CN115521298A - Preparation method of brexpiprazole - Google Patents
Preparation method of brexpiprazole Download PDFInfo
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- CN115521298A CN115521298A CN202210498690.2A CN202210498690A CN115521298A CN 115521298 A CN115521298 A CN 115521298A CN 202210498690 A CN202210498690 A CN 202210498690A CN 115521298 A CN115521298 A CN 115521298A
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- brexpiprazole
- benzo
- ipiprazole
- bis
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- ZKIAIYBUSXZPLP-UHFFFAOYSA-N brexpiprazole Chemical compound C1=C2NC(=O)C=CC2=CC=C1OCCCCN(CC1)CCN1C1=CC=CC2=C1C=CS2 ZKIAIYBUSXZPLP-UHFFFAOYSA-N 0.000 title claims abstract description 16
- 229960001210 brexpiprazole Drugs 0.000 title claims abstract description 14
- 238000002360 preparation method Methods 0.000 title description 6
- 238000000034 method Methods 0.000 claims abstract description 13
- -1 4- (benzo [ b ] thiophene-4-yl) piperazine-1-yl Chemical group 0.000 claims abstract description 8
- 239000010949 copper Substances 0.000 claims abstract description 7
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000000654 additive Substances 0.000 claims abstract description 5
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 5
- 229910052802 copper Inorganic materials 0.000 claims abstract description 5
- 239000002904 solvent Substances 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 17
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- YIKSCQDJHCMVMK-UHFFFAOYSA-N Oxamide Chemical compound NC(=O)C(N)=O YIKSCQDJHCMVMK-UHFFFAOYSA-N 0.000 claims description 6
- QOFKBVYWLUKWLL-UHFFFAOYSA-N 7-bromo-1h-quinolin-2-one Chemical compound C1=CC(=O)NC2=CC(Br)=CC=C21 QOFKBVYWLUKWLL-UHFFFAOYSA-N 0.000 claims description 4
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 3
- DLVNRQYZUQQFQT-UHFFFAOYSA-N 1,4-dioxane;2-methylpropan-2-ol Chemical compound CC(C)(C)O.C1COCCO1 DLVNRQYZUQQFQT-UHFFFAOYSA-N 0.000 claims description 2
- PHIXUCQCQUCNGS-UHFFFAOYSA-N 4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butan-1-ol Chemical compound C1CN(CCCCO)CCN1C1=CC=CC2=C1C=CS2 PHIXUCQCQUCNGS-UHFFFAOYSA-N 0.000 claims description 2
- 230000000996 additive effect Effects 0.000 claims description 2
- CUQOHAYJWVTKDE-UHFFFAOYSA-N potassium;butan-1-olate Chemical compound [K+].CCCC[O-] CUQOHAYJWVTKDE-UHFFFAOYSA-N 0.000 claims description 2
- SYXYWTXQFUUWLP-UHFFFAOYSA-N sodium;butan-1-olate Chemical compound [Na+].CCCC[O-] SYXYWTXQFUUWLP-UHFFFAOYSA-N 0.000 claims description 2
- 239000003513 alkali Substances 0.000 abstract 1
- 231100000024 genotoxic Toxicity 0.000 description 15
- 230000001738 genotoxic effect Effects 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- 150000001875 compounds Chemical class 0.000 description 10
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 6
- 239000003814 drug Substances 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- XDUUWPNOUUQXBX-UHFFFAOYSA-N 1-(1-benzothiophen-4-yl)piperazine;hydrochloride Chemical compound Cl.C1CNCCN1C1=CC=CC2=C1C=CS2 XDUUWPNOUUQXBX-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 208000024714 major depressive disease Diseases 0.000 description 3
- 201000000980 schizophrenia Diseases 0.000 description 3
- IRMXPESEXLQKHG-UHFFFAOYSA-N 1-benzothiophen-4-amine Chemical compound NC1=CC=CC2=C1C=CS2 IRMXPESEXLQKHG-UHFFFAOYSA-N 0.000 description 2
- DBSPUDKBNOZFMX-UHFFFAOYSA-N 7-hydroxyquinolin-2(1H)-one Chemical compound C1=CC(=O)NC2=CC(O)=CC=C21 DBSPUDKBNOZFMX-UHFFFAOYSA-N 0.000 description 2
