JP4902945B2 - アリピプラゾールの製造法 - Google Patents
アリピプラゾールの製造法 Download PDFInfo
- Publication number
- JP4902945B2 JP4902945B2 JP2004004204A JP2004004204A JP4902945B2 JP 4902945 B2 JP4902945 B2 JP 4902945B2 JP 2004004204 A JP2004004204 A JP 2004004204A JP 2004004204 A JP2004004204 A JP 2004004204A JP 4902945 B2 JP4902945 B2 JP 4902945B2
- Authority
- JP
- Japan
- Prior art keywords
- carbonate
- alkali metal
- aripiprazole
- hydroxide
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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- CEUORZQYGODEFX-UHFFFAOYSA-N Aripirazole Chemical compound ClC1=CC=CC(N2CCN(CCCCOC=3C=C4NC(=O)CCC4=CC=3)CC2)=C1Cl CEUORZQYGODEFX-UHFFFAOYSA-N 0.000 title claims description 41
- 229960004372 aripiprazole Drugs 0.000 title claims description 40
- 238000004519 manufacturing process Methods 0.000 title claims description 17
- -1 carbostyril compound Chemical class 0.000 claims description 36
- 238000006243 chemical reaction Methods 0.000 claims description 17
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims description 13
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 150000008041 alkali metal carbonates Chemical class 0.000 claims description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
- LISFMEBWQUVKPJ-UHFFFAOYSA-N carbostyril Natural products C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 claims description 11
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical group [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 10
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 10
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- 235000011181 potassium carbonates Nutrition 0.000 claims description 6
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 5
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 5
- 229910000032 lithium hydrogen carbonate Inorganic materials 0.000 claims description 5
- HQRPHMAXFVUBJX-UHFFFAOYSA-M lithium;hydrogen carbonate Chemical compound [Li+].OC([O-])=O HQRPHMAXFVUBJX-UHFFFAOYSA-M 0.000 claims description 5
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 5
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 5
- 239000011736 potassium bicarbonate Substances 0.000 claims description 5
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 5
- 229940086066 potassium hydrogencarbonate Drugs 0.000 claims description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- MFGOFGRYDNHJTA-UHFFFAOYSA-N 2-amino-1-(2-fluorophenyl)ethanol Chemical compound NCC(O)C1=CC=CC=C1F MFGOFGRYDNHJTA-UHFFFAOYSA-N 0.000 claims description 4
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Inorganic materials [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 claims description 4
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 3
- 229910052808 lithium carbonate Inorganic materials 0.000 claims description 3
- 239000000463 material Substances 0.000 claims 1
- 238000000034 method Methods 0.000 description 16
- 150000007514 bases Chemical class 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 150000003839 salts Chemical class 0.000 description 7
- 125000005843 halogen group Chemical group 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 229910052783 alkali metal Inorganic materials 0.000 description 3
- 150000001340 alkali metals Chemical class 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- 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 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 125000005279 aryl sulfonyloxy group Chemical group 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 229960003975 potassium Drugs 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 239000012429 reaction media Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 235000009518 sodium iodide Nutrition 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- CYQFNNSFAGXCEC-UHFFFAOYSA-N 1-(2,3-dichlorophenyl)piperazine;hydrochloride Chemical compound [Cl-].ClC1=CC=CC(N2CC[NH2+]CC2)=C1Cl CYQFNNSFAGXCEC-UHFFFAOYSA-N 0.000 description 1
