TWI258470B - Process for preparing aripiprazole - Google Patents
Process for preparing aripiprazole Download PDFInfo
- Publication number
- TWI258470B TWI258470B TW092135997A TW92135997A TWI258470B TW I258470 B TWI258470 B TW I258470B TW 092135997 A TW092135997 A TW 092135997A TW 92135997 A TW92135997 A TW 92135997A TW I258470 B TWI258470 B TW I258470B
- Authority
- TW
- Taiwan
- Prior art keywords
- group
- alkali metal
- hydroxide
- inorganic basic
- producing
- Prior art date
Links
- 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 abstract description 22
- 229960004372 aripiprazole Drugs 0.000 title claims abstract description 22
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 7
- 238000000034 method Methods 0.000 claims abstract description 31
- -1 carbostyril compound Chemical class 0.000 claims abstract description 21
- 150000007514 bases Chemical class 0.000 claims abstract description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 150000003839 salts Chemical class 0.000 claims abstract description 9
- 125000005843 halogen group Chemical group 0.000 claims abstract description 7
- 125000005279 aryl sulfonyloxy group Chemical group 0.000 claims abstract 2
- 150000001875 compounds Chemical class 0.000 claims description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical group [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- 150000008041 alkali metal carbonates Chemical class 0.000 claims description 5
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 4
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 claims description 4
- 229910000032 lithium hydrogen carbonate Inorganic materials 0.000 claims description 4
- HQRPHMAXFVUBJX-UHFFFAOYSA-M lithium;hydrogen carbonate Chemical compound [Li+].OC([O-])=O HQRPHMAXFVUBJX-UHFFFAOYSA-M 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 235000011181 potassium carbonates Nutrition 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- 239000011736 potassium bicarbonate Substances 0.000 claims description 3
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 3
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 2
- 229910052783 alkali metal Inorganic materials 0.000 claims 3
- 150000001340 alkali metals Chemical class 0.000 claims 3
- 125000000217 alkyl group Chemical group 0.000 claims 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 2
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims 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 claims 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims 1
- 150000001335 aliphatic alkanes Chemical group 0.000 claims 1
- 125000003545 alkoxy group Chemical group 0.000 claims 1
