CN102030723A - Preparation method of trihexyphenidyl hydrochloride - Google Patents
Preparation method of trihexyphenidyl hydrochloride Download PDFInfo
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- CN102030723A CN102030723A CN 201010566438 CN201010566438A CN102030723A CN 102030723 A CN102030723 A CN 102030723A CN 201010566438 CN201010566438 CN 201010566438 CN 201010566438 A CN201010566438 A CN 201010566438A CN 102030723 A CN102030723 A CN 102030723A
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- tertiary butyl
- benzhexol hcl
- methyl tertiary
- butyl ether
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Abstract
The invention relates to a preparation method of trihexyphenidyl hydrochloride. The preparation method is as follows: intermediate propiophenone piperidyl hydrochloride of the trihexyphenidyl hydrochloride is firstly prepared, crude trihexyphenidyl hydrochloride is prepared, and the crude trihexyphenidyl hydrochloride is refined; methyl tertiary butyl ether is adopted to replace diethyl ether in the preparation process of the crude trihexyphenidyl hydrochloride; and the safety problem in the existing preparation technique of the trihexyphenidyl hydrochloride that the diethyl ether is adopted as a Grignard reagent and a reaction solvent is solved.
Description
Technical field
The present invention relates to the preparation method of Benzhexol HCL.
Background technology
The chemical name of Benzhexol HCL is 1-cyclohexyl-1-phenyl-3-(piperidino)-propylate hydrochlorate, effect is the striatal cholinergic nerve path of selective exclusion, and it is less to peripheral action, thereby help recovering the balance of interior Dopamine HCL of Parkinsonian's brain and vagusstoff, improve patient's Parkinson's disease symptom, what but the preparation technology of existing Benzhexol HCL adopted always is to prepare intermediate Propiophenone piperidine hydrochlorate earlier, Benzhexol HCL is made in Propiophenone piperidine hydrochlorate and Grignard reagent polymerization, and the Grignard reagent that adopts among the preparation technology of existing Benzhexol HCL all is that the ether that adopts is as reaction solvent, but the character of ether is volatile, has stronger narcoticness, ether is inflammable simultaneously, and the production safety coefficient is low.Common ether solvent exists physical properties similar with ether and toxicity mostly.
Summary of the invention
In order to overcome above-mentioned defective, the technical problem to be solved in the present invention is: at adopting ether as the safety problem that the Grignard reagent reaction solvent exists among the existing Benzhexol HCL preparation technology, provide a kind of preparation method who does not use the Benzhexol HCL of ether.
The technical solution adopted for the present invention to solve the technical problems is: a kind of preparation method of Benzhexol HCL, its processing step is: the intermediate Propiophenone piperidine hydrochlorate for preparing Benzhexol HCL earlier, refabrication Benzhexol HCL crude product, again the Benzhexol HCL crude product refining is got the Benzhexol HCL finished product, the step of preparation process of wherein said Benzhexol HCL crude product is as follows:
Magnesium sheet, anhydrous methyl tertiary butyl ether, chlorocyclohexane and the crystalline flake of iodine (A material) are mixed to reaction to be caused, under reflux state, drip chlorocyclohexane and methyl tertiary butyl ether mixed solution (B material), drip off, insulation back flow reaction 60～90 minutes, temperature is controlled at 55～65 ℃, again to wherein slowly dripping Propiophenone piperidine hydrochlorate (C material), dripped complete insulation reaction 2～2.5 hours, temperature is controlled at 55～65 ℃, and insulation is finished, add band water beetle base tertbutyl ether, effect is separated in diversion; Heating in water bath slowly is warming up to 55～65 ℃ and reclaims methyl tertiary butyl ethers, and methyl tertiary butyl ether reclaims when finishing postcooling to 30 ℃, drips water and hydrochloric acid (D material), drips to drip off between 30～40 minutes under reflux state, reclaims methyl tertiary butyl ether simultaneously; Drip and finish, continue the recovery methyl tertiary butyl ether, treat can stop when temperature reaches 65 ℃ to reclaim, be cooled to 15～25 ℃ again, filter, water flushing 2～3 times dries, and discharging gets the Benzhexol HCL crude product.
As preferably, used each raw material mass mixture ratio in the preparation of described Benzhexol HCL crude product:
The invention has the beneficial effects as follows; adopt methyl tertiary butyl ether to replace ether in the classical reaction in the present invention in the Benzhexol HCL crude product preparation process; but not other ethers of using always in the industrial production have been adopted; ethers commonly used in the industrial production is mainly symmetry structure ethers; it is fast that symmetry ethers in the classical reaction has speed of response; but reaction is violent; the symmetry ethers has narcoticness mostly; inflammable problem; potential safety hazard in the industrial production is bigger; adopt the methyl tertiary butyl ether of asymmetry among the present invention; the steam that methyl tertiary butyl ether produces in reaction process can be used for the effect of secluding air; tertiary butyl groups in the methyl tertiary butyl ether can play the effect of protection oh group in reaction process; the boiling point (55.2 ℃) of methyl tertiary butyl ether is than ether boiling point (34.6 ℃) height simultaneously, and reaction process is easy to control comparatively gently.Adopt methyl tertiary butyl ether to replace ether in the classical reaction in the present invention in the Benzhexol HCL crude product preparation process, its production productive rate of original production process is 40%, and it is more than 60% that the present invention produces productive rate, produces productive rate and improves a lot.
