CN101448779A - Processes for the preparation of R-(+)-3-(carbamoyl methyl)-5-methylhexanoic acid and salts thereof - Google Patents
Processes for the preparation of R-(+)-3-(carbamoyl methyl)-5-methylhexanoic acid and salts thereof Download PDFInfo
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- CN101448779A CN101448779A CNA200780018528XA CN200780018528A CN101448779A CN 101448779 A CN101448779 A CN 101448779A CN A200780018528X A CNA200780018528X A CN A200780018528XA CN 200780018528 A CN200780018528 A CN 200780018528A CN 101448779 A CN101448779 A CN 101448779A
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- methyl
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- 238000000034 method Methods 0.000 title claims abstract description 110
- 150000003839 salts Chemical class 0.000 title claims abstract description 42
- NPDKTSLVWGFPQG-SSDOTTSWSA-N (3r)-3-(2-amino-2-oxoethyl)-5-methylhexanoic acid Chemical compound CC(C)C[C@H](CC(N)=O)CC(O)=O NPDKTSLVWGFPQG-SSDOTTSWSA-N 0.000 title claims abstract description 30
- 238000002360 preparation method Methods 0.000 title claims description 29
- 229960001233 pregabalin Drugs 0.000 claims abstract description 4
- 239000000203 mixture Substances 0.000 claims description 123
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 97
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 66
- 239000002253 acid Substances 0.000 claims description 58
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 57
- -1 Benzyl Amygdalate Chemical compound 0.000 claims description 50
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 48
- 150000002148 esters Chemical class 0.000 claims description 46
- LOUPRKONTZGTKE-LHHVKLHASA-N quinidine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@H]2[C@@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-LHHVKLHASA-N 0.000 claims description 44
- 239000002904 solvent Substances 0.000 claims description 44
- 238000003756 stirring Methods 0.000 claims description 43
- 239000003513 alkali Substances 0.000 claims description 41
- 229930195733 hydrocarbon Natural products 0.000 claims description 40
- 150000002430 hydrocarbons Chemical class 0.000 claims description 40
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 33
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 claims description 29
- 229910021529 ammonia Inorganic materials 0.000 claims description 28
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 27
- 229910052739 hydrogen Inorganic materials 0.000 claims description 26
- 229940009697 lyrica Drugs 0.000 claims description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 22
- 229960001404 quinidine Drugs 0.000 claims description 22
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 21
- 239000004215 Carbon black (E152) Substances 0.000 claims description 20
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 18
- 229930013930 alkaloid Natural products 0.000 claims description 18
- 150000003797 alkaloid derivatives Chemical class 0.000 claims description 18
- 239000012190 activator Substances 0.000 claims description 17
- 239000000725 suspension Substances 0.000 claims description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 16
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 16
- 125000001931 aliphatic group Chemical group 0.000 claims description 16
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 14
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 13
- 235000010755 mineral Nutrition 0.000 claims description 13
- 239000011707 mineral Substances 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- 241000157855 Cinchona Species 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 11
- 235000021513 Cinchona Nutrition 0.000 claims description 10
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 10
- AYXYPKUFHZROOJ-ZETCQYMHSA-N pregabalin Chemical compound CC(C)C[C@H](CN)CC(O)=O AYXYPKUFHZROOJ-ZETCQYMHSA-N 0.000 claims description 10
- 229960002510 mandelic acid Drugs 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 7
- 230000009435 amidation Effects 0.000 claims description 7
- 238000007112 amidation reaction Methods 0.000 claims description 7
- IAIHUHQCLTYTSF-UHFFFAOYSA-N 2,2,4-trimethylbicyclo[2.2.1]heptan-3-ol Chemical compound C1CC2(C)C(O)C(C)(C)C1C2 IAIHUHQCLTYTSF-UHFFFAOYSA-N 0.000 claims description 6
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- 238000002425 crystallisation Methods 0.000 claims description 6
- 230000008025 crystallization Effects 0.000 claims description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 6
- 230000007062 hydrolysis Effects 0.000 claims description 6
- 238000006460 hydrolysis reaction Methods 0.000 claims description 6
- 238000001556 precipitation Methods 0.000 claims description 6
- 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 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 5
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 5
- 150000008065 acid anhydrides Chemical class 0.000 claims description 5
- 150000001412 amines Chemical class 0.000 claims description 5
- 235000019270 ammonium chloride Nutrition 0.000 claims description 5
- KMPWYEUPVWOPIM-UHFFFAOYSA-N cinchonidine Natural products C1=CC=C2C(C(C3N4CCC(C(C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-UHFFFAOYSA-N 0.000 claims description 5
- KMPWYEUPVWOPIM-LSOMNZGLSA-N cinchonine Chemical compound C1=CC=C2C([C@@H]([C@H]3N4CC[C@H]([C@H](C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-LSOMNZGLSA-N 0.000 claims description 5
- 235000019253 formic acid Nutrition 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 5
- 125000004345 1-phenyl-2-propyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- WAPNOHKVXSQRPX-UHFFFAOYSA-N 1-phenylethanol Chemical compound CC(O)C1=CC=CC=C1 WAPNOHKVXSQRPX-UHFFFAOYSA-N 0.000 claims description 4
- VNOMEAQPOMDWSR-UHFFFAOYSA-N 2,2,2-trifluoro-1-phenylethanol Chemical compound FC(F)(F)C(O)C1=CC=CC=C1 VNOMEAQPOMDWSR-UHFFFAOYSA-N 0.000 claims description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical class [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 4
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 4
- ITATYELQCJRCCK-UHFFFAOYSA-N Mandelic Acid, Methyl Ester Chemical compound COC(=O)C(O)C1=CC=CC=C1 ITATYELQCJRCCK-UHFFFAOYSA-N 0.000 claims description 4
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 claims description 4
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 4
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 claims description 4
- PQLFROTZSIMBKR-UHFFFAOYSA-N ethenyl carbonochloridate Chemical compound ClC(=O)OC=C PQLFROTZSIMBKR-UHFFFAOYSA-N 0.000 claims description 4
- SAXHIDRUJXPDOD-UHFFFAOYSA-N ethyl hydroxy(phenyl)acetate Chemical compound CCOC(=O)C(O)C1=CC=CC=C1 SAXHIDRUJXPDOD-UHFFFAOYSA-N 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 claims description 4
- 229930006727 (-)-endo-fenchol Natural products 0.000 claims description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 3
- 229910052728 basic metal Inorganic materials 0.000 claims description 3
- 150000003818 basic metals Chemical class 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 150000002825 nitriles Chemical class 0.000 claims description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 3
- 235000015320 potassium carbonate Nutrition 0.000 claims description 3
- 235000017550 sodium carbonate Nutrition 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- HDECRAPHCDXMIJ-UHFFFAOYSA-N 2-methylbenzenesulfonyl chloride Chemical compound CC1=CC=CC=C1S(Cl)(=O)=O HDECRAPHCDXMIJ-UHFFFAOYSA-N 0.000 claims description 2
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 2
- 235000001258 Cinchona calisaya Nutrition 0.000 claims description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- 235000019445 benzyl alcohol Nutrition 0.000 claims description 2
- 229960004217 benzyl alcohol Drugs 0.000 claims description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 2
- 229940043279 diisopropylamine Drugs 0.000 claims description 2
- WEHWNAOGRSTTBQ-UHFFFAOYSA-N dipropylamine Chemical compound CCCNCCC WEHWNAOGRSTTBQ-UHFFFAOYSA-N 0.000 claims description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 2
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 claims description 2
- 229960000948 quinine Drugs 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 6
- 238000003916 acid precipitation Methods 0.000 claims 2
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N mandelic acid Chemical compound OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 claims 1
- 238000002156 mixing Methods 0.000 claims 1
- ZBOGUDPFEVIZIQ-UHFFFAOYSA-N toluene;dihydrochloride Chemical compound Cl.Cl.CC1=CC=CC=C1 ZBOGUDPFEVIZIQ-UHFFFAOYSA-N 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract 2
- 238000003786 synthesis reaction Methods 0.000 abstract 2
- 239000000543 intermediate Substances 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 48
- 230000003287 optical effect Effects 0.000 description 20
- 239000000376 reactant Substances 0.000 description 16
- 239000012044 organic layer Substances 0.000 description 15
- 239000002002 slurry Substances 0.000 description 15
- 238000005406 washing Methods 0.000 description 14
- 238000001291 vacuum drying Methods 0.000 description 12
- 150000001408 amides Chemical class 0.000 description 11
- 239000007787 solid Substances 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 8
- 238000003760 magnetic stirring Methods 0.000 description 8
- 238000001035 drying Methods 0.000 description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 6
- 238000001914 filtration Methods 0.000 description 5
- 238000000605 extraction Methods 0.000 description 4
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 235000011293 Brassica napus Nutrition 0.000 description 3
- 240000008100 Brassica rapa Species 0.000 description 3
- 235000000540 Brassica rapa subsp rapa Nutrition 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 150000007530 organic bases Chemical class 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- NRXIYKWMCOQUTK-QMMMGPOBSA-N (3s)-3-(2-methoxy-2-oxoethyl)-5-methylhexanoic acid Chemical compound COC(=O)C[C@@H](CC(C)C)CC(O)=O NRXIYKWMCOQUTK-QMMMGPOBSA-N 0.000 description 2
- NPDKTSLVWGFPQG-UHFFFAOYSA-N 3-(2-amino-2-oxoethyl)-5-methylhexanoic acid Chemical compound CC(C)CC(CC(N)=O)CC(O)=O NPDKTSLVWGFPQG-UHFFFAOYSA-N 0.000 description 2
- MHPUGCYGQWGLJL-UHFFFAOYSA-N 5-methyl-hexanoic acid Chemical compound CC(C)CCCC(O)=O MHPUGCYGQWGLJL-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- MUCRYNWJQNHDJH-OADIDDRXSA-N Ursonic acid Chemical compound C1CC(=O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CC[C@@H](C)[C@H](C)[C@H]5C4=CC[C@@H]3[C@]21C MUCRYNWJQNHDJH-OADIDDRXSA-N 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 230000002082 anti-convulsion Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 2
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 2
- GAVADYDSIYXWMR-MRVPVSSYSA-N methyl (3r)-3-(2-amino-2-oxoethyl)-5-methylhexanoate Chemical class COC(=O)C[C@H](CC(C)C)CC(N)=O GAVADYDSIYXWMR-MRVPVSSYSA-N 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 238000000935 solvent evaporation Methods 0.000 description 2
- 239000011877 solvent mixture Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000003944 tolyl group Chemical group 0.000 description 2
- 238000003828 vacuum filtration Methods 0.000 description 2
- HYHLWVJLJXARGY-UHFFFAOYSA-N 3-(aminomethyl)benzamide Chemical compound NCC1=CC=CC(C(N)=O)=C1 HYHLWVJLJXARGY-UHFFFAOYSA-N 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 108090000489 Carboxy-Lyases Proteins 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 238000011938 amidation process Methods 0.000 description 1
- 238000004176 ammonification Methods 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 1
- 150000007516 brønsted-lowry acids Chemical class 0.000 description 1
- 150000007528 brønsted-lowry bases Chemical class 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 238000000151 deposition Methods 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- GAVADYDSIYXWMR-UHFFFAOYSA-N methyl 3-(2-amino-2-oxoethyl)-5-methylhexanoate Chemical class COC(=O)CC(CC(C)C)CC(N)=O GAVADYDSIYXWMR-UHFFFAOYSA-N 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention provides processes for the synthesis of R-(+)-3-(carbamoylmethyl)-5-methylhexanoic acid and salts thereof, intermediates in the synthesis of S-pregabalin.
