CN101891731A - Method for synthesizing olopatatadine E-configurational isomer - Google Patents
Method for synthesizing olopatatadine E-configurational isomer Download PDFInfo
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- CN101891731A CN101891731A CN2010102376497A CN201010237649A CN101891731A CN 101891731 A CN101891731 A CN 101891731A CN 2010102376497 A CN2010102376497 A CN 2010102376497A CN 201010237649 A CN201010237649 A CN 201010237649A CN 101891731 A CN101891731 A CN 101891731A
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- olopatatadine
- isomer
- configurational
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- phosphoramide
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Abstract
The invention relates to a double-bond selective synthesis method for an olopatatadine E-configurational isomer serving as an antiallergic agent. In the method, chiral cyclic phosphoramide reacts with isoxepac under the action of strong alkali, and the reaction is controlled to generate specific-configurational phosphoramide carbanion so as to obtain the E-configurational olopatatadine isomer with high selectivity. In the process of the invention, the chiral cyclic phosphoramide is subjected to Wittig-Horner reaction to obtain the target configurational product with high yield; meanwhile, a new concept for preparing corresponding configurational double-bond by similar reactions is provided.
Description
Technical field
The invention belongs to the medicament research and development field, particularly a kind of highly selective synthetic method of anti-allergy agent Olopatatadine isomer.Its concrete structure is as follows:
Background technology
The method of existing synthetic Olopatatadine early stage (US5116863) is by Grignard reaction or Wittig reaction, generate the dominant mixture of Z configurational isomer, adopt HP-20 post (water: ethanol=1: 2), separate obtaining Z configuration Olopatatadine and E configuration Olopatatadine isomer then.
(US20070232814) can find by patent, this thinking did not change substantially in recent years, still adopt Grignard reaction or Wittig reaction type, split by finished product crystallization or employing Phenylsulfonic acid then, the Olopatatadine isomer obtains as by product crystallization or chromatography in this process.
Summary of the invention
The objective of the invention is to seek a feasible directly synthetic E configuration Olopatatadine isomer novel method.
The present invention implements by following reaction: adopt S configuration cyclic phosphines acid amides (I), under the highly basic effect, generate the phosphonic amide carbanion, add Isoxepac (II) solution then and continue reaction, the Olopatatadine isomer (III) that reaction finishes and obtains the E configuration after treatment.Reaction scheme is as follows:
The present invention includes the following step:
1, the reaction of S configuration cyclic phosphines acid amides and highly basic generates the phosphonic amide carbanion.In particular, under-78 ℃～0 ℃, reaction 1h～5h generates the phosphonic amide carbanion.Reaction solvent can be selected THF, ether etc.
2, the reaction of phosphonic amide carbanion and Isoxepac generates oxa-tetra-atomic ring intermediate, generates E configuration Olopatatadine isomer through eliminating reaction then.In particular, under-78 ℃～0 ℃, drip the supreme step product of Isoxepac solution, rise to 0 ℃～30 ℃ insulated and stirred 1h～10h after dropwising, be concentrated into and add water after doing and transfer to neutrality again, add the ethyl acetate separatory, the ester layer concentrates post crystallization and gets target product.
Advantage of the present invention and positively effect:
The present invention is to provide a feasible directly synthetic E configuration Olopatatadine isomer novel method.This method adopts S configuration cyclic phosphines acid amides to introduce chirality, thereby controls the configuration of oxa-tetra-atomic ring intermediate in reaction process, and then obtains pure E configuration Olopatatadine isomer after eliminating reaction.This reaction scheme raw material is easy to get, and stereospecificity is strong.
Embodiment
Below each embodiment further specify the present invention, but do not impose any restrictions.
Embodiment 1
With 6.00g (20.66mmol) I (R
2=-t-Bu) is dissolved among the THF120ml, stir, be cooled to-78 ℃, drip the hexane solution (2.5mol/L) of 25ml n-Butyl Lithium, dropwising the back keeps temperature to stir 1h, continue to drip the 28mlTHF solution of 2.77gII then, rise to 20 ℃ of room temperatures after dropwising and stir 3h, be concentrated into and add 100ml water after doing, dripping hydrochloric acid is transferred pH=7, adding the 150ml ethyl acetate again stirs, separatory, the ester layer is concentrated into driedly, add 30ml acetonitrile thermosol post crystallization and get target product III5.78g, yield 83%, Z/E=1/99.
1H NMR spectral data (DMSO-d
6) (chemical shift δ): 2.17 (s, 6H), 2.20-2.60 (m, 4H), 3.48 (s, 2H), 4.92 (br, 1H) 5.43 (br, 1H), 5.99 (t, J=7.2Hz, 1H), 6.68 (d, J=8.3Hz, 1H), 7.05 (dd, J=2.2 and 8.3Hz, 1H), 7.20 (d, J=2.2Hz, 1H), and 7.28-7.55 (m, 4H).
