CN103772400A - Preparation method of trans-5-chloro-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrole - Google Patents
Preparation method of trans-5-chloro-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrole Download PDFInfo
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- CN103772400A CN103772400A CN201410005892.4A CN201410005892A CN103772400A CN 103772400 A CN103772400 A CN 103772400A CN 201410005892 A CN201410005892 A CN 201410005892A CN 103772400 A CN103772400 A CN 103772400A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
Abstract
The invention belongs to the field of pharmaceutical chemistry, and provides a preparation method of an asenapine key impurity (IV) trans-5-chloro-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrole. The trans-5-chloro-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrole is prepared from trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrole used as the initial raw material. The impurity is a very key impurity for synthesizing asenapine, and is also an important intermediate for controlling the asenapine end product quality standard.
Description
Technical field
The present invention relates to pharmaceutical chemistry field, be specifically related to trans-5-chloro-2,3,3a, 12b-tetrahydrochysene-1H-dibenzo [2,3:6,7] oxa-Zhuo is [4,5-c] pyrroles's [Asenapine critical impurities (IV)] novel preparation method also.
Background technology
Novel atypical antipsychotic agents Asenapine (Chinese name asenapine), chemistry by name trans-5-is chloro-2,3,3a, also [4,5-c] pyrroles of 12b-tetrahydrochysene-2-methyl isophthalic acid H-dibenzo [2,3:6,7] oxa-Zhuo.Be to be researched and developed by Ou Jianong company, by Schering Plough company, this medicine applied for to listing.On August 14th, 2009, U.S. FDA was ratified its listing request.It is a kind of atypical antipsychotic of many target spots, is mainly used in treating grownup's schizophrenia, manic disorder mix outbreak emergency treatment with two-way affective disorder.The following I of its structural formula:
Trans-5-is chloro-2,3,3a, 12b-tetrahydrochysene-1H-dibenzo [2,3:6,7] oxa-Zhuo also [4,5-c] pyrroles's [Asenapine impurity (IV)] synthesizes a very crucial impurity of Asenapine, is also an important intermediate controlling Asenapine end product quality standard.
Due to the singularity of its structure, the method for preparing Asenapine impurity (IV) of existing report is less, as disclosed synthetic method in patent EP2468751, adopts the synthetic target compound of 10 steps, and process is loaded down with trivial details, and relates to raw material and intermediate is numerous.Another example has been reported this impurity preparation method (J. Label Compd. Radiopharm 2012 as Kuethe J.T., 55 180-185), the method that this article provides is take 1-chloroethyl chloro-formic ester as esterifying agent, reflux and prepare in ethanol/dichloromethane system, but 1-chloroethyl chloro-formic ester is high hypertoxicity, and for being subject to controlled drug.To sum up, the route of bibliographical information is more loaded down with trivial details and relate to use highly toxic product, designs a new route and prepares trans-5-chloro-2,3,3a, 12b-tetrahydrochysene-2-methyl isophthalic acid H-dibenzo [2,3:6,7] also [4,5-c] pyrroles and to avoid using highly toxic product be very necessary of oxa-Zhuo.
Summary of the invention
The invention provides a set of antipsychotic drug Asenapine critical impurities compound trans-5-for preparing chloro-2,3,3a, also [4,5-c] pyrroles's (IV) method of 12b-tetrahydrochysene-1H-dibenzo [2,3:6,7] oxa-Zhuo.Its preparation method is chloro-2,3 with trans-5-, 3a, 12b-tetrahydrochysene-2-methyl isophthalic acid H-dibenzo [2,3:6,7] oxa-Zhuo also [4,5-c] pyrroles's (I) is starting raw material, and atmospheric pressure reflux adopts esterifying agent to its end position methyl-esterified, and atmospheric pressure reflux is sloughed esterified group salify through mineral acid hydrolysis, make Asenapine impurity (IV) through mineral alkali atmospheric pressure reflux solution salt again, the method agents useful for same is simple and easy to get, and the reaction times is short, and aftertreatment is simple, by product is few, and product purity is high.Synthetic route is as follows:
Wherein Esterification Stage compound (I) is prepared the esterifying agent that compound (II) adopts and is comprised methyl-chloroformate, Vinyl chloroformate, phenyl chloroformate, chloroformic acid Bian ester, 1-chloroethyl chloro-formic ester, wherein preferred Vinyl chloroformate.Reaction solvent is methyl alcohol, ethanol, methylene dichloride, toluene, wherein preferred toluene.The temperature of reaction of required control be 0 ℃ to reflux temperature, wherein preferably 90 ℃-110 ℃, whole reaction process is carried out under normal pressure.