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 125000005605 benzo group Chemical group 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000003760 magnetic stirring Methods 0.000 description 2
- 208000011736 mal de Debarquement Diseases 0.000 description 2
- 239000002808 molecular sieve Substances 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 2
- 208000020016 psychiatric disease Diseases 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical group C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 1
- YMDZDFSUDFLGMX-UHFFFAOYSA-N 2-chloro-n-(2-chloroethyl)ethanamine;hydron;chloride Chemical compound [Cl-].ClCC[NH2+]CCCl YMDZDFSUDFLGMX-UHFFFAOYSA-N 0.000 description 1
- QPBSEYFVZDMBFW-UHFFFAOYSA-N 4-bromo-1-benzothiophene Chemical compound BrC1=CC=CC2=C1C=CS2 QPBSEYFVZDMBFW-UHFFFAOYSA-N 0.000 description 1
- AGSFPKGMQILWOY-UHFFFAOYSA-N 7-(4-aminobutoxy)-1h-quinolin-2-one Chemical compound C1=CC(=O)NC2=CC(OCCCCN)=CC=C21 AGSFPKGMQILWOY-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 239000005749 Copper compound Substances 0.000 description 1
- BATWLIVHOMDHHA-UHFFFAOYSA-N N,N-bis(2-chloroethyl)-1-benzothiophen-4-amine Chemical compound ClCCN(CCCl)c1cccc2sccc12 BATWLIVHOMDHHA-UHFFFAOYSA-N 0.000 description 1
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 1
- 238000009098 adjuvant therapy Methods 0.000 description 1
- 230000001800 adrenalinergic effect Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000008484 agonism Effects 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 150000001880 copper compounds Chemical group 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 1
- 238000005859 coupling reaction Methods 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
- 229960003638 dopamine Drugs 0.000 description 1
- 206010022437 insomnia Diseases 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 229940011389 rexulti Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- IRFHMTUHTBSEBK-QGZVFWFLSA-N tert-butyl n-[(2s)-2-(2,5-difluorophenyl)-3-quinolin-3-ylpropyl]carbamate Chemical compound C1([C@H](CC=2C=C3C=CC=CC3=NC=2)CNC(=O)OC(C)(C)C)=CC(F)=CC=C1F IRFHMTUHTBSEBK-QGZVFWFLSA-N 0.000 description 1
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a method for preparing brexpiprazole, in particular to a method for preparing brexpiprazole by reacting 7-bromoquinoline-2 (1H) -ketone with 4- (4- (benzo [ b ] thiophene-4-yl) piperazine-1-yl) butyl-1-alcohol under the conditions of a copper reagent, alkali, a solvent and additives.
Description
Technical Field
The invention relates to the field of chemical synthesis, and relates to a novel method for preparing brexpiprazole.
Background
Schizophrenia and major depression (MDD) are two of the most common serious mental diseases, the pathogenesis of which is unknown and which can lead to disability, and about 1% of people worldwide are affected by it.
On 10 days 7/2015, the united states Food and Drug Administration (FDA) approved that an ipiprazole (trade name: rexulti) tablet developed together with the north medicine of danazol and the medicine of tsukamur japan was marketed, and was suitable for the treatment of schizophrenia and the adjuvant treatment of MDD. Epipiprazole can be used for treating dopamine D 2 And 5-hydroxytryptamine 1A (5-HT) 1A ) Partial agonism of receptor and on 5-HT 2A Antagonistic effects of receptors and adrenergic alpha 2 produce anti-schizophrenia effects. The brexpiprazole has good curative effect and tolerance, and can reduce the incidence of adverse reactions such as incapability of sitting and sitting, uneasiness, insomnia and the like of patients. Therefore, the brexpiprazole has good market prospect as a multi-target anti-mental disease drug.
