CN114044772A - Epipiprazole synthesis method and intermediate thereof - Google Patents
Epipiprazole synthesis method and intermediate thereof Download PDFInfo
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- CN114044772A CN114044772A CN202111431675.8A CN202111431675A CN114044772A CN 114044772 A CN114044772 A CN 114044772A CN 202111431675 A CN202111431675 A CN 202111431675A CN 114044772 A CN114044772 A CN 114044772A
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- 238000001308 synthesis method Methods 0.000 title claims abstract description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 21
- ZKIAIYBUSXZPLP-UHFFFAOYSA-N brexpiprazole Chemical compound C1=C2NC(=O)C=CC2=CC=C1OCCCCN(CC1)CCN1C1=CC=CC2=C1C=CS2 ZKIAIYBUSXZPLP-UHFFFAOYSA-N 0.000 claims abstract description 20
- 229960001210 brexpiprazole Drugs 0.000 claims abstract description 18
- 239000011259 mixed solution Substances 0.000 claims abstract description 8
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims abstract description 7
- 239000002994 raw material Substances 0.000 claims abstract description 7
- 239000002253 acid Substances 0.000 claims abstract description 6
- 239000011230 binding agent Substances 0.000 claims abstract description 5
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims abstract description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- 239000000047 product Substances 0.000 claims description 10
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- 125000006239 protecting group Chemical group 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 239000008367 deionised water Substances 0.000 claims description 2
- 229910021641 deionized water Inorganic materials 0.000 claims description 2
- 239000012467 final product Substances 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- OTYBMLCTZGSZBG-UHFFFAOYSA-L potassium sulfate Chemical group [K+].[K+].[O-]S([O-])(=O)=O OTYBMLCTZGSZBG-UHFFFAOYSA-L 0.000 claims 1
- 229910052939 potassium sulfate Inorganic materials 0.000 claims 1
- 235000011151 potassium sulphates Nutrition 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 15
- 230000015572 biosynthetic process Effects 0.000 abstract description 12
- 238000003786 synthesis reaction Methods 0.000 abstract description 12
- -1 4-chloro-butyloxy Chemical group 0.000 abstract description 10
- 239000003814 drug Substances 0.000 abstract description 10
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- 238000000034 method Methods 0.000 abstract description 9
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- 229940079593 drug Drugs 0.000 abstract description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 abstract description 5
- 238000006482 condensation reaction Methods 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 4
- 239000000463 material Substances 0.000 abstract description 4
- 230000002194 synthesizing effect Effects 0.000 abstract description 2
- 238000007796 conventional method Methods 0.000 abstract 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 15
- 239000007787 solid Substances 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 238000003756 stirring Methods 0.000 description 10
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- 238000001514 detection method Methods 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N methyl tert-butyl ether Substances COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
- DPQAKBJISUNJNK-UHFFFAOYSA-N 7-(4-chlorobutoxy)-1h-quinolin-2-one Chemical compound C1=CC(=O)NC2=CC(OCCCCCl)=CC=C21 DPQAKBJISUNJNK-UHFFFAOYSA-N 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 238000009833 condensation Methods 0.000 description 4
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- 201000000980 schizophrenia Diseases 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
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- 238000002360 preparation method Methods 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
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- 238000007086 side reaction Methods 0.000 description 2
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- SQUNAWUMZGQQJD-UHFFFAOYSA-N 1-(4-ethylphenyl)-2-methyl-3-(piperidin-1-yl)propan-1-one Chemical compound C1=CC(CC)=CC=C1C(=O)C(C)CN1CCCCC1 SQUNAWUMZGQQJD-UHFFFAOYSA-N 0.000 description 1
- OFHAGSNEHHNRSV-UHFFFAOYSA-N 1-benzothiophene;hydrochloride Chemical compound Cl.C1=CC=C2SC=CC2=C1 OFHAGSNEHHNRSV-UHFFFAOYSA-N 0.000 description 1