- 125000003118 aryl group Chemical group 0.000 claims 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 claims 1
- 235000003599 food sweetener Nutrition 0.000 claims 1
- 229910052744 lithium Inorganic materials 0.000 claims 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- 239000003765 sweetening agent Substances 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 16
- LISFMEBWQUVKPJ-UHFFFAOYSA-N carbostyril Natural products C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 abstract description 3
- GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- 239000013078 crystal Substances 0.000 description 4
- 235000017550 sodium carbonate Nutrition 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 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
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 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
- 239000012429 reaction media Substances 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 229960003975 potassium Drugs 0.000 description 2
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 201000000980 schizophrenia Diseases 0.000 description 2
- 235000009518 sodium iodide Nutrition 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-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
- 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
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-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
- 239000004480 active ingredient Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910001516 alkali metal iodide Inorganic materials 0.000 description 1
- 230000000561 anti-psychotic effect Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000002585 base Substances 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
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 125000006612 decyloxy group Chemical group 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000003113 dilution method Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical class [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- VEIWYFRREFUNRC-UHFFFAOYSA-N hydron;piperidine;chloride Chemical compound [Cl-].C1CC[NH2+]CC1 VEIWYFRREFUNRC-UHFFFAOYSA-N 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 1
- 229910052808 lithium carbonate Inorganic materials 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 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
- 239000011159 matrix material Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- VOVZXURTCKPRDQ-CQSZACIVSA-N n-[4-[chloro(difluoro)methoxy]phenyl]-6-[(3r)-3-hydroxypyrrolidin-1-yl]-5-(1h-pyrazol-5-yl)pyridine-3-carboxamide Chemical compound C1[C@H](O)CCN1C1=NC=C(C(=O)NC=2C=CC(OC(F)(F)Cl)=CC=2)C=C1C1=CC=NN1 VOVZXURTCKPRDQ-CQSZACIVSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229910052707 ruthenium Inorganic materials 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
