CN116217440A - 一种西他列汀关键中间体的制备方法 - Google Patents
一种西他列汀关键中间体的制备方法 Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- 229960004034 sitagliptin Drugs 0.000 title claims abstract description 19
- MFFMDFFZMYYVKS-SECBINFHSA-N sitagliptin Chemical compound C([C@H](CC(=O)N1CC=2N(C(=NN=2)C(F)(F)F)CC1)N)C1=CC(F)=C(F)C=C1F MFFMDFFZMYYVKS-SECBINFHSA-N 0.000 title claims abstract description 19
- 150000001875 compounds Chemical class 0.000 claims abstract description 38
- 238000000034 method Methods 0.000 claims abstract description 23
- 239000003513 alkali Substances 0.000 claims abstract description 13
- 229940125782 compound 2 Drugs 0.000 claims abstract description 12
- 239000002253 acid Substances 0.000 claims abstract description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 8
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229940125904 compound 1 Drugs 0.000 claims abstract description 6
- 229940126214 compound 3 Drugs 0.000 claims abstract description 6
- 108090000790 Enzymes Proteins 0.000 claims abstract description 5
- 102000004190 Enzymes Human genes 0.000 claims abstract description 5
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 47
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 6
- 108700016171 Aspartate ammonia-lyases Proteins 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
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- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- 239000005515 coenzyme Substances 0.000 claims description 6
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 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
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- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 4
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- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- NGVDGCNFYWLIFO-UHFFFAOYSA-N pyridoxal 5'-phosphate Chemical compound CC1=NC=C(COP(O)(O)=O)C(C=O)=C1O NGVDGCNFYWLIFO-UHFFFAOYSA-N 0.000 claims description 4
- 150000003462 sulfoxides Chemical group 0.000 claims description 4
- 229910021529 ammonia Inorganic materials 0.000 claims description 3
- 230000003301 hydrolyzing effect Effects 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 2
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- OQAGVSWESNCJJT-UHFFFAOYSA-N isovaleric acid methyl ester Natural products COC(=O)CC(C)C OQAGVSWESNCJJT-UHFFFAOYSA-N 0.000 claims description 2
