CN116891879A - Synthesis method of buvaracetam key intermediate - Google Patents
Synthesis method of buvaracetam key intermediate Download PDFInfo
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- CN116891879A CN116891879A CN202311153556.XA CN202311153556A CN116891879A CN 116891879 A CN116891879 A CN 116891879A CN 202311153556 A CN202311153556 A CN 202311153556A CN 116891879 A CN116891879 A CN 116891879A
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- 238000001308 synthesis method Methods 0.000 title claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 127
- 238000006243 chemical reaction Methods 0.000 claims abstract description 65
- 238000000034 method Methods 0.000 claims abstract description 37
- NVTUTJMZAZZKAZ-ZCFIWIBFSA-N (4r)-4-propyloxolan-2-one Chemical compound CCC[C@H]1COC(=O)C1 NVTUTJMZAZZKAZ-ZCFIWIBFSA-N 0.000 claims abstract description 21
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 17
- 150000001299 aldehydes Chemical class 0.000 claims abstract description 16
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 15
- 108010031132 Alcohol Oxidoreductases Proteins 0.000 claims abstract description 13
- 102000005751 Alcohol Oxidoreductases Human genes 0.000 claims abstract description 13
- -1 acidAn ester Chemical class 0.000 claims abstract description 10
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 9
- 230000009471 action Effects 0.000 claims abstract description 6
- 230000009467 reduction Effects 0.000 claims abstract description 6
- 230000006340 racemization Effects 0.000 claims abstract description 4
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 3
- 238000003756 stirring Methods 0.000 claims description 45
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 23
- 239000002904 solvent Substances 0.000 claims description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 18
- 239000002253 acid Substances 0.000 claims description 17
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 16
- 239000003960 organic solvent Substances 0.000 claims description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 14
- 238000002156 mixing Methods 0.000 claims description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- HHLFWLYXYJOTON-UHFFFAOYSA-N glyoxylic acid Chemical compound OC(=O)C=O HHLFWLYXYJOTON-UHFFFAOYSA-N 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 238000010992 reflux Methods 0.000 claims description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-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
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- HGBOYTHUEUWSSQ-UHFFFAOYSA-N pentanal Chemical compound CCCCC=O HGBOYTHUEUWSSQ-UHFFFAOYSA-N 0.000 claims description 8
- 239000007868 Raney catalyst Substances 0.000 claims description 7
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 7
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical group [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 7
- 239000003054 catalyst Substances 0.000 claims description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 7
- 235000011181 potassium carbonates Nutrition 0.000 claims description 7
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 6
- 108010050375 Glucose 1-Dehydrogenase Proteins 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 102000004357 Transferases Human genes 0.000 claims description 6
- 108090000992 Transferases Proteins 0.000 claims description 6
- 239000008103 glucose Substances 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 5
- 238000009835 boiling Methods 0.000 claims description 5
- 229910052751 metal Inorganic materials 0.000 claims description 5
- 239000002184 metal Substances 0.000 claims description 5
- 239000006174 pH buffer Substances 0.000 claims description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 239000006184 cosolvent Substances 0.000 claims description 4
- 235000019441 ethanol Nutrition 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 229910017604 nitric acid Inorganic materials 0.000 claims description 4
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 2
- 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 claims 1
- DSVGQVZAZSZEEX-UHFFFAOYSA-N [C].[Pt] Chemical compound [C].[Pt] DSVGQVZAZSZEEX-UHFFFAOYSA-N 0.000 claims 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims 1
- RPNNPZHFJPXFQS-UHFFFAOYSA-N methane;rhodium Chemical compound C.[Rh] RPNNPZHFJPXFQS-UHFFFAOYSA-N 0.000 claims 1
- NCPHGZWGGANCAY-UHFFFAOYSA-N methane;ruthenium Chemical compound C.[Ru] NCPHGZWGGANCAY-UHFFFAOYSA-N 0.000 claims 1
- 229940098779 methanesulfonic acid Drugs 0.000 claims 1
- 238000005728 strengthening Methods 0.000 claims 1
- 101001110310 Lentilactobacillus kefiri NADP-dependent (R)-specific alcohol dehydrogenase Proteins 0.000 abstract description 4
- 238000000746 purification Methods 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 23
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 16
- 229940011051 isopropyl acetate Drugs 0.000 description 16
- GWYFCOCPABKNJV-UHFFFAOYSA-M isovalerate Chemical compound CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- 238000002360 preparation method Methods 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 9
- 239000000543 intermediate Substances 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- 239000000872 buffer Substances 0.000 description 7
- 230000000052 comparative effect Effects 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 230000001502 supplementing effect Effects 0.000 description 6