- 239000000243 solution Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Neurology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Biomedical Technology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Psychiatry (AREA)
- Pharmacology & Pharmacy (AREA)
- Neurosurgery (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Quinoline Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Description
1258470 政、發明說明 【發明所屬之技術領域】 本發明係關於艾瑞哌唑之製法。 【先前技術】 將以下式代表的7-丨4_〔 4- ( 2,3-二氯苯基）·】-哌哄 基〕丁氧基丨-3，4 -二氫-2 ( 1 H )· D|啉酮稱爲艾瑞哌唑：
其係用作治療精神分裂症之試劑的化合物。例如，以 在E P - A - 3 6 7 1 4 1所述含有艾瑞哌d坐之醫藥組成物作爲治療 精神分裂症之試劑，以及在第4 1冊j . M e d · C h e m .的第 6 5 8 - 6 6 7頁（1 9 9 8 )述及作爲抗精神病藥有用的艾瑞哌唑 〇 迄今已以以下通式（2 )代表之喹諾酮化合物：
(其中X係鹵素原子、低碳鏈烷磺醯氧基、芳基磺 -5- (2) 1258470 醯氧基或芳烷基磺醯氧基）與以下式（3 )代表之哌啡化 合物
C] C] HN
在無機或有機鹼性化合物的存在下及在有機溶劑或沒 有溶劑的存在下反應，以製備艾瑞哌唑。例如，在£?-八-3 6 7 1 4 1述及若必要時以加入作爲反應促進劑之鹼金屬碘 化物（如碘化鉀、碘化鈉或類似物）可以進行上述反應； 以及在其運用實例中（EP-A-367141，第5頁，第42-44 行），以碘化鈉用作反應促進劑。但是，根據£?-八-3 6 7 1 4 1所述之方法，目標艾瑞哌唑的產量不可能超過約 80%，即使使用反應促進劑。 根據EP-A-3 6 7 1 4 1，甚至在沒有溶劑的存在下進行艾 瑞哌唑的製備作用。但是，在沒有溶劑存在下的反應只可 以緩慢地進行，以及反應系統不易以攪拌維持在均勻狀態 ，因爲原料化合物及艾瑞哌唑標的兩者係固體物質。因此 ，在EP-A-3 67 1 4 1所述之方法不適合於工業製造。 再者，在EP-A-3 67 1 4 1所述之方法係以複雜的步驟獲 得艾瑞哌唑標的。 因爲以艾瑞哌唑用作醫學藥物之活性成份，故希望獲 得甚至更高純度之艾瑞哌唑。再者，爲了壓抑製造成本， 故希望生產甚至更高產量之艾瑞哌唑。 -6 - (3) 1258470 【發明內容】 本發明的目的係提供更高純度及更高產量之艾瑞哌唑 之製法。 本發明目前已發現甚至更高純度及產量之艾瑞哌唑之 製法。在化學科學領域中常見的技術經驗係在反應基質溶 解在反應系統時，則可以進行高效率的化學反應。根據上 述的經驗，一般熟悉本技藝的人不可能想到使用水作爲在 完全不溶於水之通式（2 )之D|諾酮化合物與式（3 )之哌 哄化合物或其鹽之間的反應之反應介質。此外，一般熟悉 本技藝的人可輕易預期在以通式（2)代表之_諾酮化合 物分子中的X基具有以水之水解作用轉化成羥基的非常 高的可能性。因此，一般熟悉本技藝的人可輕易預期在這 種條件下將會降低艾瑞哌唑的純度及產量。 在上述的條件下，本發明的發明者令人注目地發現係 以大膽地使用完全不能夠溶解通式（2 )之咱諾酮化合物 的水作爲反應介質及進一步使用無機鹼性化合物作爲該鹼 性化合物可以製備甚至更高純度及更高產量之艾瑞哌唑。 本發明係關於艾瑞哌唑之製法，其係以上述之通式（ 2 )代表之喹諾酮化合物與以式（3 )代表之哌畊化合物及 /或其鹽在水中及在以每莫耳喹諾酮化合物（2)計0.5至 1 〇莫耳爲範圍之無機鹼性化合物量的存在下反應，以便 於獲得以式（1 )代表之艾瑞哌唑。 本發明的詳細說明 (5) 1258470 萘基取代之直鏈或支鏈 C ! _6烷基磺醯氧基及類似物作爲 以X代表之芳烷基磺醯氧基之實例。在本發明包含以苯 甲基磺醯氧基、2 -苯基乙基磺醯氧基、4 -苯基丁基磺醯氧 基、2 -甲基苯甲基磺醯氧基、4 -甲氧基苯甲基磺醯氧基、 4 -硝基苯甲基磺醯氧基、3 -氯基苯甲基磺醯氧基及類似物 作爲以苯基取代之上述烷基磺醯氧基之實例。在本發明包 含以α -萘甲基磺醯氧基、/3 -萘甲基磺醯氧基及類似物作 爲以萘基取代之上述烷基磺醯氧基之實例。 以鹵素原子作爲X較佳，並以氯原子更佳。 以式（3 )代表之哌哄化合物及其鹽類也係已知的化 合物，將其當作本發明的另一種原料使用。 在本發明包含以例如無機鹽類（如氫氯酸鹽、硫酸鹽 、磷酸鹽、氫溴酸鹽及類似物）及有機酸鹽（如草酸鹽、 馬來酸鹽、富馬酸鹽、蘋果酸鹽、酒石酸鹽、苯甲酸鹽及 類似物）作爲該鹽。 在介於上述的通式（2)之喹諾酮化合物與式（3)之 哌畊化合物及/或其鹽之間的反應中，未特別限制彼等的 量之間的比，並可以寬廣的範圍適當地選擇彼等的量。更 特別地係可以使用以每莫耳通式（2 )之D奎諾酮化合物計 至少〇 · 5莫耳量之式（3 )之哌哄化合物及/或其鹽，並以 1至1 . 5莫耳量較佳。 在水中及在無機鹼性化合物的存在下進行本發明的反 應。 可以廣泛使用已知的化合物作爲無機鹼性化合物。例 -9 - (6) 1258470 如，在本發明包含以鹼金屬 化鉀、氫氧化絶、氫氧化鋰 如碳酸鈉、碳酸鉀、碳酸鉋 鈉、碳酸氫鉀及類似物）、 類似物）等。可以使用或單 些無機鹼性化合物。 在使用單獨一種無機鹼 碳酸鹽較佳，如碳酸鈉、碳 氫鋰、碳酸氫鈉、碳酸氫鉀 每莫耳通式（2 )代表之喹詳 並以〇 . 5至6莫耳更特別。 在使用二或多種成爲混 中，以使用鹼金屬氫氧化物 氧化鉋、氫氧化鋰或類似物 、碳酸鉀、碳酸鉋、碳酸鋰 氫鉀或類似物）的混合物形 ，則一起使用的無機鹼性化 式（2 )代表之喧諾酮化合物 至6莫耳更特別。 在本發明的方法中，經 之喹諾酮化合物重量計3至 1 5份重量較佳。
