JP2022072636A - Method for producing amide compound - Google Patents
Method for producing amide compound Download PDFInfo
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- JP2022072636A JP2022072636A JP2020182189A JP2020182189A JP2022072636A JP 2022072636 A JP2022072636 A JP 2022072636A JP 2020182189 A JP2020182189 A JP 2020182189A JP 2020182189 A JP2020182189 A JP 2020182189A JP 2022072636 A JP2022072636 A JP 2022072636A
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- -1 amide compound Chemical class 0.000 title claims abstract description 69
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 48
- 150000001875 compounds Chemical class 0.000 claims abstract description 124
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 43
- MTCFGRXMJLQNBG-UWTATZPHSA-N D-Serine Chemical compound OC[C@@H](N)C(O)=O MTCFGRXMJLQNBG-UWTATZPHSA-N 0.000 claims abstract description 18
- 229930195711 D-Serine Natural products 0.000 claims abstract description 18
- 239000012452 mother liquor Substances 0.000 claims abstract description 8
- 239000000243 solution Substances 0.000 claims description 46
- 239000002904 solvent Substances 0.000 claims description 39
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 33
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 32
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 27
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims description 18
- 238000002425 crystallisation Methods 0.000 claims description 17
- 230000008025 crystallization Effects 0.000 claims description 17
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 16
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 claims description 11
- 239000011259 mixed solution Substances 0.000 claims description 11
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 claims description 10
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 5
- 230000000397 acetylating effect Effects 0.000 claims description 4
- 125000003277 amino group Chemical group 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 16
- 238000009776 industrial production Methods 0.000 abstract description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 54
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 42
- 239000000203 mixture Substances 0.000 description 29
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 23
- 238000006243 chemical reaction Methods 0.000 description 21
- 239000003960 organic solvent Substances 0.000 description 19
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 15
- 239000007788 liquid Substances 0.000 description 15
- 238000000926 separation method Methods 0.000 description 13
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 12
- 230000008034 disappearance Effects 0.000 description 12
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 12
- 235000017557 sodium bicarbonate Nutrition 0.000 description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 11
- 239000002994 raw material Substances 0.000 description 11
- 239000012044 organic layer Substances 0.000 description 10
- 239000007864 aqueous solution Substances 0.000 description 9
- 159000000000 sodium salts Chemical class 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 229960002623 lacosamide Drugs 0.000 description 8
- VPPJLAIAVCUEMN-GFCCVEGCSA-N lacosamide Chemical compound COC[C@@H](NC(C)=O)C(=O)NCC1=CC=CC=C1 VPPJLAIAVCUEMN-GFCCVEGCSA-N 0.000 description 8
- 239000013078 crystal Substances 0.000 description 7
- 239000010410 layer Substances 0.000 description 7
- 230000009257 reactivity Effects 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 239000012266 salt solution Substances 0.000 description 6
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 5
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 5
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 5
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 5
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 5
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 description 5
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 5
- 229940011051 isopropyl acetate Drugs 0.000 description 5
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 5
- 150000002576 ketones Chemical class 0.000 description 5
- 230000003287 optical effect Effects 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- MFPWEWYKQYMWRO-UHFFFAOYSA-N tert-butyl carboxy carbonate Chemical compound CC(C)(C)OC(=O)OC(O)=O MFPWEWYKQYMWRO-UHFFFAOYSA-N 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 239000003849 aromatic solvent Substances 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000002002 slurry Substances 0.000 description 3
- UIQGEWJEWJMQSL-UHFFFAOYSA-N 2,2,4,4-tetramethylpentan-3-one Chemical group CC(C)(C)C(=O)C(C)(C)C UIQGEWJEWJMQSL-UHFFFAOYSA-N 0.000 description 2
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-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
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- 241000209094 Oryza Species 0.000 description 2
- 235000007164 Oryza sativa Nutrition 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 235000011054 acetic acid Nutrition 0.000 description 2
- 230000021736 acetylation Effects 0.000 description 2
- 238000006640 acetylation reaction Methods 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 235000015165 citric acid Nutrition 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000012022 methylating agents Substances 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 239000011736 potassium bicarbonate Substances 0.000 description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 2
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 2
- 235000009566 rice Nutrition 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- FHOAKXBXYSJBGX-RXMQYKEDSA-N (2r)-3-hydroxy-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](CO)C(O)=O FHOAKXBXYSJBGX-RXMQYKEDSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 238000003109 Karl Fischer titration Methods 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000001773 anti-convulsant effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000010908 decantation Methods 0.000 description 1
- 239000012024 dehydrating agents Substances 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- IIEWJVIFRVWJOD-UHFFFAOYSA-N ethyl cyclohexane Natural products CCC1CCCCC1 IIEWJVIFRVWJOD-UHFFFAOYSA-N 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 230000016507 interphase Effects 0.000 description 1
- 150000002642 lithium compounds Chemical class 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 1
- 229910001948 sodium oxide Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- XHFLOLLMZOTPSM-UHFFFAOYSA-M sodium;hydrogen carbonate;hydrate Chemical compound [OH-].[Na+].OC(O)=O XHFLOLLMZOTPSM-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/14—Preparation of carboxylic acid amides by formation of carboxamide groups together with reactions not involving the carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
-
- 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
- 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
- C07C269/06—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 by reactions not involving the formation of carbamate groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
本発明は、アミド化合物の製造方法に関する。 The present invention relates to a method for producing an amide compound.
ラコサミドは、鎮痛作用及び抗痙攣作用を有するアミノ酸誘導である（特許文献１：ＵＳ５７７３４７５）。 Lacosamide is an amino acid inducer having analgesic and anticonvulsant effects (Patent Document 1: US5773475).
ラコサミドの合成方法としては、特許文献２に、Ｎ－Ｂｏｃ－Ｄ－セリンをメチル化剤および有機リチウム化合物を用いるか、あるいは、メチル化剤および相間移動触媒の存在下に反応させて、Ｏ－メチル化し、次いで、Ｎ－ベンジルアミド化、脱保護、アセチル化により製造する方法が知られている。 As a method for synthesizing lacosamide, Patent Document 2 describes that N-Boc-D-serine is reacted with a methylating agent and an organic lithium compound in the presence of a methylating agent and an interphase transfer catalyst to form O-. Methods are known for the production by methylation, followed by N-benzylamidization, deprotection and acetylation.
前記特許文献２の方法で製造されるＮ－ベンジルアミドした化合物の収率は必ずしも満足いくものではなく、またラコサミドの晶析収率も必ずしも満足のいくものではない。
本発明は、ラコサミドの改良された製造方法を提供する。
The yield of the N-benzylamide compound produced by the method of Patent Document 2 is not always satisfactory, and the crystallization yield of lacosamide is not always satisfactory.
The present invention provides an improved method for producing lacosamide.
本発明者らは上記の課題を解決するために鋭意検討した結果、ラコサミドの晶析において、晶析母液の水分を調整することにより、効率よく精製された目的物が得られることを見出した。またＤ－セリンから目的物を得る工程においても改良点を見出して、下記のラコサミドの製造方法に至った。 As a result of diligent studies to solve the above problems, the present inventors have found that an efficiently purified target product can be obtained by adjusting the water content of the crystallization mother liquor in the crystallization of lacosamide. We also found improvements in the process of obtaining the desired product from D-serine, and arrived at the following method for producing lacosamide.
本発明は、ラコサミド（以下、式（１）のアミド化合物と記す。）の製造方法を提供するものである。本発明は以下の項に記載する実施態様を含むが、これらに限定されるものではない。
１．式（１）：
1. 1. Equation (1):
のアミド化合物と式（１）のアミド化合物１モル当たり２．０モル以下の水分を含む晶析母液から式（１）の化合物を晶析することを特徴とする式（１）の精製アミド化合物の製造方法。（以下、「本発明の精製アミド化合物の製造方法」と記す。）。
２．式（２）：
2. 2. Equation (2):
のアミノ化合物をアセチル化して、前項１に記載の式（１）のアミド化合物を製造する工程と、生成する式（１）のアミド化合物と、式（１）のアミド化合物１モル当たり２．０モル以下の水分を含む溶液を調製する工程および前項１に記載の工程を含む式（１）の精製アミド化合物の製造方法。
３．式（３）：
3. 3. Equation (3):
（式中、Ｂｏｃは、ｔｅｒｔ－ブトキシカルボニル基を表す。）
の化合物に塩酸を作用させ、式（２）のアミノ化合物を製造する工程および前項２に記載の工程を含む式（１）の精製アミド化合物の製造方法。
４．クロロ炭酸イソブチルの溶液中に式（４）：
A method for producing a purified amide compound of the formula (1), which comprises a step of reacting the compound of the above with hydrochloric acid to produce an amino compound of the formula (2) and the step of the above item 2.