- NIDSRGCVYOEDFW-UHFFFAOYSA-N 1-bromo-4-chlorobutane Chemical compound ClCCCCBr NIDSRGCVYOEDFW-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- AYROGFLRLRMONT-UHFFFAOYSA-N 3-(4-chlorobutoxy)-1H-quinolin-2-one Chemical compound ClCCCCOC=1C(NC2=CC=CC=C2C1)=O AYROGFLRLRMONT-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- 102000049773 5-HT2A Serotonin Receptor Human genes 0.000 description 1
- 108010072564 5-HT2A Serotonin Receptor Proteins 0.000 description 1
- 102100022738 5-hydroxytryptamine receptor 1A Human genes 0.000 description 1
- 101710138638 5-hydroxytryptamine receptor 1A Proteins 0.000 description 1
- MBOHAVAGDOGRBS-UHFFFAOYSA-N 7-(4-bromobutoxy)-1h-quinolin-2-one Chemical compound C1=CC(=O)NC2=CC(OCCCCBr)=CC=C21 MBOHAVAGDOGRBS-UHFFFAOYSA-N 0.000 description 1
- URHLNHVYMNBPEO-UHFFFAOYSA-N 7-(4-bromobutoxy)-3,4-dihydro-1h-quinolin-2-one Chemical compound C1CC(=O)NC2=CC(OCCCCBr)=CC=C21 URHLNHVYMNBPEO-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
- LKLSFDWYIBUGNT-UHFFFAOYSA-N 7-hydroxy-3,4-dihydro-1h-quinolin-2-one Chemical compound C1CC(=O)NC2=CC(O)=CC=C21 LKLSFDWYIBUGNT-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- CEUORZQYGODEFX-UHFFFAOYSA-N Aripirazole Chemical compound ClC1=CC=CC(N2CCN(CCCCOC=3C=C4NC(=O)CCC4=CC=3)CC2)=C1Cl CEUORZQYGODEFX-UHFFFAOYSA-N 0.000 description 1
- 208000014644 Brain disease Diseases 0.000 description 1
- 206010010144 Completed suicide Diseases 0.000 description 1
- 206010012239 Delusion Diseases 0.000 description 1
- 102000004980 Dopamine D2 Receptors Human genes 0.000 description 1
- 108090001111 Dopamine D2 Receptors Proteins 0.000 description 1
- 208000004547 Hallucinations Diseases 0.000 description 1
- 241000272041 Naja Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-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
- 239000002671 adjuvant Substances 0.000 description 1
- 238000009098 adjuvant therapy Methods 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000000561 anti-psychotic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229960004372 aripiprazole Drugs 0.000 description 1
- 239000003693 atypical antipsychotic agent Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- POZRVZJJTULAOH-LHZXLZLDSA-N danazol Chemical compound C1[C@]2(C)[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=CC2=C1C=NO2 POZRVZJJTULAOH-LHZXLZLDSA-N 0.000 description 1
- 229960000766 danazol Drugs 0.000 description 1
- 231100000868 delusion Toxicity 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- LHUZAYREVYDAGJ-UHFFFAOYSA-N dichloromethane;ethyl acetate;methanol Chemical compound OC.ClCCl.CCOC(C)=O LHUZAYREVYDAGJ-UHFFFAOYSA-N 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000002288 dopamine 2 receptor stimulating agent Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 229960002565 eperisone Drugs 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 229960002748 norepinephrine Drugs 0.000 description 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
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- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000012552 review Methods 0.000 description 1
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Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The application provides a synthesis method of brexpiprazole and an intermediate thereof, belonging to the technical field of pharmaceutical raw material drug synthesis. 1-tert-butyloxycarbonyl-7- (4-halogen-butyloxy) -quinoline-2-ketone and 4-piperazine-benzothiophene hydrochloride are used as initial raw materials, potassium carbonate is used as an acid-binding agent, and the mixture is refluxed and reacted in an ethanol-water mixed solution to synthesize the ipiprazole protected by tert-butyloxycarbonyl. Compared with the conventional method for synthesizing the brexpiprazole by nucleophilic substitution reaction, the method disclosed by the invention has the advantages that 1-tert-butyloxycarbonyl-7- (4-chloro-butyloxy) -quinoline-2-ketone is used as a reaction material, the intramolecular and intermolecular condensation reaction caused by 7- (4-chloro-butyloxy) -1H-quinoline-2-ketone is avoided, the reaction selectivity is high, the product quality is excellent, and the method is suitable for industrial production.
Description
Technical Field
The application relates to a synthesis method of brexpiprazole and an intermediate thereof, belonging to the technical field of pharmaceutical raw material drug synthesis.
