JP4000113B2 - (3S) -3-methoxycarbonyl-4-phenylbutyric acid metal salt and method of use thereof - Google Patents
(3S) -3-methoxycarbonyl-4-phenylbutyric acid metal salt and method of use thereof Download PDFInfo
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- JP4000113B2 JP4000113B2 JP2003562070A JP2003562070A JP4000113B2 JP 4000113 B2 JP4000113 B2 JP 4000113B2 JP 2003562070 A JP2003562070 A JP 2003562070A JP 2003562070 A JP2003562070 A JP 2003562070A JP 4000113 B2 JP4000113 B2 JP 4000113B2
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- Prior art keywords
- methoxycarbonyl
- formula
- represented
- phenylbutyric acid
- salt
- Prior art date
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- 150000003839 salts Chemical class 0.000 title claims description 40
- BUNMUVFKMIOEQU-JTQLQIEISA-N (3s)-3-benzyl-4-methoxy-4-oxobutanoic acid Chemical compound COC(=O)[C@H](CC(O)=O)CC1=CC=CC=C1 BUNMUVFKMIOEQU-JTQLQIEISA-N 0.000 title claims description 20
- 229910052751 metal Inorganic materials 0.000 title claims description 19
- 239000002184 metal Substances 0.000 title claims description 19
- 238000000034 method Methods 0.000 title claims description 14
- 238000004519 manufacturing process Methods 0.000 claims description 24
- GTOFKXZQQDSVFH-UHFFFAOYSA-N 2-benzylsuccinic acid Chemical class OC(=O)CC(C(O)=O)CC1=CC=CC=C1 GTOFKXZQQDSVFH-UHFFFAOYSA-N 0.000 claims description 23
- 238000006243 chemical reaction Methods 0.000 claims description 15
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical group [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 claims description 8
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical group [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 claims description 8
- 229910001424 calcium ion Chemical group 0.000 claims description 8
- 229910001415 sodium ion Inorganic materials 0.000 claims description 8
- ODSNARDHJFFSRH-OCAPTIKFSA-N (3as,7ar)-2,3,3a,4,5,6,7,7a-octahydro-1h-isoindole Chemical compound C1CCC[C@@H]2CNC[C@@H]21 ODSNARDHJFFSRH-OCAPTIKFSA-N 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 3
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- 238000006386 neutralization reaction Methods 0.000 claims description 2
- 229950009215 phenylbutanoic acid Drugs 0.000 claims description 2
- OBKXEAXTFZPCHS-UHFFFAOYSA-N 4-phenylbutyric acid Chemical compound OC(=O)CCCC1=CC=CC=C1 OBKXEAXTFZPCHS-UHFFFAOYSA-N 0.000 claims 2
- ZQNPDAVSHFGLIQ-UHFFFAOYSA-N calcium;hydrate Chemical compound O.[Ca] ZQNPDAVSHFGLIQ-UHFFFAOYSA-N 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 239000000543 intermediate Substances 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 14
- 150000001875 compounds Chemical class 0.000 description 13
- 239000003814 drug Substances 0.000 description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- 239000013078 crystal Substances 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- BUNMUVFKMIOEQU-UHFFFAOYSA-N 3-benzyl-4-methoxy-4-oxobutanoic acid Chemical compound COC(=O)C(CC(O)=O)CC1=CC=CC=C1 BUNMUVFKMIOEQU-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-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