4. In a solution of isobutyl chlorocarbonate, the formula (4):
（式中、Ｂｏｃは、ｔ－ブトキシカルボニル基を表す。）
のカルボン酸化合物、Ｎ－メチルモルホリンの混合溶液を滴下し、更にベンジルアミンを加える前記式（３）の化合物の製造方法。（以下、「本発明のＢｏｃ化アミド化合物の製造方法」と記す。）。
５．テトラヒドロフランおよび水を溶媒とし、アルカリ金属水酸化物の存在下、式（５）：
The method for producing the compound of the above formula (3), wherein a mixed solution of the carboxylic acid compound of No. 1 and N-methylmorpholine is added dropwise, and benzylamine is further added. (Hereinafter, it will be referred to as "the method for producing the Boc-modified amide compound of the present invention").
5. Formula (5): In the presence of an alkali metal hydroxide using tetrahydrofuran and water as solvents.
（式中、Ｂｏｃは、ｔｅｒｔ－ブトキシカルボニル基を表す。）
の化合物を硫酸ジメチルと反応させ、式（４）：
The compound of is reacted with dimethyl sulfate, and the formula (4):
（式中、Ｂｏｃは、前記のとおり。）
の化合物を製造する工程と、前項４に記載の工程を含む式（３）；
Formula (3) including the step of producing the compound of the above and the step of the above item 4.
（式中、Ｂｏｃは、ｔ－ブトキシカルボニル基を表す。）
の化合物の製造方法。（「本発明のＢｏｃ化カルボン酸化合物の製造方法」と記す。））。
６．Ｄ－セリンのアミノ基をｔ－ブトキシカルボニル化し、前項５に記載の式（５）の化合物を製造する工程と前項５の工程とを含む式（３）の化合物の製造方法。
７．前項４，５、または６に記載の式（３）の化合物の製造工程と前項３に記載の工程を含む式（１）の精製アミド化合物の製造方法。
８．式（１）の化合物と、式（１）の化合物１モル当たり２．０モル以下の水を含む前項１に記載の晶析母液。
(In the formula, Boc represents a t-butoxycarbonyl group.)
Method for producing the compound of. (It is described as "the method for producing a Boc-modified carboxylic acid compound of the present invention").
6. A method for producing a compound of formula (3), which comprises a step of t-butoxycarbonylating an amino group of D-serine to produce a compound of formula (5) according to the preceding item 5 and a step of producing the compound of formula (3).
7. A method for producing a purified amide compound of the formula (1), which comprises the step of producing the compound of the formula (3) according to the preceding item 4, 5 or 6 and the step of the above item 3.
8. The crystallization mother liquor according to item 1 above, which contains 2.0 mol or less of water per 1 mol of the compound of the formula (1) and the compound of the formula (1).
本発明の製造方法によれば、目的とするアミド化合物を効率よく精製でき、高品質の目的物を製造することができる。またラコサミドの製造工程の収率を向上させ、複数工程を効率的に繋ぐ工業的に有利な製造方法を見出した。 According to the production method of the present invention, the target amide compound can be efficiently purified, and a high-quality target product can be produced. In addition, we have found an industrially advantageous production method that improves the yield of lacosamide production processes and efficiently connects multiple processes.
以下、本発明について詳細に説明する。なお、本明細書において「含む（ｃｏｍｐｒｉｓｅ）」とは、「本質的にからなる（ｅｓｓｅｎｔｉａｌｌｙ ｃｏｎｓｉｓｔ ｏｆ）」という意味と、「のみからなる（ｃｏｎｓｉｓｔ ｏｆ）」という意味をも包含する。 Hereinafter, the present invention will be described in detail. In addition, in this specification, "comprise" also includes the meaning of "essentially consist of" and the meaning of "consist of only".
式（１）のアミド化合物と式（１）のアミド化合物１モル当たり２．０モル以下の水分を含む晶析母液から式（１）の化合物を晶析することを特徴とする式（１）の精製アミド化合物の製造方法（「本発明の精製アミド化合物の製造方法」。）について説明する。
晶析に用いられる式（１）のアミド化合物を含む溶液は、典型的には、以下のような方法で得られる。
The formula (1) is characterized by crystallizing the compound of the formula (1) from the crystallization mother liquor containing 2.0 mol or less of water per 1 mol of the amide compound of the formula (1) and the amide compound of the formula (1). The method for producing the purified amide compound of the present invention (“Method for producing the purified amide compound of the present invention”) will be described.
The solution containing the amide compound of the formula (1) used for crystallization is typically obtained by the following method.
式（１）の化合物は、例えば、式（２）の化合物をアセチル化することにより製造することができる。アセチル化には、典型的には、無水酢酸が使用される。式（２）の化合物と無水酢酸との反応においては、効率的に作業できる観点から化合物（２）の製造工程で得られた式（２）の塩酸塩を含む水溶液を使用することが好ましい。 The compound of the formula (1) can be produced, for example, by acetylating the compound of the formula (2). Acetic anhydride is typically used for acetylation. In the reaction between the compound of the formula (2) and acetic anhydride, it is preferable to use an aqueous solution containing the hydrochloride of the formula (2) obtained in the production step of the compound (2) from the viewpoint of efficient work.
反応に用いる溶媒としては、例えば水、酢酸メチル、酢酸エチル、酢酸イソプロピル等のエステル系溶媒、メチルエチルケトン、メチルイソブチルケトン等のケトン系溶媒またはこれらの混合物を溶媒として使用することができる。水と酢酸エチルの混合液が好ましい溶媒である。 As the solvent used in the reaction, for example, an ester solvent such as water, methyl acetate, ethyl acetate or isopropyl acetate, a ketone solvent such as methyl ethyl ketone or methyl isobutyl ketone or a mixture thereof can be used as the solvent. A mixture of water and ethyl acetate is the preferred solvent.
式（２）の化合物と無水酢酸（Ａｃ２Ｏ）との反応は、水酸化ナトリウム水溶液、炭酸水素ナトリウム（ＮａＨＣＯ３）、炭酸水素カリウム（ＫＨＣＯ３）、またはこれらの混合物の存在下で行ってもよい。 The reaction of the compound of formula (2) with anhydrous acetic acid (Ac 2 O) is carried out in the presence of an aqueous solution of sodium hydroxide, sodium hydrogen carbonate (NaHCO 3 ), potassium hydrogen carbonate (KHCO 3 ), or a mixture thereof. May be good.
反応温度は通常０℃から溶媒の沸点の範囲内であり、２０～５０℃の範囲が好ましい温度である。 The reaction temperature is usually in the range of 0 ° C. to the boiling point of the solvent, preferably in the range of 20 to 50 ° C.
式（２）の化合物1モルに対して、好ましくは、０．９から２．０モルの無水酢酸（Ａｃ２Ｏ）が使用され、経済性の観点から１．０から１．１モルがより好ましい。反応混合物に、例えば、分液操作、さらに重曹水、水等による分液洗浄操作を行うことにより、副生する無機塩、有機酸塩等が除去され、式（１）の化合物を含む有機溶媒溶液が得られる。 For 1 mol of the compound of formula (2), preferably 0.9 to 2.0 mol of acetic anhydride (Ac 2 O) is used, with 1.0 to 1.1 mol being more economical. preferable. By performing a liquid separation operation, for example, a liquid separation washing operation with a sodium bicarbonate solution, water, etc., the reaction mixture is removed from by-produced inorganic salts, organic acid salts, etc., and an organic solvent containing the compound of the formula (1) is contained. A solution is obtained.
