CN103254202A - Preparation method of asenapine - Google Patents
Preparation method of asenapine Download PDFInfo
- Publication number
- CN103254202A CN103254202A CN2013101840577A CN201310184057A CN103254202A CN 103254202 A CN103254202 A CN 103254202A CN 2013101840577 A CN2013101840577 A CN 2013101840577A CN 201310184057 A CN201310184057 A CN 201310184057A CN 103254202 A CN103254202 A CN 103254202A
- Authority
- CN
- China
- Prior art keywords
- preparation
- formula
- asenapine
- compound
- sainaping
- 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.)
- Pending
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 229960005245 asenapine Drugs 0.000 title abstract description 6
- VSWBSWWIRNCQIJ-GJZGRUSLSA-N (R,R)-asenapine Chemical compound O1C2=CC=CC=C2[C@@H]2CN(C)C[C@H]2C2=CC(Cl)=CC=C21 VSWBSWWIRNCQIJ-GJZGRUSLSA-N 0.000 title abstract 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 9
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 10
- 229910052782 aluminium Inorganic materials 0.000 claims description 10
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 9
- 230000002829 reductive effect Effects 0.000 claims description 8
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 abstract description 14
- 229910000085 borane Inorganic materials 0.000 abstract description 11
- 238000000034 method Methods 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 abstract 1
- 239000003153 chemical reaction reagent Substances 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 8
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- -1 (2-methoxyethoxy) sodium aluminates Chemical class 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- VSWBSWWIRNCQIJ-HUUCEWRRSA-N (S,S)-asenapine Chemical compound O1C2=CC=CC=C2[C@H]2CN(C)C[C@@H]2C2=CC(Cl)=CC=C21 VSWBSWWIRNCQIJ-HUUCEWRRSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- JFBZPFYRPYOZCQ-UHFFFAOYSA-N [Li].[Al] Chemical compound [Li].[Al] JFBZPFYRPYOZCQ-UHFFFAOYSA-N 0.000 description 4
- 239000004411 aluminium Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- 239000002904 solvent Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000002360 explosive Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000001603 reducing effect Effects 0.000 description 2
- 201000000980 schizophrenia Diseases 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- GMDCDXMAFMEDAG-CHHFXETESA-N (S,S)-asenapine maleate Chemical compound OC(=O)\C=C/C(O)=O.O1C2=CC=CC=C2[C@H]2CN(C)C[C@@H]2C2=CC(Cl)=CC=C21 GMDCDXMAFMEDAG-CHHFXETESA-N 0.000 description 1
- 208000017194 Affective disease Diseases 0.000 description 1
- 208000020925 Bipolar disease Diseases 0.000 description 1
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 1
- 208000019022 Mood disease Diseases 0.000 description 1
- 238000002485 combustion reaction Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 150000003233 pyrroles Chemical class 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 229940042084 saphris Drugs 0.000 description 1
- 231100000004 severe toxicity Toxicity 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of asenapine. According to the preparation method, the asenapine (III) is prepared from a compound I with formula 1 or a compound II with formula 2 under a vitride solution reduction condition. The method is high in yield and low in production cost due to the fact that vitride is much cheaper than borane; and moreover, vitride is safer and simpler to operate compared with the reagent used in the prior art, so that the asenapine is applicable to in-scale production.
Description
Technical field
The present invention relates to a kind of preparation method of organic compound, say it is the preparation method who can be used as schizophrenia medicine A Sainaping (Asenapine) definitely.
Background technology
A Sainaping (Asenapine), commodity are called Saphris, and by Organon BioSciences research and development, Schering Plough company produces.On August 14th, 2009, FDA ratified the emergency treatment that this medicine is used for grownup's schizophrenia, manic disorder or mixes outbreak with the two-way affective disorder of I type.