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 6
- 206010012601 diabetes mellitus Diseases 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 159000000007 calcium salts Chemical class 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 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 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 230000010030 glucose lowering effect Effects 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 235000019260 propionic acid Nutrition 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 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 3
- 239000002994 raw material Substances 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 229940124597 therapeutic agent Drugs 0.000 description 3
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-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
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical class OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- LYPRYJLVDLZWJF-RCWTXCDDSA-L calcium (3S)-3-benzyl-4-methoxy-4-oxobutanoate Chemical compound [Ca+2].COC(=O)[C@H](CC([O-])=O)CC1=CC=CC=C1.COC(=O)[C@H](CC([O-])=O)CC1=CC=CC=C1 LYPRYJLVDLZWJF-RCWTXCDDSA-L 0.000 description 2
- 239000001110 calcium chloride Substances 0.000 description 2
- 229910001628 calcium chloride Inorganic materials 0.000 description 2
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 2
- 239000000920 calcium hydroxide Substances 0.000 description 2
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 230000003914 insulin secretion Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- RZRFLJPDFLPYEC-PPHPATTJSA-M potassium (3S)-3-benzyl-4-methoxy-4-oxobutanoate Chemical compound [K+].COC(=O)[C@H](CC(=O)[O-])CC1=CC=CC=C1 RZRFLJPDFLPYEC-PPHPATTJSA-M 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- JIABLNFKJDLDDA-PPHPATTJSA-M sodium (3S)-3-benzyl-4-methoxy-4-oxobutanoate Chemical compound [Na+].COC(=O)[C@H](CC([O-])=O)CC1=CC=CC=C1 JIABLNFKJDLDDA-PPHPATTJSA-M 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 229940126585 therapeutic drug Drugs 0.000 description 2
- WTYUPLLQPRTUGY-RCWTXCDDSA-M COC(=O)[C@H](CC(=O)[O-])CC1=CC=CC=C1.[K+].COC(=O)[C@H](CC(=O)O)CC1=CC=CC=C1 Chemical compound COC(=O)[C@H](CC(=O)[O-])CC1=CC=CC=C1.[K+].COC(=O)[C@H](CC(=O)O)CC1=CC=CC=C1 WTYUPLLQPRTUGY-RCWTXCDDSA-M 0.000 description 1
- XXJJQFXXABHSQV-RCWTXCDDSA-M COC(=O)[C@H](CC(=O)[O-])CC1=CC=CC=C1.[Na+].COC(=O)[C@H](CC(=O)O)CC1=CC=CC=C1 Chemical compound COC(=O)[C@H](CC(=O)[O-])CC1=CC=CC=C1.[Na+].COC(=O)[C@H](CC(=O)O)CC1=CC=CC=C1 XXJJQFXXABHSQV-RCWTXCDDSA-M 0.000 description 1