有機溶媒溶液の水分含量の調整は、例えば、分液操作により得られた式（１）の化合物を含む溶液の溶媒とともに水を濃縮除去することにより実施できる。水分含量の調整には、例えば、硫酸ナトリウム、硫酸マグネシウム、モレキュラーシーブ等の脱水剤を用いてもよい。水分含量の確認は例えばカールフィッシャー滴定法にて測定することができる。
水分含量は式（１）の化合物1モルに対して２．０モル以下であればよい。水分含量を前記所定の量に調整した式（１）の化合物を含む有機溶媒溶液を用いて晶析は実施される。
The water content of the organic solvent solution can be adjusted, for example, by concentrating and removing water together with the solvent of the solution containing the compound of the formula (1) obtained by the liquid separation operation. For adjusting the water content, for example, a dehydrating agent such as sodium sulfate, magnesium sulfate, or molecular sieve may be used. The water content can be confirmed by, for example, the Karl Fischer titration method.
The water content may be 2.0 mol or less with respect to 1 mol of the compound of the formula (1). Crystallization is carried out using an organic solvent solution containing the compound of the formula (1) whose water content is adjusted to the predetermined amount.
有機溶媒としては、例えば酢酸メチル、酢酸エチル、酢酸イソプロピル等のエステル系溶媒、メチルエチルケトン、メチルイソブチルケトン等のケトン系溶媒またはこれらの混合物を溶媒として使用することができる。効率性の観点から式（２）の化合物をアセチル化する際の反応に用いた溶媒と同じ有機溶媒を使用することが好ましく、酢酸エチルが好ましい溶媒である。 As the organic solvent, for example, an ester solvent such as methyl acetate, ethyl acetate or isopropyl acetate, a ketone solvent such as methyl ethyl ketone or methyl isobutyl ketone or a mixture thereof can be used as the solvent. From the viewpoint of efficiency, it is preferable to use the same organic solvent as the solvent used for the reaction when acetylating the compound of the formula (2), and ethyl acetate is the preferred solvent.
有機溶媒の使用量は全体で式（１）の化合物１０重量部に対して、通常３０から１００重量部であり、３０から５０重量部が好ましい。 The total amount of the organic solvent used is usually 30 to 100 parts by weight, preferably 30 to 50 parts by weight, based on 10 parts by weight of the compound of the formula (1).
前記有機溶媒の量は濃縮により調整してもよく、さらに前記有機溶媒をその下限値より留去した後で有機溶媒を加えて、前記範囲に調整してもよい。晶析の開始温度は通常４０から７０℃の範囲で行われ、種晶を用いてもよい。前記有機溶媒溶液あるいは当該有機溶媒溶液から式（１）のアミド化合物が一部析出した晶析スラリー混合物に式（１）のアミド化合物に対する貧溶媒を加えることもできる。貧溶媒としては例えばシクロヘキサン、ｎ－ヘキサンを使用することができ、シクロヘキサンが好ましい。貧溶媒の使用量は晶析に用いた溶媒１０重量部に対して、通常３から２０重量部、３から１０重量部が好ましい。次いで、得られたスラリー混合物を冷却する。冷却温度は通常－１０℃から２０℃であり、収率および操作性の観点から－５℃～５℃が好ましい。冷却の速度は１時間に１℃～２０℃の範囲内、好ましくは１時間に５℃～２０℃の範囲で行うことができる。 The amount of the organic solvent may be adjusted by concentration, and further, the organic solvent may be added after distilling off the organic solvent from the lower limit value to adjust the amount to the above range. The starting temperature of crystallization is usually in the range of 40 to 70 ° C., and seed crystals may be used. It is also possible to add a poor solvent for the amide compound of the formula (1) to the crystallization slurry mixture in which the amide compound of the formula (1) is partially precipitated from the organic solvent solution or the organic solvent solution. As the poor solvent, for example, cyclohexane or n-hexane can be used, and cyclohexane is preferable. The amount of the poor solvent used is usually preferably 3 to 20 parts by weight and 3 to 10 parts by weight with respect to 10 parts by weight of the solvent used for crystallization. The resulting slurry mixture is then cooled. The cooling temperature is usually −10 ° C. to 20 ° C., preferably −5 ° C. to 5 ° C. from the viewpoint of yield and operability. The cooling rate can be in the range of 1 ° C. to 20 ° C. per hour, preferably in the range of 5 ° C. to 20 ° C. per hour.
冷却後の混合物には、液体中、式（１）のアミド化合物が析出しており、この固体（結晶）を取得し乾燥することにより、式（１）のアミド化合物を得る。析出した式（１）のアミド化合物は、公知の固液分離方法に従って取得することができる。具体的には、濾過、デカンテーションなどの固液分離操作が挙げられる。得られた式（１）のアミド化合物の結晶は、必要により、溶媒による洗浄を行ってもよい。洗浄に用いる溶媒としては、特に限定されないが、晶析溶媒と同じ溶媒（好ましくは酢酸エチルとシクロヘキサンの混合物）が用いられる。分離された式（１）のアミド化合物は、常圧または減圧下で乾燥することができる。 The amide compound of the formula (1) is precipitated in the liquid after cooling, and the solid (crystal) is obtained and dried to obtain the amide compound of the formula (1). The precipitated amide compound of the formula (1) can be obtained according to a known solid-liquid separation method. Specific examples thereof include solid-liquid separation operations such as filtration and decantation. The obtained crystals of the amide compound of the formula (1) may be washed with a solvent, if necessary. The solvent used for washing is not particularly limited, but the same solvent as the crystallization solvent (preferably a mixture of ethyl acetate and cyclohexane) is used. The separated amide compound of the formula (1) can be dried under normal pressure or reduced pressure.
式（２）の化合物は、通常、式（３）の化合物を、塩酸を用いて脱Ｂｏｃ（ｔ－ブトキシカルボニル）化することにより製造することができる。式（３）の化合物と塩酸を用いた脱Ｂｏｃ化の反応においては効率的に作業できる観点から、式（３）の化合物を製造する際に得られた式（３）の化合物を含む溶液を使用することが好ましい。 The compound of the formula (2) can usually be produced by de-Boc (t-butoxycarbonyl) the compound of the formula (3) with hydrochloric acid. From the viewpoint of being able to work efficiently in the de-Boc reaction using the compound of the formula (3) and hydrochloric acid, a solution containing the compound of the formula (3) obtained when producing the compound of the formula (3) is used. It is preferable to use it.
反応に用いる溶媒としてはトルエンなどの芳香族系溶媒、酢酸メチル、酢酸エチル、酢酸イソプロピル等のエステル系溶媒、メチルエチルケトン、メチルイソブチルケトン等のケトン系溶媒を溶媒として使用することができ、トルエンが好ましい。 As the solvent used for the reaction, an aromatic solvent such as toluene, an ester solvent such as methyl acetate, ethyl acetate and isopropyl acetate, and a ketone solvent such as methyl ethyl ketone and methyl isobutyl ketone can be used as the solvent, and toluene is preferable. ..
式（３）の化合物1モルに対して、好ましくは１から１０モルの塩酸が使用され、反応性、経済性の観点から３から５モルの塩酸がより好ましい。反応温度は通常０℃から溶媒の沸点内であり、１０から３０℃の範囲が好ましい。反応後は式（２）の化合物が塩酸塩として水層に含まれるため、分液により有機溶媒と分離し、水溶液として得ることができる。 For 1 mol of the compound of the formula (3), preferably 1 to 10 mol of hydrochloric acid is used, and 3 to 5 mol of hydrochloric acid is more preferable from the viewpoint of reactivity and economy. The reaction temperature is usually 0 ° C. to within the boiling point of the solvent, preferably in the range of 10 to 30 ° C. After the reaction, the compound of the formula (2) is contained in the aqueous layer as a hydrochloride, so that it can be separated from the organic solvent by liquid separation and obtained as an aqueous solution.
式（３）の化合物は、クロロ炭酸イソブチルの溶液中に式（４）のカルボン酸化合物、Ｎ－メチルモルホリンの混合溶液を滴下し、更にベンジルアミンを滴下して製造することができる。式（３）の化合物は、公知の方法で製造してもよいが、本発明のＢｏｃ化アミド化合物の製造方法によれば、より良好な収率で式（３）の化合物を製造することが可能である。 The compound of the formula (3) can be produced by dropping a mixed solution of the carboxylic acid compound of the formula (4) and N-methylmorpholine into a solution of isobutyl chlorocarbonate and further dropping benzylamine. The compound of the formula (3) may be produced by a known method, but according to the method for producing a Boc-modified amide compound of the present invention, the compound of the formula (3) can be produced in a better yield. It is possible.