Background
Epipprazole is sold under the trade name Rexulti, and has the chemical name of 7- (4- (4-benzo [ b ] thiophene-4-yl-piperazine-1-yl) butoxy) -1H-quinolin-2-one, and the structural formula of the Epipprazole is shown as a formula (1):
ipiprazole is a novel atypical antipsychotic drug developed jointly by north danazol pharmacy and tsukamur pharmaceutical corporation of japan, approved by the united states food and drug administration for marketing on 7, 10 days 2015, as an adjuvant drug for the treatment of adult patients with major depression and for the treatment of adult patients with schizophrenia. Major depression is a serious mental disorder that can lead to persistent sadness, frustration or anger, and serious can lead to suicide; schizophrenia is a chronic, severe and disabling brain disorder that can lead to delusions and hallucinations. At present, the exact mechanism of action of ipiprazole is unknown, probably mediated by a combination of partial agonist activity at the 5-HT1A receptor and dopamine D2 receptor and antagonist activity at the serotonin 5-HT2A receptor. In addition, in addition to exhibiting high affinity for these receptors, ipiprazole also exhibits high affinity for the norepinephrine α 1B/2C receptor. The brexpiprazole is an oral tablet, and the recommended dose is as follows: 2mg, 1 times/d for patients with major depression; for patients with schizophrenia, 3mg, 1 time/d. The addition of the ipiprazole has a good curative effect on severe depression, and has low adverse reaction incidence and high safety (Wang Lai Hai, Wang jin Bao, Zhang Ling, New Chinese medicine and clinical journal, 2016, 35(9), 635-.
Ipiprazole is considered to be one of the most promising drugs for the treatment of adult patients with schizophrenia and the adjuvant treatment of adult patients with major depression, after the antipsychotic marketable drug aripiprazole, with us $ 11.77 billion being marketed in 2019 worldwide. The success of the ipiprazole attracts the attention of a plurality of domestic medical companies, and 8 acceptance numbers are retrieved from the accepted variety information of the drug evaluation center of the State drug administration. There have been many reviews on the synthesis of ipiprazole (wangping, sudaozhi, journal of Chinese medicinal chemistry, 2018, 28(2), 164-plus 167; wu-yi ice, hou-hua, ling fei, hui-hui, synthetic chemistry, 2018, 26(6), 462-plus 468; xibushao, shanghai medicine, 2021, 42(17), 70-75). The industry gradually accepts the synthesis of the epipiprazole by using 4-piperazine-benzothiophene hydrochloride and 7- (4-chloro-butoxy) -1H-quinoline-2-ketone as raw materials.
(Weiming Chen, Changliang Sun, Yan Zhuang, Tianwen Hu, Fuqiang Zhu, Xiangrui Jiang, Melkamu Alemu Abame, Feipu Yang, Jin Suo, Jin Shi, Jin Shan Shen, and Haji A. Aisa, J. org. Chem.2019,84,8702, 8709.) (Weiming Chen, Jin Suo, Yongjian Liu, Yuancao Xie, Mingjun Wu, Fuqiang Zhu, Yifen Nian, Haji A. Aisa, and Juingshan, Org. Proces Res.2019, 23,852 857; Zhang, jonggan, Haji Yongliang Wu Yong Gui, Haji A. Aisa, Haji Yongshan Shen Shi, Haji Yongshan Haji Kong Shi, Haji Kongkung Cai Cao, Haji Kong Cao, Xiong Cai Cao, Hai Cao, Kong Cao, Kong Cao, Kong Cao Hao Cao, Kong Cao, Kong Cao Hao, Kong Cao Hao Cao, Kong Cao Hao, Kong Cao, Kong Cao, Kong Cao, Kong Cao Hao, Kong Cao, Kong Cao, hutianwen, chenweiming, and ho, jiang, shanghai specialization medicine science and technology limited, CN 109307716A, 2017-7-27). And the impurities generated by the synthetic route were studied in detail (Rahul Tyagi, Harnam Singh, Jagat Singh, Himanshu Arora, Vijayalaxmi Yelmeli, Mohit Jain, Sathyanarayana Girigani, and Pramod