The Chinese cultural name of the brexpiprazole is as follows: 7- [4- (4- (benzo [ b ] thiophen-4-yl) -piperazin-1-yl) butoxy ] -1H-quinolin-2-one having the following chemical structure:
several patents have reported the synthesis of ipiprazole. Patent CN2006800011923.0 is the original synthesis route patent of tsukamur pharmaceutical company, which uses 7-hydroxyquinolin-2 (1H) -one and 4-bromobenzo [ b ] thiophene as starting materials, and prepares ipiprazole by condensing 7- (4-chlorobutoxy) quinolin-2 (1H) -one and 4- (1-piperazinyl) -benzo [ b ] thiophene hydrochloride under alkaline conditions. The relevant synthetic route is as follows:
in patent CN105440026A, 7-hydroxyquinoline-2 (1H) -one is also used as a starting material, ding Wanlian and piperazinyl are sequentially introduced through two nucleophilic substitution reactions to obtain 7- (1-piperazine butoxy) -1H-quinoline-2-one, and finally benzo [ b ] thiophene fragments are introduced through a coupling reaction catalyzed by palladium acetate to prepare the ipiprazole. The synthetic route of the patent is as follows:
patent CN201610006862.4 reports a synthetic route using 4-amino-benzo [ b ] thiophene as an intermediate. 4-amino-benzo [ b ] thiophene firstly reacts with bis (2-chloroethyl) amine hydrochloride to prepare 4- (1-piperazinyl) -benzo [ b ] thiophene hydrochloride, and then the 4- (1-piperazinyl) -benzo [ b ] thiophene hydrochloride reacts with 7- (4-methanesulfonyloxy butoxy) quinoline-2 (1H) -ketone to realize the synthesis of the ipiprazole. The synthetic route of the patent is as follows:
the patent CN105541819a reports a synthetic route to the final step of preparation of ipiprazole by condensation of N, N-bis (2-chloroethyl) benzo [ b ] thiophen-4-amine with 7- (4-aminobutoxy) quinolin-2 (1H) -one under basic conditions. The synthetic route is as follows:
the final step in many current synthetic routes to ipiprazole involves the use of genotoxic/potentially genotoxic compounds (including chloroalkane chain compounds, sulfonyl compounds, etc.). The use of genotoxic and potentially genotoxic compounds can have a large impact on the quality of the final ipiprazole and requires strict control of the residual amount of these genotoxic compounds in the bulk drug ipiprazole. The use and removal of these genotoxic compounds and potentially genotoxic compounds is a significant challenge for the industrialization of ipiprazole. For this reason, the development of new process routes that do not involve the use of genotoxic/potentially genotoxic compounds is of great importance for the industrialization of ipiprazole. The structures of some genotoxic/potentially genotoxic compounds involved in the last step of the above synthetic route are as follows:
disclosure of Invention
The technical problem underlying the present invention is to provide a new synthetic process for the preparation of ipiprazole, which reaction step does not involve the use of genotoxic/potentially genotoxic compounds.
It was found that 7-bromoquinolin-2 (1H) -one reacts with 4- (4- (benzo [ b ] thiophen-4-yl) piperazin-1-yl) butan-1-ol under conditions of copper reagent, base, solvent and additives to produce ipiprazole, having the following reaction formula:
the copper reagent used in the reaction is Cu (OAc) 2 ,CuI。
The base used in the reaction is t BuONa, t BuOK。
The additive used in the reaction is oxalyl diamine compound comprising N 1 ,N 2 Bis (phenylethyl) oxalyldiamine, N 1 ,N 2 Bis (naphthalen-1-ylmethyl) oxalyldiamine.
The solvent used in the reaction is tert-butanol 1,4-dioxane, DMF.
The process route for preparing the brexpiprazole avoids the use of genotoxic compounds/potential genotoxic compounds, and the used catalyst is a copper compound with low price, so the method has obvious significance for improving the product quality of the brexpiprazole and industrially producing the brexpiprazole.
Detailed Description
The present invention will be more specifically understood from the following examples, which are given by way of illustration and are not intended to limit the scope of the present invention.
Example 1 preparation of Epipprazole
The Schlenk flask was equipped with magnetic stirring and 7-bromoquinolin-2 (1H) -one (2.25 g, 10.0 mmol), 4- (4- (benzo [ b ] b) were added sequentially under nitrogen]Thien-4-yl) piperazin-1-yl) butan-1-ol (3.50g, 12.05mmol), cuprous iodide (95 mg,0.5 mmol), potassium tert-butoxide (1.35g, 12mmol), N 1 ,N 2 Bis (phenylethyl) oxalyldiamine (150mg, 0.5 mmol) and
molecular sieves (0.5 g). The system was purged with nitrogen 3 times, and 1,4-dioxane (12 mL) was added to the reaction system under nitrogen protection. After the addition, the system was replaced with nitrogen again for 3 times, the Schlenk reaction flask was closed, and the system was heated to 80. + -. 5 ℃ and reacted for 24 hours with rapid stirring. After the reaction is finished, the system is naturally cooled to room temperature, and CH is added 2 Cl 2 (50 mL) for 10 minutes, filtered, the organic solvent removed from the filtrate under reduced pressure, and the residue recrystallized from ethanol to give brexpiprazole (white solid, 3.89g, 89.7%).