- STVVMTBJNDTZBF-VIFPVBQESA-N L-phenylalaninol Chemical compound OC[C@@H](N)CC1=CC=CC=C1 STVVMTBJNDTZBF-VIFPVBQESA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical class O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- ARLZGEXVMUDUQZ-UHFFFAOYSA-N O.O.[Ca] Chemical compound O.O.[Ca] ARLZGEXVMUDUQZ-UHFFFAOYSA-N 0.000 description 1
- WPGGHFDDFPHPOB-BBWFWOEESA-N OC([C@H](CC(N(C1)C[C@@H]2[C@H]1CCCC2)=O)Cc1ccccc1)=O Chemical compound OC([C@H](CC(N(C1)C[C@@H]2[C@H]1CCCC2)=O)Cc1ccccc1)=O WPGGHFDDFPHPOB-BBWFWOEESA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- CXUQYNVQCUOBGF-VJTUPMIESA-K [Na+].COC(=O)[C@H](CC(=O)[O-])CC1=CC=CC=C1.O.O.[Ca+2].COC(=O)[C@H](CC(=O)[O-])CC1=CC=CC=C1.COC(=O)[C@H](CC(=O)[O-])CC1=CC=CC=C1 Chemical compound [Na+].COC(=O)[C@H](CC(=O)[O-])CC1=CC=CC=C1.O.O.[Ca+2].COC(=O)[C@H](CC(=O)[O-])CC1=CC=CC=C1.COC(=O)[C@H](CC(=O)[O-])CC1=CC=CC=C1 CXUQYNVQCUOBGF-VJTUPMIESA-K 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 229940125708 antidiabetic agent Drugs 0.000 description 1
- 239000003518 caustics Substances 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- VJUGMHMTBSYTRK-JTQLQIEISA-N methyl (2s)-2-benzyl-4-chloro-4-oxobutanoate Chemical compound COC(=O)[C@H](CC(Cl)=O)CC1=CC=CC=C1 VJUGMHMTBSYTRK-JTQLQIEISA-N 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/4035—Isoindoles, e.g. phthalimide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/612—Esters of carboxylic acids having a carboxyl group bound to an acyclic carbon atom and having a six-membered aromatic ring in the acid moiety
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
-
- 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
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Diabetes (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Endocrinology (AREA)
- Emergency Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Indole Compounds (AREA)
Description
技術分野
本発明は、各種医薬品の製造中間体として有用な、一般式
更に詳しく述べれば、本発明は、例えば、インスリン分泌促進作用および血糖低下作用を有し、糖尿病治療薬として有用な、式
背景技術
３−アルコキシカルボニル−４−フェニル酪酸誘導体またはその反応性官能的誘導体は、ベンジルコハク酸部分構造を有する各種医薬品の製造中間体として用いられ、例えば、インスリン分泌促進作用及び血糖低下作用を有し、糖尿病治療薬として有用な前記式（Ａ）で表されるベンジルコハク酸誘導体およびその薬理学的に許容される塩等の製造に有用であることが記載されている（下記文献１参照）。
また、前記式（Ａ）で表される化合物を製造するにあたり、式
これに対し、これまで３−アルコキシカルボニル−４−フェニル酪酸誘導体の金属塩を製造中間体として前記式（Ａ）で表されるベンジルコハク酸誘導体を製造する報告例はなく、また３−アルコキシカルボニル−４−フェニル酪酸誘導体の金属塩の安定性に関する報告例も一切ない。
文献１：特開平４−３５６４５９号公報
文献２：特開２００１−２６１６４５号公報
前記式（Ｂ）で表される３−メトキシカルボニル−４−フェニル酪酸は、熱に対して不安定であり、室温下保存している間に徐々に分解し純度が低下してしまうという問題を有している。そのため、純度の低下した前記式（Ｂ）で表される３−メトキシカルボニル−４−フェニル酪酸を医薬品の製造中間体として使用するためには精製を行い不純物を除く必要があるが、前記式（Ｂ）で表される３−メトキシカルボニル−４−フェニル酪酸は粘性の高い油状物質のため不純物を精製により除去し医薬品の製造中間体として再び利用することは困難である。
また、純度の低下した前記式（Ｂ）で表される３−メトキシカルボニル−４−フェニル酪酸を精製せずに用いた場合でも、前記式（Ａ）で表されるベンジルコハク酸誘導体またはその薬理学的に許容される塩を製造する途中の工程もしくは最終の工程で不純物を除去することは困難である。
以上のように、従来報告されている前記式（Ｂ）で表される３−メトキシカルボニル−４−フェニル酪酸のような熱に対して不安定な化合物を製造中間体として前記式（Ａ）で表されるベンジルコハク酸誘導体を製造する方法は、純度低下により不純物を含有してしまうのを防ぐために冷却保存等の特別な装置を必要としたり、保存時の温度管理等の余分な手間を必要とするという多くの課題を有しており、工業的規模での製造およびコスト上必ずしも満足できる製造方法ではない。そのため、より効率的かつ安定して医薬品の製造中間体として供することのできる方法が求められていた。
発明の開示
本発明者らは前記の課題を解決すべく鋭意検討した結果、本発明の前記一般式（Ｉ）で表される新規な（３Ｓ）−３−メトキシカルボニル−４−フェニル酪酸のナトリウム塩およびカルシウム塩が熱に対して極めて安定であるという良好な特性を有し、また当該化合物を製造中間体として用いることにより前記式（Ａ）またはその薬理学的に許容される塩を簡便に製造できることを見出した。