Kumar, Org. Processes Res. Dev.2018,22,1471 Jun 1480, Rough, Parttin stamp, Zhang spring, Zhang Huanjiao, Small left courage, Ramote Meadon, Dunjie, Duoqing research institute Limited Hongyong, CN106892909A, 2015-12-18, Dakuai, Chengjian Fengqing, Juanjuan, Zhang Daolin, Chongqing Industrial research institute Limited, CN107525877A, 2016-6-20, Naja, Zhang David Weiyun Gmby, CN107525877A, 2016-7, CN-2016-20, CN-2017, CN-1119, CN-309, CN-1117, CN-W919, CN-R-K919, CN-K, Kogyo Cheng Jumi, Kogyo Wei Kogyo, Kogyo Wei Hakknik, Kogyo Wei Hakknik, Kogyo Kazao Wei K, Kogyo Kazak, Kogyo Kazao Kazak, Kogyo Kazak, Kogyo Kazao Wei, Kogyo Wei A918, Kogyo Kazak, Kogyo Kazao Kazak, Kogyo Hongyo Kazak, Kogyo Kazao Kazak, Kogyo Kazao K7, Kogyo K7, Kogyo K7, Kogyo K7, Kogyo K # A919, Kogyo K7, Kogyo K # A, Kogyo K # A919, Kogyo K # K, Kogyo K, K7, Kogyo K7, K # A # K7, Kogyo K # A919, K # K7, K7, Kogyo K, K7, K # A-K # K.
Disclosure of Invention
In view of the above, the present application first provides a preparation method of ipiprazole, wherein 1-tert-butyloxycarbonyl-7- (4-chloro-butyloxy) -quinolin-2-one is used as a reaction material, so that intramolecular and intermolecular condensation reactions caused by 7- (4-chloro-butyloxy) -1H-quinolin-2-one are avoided, and the preparation method is high in reaction selectivity, excellent in product quality, and suitable for industrial production.
Specifically, the method is realized through the following scheme:
a synthesis method of ipiprazole comprises the steps of taking 4-piperazine-benzothiophene hydrochloride and 1-tert-butoxy formyl-7- (4-halogen-butoxy) -quinoline-2-ketone as initial raw materials, taking potassium carbonate as an acid-binding agent, and carrying out reflux reaction in an ethanol-water mixed solution to synthesize the tert-butoxy formyl protected ipiprazole. Reacting the mixture with concentrated hydrochloric acid at high temperature in an ethanol-acetic acid mixed solution to remove a tert-butyloxycarbonyl protecting group and form ipiprazole hydrochloride, refluxing and stirring the obtained ipiprazole hydrochloride in the ethanol-acetic acid solution, neutralizing the obtained ipiprazole hydrochloride in the ethanol-water mixed solution with a sodium hydroxide solution to obtain ipiprazole, washing the obtained product with deionized water, and drying the obtained product to obtain an finished product of the ipiprazole.
The yield of the synthesis method is about 50%, the purity of the finished product is more than 99.5% through HPLC detection, and the maximum single impurity is less than 0.1%. Compared with the conventional synthesis of the epipiprazole by nucleophilic substitution reaction, the reaction material uses 1-tert-butyloxycarbonyl-7- (4-chloro-butyloxy) -quinoline-2-ketone, avoids intramolecular and intermolecular condensation reaction caused by 7- (4-chloro-butyloxy) -1H-quinoline-2-ketone, has high reaction selectivity and excellent product quality, and is suitable for industrial production.
In the process, the synthesized brexpiprazole has a structure shown in the formula (I), the starting material 4-piperazine-benzothiophene hydrochloride has a structure shown in the formula (3), and the 1-tert-butyloxycarbonyl-7- (4-halogen-butyloxy) -quinoline-2-ketone has a structure shown in the formula (4).
The nucleophilic substitution reaction is carried out by taking ethanol-water as a solvent and potassium carbonate as an acid-binding agent, the compound of the formula (1) is obtained by removing tert-butyloxycarbonyl protecting group and forming ipiprazole hydrochloride, and sodium hydroxide is neutralized, and the reaction process can be shown as the formula (5).