- RIWRFSMVIUAEBX-UHFFFAOYSA-N n-methyl-1-phenylmethanamine Chemical compound CNCC1=CC=CC=C1 RIWRFSMVIUAEBX-UHFFFAOYSA-N 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 235000007682 pyridoxal 5'-phosphate Nutrition 0.000 claims description 2
- 239000011589 pyridoxal 5'-phosphate Substances 0.000 claims description 2
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- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 238000009776 industrial production Methods 0.000 abstract description 5
- 230000007062 hydrolysis Effects 0.000 abstract description 3
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- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 20
- 239000000243 solution Substances 0.000 description 20
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- 238000001914 filtration Methods 0.000 description 10
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 10
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- 238000005070 sampling Methods 0.000 description 5
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- -1 2, 4, 5-trifluoro phenyl Chemical group 0.000 description 4
- 230000001276 controlling effect Effects 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 230000001105 regulatory effect Effects 0.000 description 4
- GAUXEYCSWSMMFZ-UHFFFAOYSA-N 1-(bromomethyl)-2,4,5-trifluorobenzene Chemical compound FC1=CC(F)=C(CBr)C=C1F GAUXEYCSWSMMFZ-UHFFFAOYSA-N 0.000 description 3
- JMXPOOVDUVHJRO-UHFFFAOYSA-N 1-(chloromethyl)-2,4,5-trifluorobenzene Chemical compound FC1=CC(F)=C(CCl)C=C1F JMXPOOVDUVHJRO-UHFFFAOYSA-N 0.000 description 3
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 150000002081 enamines Chemical class 0.000 description 3
- WJPYOCIWVYDFDT-UHFFFAOYSA-N ethyl 3-oxo-4-(2,4,5-trifluorophenyl)butanoate Chemical compound CCOC(=O)CC(=O)CC1=CC(F)=C(F)C=C1F WJPYOCIWVYDFDT-UHFFFAOYSA-N 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
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- 238000003786 synthesis reaction Methods 0.000 description 3
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- KEFQQJVYCWLKPL-ZCFIWIBFSA-N (3r)-3-azaniumyl-4-(2,4,5-trifluorophenyl)butanoate Chemical compound [O-]C(=O)C[C@H]([NH3+])CC1=CC(F)=C(F)C=C1F KEFQQJVYCWLKPL-ZCFIWIBFSA-N 0.000 description 2
- PEBWOGPSYUIOBP-UHFFFAOYSA-N 1,2,4-trifluorobenzene Chemical compound FC1=CC=C(F)C(F)=C1 PEBWOGPSYUIOBP-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- 229930040373 Paraformaldehyde Natural products 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000012069 chiral reagent Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