- MSYKRHVOOPPJKU-BDAKNGLRSA-N brivaracetam Chemical compound CCC[C@H]1CN([C@@H](CC)C(N)=O)C(=O)C1 MSYKRHVOOPPJKU-BDAKNGLRSA-N 0.000 description 5
- 229960002161 brivaracetam Drugs 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 3
- 206010010904 Convulsion Diseases 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 2
- 239000007983 Tris buffer Substances 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000003556 anti-epileptic effect Effects 0.000 description 2
- 239000001961 anticonvulsive agent Substances 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- DMEGYFMYUHOHGS-UHFFFAOYSA-N cycloheptane Chemical compound C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- HNNJFUDLLWOVKZ-VKHMYHEASA-N (2s)-2-aminobutanamide Chemical compound CC[C@H](N)C(N)=O HNNJFUDLLWOVKZ-VKHMYHEASA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010061334 Partial seizures Diseases 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- 238000009098 adjuvant therapy Methods 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 230000001037 epileptic effect Effects 0.000 description 1
- VRZVPALEJCLXPR-UHFFFAOYSA-N ethyl 4-methylbenzenesulfonate Chemical compound CCOS(=O)(=O)C1=CC=C(C)C=C1 VRZVPALEJCLXPR-UHFFFAOYSA-N 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P7/00—Preparation of oxygen-containing organic compounds
- C12P7/62—Carboxylic acid esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
- C07D307/32—Oxygen atoms
- C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
- C12P41/002—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by oxidation/reduction reactions
-
- 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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- Engineering & Computer Science (AREA)
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- Life Sciences & Earth Sciences (AREA)
- Wood Science & Technology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Microbiology (AREA)
- General Chemical & Material Sciences (AREA)
- Biotechnology (AREA)
- Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
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Abstract
The invention discloses a method for synthesizing a key intermediate of buvaracetam, belonging to the technical field of chemical synthesis. The synthesis method comprises the following steps:v (V)
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to a method for synthesizing a key intermediate of buvaracetam.
Background
Brivaracetam (Brivaracetam) is a third generation antiepileptic developed by belgium-time-of-day (UCB) and used for the treatment of partial seizures in adult and adolescent epileptic patients older than 16 years with or without concomitant adjuvant therapy of secondary systemic seizures. It has entered the three-phase clinical stage in china. Compared with other antiepileptic chemicals, the preparation has the advantages of small dosage of the brivaracetam and good tolerance.
Two intermediates are mainly required for the synthesis of the brivaracetam, and chemical names are respectively as follows: (R) -3-propyl-gamma-butyrolactone and (S) - (+) -2-aminobutanamide. The three structural formulas are as follows:
wherein the synthesis of (R) -3-propyl-gamma-butyrolactone is the most critical.
According to the inquired published patent, the synthesis of (R) -3-propyl-gamma-butyrolactone reaches tens of routes. However, by looking at the disclosed synthesis method, the defects of harsh reaction conditions, large impurities in the reaction process, multiple times of resolution in the later period and the like generally exist, and the (R) -3-propyl-gamma-butyrolactone intermediate with high purity is difficult to obtain.
Disclosure of Invention
In order to solve the defects of the prior art, the invention aims to provide a method for synthesizing a key intermediate of the brivaracetam, which has mild reaction conditions and high purity of the obtained (R) -3-propyl-gamma-butyrolactone intermediate.
In order to achieve the above purpose, the technical scheme of the invention is as follows:
in a first aspect of the present invention,
a method for synthesizing a key intermediate of buvaracetam comprises the following steps:
step 1: mixing a compound of formula V, glucose, a cosolvent and a pH buffer, and stirring; sequentially adding glucose dehydrogenase, hydrogen transferase and aldehyde ketone reductase, stirring at room temperature for reaction, controlling the pH value to be 6.9-7.1, and obtaining a compound shown in a formula VI after the reaction is finished;
the aldehyde ketone reductase is aldehyde ketone reductase which only selects the compound of the formula V with the R configuration for reduction, and the rest compound of the formula V with the S configuration is continuously converted into the compound of the formula V with the R configuration in a reaction system through racemization;
v-type VI
Step 2: the compound of formula VI is catalyzed by acid to generate single chiral (R) -3-propyl-gamma-butyrolactone.
The invention skillfully utilizes aldehyde ketoreductase which only selects the compound of the formula V with R configuration to reduce, the rest compound of the formula V with S configuration is racemized by itself to continuously convert into the compound of the formula V with R configuration, and finally, the compound of the formula VI with R configuration is only obtained. The treatment process is simple, the treatment capacity is large, expensive HPLC chiral resolution is avoided, and the synthesis cost is greatly reduced.