本発明は、ベンジルコハク酸部分構造を有する各種医薬品、例えば、糖尿病治療薬として有用な前記式（Ａ）で表されるベンジルコハク酸誘導体等の製造に好適な、保存安定性に優れた新規な製造中間体、およびその使用方法を提供するものである。
すなわち、従来製造中間体として報告されている前記式（Ｂ）で表される（３Ｓ）−３−メトキシカルボニル−４−フェニル酪酸は加温下で保存している間に分解が進行し純度が著しく低下してしまうのに対し、本発明の前記一般式（Ｉ）で表される（３Ｓ）−３−メトキシカルボニル−４−フェニル酪酸のナトリウム塩およびカルシウム塩は熱に対して極めて安定であり、加温下保存しても分解することがないことを見出した。
一方、（３Ｓ）−３−メトキシカルボニル−４−フェニル酪酸（Ｂ）の金属塩の中でもカリウム塩は熱に対して不安定であり、加温保存条件下で徐々に分解していき純度が低下してしまう。このように、金属塩の中でもナトリウム塩およびカルシウム塩のみが卓越して熱に対して安定であるという良好な特性を有していることは驚くべき事である。
上記のように、本発明の前記一般式（Ｉ）で表される（３Ｓ）−３−メトキシカルボニル−４−フェニル酪酸金属塩は、従来製造中間体として報告されている前記式（Ｂ）で表される（３Ｓ）−３−メトキシカルボニル−４−フェニル酪酸に比べ極めて熱に対して安定であるという良好な特性を有しており、これを使用することにより冷所保存等のための特別な装置を必要とすることなく、またさらに温度管理等の手間をかけることなく、効率よく、医薬品として有用な前記式（Ａ）で表されるベンジルコハク酸誘導体の製造することができるという優れた作用効果を発揮するものである。
さらには、本発明の前記一般式（Ｉ）で表される（３Ｓ）−３−メトキシカルボニル−４−フェニル酪酸金属塩は、前記式（Ｂ）で表される（３Ｓ）−３−メトキシカルボニル−４−フェニル酪酸に変換することなくその反応性官能的誘導体に誘導した後、前記式（Ｃ）で表されるシス−ヘキサヒドロイソインドリンもしくはその酸付加塩との反応を行うことが可能であり、熱的に不安定な製造中間体を再び経由する必要がないため、余分な工程や精製を行うことなく前記式（Ａ）で表されるベンジルコハク酸誘導体を簡便に製造することができる。
以上のように本発明は、前記式（Ａ）で表されるベンジルコハク酸誘導体を始めとする、ベンジルコハク酸部分構造を有する各種医薬品の製造中間体として有用であり、これを使用することにより、例えば糖尿病治療薬として有用な前記式（Ａ）で表されるベンジルコハク酸誘導体等の医薬品を効率的かつ安定的に製造することができ、工業的規模での製造上好適である。
本発明の前記一般式（Ｉ）で表される（３Ｓ）−３−メトキシカルボニル−４−フェニル酪酸金属塩は、以下の方法により製造することができる。
例えば、前記式（Ｂ）で表される（３Ｓ）−３−メトキシカルボニル−４−フェニル酪酸を、水、アセトン、メタノール、イソプロパノール、酢酸エチルなどの溶媒中、もしくはそれらの混合溶媒中、水酸化ナトリウム、もしくは水酸化カルシウムと反応させることにより、前記一般式（Ｉ）で表される（３Ｓ）−３−メトキシカルボニル−４−フェニル酪酸金属塩を簡便に製造することができる。反応温度は通常−１０〜６０℃であり、反応時間は使用する原料物質や溶媒、反応温度などにより異なるが、通常１〜２４時間である。
本発明の前記一般式（Ｉ）で表される（３Ｓ）−３−メトキシカルボニル−４−フェニル酪酸金属塩は、例えばスキーム１の方法により、血糖低下作用を有し、糖尿病治療薬として有用な前記式（Ａ）で表されるベンジルコハク酸誘導体を製造することができ、医薬品の製造中間体として極めて有用である。
スキーム１
［工程１］
前記一般式（Ｉ）で表される（３Ｓ）−３−メトキシカルボニル−４−フェニル酪酸金属塩を、不活性溶媒中、必要に応じ微量のＮ，Ｎ−ジメチルホルムアミド存在下、１〜５当量の塩化チオニルと反応させた後、減圧下溶媒を留去することにより、化合物（ＩＩ）を得ることができるが、必要に応じ化合物（ＩＩ）を単離することなくその反応溶液をそのまま次の工程に用いることもできる。反応に用いられる不活性溶媒としては、例えば、トルエン、塩化メチレン、クロロホルム、酢酸エチルなどを挙げることができる。反応温度は通常−１０〜８０℃であり、反応時間は使用する原料物質や溶媒、反応温度などにより異なるが、通常１５分間〜５時間である。
［工程２］
化合物（ＩＩ）を、溶媒中、トリエチルアミン、ジイソプロピルエチルアミン、炭酸水素ナトリウム、炭酸ナトリウム、炭酸カリウム、水酸化ナトリウム、水酸化カリウム等の塩基存在下、１〜３当量の式（Ｃ）で表されるシス−ヘキサヒドロイソインドリンもしくはその酸付加塩と反応させることにより化合物（ＩＩＩ）を得ることができる。反応に用いられる溶媒としては、例えば、水、トルエン、塩化メチレン、クロロホルム、酢酸エチル、テトラヒドロフラン、１，２−ジメトキシエタン、もしくはそれらの混合溶媒などを挙げることができる。反応温度は通常−１０〜５０℃であり、反応時間は使用する原料物質や溶媒、反応温度などにより異なるが、通常１０分間〜１２時間である。シス−ヘキサヒドロイソインドリンの酸付加塩としては、塩酸、硫酸、硝酸、リン酸等の塩が挙げることができる。
［工程３］
化合物（ＩＩＩ）をメタノール、エタノール、イソプロパノール等のアルコール類に溶解し、０〜７０℃にて、水酸化ナトリウム、水酸化カリウム等の苛性アルカリ水溶液を加え加水分解を行い、必要に応じ塩酸等の酸を用いて中和することにより、化合物（Ａ）を得ることができる。
上記のように製造した化合物（Ａ）は公知の方法に従い、その薬理学的に許容される塩とすることができる。このようなものとしては、例えば、ナトリウム塩、カリウム塩、カルシウム塩などのような無機塩基との塩、モルホリン、ピペリジン、フェニルアラニノールなどの有機アミン、あるいはアミノ酸などをあげることができる。
また、化合物（Ａ）の薬理学的に許容される塩のうち、式
前記式（Ａ）で表されるベンジルコハク酸誘導体またはその薬理学的に許容される塩の製造方法に使用する、前記式（Ｃ）で表されるシス−ヘキサヒドロイソインドリンおよびその酸付加塩は、公知の方法、例えば、下記文献３又は４記載の方法に従って製造することができる。
文献３：特開平１１−７１３４９号公報
文献４：特開２００１−２６１６４４号公報
実施例
本発明の内容を以下の参考例、実施例および試験例にてさらに詳しく説明するが、本発明は、これらに限定されるものではない。
実施例１
（３Ｓ）−３−メトキシカルボニル−４−フェニル酪酸ナトリウム塩