Further, as preferable:
the 1-tert-butyloxycarbonyl-7- (4-halogen-butyloxy) -quinolin-2-one is prepared from 7- (4-halogen-butyloxy) -1H-quinolin-2-one and tert-butyloxy formic anhydride (Boc)2O), the preparation process is shown as formula (6):
the halogen of the 1-tert-butyloxycarbonyl-7- (4-halogen-butyloxy) -quinolin-2-one is selected from the group consisting of chlorine and bromine, and more preferably, the 1-tert-butyloxycarbonyl-7- (4-halogen-butyloxy) -quinolin-2-one is 1-tert-butyloxycarbonyl-7- (4-chlorine-butyloxy) -quinolin-2-one.
The solvent is ethanol-water, and the ratio of ethanol to water is 0.2-2 (volume ratio), preferably 0.4.
The 1-tert-butyloxycarbonyl-7- (4-halo-butyloxy) -quinolin-2-one: the molar ratio of 4-piperazine-benzothiophene hydrochloride is from 0.8:1 to 1:1.2, preferably 1:1.
The reaction temperature is preferably 60 to 90 ℃ and more preferably 75 to 80 ℃.
I have referred to published literature and published patents in the development of crude drug substances of ipiprazole, decided to use the synthetic method published by the researchers in the department of medicine of Shanghai, of the Chinese academy Shanghai (Weiming Chen, Jin Suo, Yongjian Liu, Yuanchao Xie, Mingjun Wu, Fuqiiang Zhu, Yifeng Nian, Haji A. Aisa, and Jingshan Shen, org. Process Res. Dev.2019,23,852) 857), and when repeating this synthetic route, the synthesis of ipiprazole is difficult to obtain the high quality described in the literature, and the final product ipiprazole has an impurity content higher than 0.1% by HPLC analysis, and is difficult to recrystallize with the common ethanol-water system, dichloromethane-methanol-methyl tert-butyl ether system, dichloromethane-methanol-ethyl acetate system to remove it, and it is likely that the raw material from the reaction is 7- (4-chloro-butoxyquinoline-2-one, impurities (hanfeng, wangting, von bin, xun, organic chemistry, 2021,41,2831 to 2838) generated by side reactions due to intramolecular or intermolecular self-condensation occur, and specifically, see the intramolecular self-condensation reaction of 7- (4-chloro-butoxy) -1H-quinolin-2-one of formula (7) and the intramolecular self-condensation of 7- (4-chloro-butoxy) -1H-quinolin-2-one of formula (8).
Based on the above inference, we designed tert-butyloxy formic anhydride (Boc) to reduce the occurrence of intramolecular or intermolecular self-condensation side reactions caused by 7- (4-chloro-butyloxy) -1H-quinolin-2-one2O) protection of the N atom in position 1, and reaction of the resulting material with 4-piperazine-benzothiophene saltThe acid salt condensation is used for synthesizing the ipiprazole, and good effects are obtained, see formulas (9) and (10).
The synthesis method disclosed by the invention is simple in process, mild in reaction condition, high in reaction selectivity, excellent in product quality and suitable for industrial production.
Drawings
FIG. 1 is a HPLC chromatogram for detection of the synthetic intermediate of example 1;
FIG. 2 is a HPLC chromatogram for detection of the synthetic intermediate of example 2;
FIG. 3 is a HPLC chromatogram for detection of the synthetic intermediate of example 3;
FIG. 4 shows the synthesis of an intermediate of brexpiprazole in example 31H, spectrogram;
FIG. 5 shows the synthesis of intermediate C of brexpiprazole in example 313A spectrogram;
FIG. 6 is the HPLC detection spectrum of the finished product brexpiprazole.
Detailed Description
Example 1: synthesis of 7- (4-chlorobutoxy) -3, 4-dihydro-2 (1H) -quinolinone
7-hydroxy-3, 4-dihydro-2 (1H) -quinolinone (200g,1.23mol), 1-bromo-4-chlorobutane (631g,3.68mol) and potassium carbonate (254g, 1.84mol) were placed in a 5L three-necked flask in DMF (800mL) and mixed with stirring, followed by stirring at 25 ℃ for 30H, and the suspension gradually thickened. Purified water (1600mL) was slowly poured into the above 5L three-necked flask with stirring to precipitate a large amount of solid, stirring was continued for 30min, suction filtration was performed, and the solid was washed with purified water. The solid obtained above was transferred to a 1L three-necked flask, added to methyl tert-butyl ether (400mL), slurried, stirred and washed for 1h, then filtered with suction, and the solid obtained was dried under vacuum at 50 ℃ to obtain an off-white solid (258g) with a yield of about 83.6%. Purity by HPLC (see FIG. 1) was about 96.14% (with a 7- (4-bromobutoxy) -3, 4-dihydro-2 (1H) -quinolinone content of 1.76%).