The English chemical name of A Sainaping is: trans-5-chloro-2,3,3a, 12b-tetrahydro-2-methyl-1H-dibenz[2,3:6,7] oxepino[4,5-c] pyrrole; The Chinese chemical name: trans-5-chloro-2,3,3a, 12b-tetrahydrochysene-2-methyl isophthalic acid H-dibenzo [2,3:6,7] oxa-Zhuo is [4,5-c] pyrroles also; Molecular formula: C17H16ClNO; Relative molecular weight: 285.77; CAS registration number: 65576-45-6.A Sainaping since coming out, a lot of patents and bibliographical information have been arranged both at home and abroad its preparation method.But major part all is to be that starting raw material obtains the A Sainaping III through reduction with chemical compounds I or II, obtains the A Sainaping maleate with toxilic acid salify in ethanolic soln again, shown in one:
Wherein, the reductive condition of employing is mainly two kinds: a kind of is to adopt tetrahydrochysene lithium aluminium, and the aluminum chloride system is reduced and obtained the A Sainaping III, obtain the A Sainaping maleate with the toxilic acid salify again, as: US20060229352, WO2006106136, US20090209608 etc.; Another kind method is to adopt borane complex (borine dimethyl sulphide or borine tetrahydrofuran (THF)) reduction to obtain the A Sainaping III, obtains the A Sainaping maleate with the toxilic acid salify again, as CN101851242.These two kinds of reaction systems all need adopt anhydrous system, and reaction conditions requires harsh relatively, and operation is relatively more dangerous.Tetrahydrochysene lithium aluminium and borane complex are inflammable and explosive chemical, meet damp atmosphere or water generation vigorous reaction, easily cause burning or blast.Tetrahydrochysene lithium aluminium or borine that industrial a large amount of use is valuable, danger is big, cost is high.
Summary of the invention
In order to solve above-mentioned shortcoming, the invention provides a kind of preparation method of novelty, utilize red aluminium (two (2-methoxyethoxy) sodium aluminates of dihydro) to substitute tetrahydrochysene lithium aluminium or borine, chemical compounds I shown in the formula one or II are obtained compound III (A Sainaping) under red aluminum solutions reductive condition, synthetic reaction formula suc as formula two or formula three shown in, the concrete practice is: adopt structure suc as formula two or formula three shown in be raw material with chemical compounds I or II, be solvent with toluene, obtain III (A Sainaping) under the condition of red aluminium reducing, the method for recycling bibliographical information and toxilic acid salify obtain the A Sainaping maleate.
Because red aluminum solutions all will be stablized than lithium aluminum hydride or borine in moisture and air, its thermostability is also higher, can spontaneous combustion, solvability is good, is easy to dispose, and has high reducing activity, be the surrogate of the safety of lithium aluminum hydride or borine, reduced the danger of operation, greatly reduce cost, simplify the risk of post-processing operation, shortened the production cycle.
Experiment confirm provided by the present invention suc as formula two or formula three shown in the method for preparing the compound III through chemical compounds I or II yield height not only; and because red aluminium is cheaply a lot of than borine; so production cost is low; simultaneously because the borine severe toxicity is explosive; red aluminium is then much safe; so method operation provided by the invention is simpler, is suitable for large-scale production.
Embodiment
Embodiment one: in the synthetic route shown in two, wherein be raw material with the chemical compounds I, the preparation of compound III: in the 500mL there-necked flask, add 30g compound compound I, with 300mL toluene it is dissolved, drip 70% red aluminum solutions 144g under the room temperature.Reaction mixture is warming up to 40 ℃ to 50 ℃ reactions 3 hours under constantly stirring.The ice-water bath cooling drips 100mL methyl alcohol cancellation reaction down, adds the sodium hydroxide solution of 100mL water and 200mL10%, stirs a moment.Tell organic phase, water 100mL dichloromethane extraction.Merge organic phase, drying, concentrating under reduced pressure reclaims solvent, gets 26g compound III, yield 71%.
Embodiment two: in the synthetic route shown in three, be raw material with the compound ii wherein, in the 500mL there-necked flask, add 30g compound compound I, with 300mL toluene it is dissolved, drip 70% red aluminum solutions 144g under the room temperature.Reaction mixture is warming up to 40 ℃ to 50 ℃ reactions 3 hours under constantly stirring.The ice-water bath cooling drips 100mL methyl alcohol cancellation reaction down, adds the sodium hydroxide solution of 100mL water and 200mL10%, stirs a moment.Tell organic phase, water 100mL dichloromethane extraction.Merge organic phase, drying, concentrating under reduced pressure reclaims solvent, gets 25.5g compound III, yield 69%.