（３Ｓ）−３−メトキシカルボニル−４−フェニル酪酸（３．００ｇ）をアセトン（３０ｍＬ）に溶かし、氷冷撹拌下に水酸化ナトリウム（０．５７ｇ）の水（０．６０ｍＬ）溶液を加え、室温で一晩撹拌した。析出した結晶をろ取し、アセトン（１ｍＬ）で洗浄して（３Ｓ）−３−メトキシカルボニル−４−フェニル酪酸ナトリウム塩（２．９３ｇ）を得た。
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６） δ ｐｐｍ：
１．９４（１Ｈ，ｄｄ，Ｊ＝６．４，１５．４Ｈｚ），２．１５（１Ｈ，ｄｄ，Ｊ＝７．４，１５．４Ｈｚ），２．７３（２Ｈ，ｄ，Ｊ＝７．２Ｈｚ），２．８０−２．９５（１Ｈ，ｍ），３．４５（３Ｈ，ｓ），７．０５−７．３０（５Ｈ，ｍ）
実施例２
（３Ｓ）−３−メトキシカルボニル−４−フェニル酪酸カルシウム塩
（３Ｓ）−３−メトキシカルボニル−４−フェニル酪酸（０．２５ｇ）をメタノール（３ｍＬ）に溶かし、室温撹拌下に水酸化カルシウム（０．０４２ｇ）を加え同温にて２時間撹拌後、メタノール（０．６ｍＬ）を追加し、さらに室温で一晩撹拌した。結晶をろ取し、メタノール（１ｍＬ）で洗浄して（３Ｓ）−３−メトキシカルボニル−４−フェニル酪酸カルシウム塩（０．２２ｇ）を得た。
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６） δ ｐｐｍ：
２．００−２．１５（１Ｈ，ｍ），２．２０−２．３５（１Ｈ，ｍ），２．７０−２．８０（２Ｈ，ｍ），２．８５−３．００（１Ｈ，ｍ），３．４６（３Ｈ，ｓ），７．０５−７．３０（５Ｈ，ｍ）
参考例１
（３Ｓ）−３−メトキシカルボニル−４−フェニル酪酸カリウム塩
（３Ｓ）−３−メトキシカルボニル−４−フェニル酪酸（０．９８ｇ）をアセトン（２０ｍＬ）に溶かし、氷冷撹拌下に水酸化カリウム（０．２０ｇ）の水（０．５ｍＬ）溶液をを加え、減圧下に溶媒を留去した。残留物にジエチルエーテル（５０ｍＬ）を加え、室温で１０分間撹拌した。析出した結晶をろ取し、ジエチルエーテルで洗浄して（３Ｓ）−３−メトキシカルボニル−４−フェニル酪酸カリウム塩（０．６０ｇ）を得た。
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６） δ ｐｐｍ：
１．９０−２．０５（１Ｈ，ｍ），２．１０−２．２５（１Ｈ，ｍ），２．６５−２．８０（２Ｈ，ｍ），２．８５−２．９５（１Ｈ，ｍ），３．４５（３Ｈ，ｓ），７．０５−７．３５（５Ｈ，ｍ）
実施例３
ビス〔（２Ｓ）−２−ベンジル−３−（シス−ヘキサヒドロインドリン−２−イルカルボニル）プロピオン酸〕カルシウム・二水和物
（３Ｓ）−３−メトキシカルボニル−４−フェニル酪酸ナトリウム塩（５．４７ｇ）をトルエン（３０ｍＬ）に加え、氷冷撹拌下にＮ，Ｎ−ジメチルホルムアミド（０．１ｍＬ）および塩化チオニル（１．９５ｍＬ）を加え、氷冷下に５分間、室温下に３０分間撹拌した。得られた（３Ｓ）−３−メトキシカルボニル−４−フェニル酪酸クロリドを、シス−ヘキサヒドロイソインドリン・リン酸塩（５．２５ｇ）および炭酸カリウム（１５．５ｇ）の水溶液（６０ｍＬ）に、水冷撹拌下に５０分間かけて滴下した。滴下後、水冷下に３０分間撹拌し、室温下に３０分間撹拌した後、トルエン層を分取した。水層をトルエン（２０ｍＬ）で抽出し、トルエン層と合わせた後、有機層を飽和炭酸水素ナトリウム水溶液、１ｍｏｌ／Ｌの塩酸、飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥した。無水硫酸マグネシウムをろ去後、溶媒を減圧下に留去して（２Ｓ）−２−ベンジル−３−（シス−ヘキサヒドロイソインドリン−２−イルカルボニル）プロピオン酸メチル（７．８０ｇ）を得た。得られた（２Ｓ）−２−ベンジル−３−（シス−ヘキサヒドロイソインドリン−２−イルカルボニル）プロピオン酸メチル（７．８０ｇ）をイソプロパノール（１５ｍＬ）に溶かし、室温下に水酸化ナトリウム水溶液（５ｍｏｌ／Ｌ、５．４ｍＬ）を加え、室温下に１時間撹拌後、５０℃で４時間撹拌した。反応液にイソプロパノール（５ｍＬ）および水（４０ｍＬ）を加えた後、塩化カルシウム（１．７ｇ）を水（１０ｍＬ）に溶かした水溶液を５０℃撹拌下に滴下した。さらに５０℃で２時間撹拌後、放冷下に３時間撹拌して析出した結晶をろ取し、得られた結晶を水（５０ｍＬ）で洗浄して結晶（７．３８ｇ）を得た。得られた結晶（５．０ｇ）をメタノール／水より再結晶して、ビス〔（２Ｓ）−２−ベンジル−３−（シス−ヘキサヒドロインドリン−２−イルカルボニル）プロピオン酸〕カルシウム・二水和物（４．４６ｇ）を得た。
１Ｈ−ＮＭＲ（ＣＤＣｌ３） δ ｐｐｍ：
１．２０−１．６０（８Ｈ，ｍ），２．１０−２．３５（３Ｈ，ｍ），２．５５−２．６５（１Ｈ，ｍ），２．７５−２．８５（１Ｈ，ｍ），３．００−３．１０（１Ｈ，ｍ），３．１０−３．４５（５Ｈ，ｍ），３．６０−３．７０（３Ｈ，ｍ），７．１５−７．３０（５Ｈ，ｍ）
試験例１
熱安定性試験
（３Ｓ）−３−メトキシカルボニル−４−フェニル酪酸（０．１ｇ）、（３Ｓ）−３−メトキシカルボニル−４−フェニル酪酸ナトリウム塩（０．１ｇ）、（３Ｓ）−３−メトキシカルボニル−４−フェニル酪酸カルシウム塩（０．１ｇ）および（３Ｓ）−３−メトキシカルボニル−４−フェニル酪酸カリウム塩（０．１ｇ）をそれぞれ栓をしたガラス瓶中、８０℃にて加温保存し、ＨＰＬＣ（高速液体クロマトグラフィー）を用いて以下の条件にて経時的に純度を測定した。
使用カラム：Ｉｎｅｒｔｓｉｌ ＯＤＳ−３ ４．６×２５０ｍｍ
（ＧＬ Ｓｃｉｅｎｃｅｓ Ｉｎｃ．）
移動相：Ａ液 リン酸二水素カリウム水溶液 （０．０２ｍｏｌ／Ｌ）
Ｂ液 アセトニトリル
グラジエント勾配は表１の通り実施した。尚、１５分から４０分は直線勾配である。
カラム温度：２５℃
検出波長：２１０ｎｍ
分解率は加温保存前の純度と加温保存後の純度より、下記式に基づき計算した。
分解率（％）＝１００−（加温保存後の純度／加温保存前の純度）×１００
その結果は表２の通りである。
本発明の前記一般式（Ｉ）で表される（３Ｓ）−３−メトキシカルボニル−４−フェニル酪酸金属塩は、前記式（Ａ）で表されるベンジルコハク酸誘導体を始めとする、ベンジルコハク酸部分構造を有する各種医薬品の製造中間体として有用であり、これを経由することにより、例えば、糖尿病治療薬として有用な前記式（Ａ）で表されるベンジルコハク酸誘導体等の医薬品を効率的かつ安定的に製造することができ、工業的規模での製造上好適である。TECHNICAL FIELD The present invention is a general formula useful as an intermediate for the production of various pharmaceuticals.