Description
The cross reference of related application
[001] the application requires the senior interest of following U.S. Provisional Patent Application sequence number: 60/808,320 of submission on May 24th, 2006; 60/814,245 of submission on June 15th, 2006; 60/843,817 of submission on September 11st, 2006; 60/850,868 of submission on October 10th, 2006; 60/918,177 of submission on March 14th, 2007; With 60/920,348 of submission on March 26th, 2007, these all classify this paper reference as.
Invention field
[002] the present invention contain intermediate in synthetic of R-(+)-3-(carbamoyl methyl)-5-methylhexanoic acid (" R-CMH ") and salt-S-lyrica (Pregabalin) thereof-synthetic method.
Background of invention
[003] (S)-and lyrica (Pregabalin), i.e. (S)-(+)-3-(amino methyl)-5-methylhexanoic acid, a kind of compound that following chemical structure is arranged,
(S)-lyrica
It is a kind of γ-An Jidingsuan or (S)-3-isobutyl-(GABA) analogue.People find that (S)-lyrica can activate GAD (L-L-Glutamic decarboxylase).(S)-lyrica is relevant for the dose dependent protective effect of epileptic seizures, and be a kind of central nervous system (CNS) active compound.(S)-and lyrica can be used for anticonvulsion treatment, because its GAD activation can promote the generation of GABA, GABA is one of main inhibitory nerve mediator of brain, discharges in 30% brain cynapse.(S)-lyrica has pain relieving, anticonvulsion and anxiety activity.
[004] as U.S. Patent No. 5,616,793 and
24 (8), disclosed among the 862-870 (1999), (S)-and the preparation of lyrica is carried out as follows: obtain intermediate 3-(carbamoyl methyl)-5-methylhexanoic acid (" CMH "), then with its optical resolution to provide R-CMH, convert it into (S)-lyrica then, described in following flow process:
[005] the present other preparation method who needs R-CMH and salt thereof in the industry.
Brief summary of the invention
[006] in one embodiment, the preparation method of following formula (R)-(+)-3-(carbamoyl methyl)-5-methylhexanoic acid or its salt is contained in the present invention
Comprise: a) make the asymmetric open loop of 3-isobutyl-Pyroglutaric acid, obtain the chiral ester of following formula
B) make this chiral ester amidation, obtain (R)-(+)-3-(the carbamoyl methyl)-5-methyl caproate of following formula
With, randomly, c) make this (R)-(+)-3-(carbamoyl methyl)-5-methyl caproate change into (R)-(+)-3-(carbamoyl methyl)-5-methylhexanoic acid, R in the formula
1And R
2Be independently selected from a group of following composition: H, aliphatics branching or ring-type C
1-C
12Alkyl, C
6-C
9Aryl radical and CO
2H, and M is H or NH
4 +
[007] in another embodiment, R-(+)-3-(the carbamoyl methyl)-5-methylhexanoic acid of following formula or the preparation method of its salt are contained in the present invention
Comprise: a) merge 3-isobutyl-Pyroglutaric acid, a kind of chiral alcohol, a kind of C that is selected from
6-10Aromatic hydrocarbons, C
3-5Ketone, C
2-5Ether, C
2-7Ester, C
1-2Halohydrocarbon and C
1-4One group solvent and a kind of alkali that nitrile is formed obtain the chiral ester of following formula
B) mix with ammonia, obtain (R)-(+)-3-(the carbamoyl methyl)-5-methyl caproate of following formula
With, randomly, c) add a kind of acid, obtain R-(+)-3-(carbamoyl methyl)-5-methylhexanoic acid, R in the formula
1And R
2Be independently selected from a group of following composition: H, aliphatics, branching or ring-type C
1-12Hydrocarbon, C
6-9Aromatic hydrocarbons, and CO
2H; And M is H or NH
4 +
[008] in another embodiment, R-(+)-3-(the carbamoyl methyl)-5-methylhexanoic acid of following formula or the preparation method of its salt are contained in the present invention
Comprise: a) merge 3-isobutyl-Pyroglutaric acid, a kind of achirality alcohol, a kind of Chiral Amine and a kind of C that is selected from
6-10Aromatic hydrocarbons, C
2-5Ether, C
1-2Halohydrocarbon, and composition thereof one group solvent forming, obtain the chiral ester of following formula
B) mix with ammonia, obtain (R)-(+)-3-(the carbamoyl methyl)-5-methyl caproate of following formula
With, randomly, c) add a kind of acid, obtain (R)-(-)-3-(carbamoyl methyl)-5-methylhexanoic acid, R in the formula
1And R
2Be independently selected from H, aliphatics branching or ring-type C
1-12Hydrocarbon, C
6-9Aromatic hydrocarbons and CO
2One group of forming of H; And M is H or NH
4 +
[009] in another embodiment, R-(+)-3-(the carbamoyl methyl)-5-methylhexanoic acid of following formula or the preparation method of its salt are contained in the present invention
Comprise: a) chiral ester and a kind of acid activators with following formula merges
Generate a kind of activated acid derivatives of following formula
B) make this activated acid derivatives amidation, obtain a kind of carbamyl ester of following formula
C) this carbamyl ester is with a kind of acid or basic hydrolysis, obtains R-(+)-3-(carbamoyl methyl)-5-methylhexanoic acid or its salt and randomly respectively
D) make the salt of R-(+)-3-(carbamoyl methyl)-5-methylhexanoic acid change into R-(+)-3-(carbamoyl methyl)-5-methylhexanoic acid, R in the formula
1And R
2Be independently selected from H, aliphatics, branching or ring-type C
1-12Hydrocarbon, C
6-9Aromatic hydrocarbons and CO
2One group of forming of H; And LG is a kind of leavings group; Wherein this leavings group is derived from this acid activators; And wherein X is H or a kind of basic metal.
[0010] in another embodiment, the preparation method of (S)-lyrica is contained in the present invention, comprise with any preparation R-(+)-3-(carbamoyl methyl)-5-methylhexanoic acid or its salt in the above method and make R-(+)-3-(carbamoyl methyl)-5-methylhexanoic acid or its salt change into (S)-lyrica.
Detailed description of the Invention
[0011] preparation method of R-CMH is contained in the present invention, and this method is high yield, need not to split the CMH racemoid disclosed on prior art, thereby has avoided the fractionation and the recovery of undesirable enantiomorph.In addition, this method can adapt to technical scale easily.
[0012] in one embodiment, the preparation method of R-CMH or its salt is contained in the present invention, and this can be in order to flow process 1 explanation down.
Flow process 1The method for preparing R-CMH or its salt from 3-isobutyl-Pyroglutaric acid
R in the formula
1And R
2Be independently selected from H, aliphatics branching or ring-type C
1-12Hydrocarbon, C
6-9Aromatic hydrocarbons and CO
2One group of forming of H; And M is H or NH
4 +Better, R
1Be CO
2H or H; R
2Be H, C
6-9The C of aromatic hydrocarbons or aliphatics or branching
1-12Hydrocarbon; Or R
1And R
2Form a kind of ring-type C together
1-12Hydrocarbon.