In some embodiments of the invention, the method of operation of step 1 is as follows:
mixing a compound of formula V, glucose, a cosolvent and a pH buffer, and stirring; sequentially adding glucose dehydrogenase, hydrogen transferase and aldehyde ketone reductase, stirring at room temperature for reaction, controlling the pH value to be 6.9-7.1, and reacting for 48-72 h to obtain the compound shown in the formula VI after the reaction is finished.
Wherein the weight ratio of the compound of formula V to glucose to aldehyde ketoreductase to glucose dehydrogenase to hydrogen transferase is 1:1.5:0.02:0.01:0.01.
wherein the reaction temperature is 0 ℃ to 50 ℃, preferably 20 ℃ to 40 ℃, and more preferably 28 ℃ to 30 ℃.
Wherein the pH buffer is 0.1M PBS buffer, 0.2M PBS buffer, 0.1M triethanolamine buffer, 0.2M triethanolamine buffer, 0.1M tris buffer or 0.2M tris buffer, preferably 0.1M PBS buffer. Wherein the weight to volume ratio of the compound of formula V to the pH buffer is 1:1 to 100, preferably 1:20 to 50, more preferably 1:30.
wherein the co-solvent includes, but is not limited to, ethyl acetate, tetrahydrofuran, acetonitrile, glycerol, and methyl tert-butyl ether, preferably acetonitrile. Wherein the weight to volume ratio of the compound of formula V to acetonitrile is 1:1 to 10, preferably 1:3.
in some embodiments of the invention, the method of operation of step 2 is as follows:
and mixing the compound shown in the formula VI, an organic solvent and acid, heating to a micro reflux state, and reacting for 2-4 h to obtain (R) -3-propyl-gamma-butyrolactone.
Wherein the molar ratio of the compound of formula VI to the acid is 1:0.1 to 1, preferably 1:0.1 to 0.5, more preferably 1:0.2.
wherein the reaction temperature is 0 ℃ to 80 ℃, preferably 20 ℃ to 50 ℃, and more preferably 35 ℃ to 39 ℃.
Wherein the organic solvent includes, but is not limited to, ethyl acetate, isopropyl acetate, absolute ethanol, isopropanol, tetrahydrofuran and dichloromethane, preferably dichloromethane. Wherein the weight to volume ratio of the compound of formula VI to dichloromethane is 1:1 to 20, preferably 1:5 to 10, more preferably 1:8.
wherein the acid is hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, nitric acid or acetic acid, preferably p-toluenesulfonic acid.
In some embodiments of the invention, the method of synthesizing the compound of formula v comprises the steps of:
s1: reacting valeraldehyde with glyoxylic acid under the action of morpholine and strong acid to generate a compound shown in a formula I;
s2: reacting a compound of the formula I with absolute ethyl alcohol under the catalysis of weak acid to generate a compound of the formula II;
formula I formula II
S3: the compound of the formula II is catalyzed and hydrogenated by a metal catalyst to generate a compound of the formula III;
III IV
S4: removing ethanol from the compound of the formula III in a high boiling point solvent by reflux to generate a compound of the formula IV;
s5: the compound of formula IV reacts with p-toluenesulfonyl ethyl ester under the action of alkali to generate the compound of formula V.
In some embodiments of the invention, in S1, the strong acid is sulfuric acid, hydrochloric acid, nitric acid, perchloric acid, hydrobromic acid or formic acid, preferably hydrochloric acid.
In some embodiments of the invention, in S2, the weak acid is p-toluene sulfonic acid, acetic acid, methyl sulfonic acid, phosphoric acid or carbonic acid, preferably p-toluene sulfonic acid.
In some embodiments of the invention, in S3, the metal catalyst is raney nickel, palladium on carbon, platinum on carbon, rhodium on carbon or ruthenium on carbon, preferably raney nickel.
In some embodiments of the invention, in S4, the high boiling point solvent is pure water, toluene, xylene, N-dimethylformamide DMF or dimethyl sulfoxide DMSO, preferably pure water.
In some embodiments of the invention, in S5, the base is sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide, preferably potassium carbonate.
In some embodiments of the invention, the method of operation of S1 is as follows:
dissolving morpholine in an organic solvent, dropwise adding glyoxylic acid into the morpholine solution, and stirring for 1-3 h after the dropwise adding is finished; and then dripping valeraldehyde, stirring for 15-20 h after dripping, dripping concentrated hydrochloric acid after reacting, and stirring for 6-10 h to generate the compound shown in the formula I.
Wherein, the mol ratio of valeraldehyde, glyoxylic acid, morpholine and hydrochloric acid is 1: 1-3: 1-3: 1 to 3, preferably 1: 1-1.5: 1-1.5: 1 to 1.5, more preferably 1:1.1:1.2:1.7.
wherein the reaction temperature is-20 ℃ to 50 ℃, preferably-10 ℃ to 10 ℃, and more preferably 0 ℃ to 5 ℃.