Claims (2)
1. suc as formula the preparation method of compound III in 1, it is characterized in that chemical compounds I is obtained the compound III under red aluminum solutions reductive condition,
2. suc as formula the preparation method of compound III in 2,, it is characterized in that compound ii is obtained the compound III under red aluminum solutions reductive condition,
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2013101840577A CN103254202A (en) | 2013-05-19 | 2013-05-19 | Preparation method of asenapine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2013101840577A CN103254202A (en) | 2013-05-19 | 2013-05-19 | Preparation method of asenapine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103254202A true CN103254202A (en) | 2013-08-21 |
Family
ID=48958465
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2013101840577A Pending CN103254202A (en) | 2013-05-19 | 2013-05-19 | Preparation method of asenapine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103254202A (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11033512B2 (en) | 2017-06-26 | 2021-06-15 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine and silicone acrylic hybrid polymer |
| US11337932B2 (en) | 2016-12-20 | 2022-05-24 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene |
| US11648213B2 (en) | 2018-06-20 | 2023-05-16 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine |
| US12138353B2 (en) | 2016-12-20 | 2024-11-12 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine |
| US12329862B2 (en) | 2018-06-20 | 2025-06-17 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101175741A (en) * | 2005-04-07 | 2008-05-07 | 欧加农股份有限公司 | Intermediate compounds for the prepation of trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-C]pyrrole |
| CN101851242A (en) * | 2010-05-25 | 2010-10-06 | 上海皓元生物医药科技有限公司 | Preparation method of asenapine intermediate |
| CN103254201A (en) * | 2012-02-21 | 2013-08-21 | 四川科伦药物研究有限公司 | Preparation method of asenapine |
-
2013
- 2013-05-19 CN CN2013101840577A patent/CN103254202A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101175741A (en) * | 2005-04-07 | 2008-05-07 | 欧加农股份有限公司 | Intermediate compounds for the prepation of trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-C]pyrrole |
| CN101851242A (en) * | 2010-05-25 | 2010-10-06 | 上海皓元生物医药科技有限公司 | Preparation method of asenapine intermediate |
| CN103254201A (en) * | 2012-02-21 | 2013-08-21 | 四川科伦药物研究有限公司 | Preparation method of asenapine |
Non-Patent Citations (1)
| Title |
|---|
| 张思晨 等: "新型高效还原剂红铝", 《精细与专用化学品》 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11337932B2 (en) | 2016-12-20 | 2022-05-24 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene |
| US12138353B2 (en) | 2016-12-20 | 2024-11-12 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine |
| US12485099B2 (en) | 2016-12-20 | 2025-12-02 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene |
| US11033512B2 (en) | 2017-06-26 | 2021-06-15 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine and silicone acrylic hybrid polymer |
| US11648213B2 (en) | 2018-06-20 | 2023-05-16 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine |
| US12329862B2 (en) | 2018-06-20 | 2025-06-17 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103254202A (en) | Preparation method of asenapine | |
| CN101851242A (en) | Preparation method of asenapine intermediate | |
| CN106008290A (en) | Method for preparing tembotrions | |
| CN103073584A (en) | Method for preparing triphenylphosphine | |
| CN102911164A (en) | Method for preparing lapatinib key intermediate | |
| CN101851200A (en) | The synthetic method of 1-phenyl-1,2,3,4-tetrahydroisoquinoline | |
| CN102249983A (en) | Method for synthesizing tetrahydrocarbazoles compound | |
| CN104326988B (en) | A kind of synthetic method of 2,4-dichloro-5-methoxy pyrimidines | |
| CN104974057B (en) | The preparation method and important intermediate of a kind of bromfenac sodium | |
| CN106866378B (en) | Synthetic process of phloroglucinol | |
| CN108822030A (en) | A method of synthesis 1,2,3,4- Tetrahydroquinolinesas | |
| CN106046077A (en) | Tulathromycin A synthesis method | |
| CN103319551B (en) | Erythromycin 6, the preparation method of 9 imines ethers | |
| CN103044327B (en) | Preparation method of dextromethorphan | |
| CN102786541A (en) | Preparation method and application of potassium (iso)quinoline thifluoroborate | |
| CN105859761A (en) | Synthesis method of aromatic borate compounds | |
| CN103351280A (en) | Simple preparation process of 9-fluorenemethanol | |
| CN103880573A (en) | Preparation method for biphenyl-type compound | |
| CN102093247B (en) | Preparation method of 2-methyl-4-N-(2-methylbenzoyl)benzoic acid | |
| CN107629067A (en) | A kind of dithieno cyclopentadiene derivant and preparation method thereof | |
| CN103450183B (en) | A kind of preparation method of butanedioic acid Solifenacin | |
| CN108218806A (en) | A kind of preparation method of N- tertbutyloxycarbonyls morpholine -3- carboxylic acids | |
| CN102212026A (en) | Preparation method for 1-tertbutyloxycarbonyl-3-iodoazetidine | |
| CN109574811B (en) | Preparation method of anidulafungin side chain intermediate p-pentoxy terphenyl formic acid | |
| CN105330541B (en) | The synthetic method of the alkyl formate of 4 ' halogenated methyl biphenyl 2 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C05 | Deemed withdrawal (patent law before 1993) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20130821 |