[0013] better, this C
6-9Aromatic hydrocarbons is a phenyl.Better, the C of this aliphatics or branching
1-12Hydrocarbon is a methyl.Better, this ring-type C
1-12Hydrocarbon is 1,3,3-trimethylammonium dicyclo [2.2.1] heptane.R
1And R
2Better combination be respectively CO
2H and phenyl, H and H, H and Me, H and phenyl, or R
1And R
2Form 1,3 of following formula together, 3-trimethylammonium dicyclo [2.2.1] heptane
[0014] asymmetric open loop step can be with (i) a kind of chiral alcohol or is (ii) carried out with a kind of achirality alcohol that serves as the Chiral Amine combination of chiral induction agent.
[0015] when using chiral alcohol, asymmetric open loop step typically comprises and merges 3-isobutyl-Pyroglutaric acid (" IBG acid anhydrides "), a kind of chiral alcohol S-ester, a kind of C of being selected from
6-10Aromatic hydrocarbons, C
3-5Ketone, C
2-5Ether, C
2-7Ester, C
1-2Halohydrocarbon and C
1-4One group solvent and a kind of alkali that nitrile is formed.
[0016] better, this alkali is selected from sodium hydride (" NaH ") and butyllithium (" BuLi ") composition one group.Better, this alkali is mineral alkali NaH.Better, this NaH is the form of 60wt% suspension in the oil.
[0017] this chiral alcohol is opened the IBG anhydride rings in the Stereoselective mode.Therefore, those of ordinary skill can be known in the industry, and a kind of enantiomorph of this chiral alcohol causes the generation of this S-ester, and its opposite enantiomorph causes the generation of this R-ester.The example that is suitable for chiral alcohol includes but not limited to (S) fenchol, (S)-amygdalic acid, Benzyl Amygdalate, ethyl mandelate, methyl mandelate, 1-phenylethyl alcohol, 1-phenyl-2-propyl alcohol, 1-phenyl-1-propyl alcohol and trifluoromethyl-benzyl-alcohol.Better, this chiral alcohol be (S)-fenchol or (S)-amygdalic acid.
[0018] better, this C
6-10Aromatic hydrocarbons is a kind of C
6-8Aromatic hydrocarbons, better a kind of C
6-7Aromatic hydrocarbons, best toluene.Better this C
3-5Ketone is a kind of C
3-4Ketone, better a kind of C
3Ketone, best acetone.C preferably
2-5Ether is a kind of C
4-5Ether, better C
2-5Ether is tetrahydrofuran (THF) (" THF ") or methyl tertiary butyl ether (" MTBE ").Better this C
2-7Ester is a kind of C
2-5Ester, better a kind of C
2-4Ester, best a kind of C
4Ester.Good especially C
2-7Ester is an ethyl acetate.C preferably
1-2Halohydrocarbon is a kind of C
1Halohydrocarbon, better C
1-2Halohydrocarbon is methylene dichloride (" DCM ").Better this C
1-4Nitrile is a kind of C
1-2Nitrile, better a kind of C
2Nitrile, best acetonitrile (" ACN ").Best solvent is a toluene.
[0019] typically, at first merge this solvent and this chiral alcohol, then this alkali is added in this mixture so that a kind of mixture to be provided.Better, making an appointment with-78 ℃～about 110 ℃, better-40 ℃～about 40 ℃ approximately, preferably making an appointment with-20 ℃～about 20 ℃ temperature that this mineral alkali is added in this mixture.
[0020] after this alkali adds, the IBG acid anhydrides is added in this mixture.This IBG acid anhydrides can provide with net phase or solution form.When providing with the solution form, this solvent is with the above.This IBG acid anhydrides can drip.When this acid anhydrides was dropping, more handy about 0.5 hour～about 3 hours of this interpolation, better about 0.5 hour～about 1 hour time carried out.
[0021] after this IBG acid anhydrides adds, this mixture better is maintained at about 0 ℃～about 50 ℃, better about 20 ℃～about 30 ℃ temperature, to obtain the S-ester of following structure:
Better, this mixture is kept about 1～about 6 hours, better kept about 3 hours.
[0022] when using the achirality alcohol that makes up with Chiral Amine, this asymmetric open loop step typically comprises one group the solvent that merges IBG acid anhydrides, Chiral Amine, achirality alcohol and be selected from following composition: C
6-10Aromatic hydrocarbons, C
2-5Ether, C
1-2Halohydrocarbon, and composition thereof.
[0023] this C
6-10Aromatic hydrocarbons is a kind of C
6-8Aromatic hydrocarbons, better a kind of C
6-7Aromatic hydrocarbons, best toluene.C preferably
2-5Ether is a kind of C
4-5Ether, better C
2-5Ether is THF.C preferably
1-2Halohydrocarbon is a kind of C
1Halohydrocarbon, better C
1-2Halohydrocarbon is DCM.Best solvent is a toluene.
[0024] this Chiral Amine is used as the chiral induction agent of this achirality alcohol, thereby causes the Fang Tiyou of IBG acid anhydrides to select open loop.Therefore, those of ordinary skill can be known in the industry, and a kind of enantiomorph of this Chiral Amine causes the generation of S-ester, and opposite enantiomorph causes the generation of R-ester.Better, this Chiral Amine is a kind of chirality alkaloid.Better, this chirality alkaloid is a kind of cinchona alkaloid.The example that is suitable for cinchona alkaloid includes but not limited to quinidine, cinchonine and dehydro derivatives thereof.Better, this Chiral Amine is the quinidine of following structure:
Quinidine
[0025] better, this achirality alcohol is a kind of C
1-7Alcohol.Better, this C
1-7Alcohol is methyl alcohol, ethanol, propyl alcohol, propyl carbinol and benzylalcohol.Better, this C
1-7Alcohol is methyl alcohol.
[0026] typically, this achirality alcohol is added in this IBG acid anhydrides and this Chiral Amine suspension in a kind of solvent of one group that is selected from following composition: C
6-10Aromatic hydrocarbons, C
2-5Ether, C
1-2Halohydrocarbon, and composition thereof.Better, this alcohol is to add in this suspension about 20 ℃～-78 ℃ approximately ,-40 ℃ better approximately～about-60 ℃ temperature.This achirality alcohol can be added drop-wise in this suspension.When this interpolation is when dripping, the time of its more handy about 15min～about 45min carries out.
[0027] typically, this achirality alcohol interpolation in this suspension provides a kind of mixture.Better, with this mixture stir about 2～about 96 hours, better about 2～about 24 hours, to obtain the S-ester of following formula.
[0028] can using in the industry in order to the above S-ester of any one preparation in the last method, the known any method of those of ordinary skill reclaims.Such method includes but not limited to remove solvent and randomly adds acid and drying.
[0029] typically, the S-ester that is reclaimed is the mixture that abbreviates 2 kinds of diastereomers of the S-ester of following formula and R-ester as:
S-ester R-ester
The S-ester is the main diastereomer in this mixture in the formula.Better, the diastereomer ratio, with the planimeter of HPLC, being respectively S-ester/R-ester is about 80:20～about 95:5.
[0030] randomly, the non-enantiomer mixture that is reclaimed can with ammonia react before carry out crystallization, to improve the ratio of this S-ester and this R-ester.This crystallization comprises is dissolved in a kind of solvent of one group that is selected from following composition this non-enantiomer mixture: C
6-10Aromatic hydrocarbons, C
3-5Ketone, C
2-5Ether, C
2-7Ester, C
1-2Halohydrocarbon, C
1-4Nitrile, and composition thereof; With the S-ester is precipitated out from solution, and the R-ester is still stayed in this solution.Better, this diastereomer is dissolved in the solvent mixture.Solvent mixture is C preferably
6-10Aromatic hydrocarbons and C
2-7The mixture of ester.Better, this mixture is the mixture of toluene and ethyl acetate.
[0031] mixture of this diastereomer and solvent can randomly heat, and forms a kind of solution so that this non-enantiomer mixture dissolves.Better, this combined heated is arrived about 40 ℃～about 150 ℃, better about 60 ℃～about 120 ℃ temperature.Typically, with resulting solution cooling, so that this S-ester is separated out precipitation.Better, this solution is cooled to about 30 ℃～about 0 ℃, better about 20 ℃～about 2 ℃ temperature.Separate out sedimentary S-ester and can use reclaiming by filtration.
[0032] typically, crystalline S-ester is compared with initial S-ester, contains R-ester still less.Better, with the HPLC planimeter, to be respectively S-ester/R-ester be 95:5 at least to the ratio of these two kinds of diastereomers.
[0033] this amidation step comprises the S-ester that allows in the chiral ester that obtains in order to last any method and mixes and randomly add subsequently acid with ammonia.Reaction between this S-ester and the ammonia causes the R-CMH ammonium salt of following formula
Then, make itself and acid-respons, obtain R-CMH.
[0034] better, this ammonia is to provide with the solution form in a kind of solvent of one group that is selected from following composition: water, the mixture of organic solvent and water and organic solvent.Better, this organic solvent is selected from a group of following composition: methyl alcohol, ethanol, ethylene glycol, Virahol, ethyl acetate and acetonitrile.This ammonia solution can obtain by allowing ammonia be sparging in this solvent.Also can be with NH
4Cl and this ammonia and this S-ester merge.
[0035] better, the merging of this S-ester and ammonia forms a kind of mixture, holds it in-40 ℃～about 110 ℃ approximately, better about 40 ℃～about 110 ℃, best about 40 ℃～about 80 ℃ temperature, obtains the ammonium salt of R-CMH.Better, this mixture is kept about 2～about 48 hours, better about 6～30 hours.Better, this mixture keeps at about 1～about 6 normal atmosphere, better about 1～about 5 atmospheric pressure.
[0036] better, this acid is selected from HCl, HBr, H
2SO
4, H
3PO
4, a group of forming of acetate and formic acid.Better, this acid is HCl.