More specifically, the present invention has, for example, an insulin secretion promoting action and a blood glucose lowering action, and is useful as a therapeutic agent for diabetes.
Background Art A 3-alkoxycarbonyl-4-phenylbutyric acid derivative or a reactive functional derivative thereof is used as an intermediate for the production of various pharmaceuticals having a benzylsuccinic acid partial structure, and has, for example, an insulin secretion promoting action and a blood glucose lowering action. In addition, it is described that it is useful for the production of benzylsuccinic acid derivatives represented by the above formula (A) and pharmacologically acceptable salts thereof, which are useful as antidiabetic agents (see Reference 1 below). .
In producing the compound represented by the formula (A), the formula
On the other hand, there has been no report on the production of a benzylsuccinic acid derivative represented by the above formula (A) using a metal salt of a 3-alkoxycarbonyl-4-phenylbutyric acid derivative as an intermediate, and 3-alkoxycarbonyl There are no reports on the stability of metal salts of -4-phenylbutyric acid derivatives.
Literature 1: JP-A-4-356659 Literature 2: JP-A-2001-261645 3-methoxycarbonyl-4-phenylbutyric acid represented by the above formula (B) is unstable to heat and has a room temperature. It has a problem that it is gradually decomposed during storage and the purity is lowered. Therefore, in order to use 3-methoxycarbonyl-4-phenylbutyric acid represented by the above formula (B) having a reduced purity as a pharmaceutical production intermediate, it is necessary to purify and remove impurities. Since 3-methoxycarbonyl-4-phenylbutyric acid represented by B) is a highly viscous oily substance, it is difficult to remove impurities by purification and reuse it as a pharmaceutical intermediate.
Further, even when 3-methoxycarbonyl-4-phenylbutyric acid represented by the formula (B) having a reduced purity is used without purification, the benzylsuccinic acid derivative represented by the formula (A) or a drug thereof It is difficult to remove impurities in the process or the final process of producing a physically acceptable salt.
As described above, in the formula (A), a conventionally unstable compound such as 3-methoxycarbonyl-4-phenylbutyric acid represented by the formula (B) is used as a production intermediate. The method for producing the represented benzylsuccinic acid derivative requires special equipment such as cold storage in order to prevent impurities from being contained due to a decrease in purity, and requires extra labor such as temperature control during storage. Therefore, the production method is not always satisfactory in terms of production and cost on an industrial scale. Therefore, there has been a demand for a method that can be more efficiently and stably used as a pharmaceutical production intermediate.
DISCLOSURE OF THE INVENTION As a result of intensive studies to solve the above problems, the present inventors have found that the novel sodium of (3S) -3-methoxycarbonyl-4-phenylbutyric acid represented by the general formula (I) of the present invention The salt and calcium salt have good characteristics that they are extremely stable to heat, and the compound (A) or a pharmacologically acceptable salt thereof can be easily obtained by using the compound as a production intermediate. We found that it can be manufactured.
The present invention is a novel drug having excellent storage stability, suitable for production of various pharmaceuticals having a benzylsuccinic acid partial structure, for example, a benzylsuccinic acid derivative represented by the above formula (A) useful as a therapeutic drug for diabetes. A production intermediate and a method of using the same are provided.
That is, (3S) -3-methoxycarbonyl-4-phenylbutyric acid represented by the above formula (B), which has been reported as a production intermediate in the past, decomposes while being stored under heating and has a purity of Whereas the sodium salt and calcium salt of (3S) -3-methoxycarbonyl-4-phenylbutyric acid represented by the general formula (I) of the present invention are extremely stable against heat, it is remarkably lowered. It was found that it was not decomposed even when stored under heating.
On the other hand, among the metal salts of (3S) -3-methoxycarbonyl-4-phenylbutyric acid (B), the potassium salt is unstable to heat and gradually decomposes under warmed storage conditions to lower the purity. Resulting in. Thus, it is surprising that among the metal salts, only the sodium and calcium salts have the good property of being excellent in heat stability.
As described above, the (3S) -3-methoxycarbonyl-4-phenylbutyric acid metal salt represented by the general formula (I) of the present invention is represented by the formula (B) that has been reported as a production intermediate in the past. Compared to the expressed (3S) -3-methoxycarbonyl-4-phenylbutyric acid, it has a good characteristic that it is extremely stable to heat, and by using this, it is special for cold storage etc. An benzylsuccinic acid derivative represented by the above formula (A) that is useful as a pharmaceutical can be produced efficiently without the need for a simple apparatus and without further effort such as temperature control. Demonstrate operational effects.
Further, the (3S) -3-methoxycarbonyl-4-phenylbutyric acid metal salt represented by the general formula (I) of the present invention is represented by (3S) -3-methoxycarbonyl represented by the formula (B). After derivatization to the reactive functional derivative without conversion to -4-phenylbutyric acid, it is possible to carry out the reaction with cis-hexahydroisoindoline represented by the above formula (C) or an acid addition salt thereof. In addition, since it is not necessary to go through a thermally unstable production intermediate again, the benzylsuccinic acid derivative represented by the above formula (A) can be easily produced without extra steps or purification. .