- SRMLSNBGMDJSJH-UHFFFAOYSA-N 7-(4-chlorobutoxy)-3,4-dihydro-1h-quinolin-2-one Chemical compound C1CC(=O)NC2=CC(OCCCCCl)=CC=C21 SRMLSNBGMDJSJH-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 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
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 229910001516 alkali metal iodide Inorganic materials 0.000 description 1
- 229940050390 benzoate Drugs 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940001468 citrate Drugs 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000003113 dilution method Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 229940050411 fumarate Drugs 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 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
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
Description
で表されるカルボスチリル化合物と式(3)
1.本発明は、上記一般式(2)で表されるカルボスチリル化合物と式(3)で表されるピペラジン化合物及び/又はその塩とを、カルボスチリル化合物(2)に対して0.5〜10倍モル量の無機塩基性化合物の存在下に水中で反応させて、式(1)で表されるアリピプラゾールを得ることを特徴とするアリピプラゾールの製造法を提供する。
2.本発明は、無機塩基性化合物を1種単独で使用し、該塩基性化合物がアルカリ金属水酸化物、アルカリ金属炭酸物又はアルカリ金属である上記1に記載のアリピプラゾールの製造法を提供する。
3.本発明は、無機塩基性化合物を2種以上混合して使用し、該塩基性化合物がアルカリ金属水酸化物とアルカリ金属炭酸物との混合物である上記1に記載のアリピプラゾールの製造法を提供する。
4.本発明は、一般式(2)におけるXがハロゲン原子である上記2又は3に記載のアリピプラゾールの製造法を提供する。
5.本発明は、一般式(2)におけるXが塩素原子であり、無機塩基性化合物がアルカリ金属炭酸物である上記2に記載のアリピプラゾールの製造法を提供する。
6.本発明は、一般式(2)におけるXが塩素原子である上記3に記載のアリピプラゾールの製造法を提供する。
7.本発明は、アルカリ金属水酸化物が水酸化ナトリウム、水酸化カリウム、水酸化セシウム又は水酸化リチウムである上記2又は3に記載のアリピプラゾールの製造法を提供する。
8.本発明は、アルカリ金属炭酸物が炭酸ナトリウム、炭酸カリウム、炭酸セシウム、炭酸リチウム、炭酸水素リチウム、炭酸水素ナトリウム又は炭酸水素カリウムである上記2、3又は5に記載のアリピプラゾールの製造法を提供する。
9.本発明は、アルカリ金属がナトリウム又はカリウムである上記2に記載のアリピプラゾールの製造法を提供する。
炭酸カリウム36.0gを水600ml中に溶解し、この中に7−(4−クロロブトキシ)−3,4−ジヒドロカルボスチリル60.0g及び1−(2,3−ジクロロフェニル)ピペラジン・1塩酸塩69.6gを加え、90〜95℃で約4時間加熱攪拌した。次に、反応液を40℃付近まで冷却し、析出した結晶を濾取した。得られた結晶を240mlの水で洗浄した後、酢酸エチル900mlに溶解し、還流下に水/酢酸エチルの共沸物(約300ml)を留去した。残った溶液を0〜5℃まで冷却し、析出晶を濾取した。得られた結晶を酢酸エチル120mlで洗浄し、減圧乾燥(50〜60℃、50Torr、3時間)すると、98.4g(収率92.8%、純度99%)のアリピプラゾールが得られた。
mp.140℃。
カラム:YMC AM303 ODS(YMC社製)
移動層:0.02M硫酸ナトリウム/アセトニトリル/メタノール/酢酸=56/33/11/1
流速:1ml/分
検出波長:254nm UV
Claims (6)
- アルカリ金属水酸化物又はアルカリ金属炭酸物を1種単独で使用する請求項1に記載のアリピプラゾールの製造法。
- アルカリ金属水酸化物及び/又はアルカリ金属炭酸物を2種以上混合して使用する請求項1に記載のアリピプラゾールの製造法。
- アルカリ金属水酸化物及び/又はアルカリ金属炭酸物がアルカリ金属炭酸物である請求項2に記載のアリピプラゾールの製造法。
- アルカリ金属水酸化物が水酸化ナトリウム、水酸化カリウム、水酸化セシウム又は水酸化リチウムである請求項2又は3に記載のアリピプラゾールの製造法。
- アルカリ金属炭酸物が炭酸ナトリウム、炭酸カリウム、炭酸セシウム、炭酸リチウム、炭酸水素リチウム、炭酸水素ナトリウム又は炭酸水素カリウムである請求項2、3又は4に記載のアリピプラゾールの製造法。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2004004204A JP4902945B2 (ja) | 2003-01-09 | 2004-01-09 | アリピプラゾールの製造法 |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2003002996 | 2003-01-09 | ||
JP2003002996 | 2003-01-09 | ||
JP2004004204A JP4902945B2 (ja) | 2003-01-09 | 2004-01-09 | アリピプラゾールの製造法 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
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JP2011241871A Division JP5797090B2 (ja) | 2003-01-09 | 2011-11-04 | アリピプラゾールの製造法 |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2004231651A JP2004231651A (ja) | 2004-08-19 |
JP2004231651A5 JP2004231651A5 (ja) | 2005-07-14 |
JP4902945B2 true JP4902945B2 (ja) | 2012-03-21 |
Family
ID=32964638
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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JP2004004204A Expired - Lifetime JP4902945B2 (ja) | 2003-01-09 | 2004-01-09 | アリピプラゾールの製造法 |
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Country | Link |
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JP (1) | JP4902945B2 (ja) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
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ATE396178T1 (de) * | 2004-10-08 | 2008-06-15 | Suven Life Sciences Ltd | Verfahren zur herstellung von aripiprazol, und entsprechende zwischenprodukte und deren herstellung |
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