經常在從室溫至2 0 0 °C 反應，並以從約8 0至1 5 0 °C 氫氧化物（如氫氧化鈉、氫氧 及類似物）、鹼金屬碳酸鹽（ 、碳酸錐、酸氣煙、&酸氯 驗金屬（如金屬納、金屬绅及 獨或二或多種混合物形式的這 性化合物的實例中，以鹼金屬 酸鉀、碳酸鉋、碳酸鋰、碳酸 或類似物，以及其量特別係以 ί酮化合物計〇 . 5至1 0莫耳， 合物之無機鹼性化合物的實例 (如氫氧化鈉、氫氧化鉀、氫 )與鹼金屬碳酸鹽（如碳酸鈉 、碳酸氫鋰、碳酸氫鈉、碳酸 式較佳。當使用這種混合物時 合物的總量特別係以每莫耳通 丨計〇·5至10莫耳，並以0.5 常使用以每份通式（2 )代表 5 〇份重量的水量，並以5至 爲範圍之溫度下進行本發明的 較佳。經常以約1至I 〇小時 -10- 1258470 完成反應。 以攪拌進行反應可以更有利於進展本發明的反應： 可將根據本發明的方法所獲得的艾瑞哌唑根據在該領 域中慣闬的分離方式及純化方式輕易自反應混合物分離及 純化。可以例如所述及之溶劑萃取法、稀釋法、再結晶法 、管柱色層分離法、製備性薄層色層分離法及類似方法作 爲該分離及純化的方法。
根據本發明的方法，可以製備高純度及高產量的艾瑞 卩浪口坐。 因爲本發明的反應係使用水作爲反應介質，故本發明 的方法可以避免使用以環境衛生學的觀點而言不希望的物 質（如有機溶劑），不會對環境造成任何負擔及具有安全 性。 根據本發明的方法，可以簡單的步驟製備艾瑞哌Π坐。 根據本發明的方法，可以沒有任何複雜的純化步,驟_ 備具有高純度的艾瑞哌唑。
因爲本發明的方法未使用任何超過需要的試劑，纟夂q 以合乎經濟的方式製備艾瑞哌唑。 因此，以本發明的方法作爲艾瑞哌唑的工業製法+ # 有利。 【實施方式】 實例 將在以下以參考運作實例進一步說明本發明。 -11 - (8) 1258470 實例1 將3 6.0公克碳酸鉀加入6 00毫升水中，將60.0公克 7 - ( 4 -氯基丁氧基）-3 · 4 -二氫喹諾酮及6 9.6公克1 - ί 2 · 3 -二氯苯基）哌哄單氫氯酸鹽加入其中。將混合物在9 0至 9 5 °C下以攪拌加熱約小時。接著將反應混合物冷卻至約 4 ，並以過濾收集沉積之晶體。將因此獲得的晶體以
24 0毫升水淸洗及溶解在90 0毫升醋酸乙酯中，並將水/醋 酸乙酯之共沸混合物（約3 00毫升）在回流下蒸發。將殘 餘溶液冷卻至〇至5 t，並以過濾收集沉積之晶體。將因 此獲得的晶體以1 20毫升醋酸乙酯淸洗及在50托之減壓 下以5 0至6 (TC經3小時乾燥，獲得9 8.4公克艾瑞哌唑（ 產量9 2.8 %，純度9 8 % )。熔點1 4 (Γ C。 以在以下條件下的高性能液相色層分離法（HP LC ) 測量艾瑞哌唑的純度：
管柱：YMC AM303 ODS (由YMC公司所製造的） 洗提齊ϋ : 0.02 克分子量硫酸鈉/乙腈/甲醇/醋酸
=56/33/11/1 流速：1毫升/分鐘 偵測波長：2 5 4毫微米UV -12-
Claims (1)
- 公，甘劑 mmmmιι_»___ ι___ --------η Μ,,ι,| , | A 匕本j 拾 、申請專利範 圍 第92135997號專利申請案 中文申請專利範圍修正本 民國94年12月21日修正令以式（2 )代表之喹諾酮化合物(其中X代表鹵素原子、Cl-C6鏈烷磺醯氧基、可隨 意爲1至3個選自CrQ烷基、烷氧基、硝基及鹵 素原子之基團所取代之C6-C1()芳基磺醯氧基或經C6-C10 芳基所取代之Ci-Cs烷基磺醯氧基（其中的芳基環可隨意 爲1至3個選自Ci-Q烷基、d-Cs烷氧基、硝基及鹵素 原子之基團所取代））與以式（3 )代表之哌畊化合物(2)1258470⑶ 及/或其鹽在水中及在以每莫耳α奎諾酮化合物（2 )計 〇. 5至1 0莫耳量之無機鹼性化合物的存在下反應。 2 .如申請專利範圍第1項之艾瑞哌唑之製法，其中 該方法使用單獨一種無機鹼性化合物，且該無機鹼性化合 物係鹼金屬氫氧化物、鹼金屬碳酸鹽或鹼金屬。 3 ·如申請專利範圍第1項之艾瑞哌唑之製法，其中 該方法使用二或多種成混合物形式之無機鹼性化合物，且 該無機鹼性化合物之混合物係鹼金屬氫氧化物與鹼金屬碳 酸鹽之混合物。 4.如申請專利範圍第2或3項之艾瑞哌唑之製法， 其中X係鹵素原子。 5 ·如申請專利範圍第2項之艾瑞哌唑之製法，其中 X係氯原子且該無機鹼性化合物係鹼金屬碳酸鹽。 6.如申請專利範圍第3項之艾瑞哌唑之製法，其中 X係氯原子。 7 .如申請專利範圍第2或3項之艾瑞哌唑之製法， 其中該鹼金屬氫氧化物係氫氧化鈉、氫氧化鉀、氫氧化鉋 或氫氧化鋰。 8 ·如申請專利範圍第2、3或5項之艾瑞哌唑之製法 ，其中該鹼金屬碳酸鹽係碳酸鈉、碳酸鉀、碳酸鉋、碳酸 -2- 1258470 (3) 鋰、碳酸氫鋰、碳酸氫鈉或碳酸氫鉀。 9.如申請專利範圍第2項之艾瑞哌唑之製法，其中 該鹼金屬係鈉或鉀。-3-
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| US7714129B2 (en) * | 2003-12-16 | 2010-05-11 | Teva Pharmaceutical Industries Ltd. | Methods of preparing anhydrous aripiprazole form II |
| JP5546717B2 (ja) * | 2003-12-16 | 2014-07-09 | テバ ファーマシューティカル インダストリーズ リミティド | アリピプラゾール結晶質形態を調製する方法 |
| CA2555289A1 (en) * | 2004-02-05 | 2005-08-25 | Ben-Zion Dolitzky | Process for preparing aripiprazole |
| US7507823B2 (en) | 2004-05-06 | 2009-03-24 | Bristol-Myers Squibb Company | Process of making aripiprazole particles |