Table 1: data excerpt of HPLC test result of intermediate of this example
Example 2: synthesis of 7- (4-chlorobutoxy) -quinolin-2-one
7- (4-Neobutoxy) -3, 4-dihydro-2 (1H) -quinolinone (150g, 0.59mol), THF (750mL) was charged into a 1L three-necked flask, stirred at room temperature and then DDQ (161g,0.71mol) was added slowly in portions and stirred for an additional 18H. The reaction mixture was slowly poured into water (750mL) and quenched, then aqueous sodium bicarbonate (1.57mol/L,750mL) was slowly added with stirring and stirred for 1 h. Suction filtration was carried out, and the obtained solid was washed with water and vacuum-dried at 50 ℃ to give a pale yellow solid (122g) in a yield of 82.1%. Purity by HPLC (see FIG. 2) was about 97.43% (with a 7- (4-bromobutoxy) -quinolinone content of 1.67%).
Table 2: data excerpt of HPLC test result of intermediate of this example
Example 3: synthesis of 1-N-tert-butyloxycarbonyl-7- (4-chlorobutoxy) -quinolin-2-one
7- (4-Neobutoxy) -quinolin-2-one (40.2g,160mmol) and DMAP (1.9g,16mmol) were mixed in dichloromethane (200mL), and a solution of di-tert-butyl dicarbonate (70.0g,320mmol) and dichloromethane (100mL) was added dropwise with stirring at room temperature, followed by reaction at 35 ℃ for 1 h. The dichloromethane reaction solution was washed with water (100ml of X3), and then dried over anhydrous sodium sulfate. After filtration, methylene chloride was distilled off at 35 ℃ under reduced pressure, and the resulting solid was stirred and washed with methyl t-butyl ether (400mL) for 1 h. Filtration and washing of the solid with methyl tert-butyl ether and drying in vacuo gave a white solid (44.9g) in about 79.8% yield. Purity by HPLC (see FIG. 3) was about 97.88% (with 1.55% of 1-N-tert-butyloxycarbonyl-7- (4-bromobutoxy) -quinolin-2-one).
Table 3: data excerpt of HPLC test result of intermediate of this example
ESI-MS: M/z 352.00[ M + H ] (see FIGS. 4 and 5)
1H-NMR(500MHz,DMSO-d6)δ(ppm):8.41(d,J＝8.2Hz,1H),7.92(d,J＝9.0Hz,1H),7.32(d,J＝2.5Hz,1H),7.27(t,J＝2.5Hz,1H),7,19(t,J＝8.5Hz,1H),4.17(dd,J＝5.5Hz,2H),3.73(t,J＝2.5Hz,2H),2.50(t,J＝2.0Hz,2H),1.91(t,J＝2.5Hz,2H),1.52(s,9H).
13C-NMR(125MHz,DMSO-d6)δ(ppm):160.74,156.77,150.99,148.23,140.85,129.50,122.38,119.76,113.02,107.86,84.25,67.68,45.60,29.35,27.72,26.43.