Wherein carboxylate is prepared compound (III) through acid hydrolysis stage compound (II), and mineral acid is 40% Hydrogen bromide, the vitriol oil, concentrated hydrochloric acid, wherein preferred 40% Hydrogen bromide.Required control temperature of reaction be 0 ℃ to reflux temperature, wherein preferably 80 ℃-100 ℃, whole reaction is carried out under normal pressure.
Wherein separating salt phase compound (III), to prepare compound (IV) be that in target Asenapine impurity C, mineral alkali is potassium hydroxide, sodium hydroxide, salt of wormwood, sodium carbonate, wherein preferred sodium carbonate.Temperature of reaction be 0 ℃ to reflux temperature, wherein preferably 80 ℃-100 ℃, whole reaction is carried out in normal pressure water.
concrete embodiment
Following embodiment is to describe in detail the present invention, but should not be construed as limiting the invention.
Embodiment one: compound (II) synthetic:
To adding in 100 mL there-necked flasks trans-5-chloro-2,3,3a, also [4,5-c] pyrroles of 12b-tetrahydrochysene-2-methyl isophthalic acid H-dibenzo [2,3:6,7] oxa-Zhuo, adds 15.0 mL toluene and 0.74g sodium carbonate, stirs 30min and makes it abundant dissolving.The blend that adds wherein 0.76g Vinyl chloroformate and 5.0 mL toluene, slowly splashes into constant pressure funnel.Wait to drip and finish, ℃ backflow of temperature reaction liquid to 110.Monitor raw material reaction by TLC complete, go out with 20.0 mL shrends, with 20.0 mL ethyl acetate extractions, rear separatory, organic phase is with 20.0 mL washing 2 times, then with saturated aqueous common salt 20.0 mL washed twice, with anhydrous sodium sulfate drying 4 h.Suction filtration is removed filter cake, and filter cake washs with ethyl acetate, and filtrate is spin-dried for to obtain red-brown oily matter 0.7 g, yield 58.18%.
1H-NMR (CDCl
3)
δ 1.26 (t, 3H,
J = 7.2 Hz), 3.57~3.58 (m, 4H), 4.00~4.08 (m, 2H), 4.15 (
q, 2H
, J = 7.2 Hz), 7.01~7.19 (m, 7H). MS (
m/z)：[M+H]
+ 344.0.
Embodiment two: compound (III) synthetic:
In 50 mL there-necked flasks, add compound (II) 100 mg, measure 5.0 mL40% Hydrogen bromides and add constant pressure funnel, make it slowly to splash into.Wait to drip and finish, ℃ backflow of temperature reaction liquid to 80.Monitor raw material reaction by TLC complete, be spin-dried for reaction solution, obtain red solid.With 10.0 mL ethyl acetate, 30 min that pull an oar, suction filtration, with a small amount of ethyl acetate rinse filter cake.Collecting filter cake send 40 ℃ of air blast to dry.Obtain white solid 88.1 mg, yield 85.89%.
1H-NMR (DMSO-
d 6 )
δ 3.43 (m, 2H), 3.66 (m, 2H), 3.90 (m, 2H), 7.14~7.36 (m, 7H), 9.69 (brs, 2H). MS (
m/z)：[M+H]
+ 272.0.
Embodiment three: Asenapine impurity C, compound (IV) trans-5-is chloro-2,3,3a, also [4,5-c] pyrroles synthetic of 12b-tetrahydrochysene-1H-dibenzo [2,3:6,7] oxa-Zhuo:
In 50 mL there-necked flasks, add compound (III) 50 mg, add 5 mL water and 45 mg sodium carbonate, heat up and be stirred to backflow, reaction 2 h.Monitoring pH is 8.0-11.0, adds methylene dichloride 10 mL extractions.Rear separatory, organic phase is washed 2 times with 5.0 mL, then with saturated aqueous common salt 5.0 mL washed twice, with anhydrous sodium sulfate drying 4 h.Suction filtration is removed filter cake, and filter cake is with a small amount of washed with dichloromethane.Filtrate is spin-dried for, and obtains white solid 35.1g, yield 91.12%.