Example 2 preparation of Epipprazole
The Schlenk reaction flask was equipped with magnetic stirring,7-Bromoquinolin-2 (1H) -one (3.0 g, 13.39mmol), 4- (4- (benzo [ b ] ne) were added in succession under nitrogen protection]Thien-4-yl) piperazin-1-yl) butan-1-ol (4.70g, 16.18mmol), copper acetate (135mg, 0.68mmol), sodium tert-butoxide (1.55g, 16.1mmol), N 1 ,N 2 Bis (naphthalen-1-ylmethyl) oxalyldiamine (250 mg,0.68 mmol) and
molecular sieves (0.6 g). The system was purged with nitrogen 3 times, and then DMF (18 mL) was added to the reaction system under nitrogen protection. After the addition, the system was again replaced with nitrogen for 3 times, the Schlenk reaction flask was closed, and the system was heated to 80. + -. 5 ℃ and reacted for 24 hours with rapid stirring. After the reaction is finished, the system is naturally cooled to room temperature, and CH is added 2 Cl 2 (60 mL) for 10 min, filtered, the filtrate was stripped of organic solvent under reduced pressure and the residue was recrystallized from ethanol to give brexpiprazole (white solid, 4.95g, 85.3%).
Claims (6)
1. A method for preparing brexpiprazole has the following synthetic route:
2. the process according to claim 1, wherein 7-bromoquinolin-2 (1H) -one is reacted with 4- (4- (benzo [ b ] thiophen-4-yl) piperazin-1-yl) butan-1-ol in the presence of a copper reagent, a base, a solvent and additives.
3. The method according to claim 2, wherein the base used in the reaction comprises t BuONa, t BuOK。
4. The process of claim 2 wherein the solvent used in the reaction is t-butanol 1,4-dioxane, DMF.
5. The process according to claim 2, wherein the copper reagent used in the reaction is Cu (OAc) 2 ,CuI。
6. The process of claim 2, wherein the additive used in the reaction is oxalyldiamide compound comprising N 1 ,N 2 Bis (phenylethyl) oxalyldiamine, N 1 ,N 2 Bis (naphthalen-1-ylmethyl) oxalyldiamine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210498690.2A CN115521298A (en) | 2022-05-09 | 2022-05-09 | Preparation method of brexpiprazole |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210498690.2A CN115521298A (en) | 2022-05-09 | 2022-05-09 | Preparation method of brexpiprazole |
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| Publication Number | Publication Date |
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| CN115521298A true CN115521298A (en) | 2022-12-27 |
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|---|---|---|---|
| CN202210498690.2A Pending CN115521298A (en) | 2022-05-09 | 2022-05-09 | Preparation method of brexpiprazole |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101258147A (en) * | 2005-08-31 | 2008-09-03 | 大塚制药株式会社 | Derivatives of 4-piperazin-1-yl-4-benz0[B]thiophene suitable for the treatment of CNS disorders |
| CN106916148A (en) * | 2015-12-25 | 2017-07-04 | 上海科胜药物研发有限公司 | A kind of synthesis is according to a method for piperazine azoles |
| CN113372336A (en) * | 2020-02-25 | 2021-09-10 | 齐鲁制药有限公司 | Preparation method and application of brexpiprazole |
-
2022
- 2022-05-09 CN CN202210498690.2A patent/CN115521298A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101258147A (en) * | 2005-08-31 | 2008-09-03 | 大塚制药株式会社 | Derivatives of 4-piperazin-1-yl-4-benz0[B]thiophene suitable for the treatment of CNS disorders |
| CN106916148A (en) * | 2015-12-25 | 2017-07-04 | 上海科胜药物研发有限公司 | A kind of synthesis is according to a method for piperazine azoles |
| CN113372336A (en) * | 2020-02-25 | 2021-09-10 | 齐鲁制药有限公司 | Preparation method and application of brexpiprazole |
Non-Patent Citations (1)
| Title |
|---|
| CHEN, ZX ET AL.: "Oxalic Diamides and tert-Butoxide: Two Types of Ligands Enabling Practical Access to Alkyl Aryl Ethers via Cu-Catalyzed Coupling Reaction", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 141, no. 8, 28 January 2019 (2019-01-28), pages 3541 - 3549, XP055594032, DOI: 10.1021/jacs.8b12142 * |
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