[0037] better, this acid is that～quantity about 5, better about 2～about 4 pH about 0 to be enough to obtain exists.This acid is cooled off so that R-CMH separates out precipitation after adding.Better, this cooling will reach about 10 ℃～-5 ℃ approximately, better reach about 5 ℃～about 0 ℃ temperature.
[0038] R-CMH that obtains like this or its salt can reclaim with the known any method of those of ordinary skill.Such method includes but not limited to filter, use solvent extraction R-CMH or its salt, evaporating solvent and drying.
[0039] better, this asymmetric open loop and this amidation can be used as single pot process to be carried out, and does not promptly carry out this S-ester and separates.
[0040] in another embodiment, the preparation method of R-CMH and salt thereof is contained in the present invention, and this can illustrate in order to following flow process 2.
Flow process 2The method for preparing R-CMH or its salt from the R-ester
R in the formula
1And R
2Be independently selected from a group of following composition: H, aliphatics branching or ring-type C
1-2Hydrocarbon, C
6-9Aromatic hydrocarbons, and CO
2H; LG is a kind of leavings group, and wherein this leavings group is derived from this acid activators; And X is H or a kind of basic metal.Better, R
1Be CO
2H or H; R
2Be H, a kind of C
6-9Aromatic hydrocarbons or a kind of aliphatics or branching C
1-12Hydrocarbon; Or R
1And R
2Form a kind of ring-type C together
1-12Hydrocarbon.
[0041] better, this C
6-9Aromatic hydrocarbons is a phenyl.Better, this aliphatics or branching C
1-12Hydrocarbon is a methyl.Better, this ring-type C
1-12Hydrocarbon is 1,3,3-trimethylammonium dicyclo [2.2.1] heptane.R preferably
1With R
2Combination is respectively CO
2H and phenyl, H and H, H and Me, H and phenyl, perhaps R
1And R
2Form 1,3 of following formula together, 3-trimethylammonium dicyclo [2.2.1] heptane
[0042] the ester segment in this acid starting raw material can be chirality also can be achirality.
[0043] this initial R-ester can utilize the combination of this chiral alcohol or this achirality alcohol and this Chiral Amine to provide in order to last method, and prerequisite is to use the opposite enantiomorph of this chiral alcohol and this Chiral Amine.This opposite enantiomorph causes generating this R-ester rather than the S-ester as above.
[0044] example of suitable chiral alcohol includes but not limited to the opposite enantiomorph of (R)-fenchol, (R)-amygdalic acid and following alcohol: Benzyl Amygdalate, ethyl mandelate, methyl mandelate, 1-phenylethyl alcohol, 1-phenyl-2-propyl alcohol, 1-phenyl-1-propyl alcohol and trifluoromethyl-benzyl-alcohol.Better, this chiral alcohol be (R)-fenchol or (R)-amygdalic acid.
[0045] better, this Chiral Amine is a kind of chirality alkaloid.Better, this chirality alkaloid is a kind of cinchona alkaloid.The example that is suitable for cinchona alkaloid includes but not limited to quinidine, cinchovatin and their dehydro derivatives.Better, this Chiral Amine is the quinidine of following structure:
Quinidine
[0046] activation of this R-ester can be carried out like this: above R-ester, a kind of alkali and a kind of acid activators are incorporated in a kind of solvent of one group that is selected from following composition: C
6-10Aromatic hydrocarbons, C
3-5Ketone, C
2-5Ether, C
2-7Ester, C
1-2Halohydrocarbon, C
1-4Nitrile, and composition thereof, obtain the activated acid derivatives of following formula
[0047] this alkali can be a kind of organic bases or a kind of mineral alkali.Better, this organic bases is a kind of fatty amine, better a kind of C
2-12Fatty amine.Better, this C
2-12Fatty amine is selected from a group of following composition: ethamine, diethylamine, propylamine, dipropyl amine, butylamine, Tributylamine, Diisopropylamine and triethylamine.Best, this C
2-12Fatty amine is a triethylamine.
[0048] better, this mineral alkali is a kind of alkaline hydrated oxide, basic carbonate or alkaline carbonic acid hydrogen salt.Better, this alkaline hydrated oxide is sodium hydroxide or potassium hydroxide.Better, this basic carbonate is yellow soda ash or salt of wormwood.Better, this alkaline carbonic acid hydrogen salt is sodium bicarbonate or saleratus.Better, this alkali is triethylamine.
[0049] better, this C
6-10Aromatic hydrocarbons is C
6-8Aromatic hydrocarbons, better C
6-7Aromatic hydrocarbons, best toluene.Better, this C
3-5Ketone is a kind of C
3-4Ketone, better a kind of C
3Ketone, best acetone.C preferably
2-5Ether is a kind of C
4-5Ether, better C
2-5Ether is THF or MTBE.Better, this C
2-7Ester is a kind of C
2-5Ester, better a kind of C
2-4Ester, best a kind of C
4Ester.Good especially C
2-7Ester is an ethyl acetate.C preferably
1-2Halohydrocarbon is a kind of C
1Halohydrocarbon, better C
1-2Halohydrocarbon is DCM.Better, this C
1-4Nitrile is a kind of C
1-2Nitrile, better a kind of C
2Nitrile, best ACN.Best solvent is DCM.
[0050] " acid activators " this term means a kind of material that can make carbonyl activatory group that contains, that is: make this carbonyl when being caused the easier nucleophillic attack that is subjected to that becomes when attacking.Better, this acid activators is selected from a group of following composition: haloformic acid alkane ester, acid anhydrides, and sulfonic acid halide.Better, this haloformic acid alkane ester is Vinyl chloroformate or methyl-chloroformate.Better, this acid anhydrides is a kind of symmetric anhydride or mixed acid anhydride, better diacetyl oxide.Better, this sulfonic acid halide is methylsulfonyl chloride or toluene sulfonyl chloride.Better, this activator is a Vinyl chloroformate.
[0051] typically, this solvent and this initial R-ester and this alkali are merged, obtain a kind of mixture.Then, make this mixture cooling back add this acid activators.Better, make this mixture be cooled to about 20 ℃～-5 ℃ approximately, better about 5 ℃～about 0 ℃ temperature.
[0052] after this acid activators adds in this mixture, makes the temperature recovery of this mixture.Better, make this mixture go back up to about 10 ℃～about 50 ℃, better about 20 ℃～about 25 ℃.Better, the mixture of this intensification was kept about 1～about 2 hours, obtains the activated acid derivatives of following formula:
[0053] better, R
1And R
2Be H, and LG is OCO
2Et, thus the acid activation derivative of following formula is provided:
[0054] then, this activatory acid derivative is implemented the amidation process, this process comprises: above-mentioned activatory acid derivative and ammonification are closed, add a kind of acid or a kind of alkali subsequently, obtain R-CMH.The reaction of this activatory acid derivative and ammonia provides a kind of slurry that following acid amides is arranged.
[0055] this ammonia can provide as above-described.Better, this ammonia is that form with gas provides.
[0056] this acid amides can reclaim from this slurry with the known any method of those of ordinary skill in the industry.Such method includes but not limited to leach this acid amides from this slurry, washs this acid amides and makes this acid amides drying.Substituting, this acid amides can be with this acid or alkali reactions and are not separated, and promptly carry out with a pot type reaction method.
[0057] then, by making this acid amides and a kind of bronsted lowry acids and bases bronsted lowry chemical combination, make the hydrolysis of ester group of this acid amides become R-CMH or its salt.When using a kind of acid, above-mentioned amide hydrolysis becomes R-CMH.When using a kind of alkali, above-mentioned amide hydrolysis becomes the salt of R-CMH.Then, by adding a kind of acid, just can make the salt of R-CMH change into R-CMH.
[0058] this acid can be a kind of mineral acid or a kind of organic acid.Better, this mineral acid is selected from HCl, HBr, H
2SO
4, and H
3PO
4Form one group, better HCl.Better, this organic acid elder generation is from one group of acetate and formic acid composition.Best, this acid is HCl.
[0059] this alkali is a kind of mineral alkali.Better, this alkali is a kind of alkali metal base, thereby generates a kind of R-CMH an alkali metal salt during this hydrolysis.Better, this mineral alkali is selected from NaOH, KOH and LiOH composition one group, preferably NaOH.
[0060] better, this acid amides and this acid or alkali are merged, a kind of mixture is provided, the latter is at about 10 ℃～about 50 ℃, better about 20 ℃～about 25 ℃ temperature stirring.Better, this mixture stir about 1～about 10 hours, better about 2～about 8 hours obtains this R-CMH or its salt.
[0061] R-CMH that obtains like this or its salt can be used in the industry, and the known any method of those of ordinary skill reclaims.Better, this R-CMH or its salt reclaim as follows: the pH of this stirred mixture is adjusted to 1～about 6, better about 2～about 5, a kind of slurry is provided; From this slurry, leach this R-CMH or its salt; Wash this filtering R-CMH or its salt; With make this R-CMH or its salt drying.Better, this pH adjusts by a kind of alkali is added in this mixture.Better, this alkali is a kind of mineral alkali, and better this alkali is selected from a group of following composition: sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood, sodium bicarbonate, saleratus.Randomly, can use a kind of organic bases, for example ammonia.Typically, this mineral alkali can be used as a kind of solid or uses as a kind of aqueous solution.
[0062] R-CMH or its salt with above-mentioned any method preparation can change into (S)-lyrica.This conversion is passable, for example, carries out according to disclosed method among the U.S. Patent application No.2007/0073085 that classifies this paper reference as.