As described above, the present invention is useful as an intermediate for producing various pharmaceuticals having a benzylsuccinic acid partial structure, including the benzylsuccinic acid derivative represented by the above formula (A). For example, pharmaceuticals such as the benzyl succinic acid derivative represented by the above formula (A) useful as a therapeutic drug for diabetes can be produced efficiently and stably, which is suitable for production on an industrial scale.
The (3S) -3-methoxycarbonyl-4-phenylbutyric acid metal salt represented by the general formula (I) of the present invention can be produced by the following method.
For example, (3S) -3-methoxycarbonyl-4-phenylbutyric acid represented by the formula (B) is hydroxylated in a solvent such as water, acetone, methanol, isopropanol, ethyl acetate, or a mixed solvent thereof. By reacting with sodium or calcium hydroxide, the (3S) -3-methoxycarbonyl-4-phenylbutyric acid metal salt represented by the general formula (I) can be easily produced. The reaction temperature is usually −10 to 60 ° C., and the reaction time is usually 1 to 24 hours, although it varies depending on the raw material, solvent and reaction temperature used.
The (3S) -3-methoxycarbonyl-4-phenylbutyric acid metal salt represented by the above general formula (I) of the present invention has a blood glucose lowering action by, for example, the method of Scheme 1 and is useful as a therapeutic agent for diabetes. The benzyl succinic acid derivative represented by the formula (A) can be produced, and is extremely useful as an intermediate for producing a pharmaceutical product.
Scheme 1
[Step 1]
1 to 5 equivalents of (3S) -3-methoxycarbonyl-4-phenylbutyric acid metal salt represented by the general formula (I) in an inert solvent, if necessary, in the presence of a small amount of N, N-dimethylformamide. The compound (II) can be obtained by reacting with thionyl chloride, and then distilling off the solvent under reduced pressure. If necessary, the reaction solution can be used as it is without isolating the compound (II). It can also be used in the process. Examples of the inert solvent used in the reaction include toluene, methylene chloride, chloroform, ethyl acetate and the like. The reaction temperature is usually −10 to 80 ° C., and the reaction time is usually 15 minutes to 5 hours, although it varies depending on the raw material used, the solvent, the reaction temperature and the like.
[Step 2]
Compound (II) is represented by 1 to 3 equivalents of formula (C) in the presence of a base such as triethylamine, diisopropylethylamine, sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide in a solvent. Compound (III) can be obtained by reacting with cis-hexahydroisoindoline or an acid addition salt thereof. Examples of the solvent used in the reaction include water, toluene, methylene chloride, chloroform, ethyl acetate, tetrahydrofuran, 1,2-dimethoxyethane, or a mixed solvent thereof. The reaction temperature is usually −10 to 50 ° C., and the reaction time is usually 10 minutes to 12 hours, although it varies depending on the raw material used, the solvent, the reaction temperature and the like. Examples of acid addition salts of cis-hexahydroisoindoline include salts of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and the like.
[Step 3]
Compound (III) is dissolved in alcohols such as methanol, ethanol, and isopropanol, and hydrolyzed at 0 to 70 ° C. by adding a caustic aqueous solution such as sodium hydroxide and potassium hydroxide. The compound (A) can be obtained by neutralization with an acid.
The compound (A) produced as described above can be converted to a pharmacologically acceptable salt according to a known method. Examples of such compounds include salts with inorganic bases such as sodium salts, potassium salts, and calcium salts, organic amines such as morpholine, piperidine, and phenylalaninol, and amino acids.
Among the pharmacologically acceptable salts of compound (A), the formula
The cis-hexahydroisoindoline represented by the formula (C) and an acid addition salt thereof used in the method for producing the benzylsuccinic acid derivative represented by the formula (A) or a pharmacologically acceptable salt thereof Can be produced according to a known method, for example, the method described in the following literature 3 or 4.
Reference 3: Japanese Patent Application Laid-Open No. 11-71349 Reference 4: Japanese Patent Application Laid-Open No. 2001-261644 The contents of the present invention will be described in more detail with reference to the following Reference Examples, Examples, and Test Examples. It is not limited to.
Example 1
(3S) -3-Methoxycarbonyl-4-phenylbutyric acid sodium salt (3S) -3-methoxycarbonyl-4-phenylbutyric acid (3.00 g) was dissolved in acetone (30 mL), and sodium hydroxide ( 0.57 g) in water (0.60 mL) was added and stirred overnight at room temperature. The precipitated crystals were collected by filtration and washed with acetone (1 mL) to obtain (3S) -3-methoxycarbonyl-4-phenylbutyric acid sodium salt (2.93 g).
1 H-NMR (DMSO-d 6 ) δ ppm:
1.94 (1H, dd, J = 6.4, 15.4 Hz), 2.15 (1H, dd, J = 7.4, 15.4 Hz), 2.73 (2H, d, J = 7. 2Hz), 2.80-2.95 (1H, m), 3.45 (3H, s), 7.05-7.30 (5H, m)
Example 2
(3S) -3-Methoxycarbonyl-4-phenylbutyric acid calcium salt (3S) -3-methoxycarbonyl-4-phenylbutyric acid (0.25 g) was dissolved in methanol (3 mL), and calcium hydroxide (0 0.042 g) was added and stirred at the same temperature for 2 hours, methanol (0.6 mL) was added, and the mixture was further stirred overnight at room temperature. The crystals were collected by filtration and washed with methanol (1 mL) to give (3S) -3-methoxycarbonyl-4-phenylbutyric acid calcium salt (0.22 g).