式（４）の化合物とクロロ炭酸イソブチルおよびベンジルアミンとの反応においては効率的に作業できる観点から、式（４）の化合物の製造工程で得られた式（４）の化合物を含む溶液を使用することが好ましい。反応に用いる溶媒としてはトルエンなどの芳香族系溶媒、酢酸メチル、酢酸エチル、酢酸イソプロピル等のエステル系溶媒、メチルエチルケトン、メチルイソブチルケトン等のケトン系溶媒を溶媒として使用することができ、トルエンが好ましい。反応温度は１０℃以下の温度で行うことが好ましく、－１５から０℃の範囲がより好ましい。 From the viewpoint of efficient work in the reaction of the compound of the formula (4) with isobutyl chlorocarbonate and benzylamine, a solution containing the compound of the formula (4) obtained in the production step of the compound of the formula (4) is used. It is preferable to do so. As the solvent used for the reaction, an aromatic solvent such as toluene, an ester solvent such as methyl acetate, ethyl acetate and isopropyl acetate, and a ketone solvent such as methyl ethyl ketone and methyl isobutyl ketone can be used as the solvent, and toluene is preferable. .. The reaction temperature is preferably 10 ° C. or lower, more preferably −15 to 0 ° C.
クロロ炭酸イソブチル（ＩＢＣＦ）、Ｎ－メチルモルホリン（ＭＭＰ）、ベンジルアミンの使用量は式（４）の化合物１モルに対して０．９から２．０モルの使用が好ましく、１．０から１．１モルの使用がより好ましい。 The amount of isobutyl chlorocarbonate (IBCF), N-methylmorpholine (MMP), and benzylamine used is preferably 0.9 to 2.0 mol, preferably 1.0 to 1 mol, per 1 mol of the compound of the formula (4). The use of 1 mol is more preferred.
式（４）の化合物とクロロ炭酸イソブチルおよびベンジルアミンとの反応で生成する反応混合物からは、水、塩酸水、重曹水等による分液洗浄操作により副生する無機塩、有機酸塩等を除去することができ、有機層として式（３）の化合物を含む溶液を得ることができる。前記のような反応方法を採用することにより、カルボキシル基の反応性が向上し、式（３）の化合物を収率良く得ることができる。 From the reaction mixture produced by the reaction of the compound of formula (4) with isobutyl chlorocarbonate and benzylamine, inorganic salts, organic acid salts and the like produced as by-products are removed by a liquid separation washing operation with water, hydrochloric acid water, sodium bicarbonate water or the like. And a solution containing the compound of the formula (3) can be obtained as an organic layer. By adopting the reaction method as described above, the reactivity of the carboxyl group is improved, and the compound of the formula (3) can be obtained in good yield.
式（４）の化合物は、典型的には、式（５）のＢｏｃ化したＤ－セリンをテトラヒドロフラン（ＴＨＦ）および水を溶媒とし、アルカリ金属水酸化物の存在下、硫酸ジメチルと反応させて製造される。 The compound of the formula (4) is typically reacted with the Bocized D-serine of the formula (5) using tetrahydrofuran (THF) and water as a solvent and reacting with dimethyl sulfate in the presence of an alkali metal hydroxide. Manufactured.
式（５）の化合物と硫酸ジメチルとの反応においては効率的に作業できる観点から、式（５）の化合物を製造する際に得られた式（５）の化合物ナトリウム塩を含む水溶液を使用することが好ましい。追加する溶媒は反応性の観点から硫酸ジメチルを溶解させ、水と容易に混和するものが好ましく、例えばテトラヒドロフラン、アセトン、アセトニトリル、ジメチルホルムアミド、ジメチルアセトアミド、Ｎ－メチルモルホリン、ジメチルスルホキシド、メタノール、エタノール、２－プロパノール、ｔｅｒｔ－ブタノールなどを使用することができ、これらの溶媒の中でもテトラヒドロフランが好ましい。水に対する溶媒の使用量は反応性の観点から水１０重量部に対して、１から１０重量部の使用が好ましい。経済性の観点から２から５重量部の使用がより好ましい。 From the viewpoint of efficient work in the reaction of the compound of the formula (5) with dimethyl sulfate, an aqueous solution containing the sodium salt of the compound of the formula (5) obtained when producing the compound of the formula (5) is used. Is preferable. From the viewpoint of reactivity, the solvent to be added is preferably one in which dimethyl sulfate is dissolved and easily miscible with water, for example, tetrahydrofuran, acetone, acetonitrile, dimethylformamide, dimethylacetamide, N-methylmorpholine, dimethylsulfoxide, methanol, ethanol, etc. 2-propanol, tert-butanol and the like can be used, and among these solvents, tetrahydrofuran is preferable. From the viewpoint of reactivity, the amount of the solvent used with respect to water is preferably 1 to 10 parts by weight with respect to 10 parts by weight of water. From the economical point of view, it is more preferable to use 2 to 5 parts by weight.
アルカリ金属水酸化物としては水酸化ナトリウム、水酸化カリウム、水酸化リチウム等を使用することができ、その中でも水酸化ナトリウムが好ましい。アルカリ金属水酸化物の使用量は反応性の観点から硫酸ジメチルの使用量より０．０５から１モルの過剰量が好ましく、０．１から０．５モルの過剰量がより好ましい。硫酸ジメチルの使用量は式（５）の化合物１モルに対して３から１０モルが好ましく、５から８モルがより好ましい。反応温度は特に限定はないがラセミ化を防ぐ観点からより低い温度が好ましく、-１０から１０℃が好ましい。反応後の反応混合物に有機溶媒を添加し、さらに得られた混合物に酸を添加して中和することにより、式（４）のカルボン酸化合物を有機溶媒中に抽出することができる。添加する酸としては例えば塩酸、硫酸、硝酸等の無機酸；酢酸、ギ酸、プロピオン酸、シュウ酸、クエン酸等の有機酸が挙げられる。ｐＨは２以下に調整することが好ましいため、塩酸を用いるのが好ましい。抽出に用いる有機溶媒はトルエンなどの芳香族系溶媒、酢酸メチル、酢酸エチル、酢酸イソプロピル等のエステル系溶媒、メチルエチルケトン、メチルイソブチルケトン等のケトン系溶媒を使用することができ、トルエンが好ましい。抽出操作により得られた式（４）の化合物を含有する溶液は、濃縮により有機溶媒を除去することができる。 As the alkali metal hydroxide, sodium hydroxide, potassium hydroxide, lithium hydroxide and the like can be used, and among them, sodium hydroxide is preferable. From the viewpoint of reactivity, the amount of the alkali metal hydroxide used is preferably 0.05 to 1 mol, more preferably 0.1 to 0.5 mol, more than the amount of dimethyl sulfate used. The amount of dimethyl sulfate used is preferably 3 to 10 mol, more preferably 5 to 8 mol, per 1 mol of the compound of the formula (5). The reaction temperature is not particularly limited, but a lower temperature is preferable from the viewpoint of preventing racemization, and -10 to 10 ° C. is preferable. The carboxylic acid compound of the formula (4) can be extracted into the organic solvent by adding an organic solvent to the reaction mixture after the reaction and further adding an acid to the obtained mixture to neutralize the mixture. Examples of the acid to be added include inorganic acids such as hydrochloric acid, sulfuric acid and nitric acid; and organic acids such as acetic acid, formic acid, propionic acid, oxalic acid and citric acid. Since the pH is preferably adjusted to 2 or less, it is preferable to use hydrochloric acid. As the organic solvent used for extraction, an aromatic solvent such as toluene, an ester solvent such as methyl acetate, ethyl acetate and isopropyl acetate, and a ketone solvent such as methyl ethyl ketone and methyl isobutyl ketone can be used, and toluene is preferable. The organic solvent can be removed from the solution containing the compound of the formula (4) obtained by the extraction operation by concentration.
式（５）の化合物は、典型的には、Ｄ－セリンをテトラヒドロフラン（ＴＨＦ）および水を溶媒とし、塩基の存在下、Ｄ－セリンをジｔｅｒｔ－ブチルジカーボネートと反応させて製造される。 The compound of formula (5) is typically produced by reacting D-serine with tetrahydrofuran (THF) and water in the presence of a base and reacting D-serine with tert-butyl dicarbonate.