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- 239000002274 desiccant Substances 0.000 description 2
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- 238000010791 quenching Methods 0.000 description 2
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- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
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- 238000001308 synthesis method Methods 0.000 description 2
- 238000005891 transamination reaction Methods 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- KEGMJLZICKHWIR-GFCCVEGCSA-N (3r)-4-(4-fluorophenyl)-3-[(2-methylpropan-2-yl)oxycarbonylamino]butanoic acid Chemical compound CC(C)(C)OC(=O)N[C@@H](CC(O)=O)CC1=CC=C(F)C=C1 KEGMJLZICKHWIR-GFCCVEGCSA-N 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 1
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 description 1
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 description 1
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 description 1
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- 238000005804 alkylation reaction Methods 0.000 description 1
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- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 229940079593 drug Drugs 0.000 description 1
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- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
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- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- XYEOALKITRFCJJ-UHFFFAOYSA-N o-benzylhydroxylamine Chemical compound NOCC1=CC=CC=C1 XYEOALKITRFCJJ-UHFFFAOYSA-N 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- NQQWFVUVBGSGQN-UHFFFAOYSA-N phosphoric acid;piperazine Chemical compound OP(O)(O)=O.C1CNCCN1 NQQWFVUVBGSGQN-UHFFFAOYSA-N 0.000 description 1
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- CLDWGXZGFUNWKB-UHFFFAOYSA-M silver;benzoate Chemical compound [Ag+].[O-]C(=O)C1=CC=CC=C1 CLDWGXZGFUNWKB-UHFFFAOYSA-M 0.000 description 1
- 229960004115 sitagliptin phosphate Drugs 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- RTZRUVMEWWPNRR-UHFFFAOYSA-N tert-butyl n-(3-iodo-1h-pyrrolo[2,3-b]pyridin-5-yl)carbamate Chemical compound CC(C)(C)OC(=O)NC1=CN=C2NC=C(I)C2=C1 RTZRUVMEWWPNRR-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