Example 4: synthesis of Epipiprazole
4-piperazine benzothiophene hydrochloride (10.7g,42mmol) and potassium carbonate (5.8g,42mmol) were mixed in an ethanol-water mixture (ethanol: water ═ 1: 2.5, 25mL), and nitrogen was bubbled through the mixture for 60min with stirring at room temperature, 1-N-t-butoxycarbonyl-7- (4-chlorobutoxy) -quinolin-2-one (14.1g,40mmol) was added in portions at 90 ℃ and the mixture was allowed to stand for 18 hours, then cooled to room temperature, filtered, and the resulting solid was dried under vacuum to give a brown solid (about 16.9 g). The brown solid is added into ethanol (340mL) and acetic acid (21mL) for dispersion, then the mixture is mechanically stirred and heated to 80 ℃, concentrated hydrochloric acid (35 percent, 3.6mL and 34mmol) is slowly added dropwise, the mixture is stirred for 1 hour, then the mixture is cooled to below 20 ℃, the mixture is filtered by suction, the obtained solid is washed by ethanol and then dried in vacuum, and light yellow eperisone hydrochloride (about 13.4g) is obtained. The ipiprazole hydrochloride obtained above is dispersed in an ethanol-water mixed solution (ethanol: water is 1.5: 1,188mL), the temperature is increased to 80 ℃, stirring and dissolving are carried out, then activated carbon (1.4g) is added, reflux is carried out for 1h, suction filtration is carried out while the solution is hot, and then the temperature is reduced to below 20 ℃ for crystallization, thus obtaining white ipiprazole hydrochloride (about 10.8 g). Dispersing the crude ipiprazole hydrochloride (10.8 g) obtained in the step (a) into an ethanol-water mixed solution (ethanol: water is 1.5: 1,188mL), heating to 80 ℃, stirring for dissolving, then dropwise adding a sodium hydroxide aqueous solution (20%, 5.5g and 28mmol), refluxing for 1h, then cooling to 20-25 ℃, crystallizing, filtering, washing with water, and drying in vacuum to obtain a white ipiprazole solid (8.9g) with the yield of 51.3%. Purity by HPLC (see fig. 6) was about 99.77%, max monohetero 0.058% (less than 0.1%).
Table 4: data excerpt of HPLC test result of the finished product of this example
HPLC detection chromatographic conditions:
a chromatographic column: ZORBAX Eclipse Plus C185 um 4.6.6 x 250mm
Mobile phase A: 0.01M Potassium dihydrogen phosphate was adjusted to pH 7.00 with Ammonia
Mobile phase B: methanol: acetonitrile 20: 80.
The gradient elution procedure is shown in table 1.
Table 1: gradient elution procedure parameter table
Solvent: methanol: acetonitrile 20:80
Detection wavelength: column temperature at 225 nm: 25 deg.C
Flow rate: 1.0ml/min sample size: 20 μ l.
Claims (10)
1. The synthesis method of the brexpiprazole is characterized by comprising the following steps: 4-piperazine-benzothiophene hydrochloride and 1-tert-butyloxycarbonyl-7- (4-halogen-butyloxy) -quinoline-2-ketone are taken as initial raw materials, an acid-binding agent is added for nucleophilic substitution, tert-butyloxycarbonyl protecting groups are removed to form ipiprazole hydrochloride, the ipiprazole hydrochloride is neutralized to obtain the ipiprazole, and the finished product of the ipiprazole is obtained by washing with deionized water and drying.
2. The synthesis method of brexpiprazole according to claim 1, characterized in that: in the nucleophilic substitution reaction, the acid-binding agent is potassium sulfate.
3. The synthesis method of brexpiprazole according to claim 1, characterized in that: in the nucleophilic substitution reaction, a mixed solution of ethanol and water is added as a solvent.
4. The synthesis method of brexpiprazole according to claim 3, characterized in that: the volume ratio of ethanol to water in the mixed solution is 0.2-2.
5. The synthesis method of brexpiprazole according to claim 1, characterized in that: the halogen of the 1-tert-butyloxycarbonyl-7- (4-halogen-butyloxy) -quinolin-2-one is selected from the group consisting of chlorine and bromine.
6. The synthesis method of brexpiprazole according to claim 1, characterized in that: the 1-tert-butyloxycarbonyl-7- (4-halogen-butyloxy) -quinolin-2-one is prepared from 7- (4-halogen-butyloxy) -1H-quinolin-2-one and tert-butyloxy formic anhydride (Boc)2O) to obtain the final product.
7. The synthesis method of brexpiprazole according to claim 1, characterized in that: 1-tert-butyloxycarbonyl-7- (4-halo-butyloxy) -quinolin-2-one: the molar ratio of the 4-piperazine-benzothiophene hydrochloride is 0.8:1-1: 1.2.
8. The synthesis method of brexpiprazole according to claim 1, characterized in that: the nucleophilic substitution reaction temperature is 60-90 ℃.
9. The brexpiprazole intermediate according to claim 1, wherein: the structural formula of the 4-piperazine-benzothiophene hydrochloride is as follows:
10. the brexpiprazole intermediate according to claim 1, wherein: the structural formula of the 1-tert-butyloxycarbonyl-7- (4-halogen-butyloxy) -quinolin-2-one is:
wherein: x ═ Br, Cl.
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