この反応においては、溶媒として、通常、水を使用するが、有機溶媒を混合しても良い。有機溶媒は反応性の観点からジｔｅｒｔ－ブチルカルボニルを溶解させ、水と容易に混和するものが好ましく、例えばテトラヒドロフラン、アセトン、アセトニトリル、ジメチルホルムアミド、ジメチルアセトアミド、Ｎ－メチルモルホリン、ジメチルスルホキシド、メタノール、エタノール、2-プロパノール、ｔｅｒｔ－ブタノールなどを使用することができ、テトラヒドロフランが好ましい。 In this reaction, water is usually used as the solvent, but an organic solvent may be mixed. From the viewpoint of reactivity, the organic solvent preferably dissolves ditert-butylcarbonyl and is easily miscible with water, for example, tetrahydrofuran, acetone, acetonitrile, dimethylformamide, dimethylacetamide, N-methylmorpholine, dimethylsulfoxide, methanol, etc. Ethanol, 2-propanol, tert-butanol and the like can be used, preferably tetrahydrofuran.
水の使用量はＤ－セリンおよび反応によって生成する式（５）の化合物のナトリウム塩を溶解できればよく、Ｄ－セリン１０重量部に対して通常３から１０重量部である。
ジｔｅｒｔ－ブチルジカーボネートの使用量はD-セリン１モルに対して１．０から２．０モルが好ましく、１．０から１．５モルがより好ましい。
The amount of water used is only required to be able to dissolve the sodium salt of D-serine and the compound of the formula (5) produced by the reaction, and is usually 3 to 10 parts by weight with respect to 10 parts by weight of D-serine.
The amount of tert-butyl dicarbonate to be used is preferably 1.0 to 2.0 mol, more preferably 1.0 to 1.5 mol, per 1 mol of D-serine.
前記塩基としては水酸化ナトリウム、水酸化カリウム、水酸化リチウム、炭酸ナトリウム、炭酸カリウム、炭酸水素ナトリウム、炭酸水素カリウム等を使用することができ、中でも、水酸化ナトリウムが好ましく、水酸化ナトリウムと炭酸ナトリウムまたは炭酸水素ナトリウムを混合して用いてもよい。塩基の使用量はＤ－セリン1モルに対して１．０から３．０モルが好ましく、１．１から１．３モルがより好ましい。 As the base, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate and the like can be used. Among them, sodium hydroxide is preferable, and sodium hydroxide and carbonic acid are preferable. Sodium or sodium hydrogen carbonate may be mixed and used. The amount of the base used is preferably 1.0 to 3.0 mol, more preferably 1.1 to 1.3 mol, relative to 1 mol of D-serine.
Ｄ－セリンとジｔｅｒｔ－ブチルジカーボネートとの反応温度は特に限定されないが反応性の観点から３０から５０℃が好ましい。反応により生成する混合物をトルエン等の有機溶媒による分液洗浄操作により残存するジｔｅｒｔ－ブチルカルボニル試薬等を除去することができ、水層より式（５）の化合物アルカリ金属塩（好ましくはナトリウム塩）を含む溶液を得ることができる。 The reaction temperature between D-serine and ditert-butyl dicarbonate is not particularly limited, but is preferably 30 to 50 ° C. from the viewpoint of reactivity. The mixture produced by the reaction can be washed with a separate solution using an organic solvent such as toluene to remove the residual ditert-butylcarbonyl reagent and the like, and the compound alkali metal salt of the formula (5) (preferably a sodium salt) can be removed from the aqueous layer. ) Can be obtained.
本発明の方法では、Ｄ－セリンから式（１）の化合物まで、中間体（式（５）から式（２）を単離せず、溶液のまま繋いで製造することができ、工程の間の繋ぎが容易であり、効率的な工業的製造方法として優れている。この方法によれば、下記式（６）の化合物の含有量を低減した式（１）の精製アミド化合物が製造できる。
式（６）：
Equation (6):
（以下、ＯＨ体と記すこともある。）の化合物は、式（４）の製造の際に残留する原料である式（５）に由来する不純物であり、式（１）のアミド化合物に対して脱メチル化した構造を有する。 The compound of the formula (hereinafter, also referred to as an OH compound) is an impurity derived from the formula (5), which is a raw material remaining in the production of the formula (4), with respect to the amide compound of the formula (1). Has a demethylated structure.
本発明の方法では、式（１）のアミド化合物はＤ－セリンから良好な収率で製造することができ、得られた式（１）のアミド化合物の純度は、通常、９９．９％以上、さらに９９．９５％以上にすることができる。また、得られた式（１）のアミド化合物の中のＯＨ体の含有量を、通常０．０５％未満、さらに０．０３％未満に低減できる。 In the method of the present invention, the amide compound of the formula (1) can be produced from D-serine in a good yield, and the purity of the obtained amide compound of the formula (1) is usually 99.9% or more. In addition, it can be 99.95% or more. Further, the content of the OH compound in the obtained amide compound of the formula (1) can be usually reduced to less than 0.05%, further to less than 0.03%.
本発明のアミド化合物の製造工程の典型的な例を以下のスキームに示す。
以下、本発明を更に詳しく説明するため実施例を挙げる。しかし、本発明はこれら実施例等に限定されるものではない。 Hereinafter, examples will be given to explain the present invention in more detail. However, the present invention is not limited to these examples and the like.
製造例１
１）式（５）の化合物の製造
水（３５０ｍＬ）、２５％水酸化ナトリウム水溶液（１５２ｇ，０．９５モル）、炭酸水素ナトリウム（１６ｇ，０．１９モル）、Ｄ－セリン （１００ｇ，０．９５モル）の混合液を４０℃に昇温し、テトラヒドロフラン（５０ｍＬ）を加えた。この溶液にジｔｅｒｔ－ブチルジカーボーネート（２４９ｇ， １．１４モル）とテトラヒドロフラン（５０ｍＬ）の混合液を４０℃で３ｈ以上かけて滴下した。４０℃で保温し、原料消失を確認後、トルエン（２００ｍＬ）を加え、４０℃で分液洗浄を行い、水層より式（５）の化合物のナトリウム塩溶液を得た。式（５）の化合物の収率は１００％、ＨＰＬＣ純度９７．６％であった。
Production Example 1
1) Production of the compound of formula (5) Water (350 mL), 25% aqueous sodium hydroxide solution (152 g, 0.95 mol), sodium hydrogen carbonate (16 g, 0.19 mol), D-serine (100 g, 0. The temperature of the mixed solution of 95 mol) was raised to 40 ° C., and tetrahydrofuran (50 mL) was added. A mixed solution of tert-butyl dicarbonate (249 g, 1.14 mol) and tetrahydrofuran (50 mL) was added dropwise to this solution at 40 ° C. over 3 hours. After keeping the temperature at 40 ° C. and confirming the disappearance of the raw materials, toluene (200 mL) was added, and liquid separation washing was performed at 40 ° C. to obtain a sodium salt solution of the compound of the formula (5) from the aqueous layer. The yield of the compound of the formula (5) was 100%, and the HPLC purity was 97.6%.
２）式（４）の化合物の製造
式（５）の化合物のナトリウム塩溶液（０．４８モル）にテトラヒドロフラン（１６０ｍＬ）を加えた後、０℃に冷却し、温度を保ちながらジメチル硫酸（４２０ｇ，３．３３モル）と５０％水酸化ナトリウム水溶液（２８５ｇ， ３．５７モル）を０℃で併注した。併注後、約２ｈかけて２０℃に昇温して保温した。原料消失を確認後、トルエン（５００ｍＬ）を加え、２０℃で３５％塩酸を加えてｐＨを１～２に調整した。分液後、得られた有機層を２０℃で２０％食塩水（１００ｍＬ）にて洗浄した。得られた有機層より溶媒を約３５０ｇ分減圧留去し、式（４）の化合物の溶液を得た。式（５）の化合物からの式（４）の化合物の収率は９９％、ＨＰＬＣ純度９６．３％、光学純度は９７．６％であった。
2) Production of the compound of formula (4)
After adding hydroxide (160 mL) to a sodium salt solution (0.48 mol) of the compound of the formula (5), cool to 0 ° C., and maintain the temperature with dimethyl sulfate (420 g, 3.33 mol) and 50% water. Aqueous sodium oxide solution (285 g, 3.57 mol) was co-injected at 0 ° C. After the combined injection, the temperature was raised to 20 ° C. over about 2 hours to keep the temperature warm. After confirming the disappearance of the raw materials, toluene (500 mL) was added, and 35% hydrochloric acid was added at 20 ° C. to adjust the pH to 1-2. After the liquid separation, the obtained organic layer was washed with 20% saline solution (100 mL) at 20 ° C. The solvent was distilled off from the obtained organic layer under reduced pressure for about 350 g to obtain a solution of the compound of the formula (4). The yield of the compound of the formula (4) from the compound of the formula (5) was 99%, the HPLC purity was 96.3%, and the optical purity was 97.6%.