Embodiment 2
With 6.00g (24.16mol) I (R
2=-Me) is dissolved among the THF120ml, stir, be cooled to-78 ℃, drip the hexane solution (2.5mol/L) of 29ml n-Butyl Lithium, dropwising the back keeps temperature to stir 1h, continue to drip the 33mlTHF solution of 3.24gII then, rise to 20 ℃ of room temperatures after dropwising and stir 4h, be concentrated into and add 100ml water after doing, dripping hydrochloric acid is transferred pH=7, adding the 150ml ethyl acetate again stirs, separatory, the ester layer is concentrated into driedly, add 30ml acetonitrile thermosol post crystallization and get target product III6.36g, yield 78%, Z/E=1.5/98.5.
Embodiment 3
With 6.00g (24.16mol) I (R
2=-Me) is dissolved among the ether 120ml, stir, be cooled to-78 ℃, drip the hexane solution (2.5mol/L) of 29ml n-Butyl Lithium, dropwising the back keeps temperature to stir 1h, continue to drip the ml diethyl ether solution of 3.24gII then, rise to 20 ℃ of room temperatures after dropwising and stir 4h, be concentrated into and add 100ml water after doing, dripping hydrochloric acid is transferred pH=7, adding the 150ml ethyl acetate again stirs, separatory, the ester layer is concentrated into driedly, add 30ml acetonitrile thermosol post crystallization and get target product III6.11g, yield 75%, Z/E=1.5/98.5.
Claims (3)
1. one kind via following structure
The step of the synthetic Olopatatadine isomer of compound as follows:
2. according to claim 1, the new synthetic method of Olopatatadine isomer is characterized in that adopting the chiral ring phosphonic amide to react through Wittig-Horner, reaches the purpose of the two key configurations of control product.
3. according to claim 1, the new synthetic method of Olopatatadine isomer is characterized in that the nitrogen substituting group of chiral ring phosphonic amide comprises other group that the personage can associate easily in methyl, ethyl, sec.-propyl, the tertiary butyl, uncle's heptyl and other industry.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010237649.7A CN101891731B (en) | 2010-07-27 | 2010-07-27 | Method for synthesizing olopatatadine E-configurational isomer |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010237649.7A CN101891731B (en) | 2010-07-27 | 2010-07-27 | Method for synthesizing olopatatadine E-configurational isomer |
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| Publication Number | Publication Date |
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| CN101891731A true CN101891731A (en) | 2010-11-24 |
| CN101891731B CN101891731B (en) | 2015-04-15 |
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| CN201010237649.7A Expired - Fee Related CN101891731B (en) | 2010-07-27 | 2010-07-27 | Method for synthesizing olopatatadine E-configurational isomer |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104031020A (en) * | 2014-06-04 | 2014-09-10 | 北京嘉林药业股份有限公司 | Preparation method of o-hydroxyl Olopatadine |
| CN103664861B (en) * | 2013-12-18 | 2018-01-30 | 北京华禧联合科技发展有限公司 | A kind of new method that Olopatadine hydrochloride is prepared with high activity organic zinc reagent |
| CN112457287A (en) * | 2020-12-09 | 2021-03-09 | 重庆西南制药二厂有限责任公司 | Preparation method of E-olopatadine |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070232814A1 (en) * | 2006-03-28 | 2007-10-04 | Thomas Bader | Polymorphic forms of olopatadine hydrochloride and methods for producing olopatadine and salts thereof |
-
2010
- 2010-07-27 CN CN201010237649.7A patent/CN101891731B/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070232814A1 (en) * | 2006-03-28 | 2007-10-04 | Thomas Bader | Polymorphic forms of olopatadine hydrochloride and methods for producing olopatadine and salts thereof |
Non-Patent Citations (1)
| Title |
|---|
| SCOTT E. DENMARK，ET AL.: "Stereoselective Alkylations of Chiral, Phosphorus-Stabilized Benzylic Carbanions", 《J. ORG. CHEM.》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103664861B (en) * | 2013-12-18 | 2018-01-30 | 北京华禧联合科技发展有限公司 | A kind of new method that Olopatadine hydrochloride is prepared with high activity organic zinc reagent |
| CN104031020A (en) * | 2014-06-04 | 2014-09-10 | 北京嘉林药业股份有限公司 | Preparation method of o-hydroxyl Olopatadine |
| CN104031020B (en) * | 2014-06-04 | 2016-08-24 | 北京嘉林药业股份有限公司 | A kind of preparation method of adjacent hydroxyl olopatadine |
| CN112457287A (en) * | 2020-12-09 | 2021-03-09 | 重庆西南制药二厂有限责任公司 | Preparation method of E-olopatadine |
| CN112457287B (en) * | 2020-12-09 | 2024-02-06 | 重庆西南制药二厂有限责任公司 | Preparation method of E-olopatadine |
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| CN101891731B (en) | 2015-04-15 |
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