Embodiment
The asymmetric open loop of IBG-acid anhydrides
Embodiment 1: the preparation of turnip ester
[0063] in a there-necked flask (0.25L), adds toluene (140mL), fenchol (9.26g) and NaH-60% (2.4g).With this mixture heating up to 80 ℃, be cooled to 5 ℃ then.3-isobutyl-Pyroglutaric acid (6.8g)/methyl alcohol (25mL) drips of solution is added in this mixture.This solution was stirring at room 3 hours.Solvent evaporation to doing, is obtained thick ester.This solid is in 55 ℃ of vacuum-dryings.
Embodiment 2:(S), (R)-separation of turnip ester
[0064] the thick ester with embodiment 1 preparation adds in the mixture of ethyl acetate and toluene, and is heated to 80 ℃ (in 40 ℃～100 ℃ scopes) until dissolving.Solution is cooled to 2 ℃ (in 0 ℃～20 ℃ scopes), obtains a kind of (S)-3-that from this mixture, filters out (1,3,3-trimethylammonium dicyclo [2.2.1] heptane-2-yl) carbonyl) methyl)-yellow solid of 5-methylhexanoic acid (turnip ester).
Embodiment 3:(S), (R)-preparation of mandelate with separate
[0065] in a there-necked flask (0.25L), adds toluene (70mL), S-amygdalic acid (3.04g) and NaH-60% (1.6g).This mixture heating up is refluxed and cool to room temperature.Drip 3-isobutyl-Pyroglutaric acid (3.4g).
[0066] this solution was stirring at room 6 hours.With solvent evaporation, residue obtains the pale solid of (S)-4-(((S)-carboxyl (phenyl) methoxyl group) carbonyl)-3-isobutyl-butyric acid (mandelate) with ethyl acetate and toluene mixture crystallization.
[0067] this solid is 55 ℃ of vacuum-dryings.
The alkaloidal asymmetric open loop of chirality of embodiment 4:IBG-acid anhydrides
[0068] in a there-necked flask (0.25L), adds quinidine (11mmol), 3-isobutyl-Pyroglutaric acid (10mmol) and toluene (50mL).This mixture is cooled to-55 ℃.Methyl alcohol (30mmol) is added drop-wise in this refrigerative suspension with the 10min time.This reactant was stirred 96 hours.Solution concentration is extremely done, resulting residue is dissolved in the diethyl ether (65mL).This solution washs with HCl-2N, the ether back extraction of this water layer.The organic layer that merges MgSO4 drying, filtration.Filtrate is evaporated to dried.
The alkaloidal asymmetric open loop of chirality of embodiment 5:IBG acid anhydrides
[0069] at-75 ℃ with methyl alcohol (6.2mL, 153mmol) add an outfit magnetic stirring apparatus and added quinidine (7.14g to, 22mmol), 3-isobutyl-Pyroglutaric acid (3.28g, 19.3mmol) and toluene (100mL is in the dry 250mL single necked round bottom flask of 30.5vol) flame.Reactant stirred 21 hours.With solution concentration to doing, resulting residue being dissolved in the diethyl ether (125mL).HCl-2N (40mL * 3) washing of this solution, water ether back extraction.The water that merges is evaporated to dried, provides the yellow oil (optical purity 90%, productive rate 91%) of 3.56g S-half ester ((S)-3-((methoxycarbonyl) methyl)-5-methylhexanoic acid).
The alkaloidal asymmetric open loop of chirality of embodiment 6:IBG acid anhydrides
[0070] at-50 ℃ with methyl alcohol (6.2mL, 153mmol) add an outfit magnetic stirring apparatus and added quinidine (7.14g to, 22mmol), 3-isobutyl-Pyroglutaric acid (3.28g, 19.3mmol) and toluene (100mL is in three mouthfuls of round-bottomed flasks of 250mL 30.5vol).Reactant stirred 2 hours.This slurry H
2SO
4-2N (40mL * 3) washing.Organic layer is evaporated to dried, obtains 3.7g S-half ester yellow oil (optical purity 90%, productive rate 95%).
The alkaloidal asymmetric open loop of chirality of embodiment 7:IBG acid anhydrides
[0071] at-78 ℃ with methyl alcohol (6.2mL, 153mmol) add an outfit magnetic stirring apparatus and added quinidine (12.5g to, 38.6mmol), 3-isobutyl-Pyroglutaric acid (3.28g, 19.3mmol) and toluene (100mL is in three mouthfuls of round-bottomed flasks of 250mL 30.5vol).Reactant stirred 22.5 hours.This slurry washs with HCl-2N (40mL * 3).Organic layer is evaporated to dried, obtains 3.63g S-half ester yellow oil (optical purity 90%, productive rate 93%).
The alkaloidal asymmetric open loop of chirality of embodiment 8:IBG acid anhydrides
[0072] at-78 ℃ with methyl alcohol (6.2mL, 153mmol) add an outfit magnetic stirring apparatus and added quinidine (7.14g to, 22mmol), 3-isobutyl-Pyroglutaric acid (3.28g, 19.3mmol) and toluene (33mL is in three mouthfuls of round-bottomed flasks of 250mL 10vol).Reactant stirred 19 hours.This solution washs with HCl-2N (25mL * 3).Organic layer is evaporated to dried, provides 3.38g S-half ester yellow oil (optical purity 90%, productive rate 87%).
The alkaloidal asymmetric open loop of chirality of embodiment 9:IBG acid anhydrides
[0073] at-78 ℃ with methyl alcohol (6.2mL, 153mmol) add an outfit magnetic stirring apparatus and added quinidine (7.14g to, 22mmol), 3-isobutyl-Pyroglutaric acid (3.28g, 19.3mmol) and toluene (100mL is in three mouthfuls of round-bottomed flasks of 250mL 30vol).Reaction was stirred 2 hours.This slurry H
2SO
4-2N (40mL * 3) washing.Organic layer is evaporated to dried, provides 3.4g S-half ester yellow oil (optical purity 95%, productive rate 93%).
The alkaloidal asymmetric open loop of chirality of embodiment 10:IBG acid anhydrides
[0074]-50 ℃ to stir, 3-isobutyl-Pyroglutaric acid (88mmol) and quinidine (100mmol) be to drip methyl alcohol (273mmol) in the suspension in toluene (30vol).This reactant stirs 17h at-50 ℃.This solution H
2SO
4-2N washing.This organic phase is evaporated to dried, obtains S-half ester (optical purity 94%, productive rate 94%).
The alkaloidal asymmetric open loop of chirality of embodiment 11:IBG acid anhydrides
[0075]-50 ℃ to stir, drip methyl alcohol (59.8mmol) in 3-isobutyl-Pyroglutaric acid (19.3mmol) and the suspension of quinidine (22mmol) in toluene (20vol).This reactant stirs 17h at-50 ℃.This solution H
2SO
4-2N washing.This organic layer is evaporated to dried, obtains S-half ester (optical purity 95%, productive rate 89%).
The alkaloidal asymmetric open loop of chirality of embodiment 12:IBG acid anhydrides
[0076]-50 ℃ to stir, drip methyl alcohol (59.8mmol) in 3-isobutyl-Pyroglutaric acid (19.3mmol) and the suspension of quinidine (22mmol) in toluene (10vol).This reactant stirs 4h at-50 ℃.This solution H
2SO
4-2N washing.This organic layer is evaporated to dried, obtains S-half ester (optical purity 94%, productive rate 92%).
The alkaloidal asymmetric open loop of chirality of embodiment 13:IBG acid anhydrides
[0077]-50 ℃ to stir, drip methyl alcohol (193mmol) in 3-isobutyl-Pyroglutaric acid (19.3mmol) and the suspension of quinidine (22mmol) in toluene (30vol).This reactant stirs 16h at-50 ℃.This solution H
2SO
4-2N washing.Organic layer is evaporated to dried, obtains S-half ester (optical purity 95%, productive rate 83%).
The alkaloidal asymmetric open loop of chirality of embodiment 14:IBG acid anhydrides
[0078]-50 ℃ to stir, drip methyl alcohol (59.8mmol) in 3-isobutyl-Pyroglutaric acid (19.3mmol) and the suspension of quinidine (22mmol) in toluene (10vol).This reactant stirs 22h at-50 ℃.This solution H
2SO
4-2N washing.This organic layer is evaporated to dried, obtains S-half ester (optical purity 91%, productive rate 92%).
The alkaloidal asymmetric open loop of chirality of embodiment 15:IBG acid anhydrides
[0079]-50 ℃ to stir, drip methyl alcohol (837mmol) in 3-isobutyl-Pyroglutaric acid (270mmol) and the suspension of quinidine (308mmol) in toluene (10vol).This reactant stirs 3h at-50 ℃.This solution H
2SO
4-2N washing.This organic layer is evaporated to dried, obtains S-half ester (optical purity 95%, productive rate 84%).
The alkaloidal asymmetric open loop of chirality of embodiment 16:IBG acid anhydrides
[0080]-50 ℃ to stir, drip methyl alcohol (59.8mmol) in 3-isobutyl-Pyroglutaric acid (19.3mmol) and the suspension of cinchonine (22mmol) in toluene (30vol).This reactant stirs 15h at-50 ℃.This solution H
2SO
4-2N washing.This organic layer is evaporated to dried, obtains S-half ester (optical purity 78%, productive rate 99%).