３）式（３）の化合物の製造
クロロ炭酸イソブチル（６７ｇ，０．４９モル）とトルエン（２２０ｍＬ）を混合し、－１０℃に冷却した。この溶液に式（４）の化合物の溶液（０．４７モル）にＮ－メチルモルホリン（５０ｇ，０．４９モル）を加えた混合液を－１０で滴下した。混合物を－１０℃で保温し、原料の消失を確認後、イソプロピルアルコール（４４ｍＬ）とベンジルアミン（５２ｇ，０．４９モル）の混合液を－１０℃で滴下した。滴下終了後、約２ｈかけて１０℃に昇温し、保温した。中間体の消失を確認後、混合物を水（１９６ｍＬ）、３．５％塩酸（９８ｍＬ）、８％炭酸水素ナトリウム水溶液（９８ｍＬ）で順次、洗浄し、式（３）の化合物のトルエン溶液を得た。式（４）の化合物からの式（３）の化合物の収率は９6．９％であった。
3) Preparation of compound of formula (3) Isobutyl chlorocarbonate (67 g, 0.49 mol) and toluene (220 mL) were mixed and cooled to −10 ° C. A mixed solution prepared by adding N-methylmorpholine (50 g, 0.49 mol) to a solution (0.47 mol) of the compound of the formula (4) to this solution was added dropwise at −10. The mixture was kept warm at −10 ° C., and after confirming the disappearance of the raw materials, a mixed solution of isopropyl alcohol (44 mL) and benzylamine (52 g, 0.49 mol) was added dropwise at −10 ° C. After the completion of the dropping, the temperature was raised to 10 ° C. over about 2 hours to keep the temperature warm. After confirming the disappearance of the intermediate, the mixture was washed successively with water (196 mL), 3.5% hydrochloric acid (98 mL) and 8% aqueous sodium hydrogen carbonate solution (98 mL) to obtain a toluene solution of the compound of the formula (3). rice field. The yield of the compound of the formula (3) from the compound of the formula (4) was 96.9%.
４）式（２）のアミノ化合物の製造
式（３）の化合物トルエン溶液（０．４４モル）を１５℃に温調し、温度を保ちながら３５％塩酸（１６７ｇ，１．６０モル）を滴下した。混合物を１５℃で保温し、原料の消失を確認した。５℃に冷却後、混合物に水（９６ｍＬ）を滴下、分液し、水層より式（２）のアミノ化合物塩酸塩の水溶液を得た。
4) Production of amino compound of formula (2) The temperature of the compound toluene solution of formula (3) (0.44 mol) was adjusted to 15 ° C., and 35% hydrochloric acid (167 g, 1.60 mol) was added dropwise while maintaining the temperature. bottom. The mixture was kept warm at 15 ° C., and the disappearance of the raw material was confirmed. After cooling to 5 ° C., water (96 mL) was added dropwise to the mixture, and the mixture was separated to obtain an aqueous solution of the amino compound hydrochloride of the formula (2) from the aqueous layer.
５）式（１）の精製アミド化合物の製造
式（２）の化合物の塩酸塩水溶液に３０℃以下で５０％水酸化ナトリウム水溶液（１１０ｇ，１．３７モル）を滴下し、炭酸水素ナトリウム（２７ｇ，０．３２モル）を加えた。このなかにさらに酢酸エチル（７２０ｍＬ）を加えた後、３５℃に昇温し、温度を保ちながら無水酢酸（４７ｇ，０．４６モル）を滴下した。混合物を３５℃で保温し、原料の消失を確認後、混合物を分液し、続いて８％炭酸水素ナトリウム水溶液（９６ｍＬ）、水（４８ｍＬ）で洗浄した。得られた有機層中のＯＨ体の含有量は０．３％であった。（OH体の含有量とは、高速液体クロマトグラムにおけるピークの面積値から次の式に基づき計算された値である（式（６）のOH体の面積値/(式（６）のOH体の面積値＋式（１）の化合物の面積値)）×１００）。得られた有機層に酢酸エチル（１４１ｍＬ）を加えた後、溶媒を約７００ｇ減圧留去した。留去残に酢酸エチル１８８ｍＬを加えた後に５０℃以上にて濾過、酢酸エチル５０ｍＬで洗浄した。濾洗液に酢酸エチル（５００ｍＬ）を加えた後、溶媒を約４２０ｇ減圧留去した。留去残中の水分が式（１）の化合物１モルに対して２．０モル以下となっていることを確認した後に６０℃に温調し、種晶を接種後、２時間保温した。生成したスラリーマスにシクロヘキサン（２３５ｍＬ）を１時間以上かけて滴下した後に１時間保温し、約６時間かけて０℃に冷却した。濾過後、０℃に冷却したシクロヘキサン（１４１ｍＬ）と酢酸エチル（１４１ｍＬ）の混合溶液で洗浄、得られた結晶を減圧乾燥し、精製された式（１）の化合物を得た。得量 ９２．３ｇ、収率８４．２％（Ｄ－セリンからの通算収率８０．７％）。ＨＰＬＣ純度 ９９．９８％（ＯＨ体 ０．０２％）、光学純度 ９９．９％ ｅｅ。
5) Production of the purified amide compound of the formula (1) A 50% sodium hydroxide aqueous solution (110 g, 1.37 mol) was added dropwise to the hydrochloride aqueous solution of the compound of the formula (2) at 30 ° C. or lower, and sodium hydrogencarbonate (27 g) was added dropwise. , 0.32 mol) was added. Ethyl acetate (720 mL) was further added thereto, the temperature was raised to 35 ° C., and acetic anhydride (47 g, 0.46 mol) was added dropwise while maintaining the temperature. The mixture was kept warm at 35 ° C., and after confirming the disappearance of the raw materials, the mixture was separated and then washed with 8% aqueous sodium hydrogen carbonate solution (96 mL) and water (48 mL). The content of OH compound in the obtained organic layer was 0.3%. (The content of OH compound is a value calculated from the area value of the peak in the high-speed liquid chromatogram based on the following equation (area value of OH compound in equation (6) / OH compound in equation (6). Area value of + area value of compound of formula (1))) × 100). After adding ethyl acetate (141 mL) to the obtained organic layer, about 700 g of the solvent was distilled off under reduced pressure. After adding 188 mL of ethyl acetate to the distillate, the mixture was filtered at 50 ° C. or higher and washed with 50 mL of ethyl acetate. After adding ethyl acetate (500 mL) to the lotion, about 420 g of the solvent was distilled off under reduced pressure. After confirming that the water content in the distillate residue was 2.0 mol or less with respect to 1 mol of the compound of the formula (1), the temperature was adjusted to 60 ° C., and the seed crystals were inoculated and kept warm for 2 hours. Cyclohexane (235 mL) was added dropwise to the produced slurry mass over 1 hour, the mixture was kept warm for 1 hour, and cooled to 0 ° C. over about 6 hours. After filtration, the mixture was washed with a mixed solution of cyclohexane (141 mL) and ethyl acetate (141 mL) cooled to 0 ° C., and the obtained crystals were dried under reduced pressure to obtain a purified compound of the formula (1). The yield was 92.3 g and the yield was 84.2% (total yield from D-serine was 80.7%). HPLC purity 99.98% (OH body 0.02%), optical purity 99.9% ee.