Claims (8)
1. the preparation method of an Asenapine (asenapine) critical impurities (IV), it is characterized in that using compound trans-5-chloro-2,3,3a, 12b-tetrahydrochysene-2-methyl isophthalic acid H-dibenzo [2,3:6,7] oxa-Zhuo also [4,5-c] pyrroles's (I) is starting raw material, under esterifying reagent, its end position methyl-esterified is generated to compound (II), compound (II) is prepared compound (III) through mineral acid hydrolysis, and compound (III) makes asenapine impurity (IV) through mineral alkali hydrolysis
2. according to the process of claim 1 wherein that the esterifying reagent that compound (I) is prepared compound (II) is methyl-chloroformate, Vinyl chloroformate, phenyl chloroformate, chloroformic acid Bian ester, 1-chloroethyl chloro-formic ester; Reaction solvent is methyl alcohol, ethanol, methylene dichloride, toluene; Temperature of reaction is 0 ℃ of reflux temperature to reaction system.
3. according to the method for claim 2, wherein esterifying reagent is Vinyl chloroformate, and reaction solvent is toluene.
4. according to the method for claim 1, the mineral acid that compound (II) is prepared compound (III) is 40% Hydrogen bromide, the vitriol oil, concentrated hydrochloric acid, and temperature of reaction is 0 ℃ of reflux temperature to reaction system.
5. according to the method for claim 4, mineral acid is 40% Hydrogen bromide.
6. according to the method for claim 1, the mineral alkali that compound (III) is prepared compound (IV) is potassium hydroxide, sodium hydroxide, salt of wormwood, sodium carbonate.
7. according to the method for claim 6, mineral alkali is sodium carbonate.
8. according to the method for claim 1, the consumption mol ratio of compound (I) and esterifying reagent is between 1:1.5 to 1:2.5; The consumption solid-to-liquid ratio of compound (II) and mineral acid is between 1:3 to 1:10; The consumption mol ratio of compound (III) and mineral alkali is between 1:2 to 1:3.
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| CN201410005892.4A CN103772400A (en) | 2014-01-07 | 2014-01-07 | Preparation method of trans-5-chloro-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrole |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105566336A (en) * | 2016-01-08 | 2016-05-11 | 万特制药(海南)有限公司 | Novel method for removing methyl impurity in preparation of asenapine |
| US10898449B2 (en) | 2016-12-20 | 2021-01-26 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine |
| 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 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4145434A (en) * | 1976-05-24 | 1979-03-20 | Akzona Incorporated | Tetracyclic derivatives and pharmaceutical compositions of matter |
| EP2468751A2 (en) * | 2010-12-24 | 2012-06-27 | Medichem, S.A. | Processes for the preparation of 5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrole |
-
2014
- 2014-01-07 CN CN201410005892.4A patent/CN103772400A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4145434A (en) * | 1976-05-24 | 1979-03-20 | Akzona Incorporated | Tetracyclic derivatives and pharmaceutical compositions of matter |
| EP2468751A2 (en) * | 2010-12-24 | 2012-06-27 | Medichem, S.A. | Processes for the preparation of 5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrole |
Non-Patent Citations (1)
| Title |
|---|
| JEFFREY T. KUETHE: "Synthesis of stable isotope-labeled metabolites of asenapine", 《JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS》 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105566336A (en) * | 2016-01-08 | 2016-05-11 | 万特制药(海南)有限公司 | Novel method for removing methyl impurity in preparation of asenapine |
| US10898449B2 (en) | 2016-12-20 | 2021-01-26 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine |
| US10980753B2 (en) | 2016-12-20 | 2021-04-20 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine |
| US11337932B2 (en) | 2016-12-20 | 2022-05-24 | 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 |
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Application publication date: 20140507 |