Wherein the organic solvent is one of alkane solvents such as n-pentane, n-hexane, n-heptane, cyclohexane, cycloheptane, and the like, and is preferably n-heptane. Wherein the weight volume ratio of valeraldehyde to n-heptane is 1:2 to 10, preferably 1:3 to 6, more preferably 1:3.6.
in some embodiments of the invention, the method of operation of S2 is as follows: and mixing absolute ethyl alcohol, the compound of the formula I, p-toluenesulfonic acid and an organic solvent, stirring and heating to a reflux state, and reacting for 12-15 h to obtain the compound of the formula II.
Wherein, the mol ratio of the compound of the formula I, the p-toluenesulfonic acid and the absolute ethyl alcohol is 1: 0.1-1: 1 to 200, preferably 1:0.1 to 0.5:1 to 100, more preferably 1:0.1:12.2.
wherein the reaction temperature is 0 ℃ to 100 ℃, preferably 50 ℃ to 80 ℃, and more preferably 70 ℃ to 75 ℃.
Wherein the organic solvent is a linear-chain normal alcohol such as absolute methanol, absolute ethanol, absolute n-propanol, absolute n-butanol, etc., preferably absolute ethanol. Wherein the weight-volume ratio of the compound of the formula I to the absolute ethyl alcohol is 1:1 to 10, preferably 1:3 to 6, more preferably 1:5.
in some embodiments of the invention, the method of operation of S3 is as follows:
mixing an organic solvent, a compound of the formula II and Raney nickel, stirring and heating, replacing air in a reaction device with nitrogen, replacing nitrogen with hydrogen, and then starting the reaction, and reacting for 3-5 hours to obtain the compound of the formula III.
Wherein the mass ratio of the compound of the formula II to the Raney nickel is 1:0.1 to 1, preferably 1:0.1 to 0.5, more preferably 1:0.15.
wherein the reaction temperature is 0 ℃ to 50 ℃, preferably 20 ℃ to 40 ℃, and more preferably 25 ℃ to 30 ℃.
Wherein the organic solvent includes, but is not limited to, ethyl acetate, isopropyl acetate, 95% ethanol, absolute ethanol, and isopropanol, preferably isopropyl acetate or isopropanol, and more preferably isopropyl acetate. Wherein the weight-to-volume ratio of the compound of the formula II to isopropyl acetate is 1:1 to 10, preferably 1:3 to 6, more preferably 1:5.
in some embodiments of the invention, the method of operation of S4 is as follows:
and mixing pure water with the compound shown in the formula III, stirring and heating to a micro-reflux state, and preserving heat for 2-4 hours to obtain the compound shown in the formula IV.
Wherein the reaction temperature is 0 ℃ to 150 ℃, preferably 80 ℃ to 110 ℃, and more preferably 90 ℃ to 95 ℃.
Wherein the weight ratio of the compound of formula III to pure water is 1:1 to 25, preferably 1:1 to 15, more preferably 1:10.
in some embodiments of the invention, the method of operation of S5 is as follows:
mixing an organic solvent and a compound shown in a formula IV, stirring, adding potassium carbonate, and stirring for 1-2 h; and then adding p-toluenesulfonyl ethyl ester, and continuing stirring for 20-25 hours to obtain the compound of the formula V.
Wherein, the mol ratio of the compound of the formula IV, potassium carbonate and ethyl p-toluenesulfonate is 1: 1-3: 1 to 3, preferably 1: 1-1.5: 1 to 2, more preferably 1:1.2:1.5.
wherein the reaction temperature is-10 ℃ to 50 ℃, preferably 10 ℃ to 30 ℃, and more preferably 15 ℃ to 20 ℃.
Among them, the organic solvents include, but are not limited to, ethyl acetate, isopropyl acetate, acetone, absolute ethanol, isopropyl alcohol and toluene, preferably isopropyl acetate. Wherein the weight-to-volume ratio of the compound of the formula IV to isopropyl acetate is 1:1 to 10, preferably 1:3 to 6, more preferably 1:4.
the beneficial effects of the invention are as follows:
the method for synthesizing the buvaracetam key compound has the advantages of easily available raw materials, simple reaction operation, mild reaction conditions and easy control. The aldehyde ketone reductase which is reduced by only selecting the compound of the formula V with the R configuration is skillfully utilized, the rest compound of the formula V with the S configuration is racemized by itself and continuously converted into the compound of the formula V with the R configuration, and finally, the compound of the formula VI with the R configuration is only obtained. The treatment process is simple, the treatment capacity is large, expensive HPLC chiral resolution is avoided, and the synthesis cost is greatly reduced.