1 H-NMR (DMSO-d 6 ) δ ppm:
2.00-2.15 (1H, m), 2.20-2.35 (1H, m), 2.70-2.80 (2H, m), 2.85-3.00 (1H, m ), 3.46 (3H, s), 7.05-7.30 (5H, m)
Reference example 1
(3S) -3-Methoxycarbonyl-4-phenylbutyric acid potassium salt (3S) -3-methoxycarbonyl-4-phenylbutyric acid (0.98 g) was dissolved in acetone (20 mL), and potassium hydroxide ( 0.20 g) in water (0.5 mL) was added, and the solvent was distilled off under reduced pressure. Diethyl ether (50 mL) was added to the residue, and the mixture was stirred at room temperature for 10 minutes. The precipitated crystals were collected by filtration and washed with diethyl ether to obtain (3S) -3-methoxycarbonyl-4-phenylbutyric acid potassium salt (0.60 g).
1 H-NMR (DMSO-d 6 ) δ ppm:
1.90-2.05 (1H, m), 2.10-2.25 (1H, m), 2.65-2.80 (2H, m), 2.85-2.95 (1H, m ), 3.45 (3H, s), 7.05-7.35 (5H, m)
Example 3
Bis [(2S) -2-benzyl-3- (cis-hexahydroindolin-2-ylcarbonyl) propionic acid] calcium dihydrate (3S) -3-methoxycarbonyl-4-phenylbutyric acid sodium salt (5 .47 g) was added to toluene (30 mL), and N, N-dimethylformamide (0.1 mL) and thionyl chloride (1.95 mL) were added with ice-cooling and stirring. The mixture was cooled with ice for 5 minutes and at room temperature for 30 minutes. Stir. The obtained (3S) -3-methoxycarbonyl-4-phenylbutyric acid chloride was added to an aqueous solution (60 mL) of cis-hexahydroisoindoline phosphate (5.25 g) and potassium carbonate (15.5 g) with water-cooling. The mixture was added dropwise over 50 minutes with stirring. After dropping, the mixture was stirred for 30 minutes under water cooling, and stirred for 30 minutes at room temperature, and then the toluene layer was separated. The aqueous layer was extracted with toluene (20 mL) and combined with the toluene layer, and then the organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution, 1 mol / L hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. After anhydrous magnesium sulfate was filtered off, the solvent was distilled off under reduced pressure to obtain methyl (2S) -2-benzyl-3- (cis-hexahydroisoindoline-2-ylcarbonyl) propionate (7.80 g). It was. The obtained methyl (2S) -2-benzyl-3- (cis-hexahydroisoindoline-2-ylcarbonyl) propionate (7.80 g) was dissolved in isopropanol (15 mL), and an aqueous sodium hydroxide solution ( 5 mol / L, 5.4 mL) was added, and the mixture was stirred at room temperature for 1 hour and then at 50 ° C. for 4 hours. Isopropanol (5 mL) and water (40 mL) were added to the reaction solution, and then an aqueous solution in which calcium chloride (1.7 g) was dissolved in water (10 mL) was added dropwise with stirring at 50 ° C. The mixture was further stirred at 50 ° C. for 2 hours and then allowed to cool for 3 hours. The precipitated crystals were collected by filtration, and the obtained crystals were washed with water (50 mL) to obtain crystals (7.38 g). The obtained crystals (5.0 g) were recrystallized from methanol / water to give bis [(2S) -2-benzyl-3- (cis-hexahydroindolin-2-ylcarbonyl) propionic acid] calcium dihydrate. A Japanese product (4.46 g) was obtained.
1 H-NMR (CDCl 3 ) δ ppm:
1.20-1.60 (8H, m), 2.10-2.35 (3H, m), 2.55-2.65 (1H, m), 2.75-2.85 (1H, m ), 3.00-3.10 (1H, m), 3.10-3.45 (5H, m), 3.60-3.70 (3H, m), 7.15-7.30 (5H) , M)
Test example 1
Thermal stability test (3S) -3-methoxycarbonyl-4-phenylbutyric acid (0.1 g), (3S) -3-methoxycarbonyl-4-phenylbutyric acid sodium salt (0.1 g), (3S) -3- Calcium-4-methoxybutyric acid calcium salt (0.1 g) and (3S) -3-methoxycarbonyl-4-phenylbutyric acid potassium salt (0.1 g) were stored at 80 ° C. in a glass bottle capped. Then, the purity was measured over time using HPLC (high performance liquid chromatography) under the following conditions.
Column used: Inertsil ODS-3 4.6 × 250 mm
(GL Sciences Inc.)
Mobile phase: Liquid A Potassium dihydrogen phosphate aqueous solution (0.02 mol / L)
Liquid B Acetonitrile gradient was carried out as shown in Table 1. In addition, 15 minutes to 40 minutes is a linear gradient.
Detection wavelength: 210 nm
The decomposition rate was calculated based on the following formula from the purity before warm storage and the purity after warm storage.
Decomposition rate (%) = 100− (purity after warm storage / purity before warm storage) × 100
The results are shown in Table 2.
Claims (5)
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| PCT/JP2003/000341 WO2003062186A1 (en) | 2002-01-22 | 2003-01-17 | Metal salts of (3s)-3-methoxycarbonyl-4-phenylbutyric acid and usage thereof |
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| JP4918257B2 (en) | 2005-12-27 | 2012-04-18 | キッセイ薬品工業株式会社 | Asymmetric reduction method |
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