The alkaloidal asymmetric open loop of chirality of embodiment 17:IBG acid anhydrides
[0081]-50 ℃ to stir, drip methyl alcohol (59.8mmol) in 3-isobutyl-Pyroglutaric acid (19.3mmol) and the suspension of cinchovatin (22mmol) in toluene (30vol).This reactant stirs 15h at-50 ℃.This solution H
2SO
4-2N washing.This organic layer is evaporated to dried, obtains R-half ester (optical purity 68%, productive rate 100%).
The alkaloidal asymmetric open loop of chirality of embodiment 18:IBG acid anhydrides
[0082]-78 ℃ to stir, drip methyl alcohol (59.8mmol) in 3-isobutyl-Pyroglutaric acid (19.3mmol) and the suspension of cinchonine (22mmol) in toluene (30vol).This reactant stirs 19h at-50 ℃.This solution H
2SO
4-2N washing.This organic layer is evaporated to dried, obtains S-half ester (optical purity 74%, productive rate 90%).
The alkaloidal asymmetric open loop of chirality of embodiment 19:IBG acid anhydrides
[0083] at-70 ℃ with methyl alcohol (6.2mL, 153mmol) be added drop-wise to an outfit magnetic stirring apparatus and added quinine (7.14g, 22mmol), 3-isobutyl-Pyroglutaric acid (3.28g, 19.3mmol) and toluene (100mL is in three mouthfuls of round-bottomed flasks of 250mL 30vol).This reactant stirs 17h.To doing, resulting residue is dissolved in the diethyl ether (125mL) with this solution concentration.This solution washs with HCl-2N (40mL * 3).Organic layer is evaporated to dried, obtains 3.7gR-half ester yellow oil (optical purity 80%, productive rate 95%).
Amidation
Embodiment 20
[0084] in a there-necked flask (0.25L), adds NH
3Water (40mL) and S-Me half ester (4g).This mixture heats 6h in 80 ℃ under pressure (5Atm).This solution cool to room temperature, interpolation HCl are reached pH1.This mixture is cooled to 0 ℃, with R-CMH leach, 55 ℃ of vacuum-dryings.
Embodiment 21
[0085] in a 50mL there-necked flask, adds 22%NH
3Water (25mL, 8vol) and the S-CMH methyl esters (MS-1750,3.16g).This solution is at stirring at room 92h.Add 37%HCl and reach pH3.White slurry is cooled to 0 ℃, with R-CMH leach, at 55 ℃ of vacuum-drying 14h, obtain 3.65g R-CMH white powder (optical purity 90%, productive rate 100%).
Embodiment 22
[0086] in an autoclave, adds 22%NH
3Water (25mL, 12.5vol) and the S-CMH methyl esters (MS-1848,2g).This solution stirs 7h in 75 ℃ under 2Atm.Add 37%HCl and reach pH3.Ethyl acetate (200mL) is added in this white slurry, and this precipitation agent is still stayed aqueous phase.Add water (20mL), obtain clear solution (2 phase).Behind vigorous stirring 10min, be separated 2.Organic phase is evaporated to dried, provides 1.62g R-CMH (optical purity 80%, productive rate 80%).
Embodiment 23
[0087] in a 100mL there-necked flask, adds 22% NH
3Water (25mL, 12.5vol) and the S-CMH methyl esters (GE-11426,2g).This solution stirs 25h at 40 ℃.Add 37% HCl, reach pH=3.This white slurry vacuum filtration, filter cake water (5mL) washing.White depositions obtains 2.45g R-CMH white powder (optical purity 87%, productive rate 100%) at 55 ℃ of vacuum-drying 17h.
Embodiment 24
[0088] in an autoclave (0.1L), adds NH
3Water (25mL) and S-methyl esters (2g).This mixture heats 8h in 70 ℃ under pressure (1.5bar).With the solution cool to room temperature, add 37% HCl, obtain pH3.Add NH
4Cl (1.8g) is to induce the R-CMH precipitation.With sedimentary R-CMH filtration, at 55 ℃ of vacuum-dryings (optical purity 84%, productive rate 60%).
Embodiment 25
[0089] in an autoclave (0.1L), adds NH
3Water (60mL) and S-methyl esters (10g).This mixture heats 25h in 70 ℃ under pressure (1.5bar).With this solution cool to room temperature, add 37%HCl and reach pH3.Add NH
4Cl (1.8g) is to induce this R-CMH precipitation.With sedimentary R-CMH filtration, at 55 ℃ of vacuum-dryings (productive rate 100%).
Embodiment 26
[0090] S-methyl esters (GE-1381,20mmol) solution 30% NH in toluene (10vol)
4OH (2.6vol * 2) extraction, as clear solution at stirring at room 16h.With 30%NH
4OH (5.2vol) adds in this solution, at room temperature stirs 72h.This solution 75%H
2SO
4Be acidified to pH3, be evaporated to dried.Residue leaches solid, acetone evaporated is extremely done with acetone (20vol) development.Resulting residue water (20vol) slurry 17h.This throw out vacuum filtration and in vacuum drying oven in 55 ℃ of dry 20h.
Embodiment 27
[0091] in a single port flask (0.1L), adds NH
3Water (18mL), S-ester (3g) and ammonium chloride (0.8g, 1eq).With this solution be heated to 40 ℃ and stir 24h in this temperature, at stirring at room 18.5h.This solution evaporation is extremely done.Add distilled water (15vol) and add HCl to reach pH4.This mixture stirring is spent the night; With R-CMH leach, 55 ℃ of vacuum-dryings.
The pot process of embodiment 28:R-CMH is synthetic
[0092] at-50 ℃, to stir, drip methyl alcohol (365mmol) in 3-isobutyl-Pyroglutaric acid (118mmol) and the dispersion liquid of quinidine (134mmol) in toluene (10vol).This reactant stirs 17h at-50 ℃.This solution H
2SO
4-2N washing.Organic layer is filtered, is extracted into 25%NH
4OH (aq.) (10vol) in.This aqueous solution in an airtight flask in 40 ℃ stir 24h, at stirring at room 48h.Add 37%HCl and reach pH3.This slurry is at stirring at room 20h, be cooled to 5 ℃ then.With R-CMH leach, 55 ℃ of vacuum-dryings.
Embodiment 29:(S)-preparation of 3-(carbamoyl methyl)-5-methylhexanoic acid methyl esters
[0093] round-bottomed flask is equipped with magnetic stirring apparatus and to wherein adding methylene dichloride (100mL), (S)-3-((methoxycarbonyl) methyl)-5-methylhexanoic acid (20g) and adding triethylamine (0.77g), being cooled to 0～5 ℃, adds Vinyl chloroformate (9g) subsequently.This mixture stirs 1～2h 20～25 ℃ temperature, uses 25% ammonia soln (100mL) quencher subsequently.With resulting slurry filter, wash with water, drying, obtain the solid of (R)-3-(carbamoyl methyl)-5-methylhexanoic acid methyl esters.
Embodiment 30:(R)-(+)-preparation of 3-(carbamoyl methyl)-5-methylhexanoic acid (R-CMH)
[0094] flask is equipped with magnetic stirring apparatus and to wherein adding 3N HCl (100mL) and (R)-3-(carbamoyl methyl)-5-methylhexanoic acid methyl esters (20g).This mixture stirs 1～10h, uses 47% NaOH quencher to pH3 subsequently 20～25 ℃ temperature.With resulting slurry filter, wash with water, drying, obtain the white solid of (R)-3-(carbamoyl methyl)-5-methylhexanoic acid.
Embodiment 31:(R)-CMH is to the conversion of (S)-lyrica: U.S. Patent Application Publication
The embodiment 12 of No.2007/0073085
Pack in [0095] reactor (0.5L) water (165mL) and NaOH (35.5g) obtain a kind of solution.This solution is cooled to 15 ℃, adds (R)-CMH (33g).The limit remains on 25 ℃ with the dropping Br of bottom with temperature
2(28.51g).This mixture heats 15min at 60 ℃, is cooled to 15 ℃ then.Add isopropylcarbinol (100mL), add H then
2SO
4(66%) solution (33mL).Be separated water isopropylcarbinol (83mL) extraction with 2.In the organic phase that merges, add Bu
3N (34.2g) is cooled to 2 ℃ with mixture, stirs 2h.With solid leach, wash, 55 ℃ of vacuum-dryings, (S)-lyrica is provided, its total purity is 99.86% HPLC area.
Embodiment 32:(R)-the CMH sodium salt is to the conversion of (S)-lyrica
Pack in [0096] reactor water and NaOH obtain a kind of solution.This solution is cooled to about 15 ℃, adds (R)-CMH sodium salt.The limit is maintained at about 25 ℃ with temperature and drips Br with about 15min time with bottom in this reactor
2Resulting mixture is cooled to about 15 ℃ then at about 60 ℃ of about 15min of heating.Add isopropylcarbinol, add H then
2SO
4(66%) solution forms a kind of two-phase mixture.This two is separated, and water extracts with isopropylcarbinol.In the organic phase that merges, add Bu
3N is cooled to about 2 ℃, stir about 2h with this mixture.With resulting solid leach, wash, 55 ℃ of vacuum-dryings, (S)-lyrica is provided.
