis method according to claim 1, wherein: intermediate formula IV generates intermediate formula V reaction, transition metal-chiral phosphine ligand complex catalyst structure is: m (L) (P) X, wherein M is Rh; l=1, 5-cyclooctadiene; the reaction medium can be dichloromethane, methanol, tetrahydrofuran, acetonitrile, ethyl acetate, toluene or a mixed solvent; the P is BINAP series, scRp-DuanPhos, rcSp-DuanPhos, SSRR-TangPhos, RRSS-TangPhos, duPhos series such as Me-DuPhos, or BPE; the temperature is 10-100 ℃.
8. The method of synthesis according to claim 7, wherein: the catalyst is [ Rh (cod) (2R, 5R-Me-Duphos)]BF 4 、[Rh(cod)(2S,5S-Me-Duphos)]BF 4 、[Rh(cod)(2R,5R-Et-Duphos)]BF 4 、[Rh(cod)(2R,5R-Et-Duphos)]BF 4 。
9. The method of synthesis according to claim 7, wherein: the reaction temperature is 20-30 ℃.
10. The method of synthesis according to claim 7, wherein: the hydrogen pressure is 10-50 bar.
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| PCT/CN2022/134880 WO2023098640A1 (en) | 2021-11-30 | 2022-11-29 | Preparation method for drug intermediate |
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