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- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
- C07C227/20—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters by hydrolysis of N-acylated amino-acids or derivatives thereof, e.g. hydrolysis of carbamates
-
- 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
- C12P13/00—Preparation of nitrogen-containing organic compounds
- C12P13/001—Amines; Imines
-
- 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
Abstract
本发明提供了一种西他列汀关键中间体(化合物1)的制备方法,属于药物化学领域。具体方法为:化合物4经与氨基供体在酶催化作用下制备得到化合物3,化合物3经酸或者碱水解得到化合物2,化合物2和Boc酸酐反应得到西他列汀关键中间体化合物1。该方法步骤简单易控,成本相对低廉,所得产物收率高、纯度高,适合工业化生产。
Description
技术领域
本发明属于药物化学领域,涉及药物中间体的制备方法,具体涉及一种西他列汀关键中间体的制备方法。
背景技术
西他列汀于2006年首次在美国上市,是首个口服有效,选择性DPP-IV抑制剂药物,每天口服一次,用于治疗Ⅱ型糖尿病。自上市以来,西他列汀已进入60个国家,全球超过1500万处方配药。其商品名为(Sitagliptin/>),化学名为7-[(3R)-3-氨基-1-氧代-4-(2,4,5-三氟苯基)丁基]-5,6,7,8-四氢-3-(三氟甲基)-1,2,4-三唑[4,3-a]哌嗪磷酸盐一水合物,结构式如下所示:
BOC丁酸为制备原料药西他列汀的关键中间体(如式化合物(1)),可经缩合、水解、成盐等步骤制备得到磷酸西他列汀,为化学法制备西他列汀的首选路线,合成路线如下所示:
作为制备西他列汀的起始物料,BOC丁酸(化合物(1))有大量的专利文献对其制备方法进行了报道。其中,Merck公司首次在专利WO2003004498中报道了以Schollkopf试剂(2s)-(+)-2,5-二氢-3,6-二甲基-2-异丙基吡嗪为起始物料,经烃化、开环、酯化、水解、Amdt-Eistert反应得化合物(1)。该方法是Merck合成BOC丁酸的第一代合成方法,其路线如下:
该路线中使用了价格昂贵的手性辅基Schollkopf试剂、苯甲酸银,且反应中正丁基锂、重氮甲烷需要苛刻的反应条件,不利于工业化生产。
Merck公司随后在专利文献WO2004087650C中报道了该化合物(1)的改进合成方法,如路线二所示:
该路线使用具有对映选择性的还原剂(s)-Binap-RuCl2,通过氢化反应生成(S)-配位的化合物,之后所得的化合物再次被水解,然后与邻苄基羟胺发生偶联反应而生成中间体。在三苯基膦及偶氮二羧酸二异丙酯存在的条件下发生环缩合反应,再水解得到目标物。然而,上述方法的问题在于其整个工艺过程冗长,由此导致反应产量低且反应需长时间进行。
另一种选择是在专利WO2004085661中以4-(2,4,5-三氟苯基)-3-羰基丁酸甲酯为原料,以S-苯甘氨酰胺为诱导辅基,用二氧化铂还原烯胺,然后用氢氧化钯脱去保护基得到成品,该方法引入手性诱导源,催化氢化得到烯胺的ee%值较高,但手性试剂及催化剂较为昂贵。其工艺合成路线如下:
专利WO 04/085661、WO 09/085990、WO 2010/032264、WO 11/025932都采用了类似的方法进行制备西他列汀,但该路线最终需要脱去较大基团的手性试剂,原子经济性较差,且工艺中离去手性基团需要使用大量的催化剂。例如,在原研厂Merck公司的专利WO 04/085661中,最后一步脱除保护基需要使用Pd(OH)2/C(其中Pd(OH)2的含量为20%),其用量为反应物重量的30%,大幅度增加了工业化生产的成本。
TEVA公司在专利文献WO2009064467中公开了以三氟苯乙酸为起始原料,经醋酸铵反应制备烯胺,再经过[Rh(COD)Cl]2为催化剂,JosiphosI型配体做辅基催化氢化得到目标物。
合成路线如下:
该路线该路线步骤简短,操作方便,但需要贵金属和较难制备的金属配体共同催化氢化,操作条件比较严格等等,这些不利因素均给工业化生产实施加大了难度。
综上所述,上述各方法中存在反应步骤长、工艺涉及有毒有害化学试剂以及后处理繁琐、成本较高等问题。因此,在工业化制备西他列汀中间体BOC丁酸的技术中,需要一种集便利性、优良性和低廉性为一体的技术来制备具有药物活性的西他列汀及其关键中间体。
发明内容
本发明针对现有技术存在的问题,提供了一种能够适合工业化生产、操作简易且成本相对低廉的西他列汀中间体BOC丁酸,即化合物1的制备方法。
为实现上述目的,本发明采用的技术方案如下:
一种西他列汀关键中间体的制备方法,所述西他列汀关键中间体如化合物1所示;包括如下步骤:
(1)化合物4与氨基供体在酶催化作用下反应,得到化合物3;
(2)化合物3在酸或碱的作用下,水解得到化合物2;
(3)化合物2和Boc酸酐反应,得到西他列汀关键中间体化合物1。