Claims (81)
1. (R)-(+)-3-(the carbamoyl methyl)-5-methylhexanoic acid of following formula or the preparation method of its salt
Comprise: a) make the asymmetric open loop of 3-isobutyl-Pyroglutaric acid, obtain the chiral ester of following formula
B) make this chiral ester amidation, obtain (R)-(+)-3-(the carbamoyl methyl)-5-methyl caproate of following formula
With, randomly,
C) make this (R)-(+)-3-(carbamoyl methyl)-5-methyl caproate change into (R)-(+)-3-(carbamoyl methyl)-5-methylhexanoic acid,
R in the formula
1And R
2Be independently selected from a group of following composition: H, aliphatics branching or ring-type C
1-C
12Alkyl, C
6-C
9Aromatic hydrocarbyl and CO
2H, and M is H or NH
4 +
2. the process of claim 1 wherein C
6-9Aromatic hydrocarbons is a benzyl, aliphatics or branching C
1-12Hydrocarbon is a methyl, and ring-type C
1-12Hydrocarbon is 1,3,3-trimethylammonium dicyclo [2.2.1] heptane.
3. claim 1 or 2 method, wherein R
1And R
2Combination be respectively CO
2H and benzyl, H and H, H and Me, H and benzyl, or R
1And R
2Form 1,3 together, 3-trimethylammonium dicyclo [2.2.1] heptane.
4. the method for any one in the claim 1～3, wherein this open loop is undertaken by merging 3-isobutyl-Pyroglutaric acid and a kind of chiral alcohol.
5. the method for any one in the claim 1～3, wherein this open loop is undertaken by merging 3-isobutyl-Pyroglutaric acid, a kind of achirality alcohol and a kind of Chiral Amine.
6. the preparation method of (S)-lyrica (pregabalin) comprises:
A) prepare R-(+)-3-(carbamoyl methyl)-5-methylhexanoic acid or its salt with the method for any one in the claim 1～5; With
B) make R-(+)-3-(carbamoyl methyl)-5-methylhexanoic acid or its salt change into (S)-lyrica.
7. R-(+)-3-(the carbamoyl methyl)-5-methylhexanoic acid of following formula or the preparation method of its salt
Comprise: a) merge 3-isobutyl-Pyroglutaric acid, a kind of chiral alcohol, a kind of C that is selected from
6-10Aromatic hydrocarbons, C
3-5Ketone, C
2-5Ether, C
2-7Ester, C
1-2Halohydrocarbon and C
1-4One group solvent and a kind of alkali that nitrile is formed obtain the chiral ester of following formula
B) mix with ammonia, obtain (R)-(+)-3-(the carbamoyl methyl)-5-methyl caproate of following formula
With, randomly,
C) add a kind of acid, obtain R-(+)-3-(carbamoyl methyl)-5-methylhexanoic acid,
R in the formula
1And R
2Be independently selected from a group of following composition: H, aliphatics, branching or ring-type C
1-12Hydrocarbon, C
6-9Aromatic hydrocarbons, and CO
2H; And M is H or NH
4 +
8. the method for claim 7, wherein this alkali is selected from one group that sodium hydride and butyllithium are formed.
9. claim 7 or 8 method, wherein this chiral alcohol is selected from a group of following composition: (S)-fenchol, (S)-and amygdalic acid, Benzyl Amygdalate, ethyl mandelate, methyl mandelate, 1-phenylethyl alcohol, 1-phenyl-2-propyl alcohol, 1-phenyl-1-propyl alcohol, and trifluoromethyl-benzyl-alcohol.
10. the method for any one in the claim 7～9, wherein this chiral alcohol is (S)-fenchol or (S)-amygdalic acid.
11. the method for any one in the claim 7～10, wherein this solvent is selected from a group of following composition: C
6-8Aromatic hydrocarbons, C
3-4Ketone, C
4-5Ether, C
2-5Ester, C
1Halohydrocarbon, and C
1-2Nitrile.
12. the method for any one in the claim 7～11, wherein this solvent is selected from a group of following composition: toluene, acetone, tetrahydrofuran (THF), methyl tertiary butyl ether, ethyl acetate, methylene dichloride, and acetonitrile.
13. the method for any one in the claim 7～12 wherein merges this solvent and this chiral alcohol, forms a kind of mixture, and this alkali and this 3-isobutyl-Pyroglutaric acid are added in this mixture in succession.
14. the method for claim 13, wherein this alkali is to add in this mixture in about-78 ℃～about 110 ℃ temperature.
15. the method for any one in the claim 7～14, wherein the combination of step a) is maintained at about 0 ℃～about 50 ℃ temperature to obtain this chiral ester.
16. the method for any one in the claim 7～14, wherein this chiral ester be with crystalline before this ammonia mixes.
17. the method for claim 16, wherein this chiral ester is with one group the solvent crystallization that is selected from following composition: C
6-10Aromatic hydrocarbons, C
3-5Ketone, C
2-5Ether, C
2-7Ester, C
1-2Halohydrocarbon, C
1-4Nitrile, and composition thereof.
18. the method for claim 16 or 17, wherein this chiral ester is with the crystalline mixture of toluene and ethyl acetate.
19. the method for any one in the claim 7～18, wherein this ammonia is that form with solution provides.
20. the method for claim 19, wherein this ammonia is the solution in a kind of solvent of one group that is selected from following composition: water, organic solvent, or the mixture of water and organic solvent.
21. the method for claim 19 or 20, wherein this ammonia solution provides with following any method: a) allow ammonia be sparging in this solvent; B) ammonium chloride is added in the mixture that step b) obtains; Or c) method a) and b) combination.
22. the method for any one in the claim 7～21, wherein the mixture of step b) is maintained at about-40 ℃～about 110 ℃ temperature, obtains R-(+)-3-(carbamoyl methyl)-5-methyl caproate.
23. the method for any one in the claim 7～22, wherein the mixture of step b) is maintained at about 1～about 6 atmospheric pressure, obtains R-(+)-3-(carbamoyl methyl)-5-methyl caproate.
24. the method for any one in the claim 7～23, wherein this acid is selected from a group of following composition: HCl, HBr, H
2SO
4, H
3PO
4, acetate, and formic acid.
25. the method for any one in the claim 7～24, wherein this acid is to exist with the quantity that is enough to obtain about pH of 0～about 5.
26. the method for any one in the claim 7～25, wherein step c) further comprises the temperature that is cooled to about 10 ℃～about-5 ℃, so that R-(+)-3-(carbamoyl methyl)-5-methylhexanoic acid precipitation.
27. (S)-and the preparation method of lyrica, comprise
A) prepare R-(+)-3-(carbamoyl methyl)-5-methylhexanoic acid or its salt with the method for any one in the claim 7～26; With
B) make R-(+)-3-(carbamoyl methyl)-5-methylhexanoic acid or its salt change into (S)-lyrica.
28. R-(+)-3-(the carbamoyl methyl)-5-methylhexanoic acid of following formula or the preparation method of its salt
Comprise: a) merge 3-isobutyl-Pyroglutaric acid, a kind of achirality alcohol, a kind of Chiral Amine and a kind of C that is selected from
6-10Aromatic hydrocarbons, C
2-5Ether, C
1-2Halohydrocarbon, and composition thereof one group solvent forming, obtain the chiral ester of following formula
B) mix with ammonia, obtain (R)-(+)-3-(the carbamoyl methyl)-5-methyl caproate of following formula
With, randomly,
C) add a kind of acid, obtain (R)-(-)-3-(carbamoyl methyl)-5-methylhexanoic acid,
R in the formula
1And R
2Be independently selected from H, aliphatics branching or ring-type C
1-12Hydrocarbon, C
6-9Aromatic hydrocarbons and CO
2One group of forming of H; And M is H or NH
4 +
29. the method for claim 28, wherein this solvent is selected from a group of following composition: C
6-8Aromatic hydrocarbons, C
4-5Ether, and C
1Halohydrocarbon.
30. the method for claim 28 or 29, wherein this solvent is selected from a group of following composition: toluene, tetrahydrofuran (THF) and toluene dichloride.
31. the method for any one in the claim 28～30, wherein this Chiral Amine is a kind of chirality alkaloid.
32. the method for claim 31, wherein this chirality alkaloid is a kind of cinchona alkaloid.
33. the method for claim 32, wherein this cinchona alkaloid is selected from a group of following composition: quinidine, cinchonine and their dehydro derivatives.
34. the method for claim 32 or 33, wherein this cinchona alkaloid is a quinidine.
35. the method for any one in the claim 28～34, wherein this achirality alcohol is a kind of C
1-7Alcohol.
36. the method for any one in the claim 28～35, wherein this achirality alcohol is methyl alcohol, ethanol, propyl alcohol, propyl carbinol or benzylalcohol.
37. the method for any one in the claim 28～36, wherein this achirality alcohol is to add in the suspension of 3-isobutyl-Pyroglutaric acid, Chiral Amine and solvent.
38. the method for claim 37, wherein this achirality alcohol is to add in this suspension about 20 ℃～about-78 ℃ temperature.
39. the method for any one in the claim 28～38, wherein this chiral ester be with crystalline before this ammonia mixes.
40. the method for claim 39, wherein this chiral ester is with one group the solvent crystallization that is selected from following composition: C
6-10Aromatic hydrocarbons, C
3-5Ketone, C
2-5Ether, C
2-7Ester, C
1-2Halohydrocarbon, C
1-4Nitrile, and composition thereof.
41. the method for claim 39 or 40, wherein this chiral ester is the admixture solvent crystalline with a kind of toluene and ethyl acetate.
42. the method for claim 40 or 41, wherein this crystallization comprises and merges this chiral ester and this solvent; This combined heated is formed a kind of solution to about 40 ℃～about 150 ℃ temperature; With make this solution be cooled to about 30 ℃～about 0 ℃ temperature so that this chiral ester is separated out precipitation.
43. the method for claim 28～42, wherein this ammonia is that form with solution provides.
44. the method for claim 43, wherein this ammonia is the solution in a kind of solvent of one group that is selected from following composition: water, organic solvent, or the mixture of water and organic solvent.