In the method for synthesizing the buvaracetam key compound (R) -3-propyl-gamma-butyrolactone, aldehyde ketone reductase which only selects the compound of the formula V with R configuration for reduction is adopted for chiral reduction of the compound of the formula V, and the rest compound of the formula V with S configuration can be continuously converted into the compound of the formula V with R configuration through racemization in a reaction system, so that the yield of the (R) -3-propyl-gamma-butyrolactone in the reaction step is high and can reach 95% -97%, the purity is also high (ee value is up to 99%), the quality requirement can be met without resolution or further purification, and the overall synthesis cost is more advantageous.
Detailed Description
In order to enable those skilled in the art to more clearly understand the technical scheme of the present invention, the technical scheme of the present invention will be described in detail with reference to specific embodiments.
The aldehyde ketoreductase enzymes used in the examples below were purchased from tsuzhou hanse biotechnology limited.
Example 1
A synthetic method of a key intermediate (R) -3-propyl-gamma-butyrolactone of buvaracetam comprises the following synthetic route:
the method comprises the following steps:
in a first step, the preparation of a compound of formula I
N-heptane (155 ml), morpholine (52.27 g,0.6 mol) were added to the reaction flask and stirred for 10 min. Then, the temperature was controlled by ice bath, and 50% glyoxylate (81.44 g,0.55 mol) was added dropwise. The temperature is controlled to be not more than 40 ℃. After the completion of the dropwise addition, stirring was continued at this temperature for 2 h. Then valeraldehyde (43.06 g,0.5 mol) was added dropwise while controlling the temperature at not more than 40 ℃. After the completion of the dropwise addition, stirring at this temperature was continued for 18 h. TLC then detects the progress of the reaction (PE: ea=3:1), and after completion of the reaction Wen Dijia concentrated hydrochloric acid 87 g is controlled, and stirring is continued at this temperature for 6 h. The n-heptane layer was separated and the aqueous phase was further washed with 100 ml n-heptane to remove impurities. The aqueous phase was then extracted with 200 ml of x 2 dichloromethane. The solvent was recovered under reduced pressure to give the compound of formula I (black oil) 57.57 g in 81% yield.
In a second step, the compounds of formula II
Absolute ethanol (284.3 ml), a compound of formula i (56.86 g,0.4 mol), p-toluene sulfonic acid (7.12 g,0.04 mol) were added to a 500 ml reaction flask and stirred to raise the temperature. The temperature is raised to a micro-reflux state to react 12 h. The solvent was then recovered under reduced pressure until no more was distilled off, giving an oil. 120 ml dichloromethane, 120 ml water were then added. And (5) stirring and layering. The wash with 120 ml water was continued. The organic phase was dried over anhydrous sodium sulfate, filtered off with suction, and the solvent was recovered under reduced pressure to give the compound of formula ii (oil) 61.27, g in 90% yield.
Third step, preparation of Compounds of formula III
Isopropyl acetate (305, ml), a compound of formula II (61 g,0.358 mol), raney nickel (9.15, g) were added separately to a single port reaction flask and heated to 25-30℃with stirring. The nitrogen balloon was replaced 3 times with air and the hydrogen balloon was replaced 3 times with nitrogen. Then, the hydrogen absorption reaction starts, reaction 3 h. And (5) detecting the raw materials by gas phase, and finishing the consumption of the raw materials. The catalyst was filtered off by suction filtration. The mother liquor was depressurized to recover the solvent. The compound of formula iii (oil) 55 g was obtained in 90.16% yield.
Fourth step, preparation of Compounds of formula IV
Purified water (550 ml), a compound of formula III (55 g,0.319 mol) was added to the reaction flask, stirred and heated to a slightly refluxed state, and incubated for 2.2 h. Then cooling to room temperature, adding isopropyl acetate 120 ml, stirring and layering. And adding isopropyl acetate into the water phase, and stirring and layering. The organic phases were combined and the solvent recovered under reduced pressure to give the compound of formula iv (oil) 39.13 g in 85% yield.
Fifth step, preparation of Compound of formula V
Isopropyl acetate (156 ml), a compound of formula IV (39 g,0.27 mol) was added to a reaction flask and stirred at a temperature of 15℃to 20 ℃. Potassium carbonate (44.86 g,0.325 mol) was then added and stirred for one hour. Then, p-toluenesulfonyl ethyl ester (81.1 g,0.405 mol) was added thereto, and stirring at this temperature was continued for 24. 24 h. Water 200 was then added ml and the layers separated. The organic phase was further washed with water 100 ml, separated, dried over anhydrous sodium sulfate and the solvent recovered under reduced pressure to give the compound of formula V (oil) 40.45 g in 87% yield.