在本发明的一些实施方式中,步骤(1)中所述氨基供体选自氨气、异丙胺、手性甲基苄胺(例如R-甲基苄胺和/或S-甲基苄胺)和D-丙氨酸中的一种或多种。所述氨基供体的用量可不作具体限定,只要不影响转氨反应的进行即可。优选地,所述氨基供体与化合物4的质量比为0.1:1-1:1,更优选0.3:1-0.8:1。
在本发明的一些实施方式中,步骤(1)中所述酶为重组天冬氨酸酶,所述重组天冬氨酸酶与化合物4的质量比为1:0.5~20,优选1:0.5~10。
本发明所述重组天冬氨酸酶根据专利文献CN108374027A实施例1制备。
在本发明的一些实施方式中,步骤(1)所述反应在溶剂中进行,,所述溶剂为水或有机溶剂;进一步地,所述有机溶剂可溶解化合物4即可;更进一步地,所述有机溶剂选自亚砜类溶剂和/或醋酸酯类溶剂;更进一步地,所述亚砜类溶剂优选N,N-二甲基亚砜(DMSO);所述醋酸酯类溶剂优选醋酸异丁酯。
在本发明的一些实施方式中,步骤(1)所述反应优选在pH值为8.0-10.0的条件下进行。所述pH值可通过有机合成领域常规的酸或碱进行调节,例如当反应体系的pH值超过10.0,可通过加入酸将反应体系的pH值调至8.0-10.0之间;当反应体系的pH值低于8.0,可通过加入碱将反应体系的pH值调至8.0-10.0之间。所述的酸优选无机酸,例如盐酸。所述的碱与优选有机碱,例如氨水。
在本发明的一些实施方式中,步骤(1)所述反应在辅酶的存在下进行。所述辅酶优选磷酸吡哆醛。所述辅酶的用量可不作具体限定,只要不影响转氨反应的进行即可。所述辅酶与化合物4的质量比为0.001:1-0.01:1,更优选0.005:1-0.006:1。
在本发明的一些实施方式中,步骤(2)中所述酸选自盐酸、硫酸、三氟乙酸、磺酸、醋酸中的一种或多种;所述碱选自氢氧化钠、氢氧化钾、碳酸钾、碳酸钠、吡啶、三乙胺、液碱中的一种或多种。
相对于现有技术,本发明具有以下有益效果:
本发明提供的一种西他列汀中间体BOC丁酸的制备方法采用了完全不同于现有技术的合成方法制得,条件简单,无高温高压反应,所用原料、催化剂均可大量商业化购买,且工艺稳定,没有产生大量的三废,对环境污染小,很适合工业化大规模生产。
具体实施方式
下面将对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。另外,值得说明的是,本发明所涉及的原料如无特殊说明均为普通市售产品。
实施例1:2,4,5-三氟苯甲基氯(化合物6-1)的制备
在1000ml的四口反应瓶中加入浓硫酸100ml,降温到20℃,加入多聚甲醛85.2g(相当于单体甲醛2.84mol),氯化钠224.0g(3.83mol),最后加入1,2,4-三氟苯203.2g(1.54mol),40℃保温反应10小时,将反应液倒入冰水中淬灭,分出有机层,水洗至中性,有机层硫酸镁干燥。过滤除去硫酸镁,母液减压蒸馏再精馏,得产品2,4,5-三氟苯甲基氯236.5g,含量99.8%,收率85.1%。
实施例2:2,4,5-三氟苯甲基溴(化合物6-2)的制备
在1000ml的四口反应瓶中加入浓硫酸100ml,降温到20℃,加入多聚甲醛85.2g(相当于单体甲醛2.84mol),溴化钠394.0g(3.83mol),最后加入1,2,4-三氟苯203.2g(1.54mol),40℃保温反应10小时,将反应液倒入冰水中淬灭,分出有机层,水洗至中性,有机层硫酸镁干燥。过滤除去硫酸镁,母液减压蒸馏再精馏,得产品2,4,5-三氟苯甲基溴306.0g,含量99.7%,收率88.4%
实施例3:(E,Z)-4-(2,4,5-三氟甲基苯)-2-丁烯酸叔丁酯(化合物4-1)的制备
将化合物6-1 150.0g,化合物5 120.0g,双二亚苄基丙酮钯Pd(dab)22.38g,三乙胺173ml投入三口反应瓶中,搅拌溶清。控温90~100℃反应15h,取样HPLC中控,直至反应液中化合物6-1的残留量≤2.0%,反应终止。过滤除去催化剂,滤液加入水500ml,甲苯300ml萃取分层。水层用200ml甲苯再萃取一次,合并有机层,硫酸镁干燥,过滤除去硫酸镁,滤液浓缩蒸干得黄色油状物131.0g,收率57.9%,GC纯度为93.5%(cis:trans=15%:85%)。
实施例4:(E,Z)-4-(2,4,5-三氟甲基苯)-2-丁烯酸叔丁酯(化合物4-1)的制备
将化合物6-2 150.0g,化合物5 94.8g,双二亚苄基丙酮钯Pd(dab)2 1.92g,三乙胺138ml投入三口反应瓶中,搅拌溶清。控温90~100℃反应15h,取样HPLC中控,直至反应液中化合物6-2的残留量≤2.0%,反应终止。过滤除去催化剂,滤液加入水500ml,甲苯300ml萃取分层。水层用200ml甲苯再萃取一次,合并有机层,硫酸镁干燥,过滤除去硫酸镁,滤液浓缩蒸干得黄色油状物117.0g,收率64.5%,GC纯度为95.5%(cis:trans=13%:87%)。
实施例5:(E,Z)-4-(2,4,5-三氟甲基苯)-2-丁烯酸苯甲酯(化合物4-2)的制备
将化合物6-1 150.0g,化合物5-1 152.0g,双二亚苄基丙酮钯Pd(dab)2 2.38g,三乙胺173ml投入三口反应瓶中,搅拌溶清。控温90~100℃反应15h,取样HPLC中控,直至反应液中化合物6-1的残留量≤2.0%,反应终止。过滤除去催化剂,滤液加入水500ml,甲苯300ml萃取分层。水层用200ml甲苯再萃取一次,合并有机层,硫酸镁干燥,过滤除去硫酸镁,滤液浓缩蒸干得黄色油状物167.7g,收率65.9%,GC纯度为93.5%(cis:trans=10%:90%)。
实施例6:(R)-3-氨基-4-(2,4,5-三氟苯基)丁酸叔丁酯(化合物3-1)的制备
将水300.0g,三乙醇胺2.8g和异丙胺25.0g加入反应瓶,搅拌溶清。室温滴加盐酸,调节pH=8.8~9.2。控温≤40℃,加入重组天冬氨酸酶42.0g,搅拌均匀。滴加适量异丙胺调节pH值维持在8.8~9.2。