製造例２
１）式（５）の化合物の製造
水３３０ｍＬ）、２５％水酸化ナトリウム水溶液（１８３ｇ， １．１４モル）、Ｄ－セリン （１００ｇ， ０．９５モル）の混合液を４０℃に昇温し、テトラヒドロフラン（５０ｍＬ）を加えた。この溶液にジｔｅｒｔ－ブチルジカーボーネート（２４９ｇ， １．１４モル）とテトラヒドロフラン（５０ｍＬ）の混合液を４０℃で３ｈ以上かけて滴下した。４０℃で保温し、原料消失を確認後、トルエン（２００ｍＬ）を加え、４０℃で分液洗浄を行い、水層より式（５）の化合物のナトリウム塩溶液を得た。式（５）の化合物の収率は１００％、ＨＰＬＣ純度９８．６％であった。
Manufacturing example 2
1) Production of the compound of formula (5) Water 330 mL), 25% aqueous sodium hydroxide solution (183 g, 1.14 mol), and D-serine (100 g, 0.95 mol) were heated to 40 ° C. , Tetrahydrofuran (50 mL) was added. A mixed solution of tert-butyl dicarbonate (249 g, 1.14 mol) and tetrahydrofuran (50 mL) was added dropwise to this solution at 40 ° C. over 3 hours. After keeping the temperature at 40 ° C. and confirming the disappearance of the raw materials, toluene (200 mL) was added, and liquid separation washing was performed at 40 ° C. to obtain a sodium salt solution of the compound of the formula (5) from the aqueous layer. The yield of the compound of the formula (5) was 100%, and the HPLC purity was 98.6%.
２）式（４）の化合物の製造
式（５）の化合物のナトリウム塩溶液（０．４８モル）にテトラヒドロフラン（１６０ｍＬ）を加えた後、０℃に冷却し、温度を保ちながらジメチル硫酸（４２０ｇ，３．３３モル）を滴下した。続いて５０％水酸化ナトリウム水溶液（２８５ｇ，３．５７モル）を０℃で滴下した。０℃で保温し、原料消失を確認後、トルエン（１０００ｍＬ）を加え、０℃で３５％塩酸を加えてｐＨを１～２に調整した。分液後、得られた有機層を０℃で２０％食塩水（１００ｍＬ）にて洗浄した。得られた有機層より溶媒を約７００ｇ減圧留去し、式（４）の化合物の溶液を得た。式（５）の化合物からの式（４）の化合物の収率は９９％、ＨＰＬＣ純度９６．４％、光学純度は９８．９％であった。
2) Production of the compound of formula (4)
Tetrahydrofuran (160 mL) was added to a sodium salt solution (0.48 mol) of the compound of the formula (5), the mixture was cooled to 0 ° C., and dimethyl sulfate (420 g, 3.33 mol) was added dropwise while maintaining the temperature. Subsequently, a 50% aqueous sodium hydroxide solution (285 g, 3.57 mol) was added dropwise at 0 ° C. After keeping the temperature at 0 ° C. and confirming the disappearance of the raw materials, toluene (1000 mL) was added, and 35% hydrochloric acid was added at 0 ° C. to adjust the pH to 1-2. After the liquid separation, the obtained organic layer was washed with 20% saline solution (100 mL) at 0 ° C. About 700 g of the solvent was distilled off from the obtained organic layer under reduced pressure to obtain a solution of the compound of the formula (4). The yield of the compound of the formula (4) from the compound of the formula (5) was 99%, the HPLC purity was 96.4%, and the optical purity was 98.9%.
比較例１
１）式（５）の化合物の製造
水（１２５ｍＬ）、炭酸水素ナトリウム水溶液（２４ｇ， １．１４モル）、Ｄ－セリン （２５ｇ， ０．２４モル）の混合液を３０℃に昇温した。この溶液にジｔｅｒｔ－ブチルジカーボーネート（６０ｇ， ０．２７モル）を滴下した。３０℃で保温し、原料消失を確認後、トルエン（５０ｍＬ）を加え、３０℃で分液洗浄を行い、水層より式（５）の化合物のナトリウム塩溶液を得た。式（５）の化合物の収率は１００％、ＨＰＬＣ純度９９．４％であった。
Comparative Example 1
1) Preparation of the compound of formula (5) A mixed solution of water (125 mL), an aqueous sodium hydrogen carbonate solution (24 g, 1.14 mol) and D-serine (25 g, 0.24 mol) was heated to 30 ° C. Ditert-butyl dicarbonate (60 g, 0.27 mol) was added dropwise to this solution. After keeping the temperature at 30 ° C. and confirming the disappearance of the raw materials, toluene (50 mL) was added, and liquid separation washing was performed at 30 ° C. to obtain a sodium salt solution of the compound of the formula (5) from the aqueous layer. The yield of the compound of the formula (5) was 100%, and the HPLC purity was 99.4%.
２）式（４）の化合物の製造
式（５）の化合物のナトリウム塩溶液（０．１４モル）にテトラヒドロフラン（４５ｍＬ）を加えた後、０℃に冷却し、５０％水酸化ナトリウム水溶液（５．７ｇ，０．０７モル）を加えた。続いて温度を保ちながらジメチル硫酸（１０８ｇ，０．８６モル）と５０％水酸化ナトリウム水溶液（６９ｇ， ０．８６モル）を０℃で併注した。併注後、０℃で保温し、原料消失を確認後、トルエン（１５０ｍＬ）を加え、０℃で３５％塩酸を加えてｐＨを１～２に調整した。分液後、得られた有機層を０℃で２０％食塩水（３０ｍＬ）にて洗浄した。得られた有機層より、式（４）の化合物の溶液を得た。式（５）の化合物からの式（４）の化合物の収率は９９％、ＨＰＬＣ純度９６．６％、光学純度は９７．６％であった。
2) Production of the compound of formula (4)
After adding tetrahydrofuran (45 mL) to a sodium salt solution (0.14 mol) of the compound of the formula (5), cool to 0 ° C., and add a 50% aqueous sodium hydroxide solution (5.7 g, 0.07 mol). rice field. Subsequently, while maintaining the temperature, dimethyl sulfate (108 g, 0.86 mol) and a 50% aqueous sodium hydroxide solution (69 g, 0.86 mol) were co-injected at 0 ° C. After the combined injection, the temperature was kept at 0 ° C., and after confirming the disappearance of the raw material, toluene (150 mL) was added, and 35% hydrochloric acid was added at 0 ° C. to adjust the pH to 1-2. After the liquid separation, the obtained organic layer was washed with 20% saline solution (30 mL) at 0 ° C. From the obtained organic layer, a solution of the compound of the formula (4) was obtained. The yield of the compound of the formula (4) from the compound of the formula (5) was 99%, the HPLC purity was 96.6%, and the optical purity was 97.6%.
３）式（３）の化合物の製造
式（４）の化合物の溶液（０．１４モル）を－１０℃に冷却し、温度を保ちながらクロロ炭酸イソブチル（２１．５ｇ，０．１６モル）、Ｎ－メチルモルホリン（２１．６ｇ，０．２１モル）の順で滴下した。混合物を－１０℃で保温し、原料の消失を確認後、イソプロパノール（１５ｍＬ）とベンジルアミン（１６．０ｇ， ０．１５モル）の混合液を－１０℃で滴下した。滴下終了後、約２ｈかけて１０℃に昇温し、保温した。中間体の消失を確認後、混合物を水（６０ｍＬ）、３．５％塩酸（３０ｍＬ）、８％炭酸水素ナトリウム水溶液（３０ｍＬ）で洗浄し、有機層として式（３）の化合物のトルエン溶液を得た。式（４）の化合物からの式（３）の化合物の収率は８７．８％であった。
3) Production of the compound of formula (3)
The solution of the compound of the formula (4) (0.14 mol) was cooled to −10 ° C., and while maintaining the temperature, isobutyl chlorocarbonate (21.5 g, 0.16 mol) and N-methylmorpholine (21.6 g, 0) were used. .21 mol) was added dropwise in this order. The mixture was kept warm at −10 ° C., and after confirming the disappearance of the raw materials, a mixed solution of isopropanol (15 mL) and benzylamine (16.0 g, 0.15 mol) was added dropwise at −10 ° C. After the completion of the dropping, the temperature was raised to 10 ° C. over about 2 hours to keep the temperature warm. After confirming the disappearance of the intermediate, the mixture was washed with water (60 mL), 3.5% hydrochloric acid (30 mL) and 8% aqueous sodium hydrogen carbonate solution (30 mL), and a toluene solution of the compound of the formula (3) was used as an organic layer. Obtained. The yield of the compound of the formula (3) from the compound of the formula (4) was 87.8%.