Sixth step, preparation of Compounds of formula VI
The compound of formula v (40 g), glucose (60 g), acetonitrile (120 ml), 0.1M in PBS buffer (1200 ml) were added to the reaction flask. Stirring and controlling the temperature to be 28-30 ℃. Glucose dehydrogenase (0.4 g), hydrogen transferase (0.4 g) and aldehyde ketone reductase (0.8 g) are added in sequence, and the reaction is stirred at the speed of 800 minutes. During which the pH will continue to decrease. And (3) continuously controlling the pH to be between 6.9 and 7.1 by using a pH automatic control liquid supplementing machine to react 48 and h, and stopping liquid supplementing by using the pH automatic control liquid supplementing machine, thus finishing the reaction. Then, methylene chloride 120, 120 ml was added, stirred, filtered, separated, dried over anhydrous sodium sulfate and the solvent was recovered under reduced pressure to give 36.42 g of the compound (oily substance) of the formula VI with an ee value of 99% and a yield of 90%.
Seventh step, preparation of (R) -3-propyl-gamma-butyrolactone compound
The compound of formula VI (36 g,0.206 mol), methylene chloride (288 ml), p-toluene sulfonic acid (7.33 g,0.0412 mol) were added to a reaction flask and heated to a slightly refluxed state for reaction 2 h. Water (288 ml) was then added and the layers were separated with stirring. And then washed once with water 288 ml. Separating liquid and drying with anhydrous sodium sulfate. The solvent was recovered under reduced pressure to give (R) -3-propyl-gamma-butyrolactone 25 as an oil g in a yield of 95% and an ee value of 99%.
[α]D 25 = +5.4 (c 0.2,CHCl 3 ). 1 H NMR (500 MHz, CDCl 3 ): δ 4.41 (dd, J = 10.8 Hz, J= 9.0 Hz, 1H), 3.92 (dd, J = 10.8 Hz, J = 8.4 Hz, 1H), 2.65-2.54 (m,2H), 2.18 (dd, J = 19.8. Hz, J = 9.0 Hz, 1H), 1.47-1.44 (m, 2H), 1.37-1.33 (m, 2H), 0.94(t, J = 8.4 Hz, 3H)
Example 2
A method for synthesizing a buvaracetam key formula (R) -3-propyl-gamma-butyrolactone, which has the same synthetic route as that of example 1, comprises the following steps:
in a first step, the preparation of a compound of formula I
N-heptane (1550 ml), morpholine (522.7 g,6 mol) were added to the flask and stirred for 10 minutes. Then ice bath temperature control, 50% glyoxylate (814.4 g,5.5 mol) was added dropwise, during which the temperature was controlled to be not more than 40 ℃. After the addition was completed, stirring was continued at this temperature for 2 hours. Then valeraldehyde (430.6 g,5.0 mol) was added dropwise while controlling the temperature at not more than 40 ℃. After the completion of the dropwise addition, stirring at this temperature was continued for 18 h. TLC then detects the progress of the reaction (PE: ea=3:1), and after completion of the reaction Wen Dijia concentrated hydrochloric acid 870 g is controlled, stirring is continued at this temperature for 6 h. The n-heptane layer was separated and the aqueous phase was further washed with 1000 n-heptane ml to remove impurities. The aqueous phase was then extracted with 2000 ml of x 2 dichloromethane. The solvent was recovered under reduced pressure to give the compound of formula I (black oil) 580.7 g in 81.7% yield.
In a second step, the compounds of formula II
Absolute ethanol (2903.5 ml), compound of formula I (580.7 g,4.085 mol), p-toluene sulfonic acid (72.98 g,0.41 mol) were added to a 5000 ml reaction flask and stirred to raise the temperature. The temperature is raised to a micro-reflux state to react 12 h. The solvent was then recovered under reduced pressure until no more was distilled off, giving an oil. Then 1200 ml dichloromethane, 1200 ml water are added. And (5) stirring and layering. The wash with 1200 ml water was continued. The organic phase was dried over anhydrous sodium sulfate, suction filtered and the solvent recovered under reduced pressure to give the compound of formula II (oil) 625.7 g in 90% yield.
Third step, preparation of Compounds of formula III
Isopropyl acetate (3128.5 ml), a compound (625.7 g,3.676 mol) of the formula II and Raney nickel (93.8 g) are respectively added into a single-port reaction bottle, and the temperature is raised to 25-30 ℃ by stirring. The nitrogen balloon was replaced 3 times with air and the hydrogen balloon was replaced 3 times with nitrogen. Then, the hydrogen absorption reaction starts, reaction 3 h. And (5) detecting the raw materials by gas phase, and finishing the consumption of the raw materials. The catalyst was filtered off by suction filtration. The mother liquor was depressurized to recover the solvent. The compound of formula iii (oil) 633.08 g was obtained in 93% yield.