控温35~40℃,加入二甲基亚砜77.0g,再升温至40~50℃,将化合物4-1 22.3g溶解在DMSO溶液中并滴加至上述反应液中。维持温度在45~50℃,保温反应12h,取样检测HPLC,当反应液中底物化合物2≤2.0%,为反应终点。
降温至10~20℃,滴加盐酸调pH=1,加入硅藻土,过滤,滤液加入二氯甲烷100ml/次萃取两次,分去二氯甲烷层。水层滴加液碱调PH≈12-13左右,再加入二氯甲烷200ml萃取,分层。上层水层再用200ml二氯甲烷萃取一次,合并有机相,加入水200ml洗涤有机相,分层,有机相加入硫酸钠干燥。过滤除去干燥剂,减压蒸干二氯甲烷,加入甲醇100ml,搅拌溶解,待用。
实施例7:(R)-3-氨基-4-(2,4,5-三氟苯基)丁酸(化合物2)的制备
将上步化合物3-1的甲醇溶液,加入水100ml,投入三口反应瓶中,搅拌溶清。控温20~30℃分批加入30%液碱80.0g。滴毕,升温至60~70℃,搅拌反应2~3h,取样HPLC中控,直至反应液中化合物3-1的残留量≤0.5%,反应结束。将上述反应液降至室温,减压蒸去甲醇。往溶液中加入甲苯150ml萃取,分去有机相。下层水层用1N盐酸溶液调PH=3~4,析出大量白色固体,过滤,滤饼少量水洗涤。烘干得白色晶体12.7g。合收率66.5%,GC纯度为98.5%。
实施例8:(R)-N-叔丁氧羰基-3-氨基-4-(4-氟苯基)丁酸(化合物1)的制备
将化合物2 30.0g,甲醇50ml,二碳酸二叔丁酯33.7g,投入至反应瓶中,搅拌溶清。室温滴加30%碳酸钾水溶液90.0g,控温20~30℃搅拌反应2~3h,取样HPLC中控,直至反应液中化合物2的残留量≤0.2%,反应结束。将上述反应液降至室温,减压蒸去甲醇。往溶液中加入醋酸调PH=6~7,再加入甲苯100ml萃取,分去有机相。下层水层用50ml甲苯再萃取一次,合并有机层,减压蒸去部分溶剂,析出大量白色固体。过滤,滤饼少量水洗涤。烘干得白色晶体80.3g。收率91.9%,GC纯度为98.5%。
实施例9:(R)-3-氨基-4-(2,4,5-三氟苯基)丁酸苯甲酯(化合物3-2)的制备
将水300.0g,三乙醇胺2.81g和异丙胺25.0g加入反应瓶,搅拌溶清。室温滴加盐酸,调节pH=8.8~9.2。控温≤40℃,加入重组天冬氨酸酶43.0g,搅拌均匀。滴加适量异丙胺调节pH值维持在8.8~9.2。
控温35~40℃,加入二甲基亚砜78.0g,再升温至40~50℃,将化合物4-2 23.6g溶解在DMSO溶液中并滴加至上述反应液中。维持温度在45~50℃,保温反应12h,取样检测HPLC,当反应液中底物化合物2≤2.0%,为反应终点。降温至10~20℃,滴加盐酸调pH=1,加入硅藻土,过滤,滤液加入二氯甲烷100ml/次萃取两次,分去二氯甲烷层。水层滴加液碱调pH≈12-13左右,再加入二氯甲烷200ml萃取,分层。上层水层再用200ml二氯甲烷萃取一次,合并有机相,加入水200ml洗涤有机相,分层,有机相加入硫酸钠干燥。过滤除去干燥剂,减压蒸干二氯甲烷,加入甲醇100ml,搅拌溶解,待用。
实施例10:(R)-3-氨基-4-(2,4,5-三氟苯基)丁酸(化合物2)的制备
将上步化合物3-2的甲醇溶液,加入水100ml,投入三口反应瓶中,搅拌溶清。控温20~30℃分批加入30%液碱80.0g。滴毕,升温至60~70℃,搅拌反应2~3h,取样HPLC中控,直至反应液中化合物3-1的残留量≤0.5%,反应结束。将上述反应液降至室温,减压蒸去甲醇。往溶液中加入甲苯150ml萃取,分去有机相。下层水层用1N盐酸溶液调pH=3~4,析出大量白色固体,过滤,滤饼少量水洗涤。烘干得白色晶体12.2g。合收率68%,GC纯度为97.5%。
最后应当说明的是,以上内容仅用以说明本发明的技术方案,而非对本发明保护范围的限制,本领域的普通技术人员对本发明的技术方案进行的简单修改或者等同替换,均不脱离本发明技术方案的实质和范围。
Claims (10)
2.根据权利要求1所述的制备方法,其特征在于,步骤(1)中所述氨基供体选自氨气、异丙胺、手性甲基苄胺和D-丙氨酸中的一种或多种。
3.根据权利要求1或2所述的制备方法,其特征在于,步骤(1)中所述氨基供体与化合物4的质量比为0.1:1-1:1,更优选0.3:1-0.8:1。
4.根据权利要求1所述的制备方法,其特征在于,步骤(1)中所述酶为重组天冬氨酸酶。
5.根据权利要求4所述的制备方法,其特征在于,步骤(1)中所述重组天冬氨酸酶与化合物4的质量比为1:0.5~20,优选1:0.5~10。
6.根据权利要求1所述的制备方法,其特征在于,步骤(1)所述反应在溶剂中进行,所述溶剂为水或有机溶剂;优选地,所述有机溶剂选自亚砜类溶剂和/或醋酸酯类溶剂;更优选地,所述亚砜类溶剂为N,N-二甲基亚砜;所述醋酸酯类溶剂为醋酸异丁酯。
7.根据权利要求1所述的制备方法,其特征在于,步骤(1)所述反应在pH值为8.0-10.0的条件下进行。
8.根据权利要求1所述的制备方法,其特征在于,步骤(1)所述反应在辅酶的存在下进行,所述辅酶为磷酸吡哆醛。
9.根据权利要求8所述的制备方法,其特征在于,步骤(1)中所述辅酶与化合物4的质量比为0.001:1-0.01:1,更优选0.005:1-0.006:1。
10.根据权利要求1所述的制备方法,其特征在于,步骤(2)中所述酸选自盐酸、硫酸、三氟乙酸、磺酸、醋酸中的一种或多种;所述碱选自氢氧化钠、氢氧化钾、碳酸钾、碳酸钠、吡啶、三乙胺、液碱中的一种或多种。
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