| CN101068789B (zh) * | 2004-10-08 | 2010-12-15 | 苏文生命科学有限公司 | 用于制备阿立哌唑的新中间体及其制备方法、阿立哌唑的制备方法 |
| DE102005048695A1 (de) * | 2004-10-12 | 2006-05-18 | Chemagis Ltd. | Verfahren zur Herstellung und Reinigung von Carbostyrilverbindungen wie beispielsweise Aripiprazol und 7-(4-Halobutoxy)-3,4-dihydro-2(1H)-quinolinonen |
| CN101111481A (zh) * | 2004-11-18 | 2008-01-23 | 斯索恩有限公司 | 制备结晶阿立哌唑的方法 |
| CN1303068C (zh) * | 2005-01-11 | 2007-03-07 | 中国人民解放军第二军医大学 | 一种阿立哌唑的制备方法 |
| TWI320783B (en) | 2005-04-14 | 2010-02-21 | Otsuka Pharma Co Ltd | Heterocyclic compound |
| CA2622758A1 (en) | 2005-09-15 | 2007-03-29 | Elan Pharma International, Limited | Nanoparticulate aripiprazole formulations |
| BRPI0608185A2 (pt) * | 2005-12-22 | 2009-11-17 | Teva Pharma | processo para redução do tamanho de partìcula de aripiprazol |
| US20070149782A1 (en) * | 2005-12-23 | 2007-06-28 | Michael Brand | Methods of preparing a crystalline form of 7-(4-chlorobutoxy)-3,4-dihydro-2(1h)-quinolinone and the use thereof in the synthesis of Aripiprazole |
| EP1845088B1 (en) * | 2006-04-10 | 2009-07-22 | Ranbaxy Laboratories Limited | An improved process for the preparation of aripipirazole |
| BRPI0811844A2 (pt) | 2007-05-21 | 2014-11-18 | Reviva Pharmaceuticals Inc | Composto, e, método para tratar um paciente |
| EP2299814A4 (en) | 2008-05-27 | 2011-06-15 | Reviva Pharmaceuticals Inc | COMPOSITIONS, SYNTHESIS AND METHOD FOR USE OF ANTIPSYCHOTICS ON PIPERAZINE BASIS |
| CN101781246B (zh) * | 2009-01-15 | 2012-02-29 | 成都康弘药业集团股份有限公司 | 一种合成阿立哌唑的改进方法 |
| NZ595263A (en) | 2009-02-26 | 2013-06-28 | Compositions, synthesis, and methods of utilizing arylpiperazine derivatives | |
| JOP20200109A1 (ar) | 2012-04-23 | 2017-06-16 | Otsuka Pharma Co Ltd | مستحضر قابل للحقن |
| US20180155290A1 (en) * | 2015-05-08 | 2018-06-07 | Davuluri Ramamohan Rao | Improved Process for the Preparation of Aripiprazole with Reduced Particle Size |
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| JPS54130587A (en) * | 1978-03-30 | 1979-10-09 | Otsuka Pharmaceut Co Ltd | Carbostyryl derivative |
| DE3034237A1 (de) † | 1979-09-18 | 1981-04-16 | Otsuka Pharmaceutical Co. Ltd., Tokyo | Carbostyrilderivate, verfahren zu ihrer herstellung und diese verbindungen enthaltende, antihistaminisch wirkende mittel |
| JP2608788B2 (ja) * | 1988-10-31 | 1997-05-14 | 大塚製薬 株式会社 | 精神分裂病治療剤 |
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| JP4060523B2 (ja) † | 1999-11-24 | 2008-03-12 | 大塚製薬株式会社 | カルボスチリル誘導体の製造法 |
| AR033485A1 (es) † | 2001-09-25 | 2003-12-26 | Otsuka Pharma Co Ltd | Sustancia medicinal de aripiprazol de baja higroscopicidad y proceso para la preparacion de la misma |
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