45. the method for claim 44, wherein this ammonia solution provides with following any method: a) allow ammonia be sparging in this solvent; B) ammonium chloride is added in the mixture that step b) obtains; Or c) method a) and b) combination.
46. the method for any one in the claim 28～45, wherein the mixture of step b) is maintained at about-40 ℃～about 110 ℃ temperature, obtains R-(+)-3-(carbamoyl methyl)-5-methyl caproate.
47. the method for any one in the claim 28～46, wherein the mixture with step b) is maintained at about 1～about 6 atmospheric pressure, obtains R-(+)-3-(carbamoyl methyl)-5-methylhexanoic acid.
48. the method for any one in the claim 28～47, wherein this acid is selected from a group of following composition: HCl, HBr, H
2SO
4, H
3PO
4, acetate, and formic acid.
49. the method for any one in the claim 28～48, wherein this acid is to exist with the quantity that is enough to obtain about pH of 0～about 5.
50. the method for any one in the claim 28～49, wherein step c) further comprises the temperature that is cooled to about 10 ℃～about-5 ℃, so that R-(+)-3-(carbamoyl methyl)-5-methylhexanoic acid precipitation.
51. (S)-and the preparation method of lyrica, comprise
A) prepare R-(+)-3-(carbamoyl methyl)-5-methylhexanoic acid or its salt with the method for any one in the claim 28～50; With
B) make R-(+)-3-(carbamoyl methyl)-5-methylhexanoic acid or its salt change into (S)-lyrica.
52. R-(+)-3-(the carbamoyl methyl)-5-methylhexanoic acid of following formula or the preparation method of its salt
Comprise: a) chiral ester with following formula merges with a kind of acid activators and a kind of alkali
Generate a kind of activated acid derivatives of following formula
B) make this activated acid derivatives amidation, obtain a kind of carbamyl ester of following formula
C) this carbamyl ester is with a kind of acid or basic hydrolysis, obtains R-(+)-3-(carbamoyl methyl)-5-methylhexanoic acid or its salt and randomly respectively
D) make the salt of R-(+)-3-(carbamoyl methyl)-5-methylhexanoic acid change into R-(+)-3-(carbamoyl methyl)-5-methylhexanoic acid,
R in the formula
1And R
2Be independently selected from H, aliphatics, branching or ring-type C
1-12Hydrocarbon, C
6-9Aromatic hydrocarbons and CO
2One group of forming of H; And LG is a kind of leavings group; Wherein this leavings group is derived from this acid activators; And wherein X is H or a kind of basic metal.
53. the method for claim 52, wherein C
6-9Aromatic hydrocarbons is a benzyl, aliphatics or branching C
1-12Hydrocarbon is a methyl, and ring-type C
1-12Hydrocarbon is 1,3,3-trimethylammonium dicyclo [2.2.1] heptane.
54. the method for claim 52 or 53, wherein R
1And R
2Combination be respectively CO
2H and benzyl, H and H, H and Me, H and benzyl, or R
1And R
2Form 1,3 together, 3-trimethylammonium dicyclo [2.2.1] heptane.
55. the method for any one in the claim 52～54, wherein the preparation method of this chiral ester is as follows:
A) merge 3-isobutyl-Pyroglutaric acid, a kind of chiral alcohol, a kind of solvent of one group that is selected from following composition: C
6-10Aromatic hydrocarbons, C
3-5Ketone, C
2-5Ether, C
2-7Ester, C
1-2Halohydrocarbon and C
1-4Nitrile, and a kind of mineral alkali; Or
B) merge 3-isobutyl-Pyroglutaric acid, a kind of achirality alcohol, a kind of Chiral Amine and a kind of solvent of one group that is selected from following composition: C
6-10Aromatic hydrocarbons, C
2-5Ether, C
1-2Halohydrocarbon, and composition thereof.
56. the method for claim 55, wherein this chiral alcohol is selected from a group of following composition: (R)-and fenchol, (R)-amygdalic acid, Benzyl Amygdalate, ethyl mandelate, methyl mandelate, 1-phenylethyl alcohol, 1-phenyl-2-propyl alcohol, 1-phenyl-1-propyl alcohol, and trifluoromethyl-benzyl-alcohol.
57. the method for claim 55 or 56, wherein this chiral alcohol is (R)-fenchol or (R)-amygdalic acid.
58. the method for any one in the claim 55～57, wherein this Chiral Amine is a kind of chirality alkaloid.
59. the method for claim 58, wherein this chirality alkaloid is a kind of cinchona alkaloid.
60. the method for claim 59, wherein this cinchona alkaloid is selected from a group of following composition: quinidine, cinchonine and their dehydro derivatives.
61. the method for claim 59 or 60, wherein this cinchona alkaloid is a quinine.
62. the method for any one in the claim 52～61, wherein the alkali of step a) is a kind of fatty amine, a kind of alkaline hydrated oxide, a kind of basic carbonate or a kind of alkaline carbonic acid hydrogen salt.
63. the method for any one in the claim 52～62, wherein the alkali of step a) is ethamine, diethylamine, propylamine, dipropyl amine, butylamine, Tributylamine, Diisopropylamine, triethylamine, sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood, sodium bicarbonate or saleratus.
64. the method for any one in the claim 52～63, wherein this chiral ester, acid activators and alkali are to merge in the presence of a kind of solvent of one group that is selected from following composition: C
6-10Aromatic hydrocarbons, C
3-5Ketone, C
2-5Ether, C
2-7Ester, C
1-2Halohydrocarbon, C
1-4Nitrile, and composition thereof.
65. the method for claim 64, wherein this solvent is selected from a group of following composition: C
6-8Aromatic hydrocarbons, C
3-4Ketone, C
4-5Ether, C
2-5Ester, C
1-halohydrocarbon and C
1-2Nitrile.
66. the method for claim 64 or 65, wherein this solvent is selected from a group of following composition: toluene, acetone, tetrahydrofuran (THF), methyl tertiary butyl ether, ethyl acetate, methylene dichloride and acetonitrile.
67. the method for any one in the claim 64～66 wherein merges this solvent and this chiral ester and this alkali, obtains a kind of mixture, and this acid activators is added in this mixture.
68. the method for claim 67 wherein is cooled to the mixture of solvent, acid and alkali about 20 ℃～-5 ℃ temperature approximately, adds this acid activators then.
69. the method for claim 68 wherein, after this acid activators adds, is warmed up to about 10 ℃～about 50 ℃ temperature with this mixture.
70. the method for any one in the claim 52～69, wherein this acid activators is selected from a group of following composition: haloformic acid alkane ester, acid anhydrides and sulfonic acid halide.
71. the method for any one in the claim 52～70, wherein this acid activators is Vinyl chloroformate, methyl-chloroformate, diacetyl oxide, methylsulfonyl chloride or toluene sulfonyl chloride.
72. the method for any one, wherein R in the claim 52～71
1And R
2Be H, and LG is OCO
2Et.
73. the method for any one in the claim 52～72, wherein this activatory acid derivative is amidated by mixing with ammonia.
74. the method for claim 73, wherein this ammonia is that form with solution provides.
75. the method for claim 74, wherein this ammonia is the solution in a kind of solvent of one group that is selected from following composition: water, organic solvent, or the mixture of water and organic solvent.
76. the method for claim 74 or 75, wherein ammonia solution provides with following any method: a) allow ammonia be sparging in this solvent; B) ammonium chloride is added in the mixture that step b) obtains; Or c) method a) and b) combination, promptly allow ammonia be sparging in this solvent or ammonium chloride added in the mixture that step b) obtains.
77. the method for any one in the claim 52～76, wherein this acid is selected from a group of following composition: HCl, HBr, H
2SO
4, H
3PO
4, acetate or formic acid.
78. the method for any one in the claim 52～77, wherein the alkali of step c) is a kind of mineral alkali.
79. the method for claim 78, wherein this mineral alkali is selected from a group of following composition: NaOH, KOH and LiOH.
80. the method for any one in the claim 52～79, wherein step c) further is included in about 10 ℃～about 50 ℃ temperature stirring.
81. (S)-and the preparation method of lyrica, comprise:
A) prepare R-(+)-3-(carbamoyl methyl)-5-methylhexanoic acid or its salt with the method for any one in the claim 52～80; With
B) make R-(+)-3-(carbamoyl methyl)-5-methylhexanoic acid or its salt change into (S)-lyrica.
Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US80832006P | 2006-05-24 | 2006-05-24 | |
| US60/808,320 | 2006-05-24 | ||
| US60/814,245 | 2006-06-15 | ||
| US60/843,817 | 2006-09-11 | ||
| US60/850,868 | 2006-10-10 | ||
| US60/918,177 | 2007-03-14 | ||
| US60/920,348 | 2007-03-26 |
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| CN102753702A (en) * | 2009-07-28 | 2012-10-24 | 株式会社钟化 | Method for producing optically active 3-substituted glutaric acid monoamide |
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| CN104086439B (en) * | 2014-06-30 | 2018-11-16 | 浙江华海药业股份有限公司 | A kind of recovery method of pregabalin intermediate resolving agent (R)-(+)-α-phenylethylamine |
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| CN105481801A (en) * | 2015-12-11 | 2016-04-13 | 惠州市莱佛士制药技术有限公司 | Preparation method of pregabalin chiral intermediate |
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| CN112739683B (en) * | 2018-09-12 | 2024-04-16 | 上海宣泰医药科技股份有限公司 | Preparation method of brivaracetam and intermediate thereof |
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