Fourth, the preparation of the compound of formula IV:
purified water (6330 ml) and a compound of formula III (633 g,3.675 mol) were added to a reaction flask, stirred and heated to a slightly reflux state, and the temperature was kept at 2 h. Then cooling to room temperature, adding isopropyl acetate 1200 ml, stirring and layering. And adding isopropyl acetate into the water phase, and stirring and layering. The organic phases were combined and the solvent recovered under reduced pressure to give the compound of formula iv (oil) 460.95 g in 87% yield.
Fifth step, preparation of Compound of formula V
Adding isopropyl acetate (1843.8 ml) and a compound (460.95 g,3.197 mol) of formula IV into a reaction bottle, stirring and controlling the temperature between 15 ℃ and 20 ℃. Potassium carbonate (530.17 g,3.836 mol) was then added and stirred for one hour. P-toluenesulfonyl ethyl ester (959.2 g,4.79 mol) was then added and stirring 24 h continued at this temperature. Water 2000 ml was then added and the layers separated. The organic phase was further washed with water 1000 ml, separated, dried over anhydrous sodium sulfate and the solvent recovered under reduced pressure to give the compound of formula V (oil) 501 g in 91% yield.
Sixth step, preparation of Compounds of formula VI
The compound of formula v (501 g), glucose (751.5 g), acetonitrile (1503 ml), 0.1M in PBS buffer (15030 ml) were added to a 30L glass reaction vessel. Stirring and controlling the temperature to be 28-30 ℃. Glucose dehydrogenase (5.01 g), hydrogen transferase (5.01 g) and aldehyde ketone reductase (10.02 g) are added in sequence, and the reaction is stirred at the speed of 800 minutes. During which the pH will continue to decrease. And (3) continuously controlling the pH to be between 6.9 and 7.1 by using a pH automatic control liquid supplementing machine to react 48 and h, and stopping liquid supplementing by using the pH automatic control liquid supplementing machine, thus finishing the reaction. Dichloromethane 1200 ml was then added, stirred, filtered, separated, dried over anhydrous sodium sulfate and the solvent recovered under reduced pressure to give 481.53 g of the compound of formula VI (oil), 99% ee and 95% yield.
Seventh step, preparation of (R) -3-propyl-gamma-butyrolactone compound
The compound of formula VI (481.53 g,2.76 mol), methylene chloride (3852.24 ml) and p-toluene sulfonic acid (94.94 g,0.552 mol) were added to a reaction flask and heated to a slightly refluxed state for reaction 2 h. Water (3852.24 ml) was then added and the layers were separated by stirring. And then washed once with water 3852.24 ml. Separating liquid and drying with anhydrous sodium sulfate. The solvent was recovered under reduced pressure to give (R) -3-propyl-gamma-butyrolactone 343.14 g as an oil in 97% yield and 99% ee.
[α]D 25 = +5.4 (c 0.2,CHCl 3 ). 1 H NMR (500 MHz, CDCl 3 ): δ 4.41 (dd, J = 10.8 Hz, J= 9.0 Hz, 1H), 3.92 (dd, J = 10.8 Hz, J = 8.4 Hz, 1H), 2.65-2.54 (m,2H), 2.18 (dd, J = 19.8. Hz, J = 9.0 Hz, 1H), 1.47-1.44 (m, 2H), 1.37-1.33 (m, 2H), 0.94(t, J = 8.4 Hz, 3H)
The routes described in the literature and patents are repeated to obtain data on yield and purity, which is compared with the data of the present invention:
comparative example 1: method for preparing (R) -3-propyl-gamma-butyrolactone of example 1 in CN 109134406A
Comparative example 2: method for preparing (R) -3-propyl-gamma-butyrolactone of example 2 in CN 109134406A
Comparative example 3: method for preparing (R) -3-propyl-gamma-butyrolactone of example 3 in CN 109134406A
Compound 1 of comparative examples 1, 2 and 3 was prepared by the preparation method of paragraphs 69 to 74 of the specification, which is the same as the "preparation of intermediate I compound in the first step" of the examples of the present invention. The yield of compound 1 was 90%.
The comparison is shown in table 1:
TABLE 1 comparison of the Synthesis of different Buvaracetam intermediates (R) -3-propyl-gamma-butyrolactone
As can be seen from the data in table 1:
compared with comparative examples 1, 2 and 3, the difference between examples 1 and 2 is that the compound of formula IV reacts with p-toluenesulfonyl ethyl ester under the action of alkali to generate the compound of formula V, then the aldehyde ketone reductase which only selects the compound of formula V with R configuration is used for reduction is skillfully used for chiral resolution of the compound of formula V, the rest compound of formula V with S configuration is racemized by itself and continuously converted into the compound of formula V with R configuration, and finally the compound of formula VI with R configuration is only obtained. The method has the advantages of simple treatment process, large treatment capacity, avoiding expensive HPLC chiral resolution, greatly reducing synthesis cost, mild reaction conditions, high yield up to 95%, less impurities and high purity of the obtained (R) -3-propyl-gamma-butyrolactone.