参考例１、２および製造例６，７，８
式（６）のＯＨ体の含有量がそれぞれ表１に示すとおりである式（１）の化合物の晶析前マス（晶析母液）において表１に記載のそれぞれの水分含量に設定する以外は、製造例５と同じ溶媒、溶媒比率にて晶析、ろ過、洗浄を行い、得られた結晶を減圧乾燥して式（１）の化合物を得た。得られた結晶中の式（６）のＯＨ体の含有量および式（３）の化合物からの式（１）の化合物からの収率を表１に示す。
Reference Examples 1 and 2 and Production Examples 6, 7, 8
The content of the OH compound of the formula (6) is as shown in Table 1, except that the water content of the compound of the formula (1) is set to each water content shown in Table 1 in the pre-crystallization mass (crystallization mother liquor). , Crystallization, filtration and washing were carried out with the same solvent and solvent ratio as in Production Example 5, and the obtained crystals were dried under reduced pressure to obtain the compound of the formula (1). Table 1 shows the content of the OH compound of the formula (6) in the obtained crystal and the yield from the compound of the formula (1) from the compound of the formula (3).
比較例２ 特許文献２に記載の方法
１）式（４）の化合物の製造
トルエン（７５mL）、式（５）の化合物（１５ｇ，０．０７モル）とテトラブチルアンモニウムブロミド（０．９ｇ，０．００３モル）の懸濁液を１０℃以下に冷却した。これに、２０％水酸化ナトリウム水溶液（１４．６ｇ，０．０７モル）を加え、得られた混合物を３０分間熟成した。温度を１０℃以下に保持しながらジメチル硫酸（３６．９ｇ，０．２９モル）と５０％水酸化ナトリウム水溶液（２６．５ｇ，０．３３モル）を加え、反応混合物を１時間以上熟成した。混合物に水（４５mL）を加えて分液した。水層を５０％クエン酸水溶液でｐH３．５以下にして塩化メチレン（２×６２mL，１×４５mL）で抽出し、抽出液を混合、脱水濃縮し、式（４）の化合物を得た。（濃縮後２３．８ｇ，見かけ収率１００％，HPLC純度９５．６％，光学純度９６．５％）
Comparative Example 2 Method 1 described in Patent Document 2) Production of compound of formula (4) Toluene (75 mL), compound of formula (5) (15 g, 0.07 mol) and tetrabutylammonium bromide (0.9 g, 0) The suspension of (.003 mol) was cooled to 10 ° C. or lower. A 20% aqueous sodium hydroxide solution (14.6 g, 0.07 mol) was added thereto, and the obtained mixture was aged for 30 minutes. While keeping the temperature below 10 ° C., dimethyl sulfate (36.9 g, 0.29 mol) and a 50% aqueous sodium hydroxide solution (26.5 g, 0.33 mol) were added, and the reaction mixture was aged for 1 hour or more. Water (45 mL) was added to the mixture and the mixture was separated. The aqueous layer was set to pH 3.5 or less with a 50% aqueous citric acid solution and extracted with methylene chloride (2 × 62 mL, 1 × 45 mL), and the extracts were mixed, dehydrated and concentrated to obtain the compound of the formula (4). (23.8 g after concentration, apparent yield 100%, HPLC purity 95.6%, optical purity 96.5%)
２）式（３）の化合物の製造
式（４）の化合物溶液を－１０℃以下に冷却し、クロロ炭酸イソブチル（９．０mL，０．０７モル）を－５℃以下で加え、続いてN－メチルモルホリン（７．６ｍＬ，０．０７モル）を－５℃以下で加え、混合物を－５℃以下で３０分以上熟成した。塩化メチレンに溶解したベンジルアミン（７．８ｍＬ，０．０７モル）を－５℃以下で加え、混合物を室温に加温した。１時間以上熟成した後、混合物を水（２９ｍＬ）、１Ｎ－塩酸水溶液（２９ｍＬ）、８％炭酸水素ナトリウム水溶液（２９ｍＬ）および水（２９ｍＬ）で洗浄して式（３）の化合物溶液を得た。式（４）の化合物からの式（３）の化合物の収率は９０．７％であった。
2) Preparation of compound of formula (3) Cool the compound solution of formula (4) to -10 ° C or lower, add isobutyl chlorocarbonate (9.0 mL, 0.07 mol) at -5 ° C or lower, and then N. -Methylmorpholine (7.6 mL, 0.07 mol) was added at −5 ° C. or lower, and the mixture was aged at −5 ° C. or lower for 30 minutes or longer. Benzylamine (7.8 mL, 0.07 mol) dissolved in methylene chloride was added below −5 ° C. and the mixture was heated to room temperature. After aging for 1 hour or more, the mixture was washed with water (29 mL), 1N-hydrochloric acid aqueous solution (29 mL), 8% sodium hydrogen carbonate aqueous solution (29 mL) and water (29 mL) to obtain a compound solution of the formula (3). .. The yield of the compound of the formula (3) from the compound of the formula (4) was 90.7%.
本発明の方法によれば、高品質のアミド化合物を効率よく製造することができる。 According to the method of the present invention, a high quality amide compound can be efficiently produced.
Claims (8)
のアミド化合物と式（１）のアミド化合物１モル当たり２．０モル以下の水分を含む晶析母液から式（１）の化合物を晶析することを特徴とする式（１）の精製アミド化合物の製造方法。 Equation (1):
The purified amide compound of the formula (1), which comprises crystallizing the compound of the formula (1) from the crystallization mother liquor containing 2.0 mol or less of water per mol of the amide compound of the formula (1) and the amide compound of the formula (1). Manufacturing method.
のアミノ化合物をアセチル化して、請求項１に記載の式（１）のアミド化合物を製造する工程と、生成する式（１）のアミド化合物と、式（１）のアミド化合物１モル当たり２．０モル以下の水分を含む溶液を調製する工程および請求項１に記載の工程を含む式（１）の精製アミド化合物の製造方法。 Equation (2):
2. The step of acetylating the amino compound of the above to produce the amide compound of the formula (1) according to claim 1, the amide compound of the formula (1) to be produced, and the amide compound of the formula (1) per mol. A method for producing a purified amide compound of the formula (1), which comprises a step of preparing a solution containing 0 mol or less of water and the step of claim 1.
（式中、Ｂｏｃは、ｔｅｒｔ－ブトキシカルボニル基を表す。）
の化合物に塩酸を作用させ、式（２）のアミノ化合物を製造する工程および請求項２に記載の工程を含む式（１）の精製アミド化合物の製造方法。 Equation (3):
(In the formula, Boc represents a tert-butoxycarbonyl group.)
A method for producing a purified amide compound of the formula (1), which comprises a step of reacting the compound of the above with hydrochloric acid to produce an amino compound of the formula (2) and the step of claim 2.
（式中、Ｂｏｃは、ｔｅｒｔ－ブトキシカルボニル基を表す。）
のカルボン酸化合物、Ｎ－メチルモルホリンの混合溶液を滴下し、更にベンジルアミンを加える請求項３に記載の式（３）の化合物の製造方法。 In a solution of isobutyl chlorocarbonate, the formula (4):
(In the formula, Boc represents a tert-butoxycarbonyl group.)
The method for producing a compound of the formula (3) according to claim 3, wherein a mixed solution of the carboxylic acid compound of No. 1 and N-methylmorpholine is added dropwise, and benzylamine is further added.
（式中、Ｂｏｃは、ｔｅｒｔ－ブトキシカルボニル基を表す。）
を硫酸ジメチルと反応させ、式（４）：
の化合物を製造する工程と、請求項４に記載の工程を含む式（３）；
（式中、Ｂｏｃは、ｔｅｒｔ－ブトキシカルボニル基を表す。）
の化合物の製造方法。 Formula (5): In the presence of an alkali metal hydroxide using tetrahydrofuran and water as solvents.
(In the formula, Boc represents a tert-butoxycarbonyl group.)
Was reacted with dimethyl sulfate, and the formula (4):
Formula (3) including the step of producing the compound according to claim 4 and the step according to claim 4.
(In the formula, Boc represents a tert-butoxycarbonyl group.)
Method for producing the compound of.
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