In comparative examples 1, 2 and 3, chiral resolution of the compound 3 was performed by utilizing the difference of the reactions between different chiral molecules and chiral resolving agents, the reaction conditions were severe, the conversion rate was very low, and the yield was 36% at maximum.
The above description is only of the preferred embodiments of the present invention and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A method for synthesizing a buvaracetam key compound is characterized by comprising the following steps of: the method comprises the following steps:
step 1: mixing a compound of formula V, glucose, a cosolvent and a pH buffer, and stirring; sequentially adding glucose dehydrogenase, hydrogen transferase and aldehyde ketone reductase, stirring at room temperature for reaction, controlling the pH value to be 6.9-7.1, and obtaining a compound shown in a formula VI after the reaction is finished;
the aldehyde ketone reductase is aldehyde ketone reductase which only selects the compound of the formula V with the R configuration for reduction, and the rest compound of the formula V with the S configuration is continuously converted into the compound of the formula V with the R configuration in a reaction system through racemization;
v-type VI
Step 2: the compound of formula VI is catalyzed by acid to generate single chiral (R) -3-propyl-gamma-butyrolactone.
2. The synthesis method according to claim 1, wherein: the operation method of the step 2 is as follows:
mixing a compound shown in a formula VI, an organic solvent and acid, heating to a micro reflux state for reaction, and obtaining the (R) -3-propyl-gamma-butyrolactone after the reaction is finished.
3. The synthesis method according to claim 1 or 2, characterized in that: in step 2, the acid is hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, nitric acid or acetic acid.
4. The synthesis method according to claim 1, wherein: the synthesis method of the compound of the formula V comprises the following steps:
s1: reacting valeraldehyde with glyoxylic acid under the action of morpholine and strong acid to generate a compound I;
s2: reacting the compound I with absolute ethyl alcohol under the catalysis of weak acid to generate a compound II;
formula I formula II
S3: the compound of the formula II is catalyzed and hydrogenated by a metal catalyst to generate a compound of the formula III;
III IV
S4: removing ethanol from the compound of the formula III in a high boiling point solvent by reflux to generate a compound of the formula IV;
s5: the compound of formula IV reacts with p-toluenesulfonyl ethyl ester under the action of alkali to generate the compound of formula V.
5. The method of synthesis according to claim 4, wherein: in S1, the strong acid is sulfuric acid, hydrochloric acid, nitric acid, perchloric acid, hydrobromic acid or formic acid;
or, in S2, the weak acid is p-toluenesulfonic acid, acetic acid, methanesulfonic acid, phosphoric acid or carbonic acid;
or in S3, the metal catalyst is Raney nickel, palladium carbon, platinum carbon, rhodium carbon or ruthenium carbon;
or in S4, the high boiling point solvent is water, toluene, dimethylbenzene, N-dimethylformamide DMF or dimethyl sulfoxide DMSO;
or in S5, the alkali is sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide.
6. The method of synthesis according to claim 4, wherein: the operation method of S1 is as follows: dissolving morpholine in an organic solvent, dropwise adding glyoxylic acid into the morpholine solution, and stirring after the dropwise adding is finished; and then dripping valeraldehyde, stirring after dripping, dripping strengthening acid after the reaction is finished, and stirring to generate the compound shown in the formula I.
7. The method of synthesis according to claim 4, wherein: the operation method of S2 is as follows: and mixing absolute ethyl alcohol, the compound shown in the formula I and weak acid, stirring and heating to a reflux state for reaction, and obtaining the compound shown in the formula II after the reaction is completed.
8. The method of synthesis according to claim 4, wherein: the operation method of S3 is as follows: mixing an organic solvent, a compound of the formula II and a metal catalyst, stirring and heating, replacing air in a reaction device with nitrogen, replacing nitrogen with hydrogen, and then starting the reaction to obtain the compound of the formula III after the reaction is finished.
9. The method of synthesis according to claim 4, wherein: the operation method of S4 is as follows: mixing the high boiling point solvent with the compound of the formula III, stirring and heating to a micro-reflux state, preserving heat, and obtaining the compound of the formula IV after the reaction is finished.
10. The method of synthesis according to claim 4, wherein: the operation method of S5 is as follows: mixing the organic solvent with the compound of formula IV, stirring, adding alkali, and stirring again; then adding p-toluenesulfonyl ethyl ester, continuously stirring, and obtaining the compound of the formula V after the reaction is finished.
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