Embodiment
To help to understand the present invention by following examples, but not limit content of the present invention.Especially the data among the embodiment do not limit the consumption of each composition in the invention.
The chemical equation of the Benzhexol HCL crude product preparation among the present invention is as follows:
Embodiment 1:
The preparation method of Benzhexol HCL, its processing step is: the intermediate Propiophenone piperidine hydrochlorate for preparing Benzhexol HCL earlier, refabrication Benzhexol HCL crude product, again the Benzhexol HCL crude product refining is got the Benzhexol HCL finished product, the step of preparation process of wherein said Benzhexol HCL crude product is as follows:
Used each raw material mass mixture ratio such as following table in the preparation of Benzhexol HCL crude product:
Drop into magnesium sheet, anhydrous methyl tertiary butyl ether, chlorocyclohexane and the crystalline flake of iodine (A material) in the reactor of dried and clean, grignard reaction must be definitely anhydrous, and various raw materials and intermediate all must be dried, and reactor must be cleaned, oven dry.Open stirring, build the reactor flap that feeds intake, temperature is 55～65 ℃ in the control, and is to be triggered, about 20 minutes of initiation time.
To be triggered finishing, under reflux state, temperature is 55～65 ℃ in the control, drips chlorocyclohexane and methyl tertiary butyl ether (B material), and causing must be fully.If the magnesium sheet nondiscoloration, or when dripping chlorocyclohexane and methyl tertiary butyl ether, do not play back flow reaction, then explanation causes, and can't drip, with the erosion control material again.
Dropwise, under 55～65 ℃ of conditions, stirred 1 hour.Keep refluxing, add Propiophenone piperidine hydrochlorate (C material), the dropping time is one hour, dropwises, and between 55～65 ℃, is incubated 2 hours.Insulation is finished, and adds band water beetle base tertbutyl ether, and effect is separated in diversion.Heating in water bath is warmed up to 60 ℃.Open freezingly, when being cooled to 30 ℃, dripping hydrochloric acid and water (D material) drip under reflux state, drip off between 30～40 minutes, reclaim methyl tertiary butyl ether simultaneously, drip to finish, and continue to reclaim methyl tertiary butyl ether and treat can stop when temperature reaches 60 ℃ to reclaim.Be cooled to 15～25 ℃, material is put into the whizzer water dumping, water flushing 2 times dries, and discharging gets the Benzhexol HCL crude product.
Embodiment 2:
The preparation method of Benzhexol HCL, its processing step is: the intermediate Propiophenone piperidine hydrochlorate for preparing Benzhexol HCL earlier, refabrication Benzhexol HCL crude product, again the Benzhexol HCL crude product refining is got the Benzhexol HCL finished product, the step of preparation process of wherein said Benzhexol HCL crude product is as follows:
Used each raw material mass mixture ratio such as following table in the preparation of Benzhexol HCL crude product:
Drop into magnesium sheet, anhydrous methyl tertiary butyl ether, chlorocyclohexane and the crystalline flake of iodine (A material) in the reactor of dried and clean, grignard reaction must be definitely anhydrous, and various raw materials and intermediate all must be dried, and reactor must be cleaned, oven dry.Open stirring, build the reactor flap that feeds intake, temperature is 55～65 ℃ in the control, and is to be triggered, about 20 minutes of initiation time.
To be triggered finishing, under reflux state, temperature is 55～65 ℃ in the control, drips chlorocyclohexane and methyl tertiary butyl ether (B material), and causing must be fully.If the magnesium sheet nondiscoloration, or when dripping chlorocyclohexane and methyl tertiary butyl ether, do not play back flow reaction, then explanation causes, and can't drip, with the erosion control material again.
Dropwise, under 55～65 ℃ of conditions, stirred 90 minutes.Keep refluxing, add Propiophenone piperidine hydrochlorate (C material), the dropping time is 1.5 hours, dropwises, and between 55～65 ℃, is incubated 2.5 hours.Insulation is finished, and adds band water beetle base tertbutyl ether, and effect is separated in diversion.Heating in water bath is warmed up to 60 ℃.Open freezingly, when being cooled to 30 ℃, dripping hydrochloric acid and water (D material) drip under reflux state, drip off between 30～40 minutes, reclaim methyl tertiary butyl ether simultaneously, drip to finish, and continue to reclaim methyl tertiary butyl ether and treat can stop when temperature reaches 65 ℃ to reclaim.Be cooled to 15～25 ℃, material is put into the whizzer water dumping, water flushing 3 times dries, and discharging gets the Benzhexol HCL crude product.
Claims (2)
1. the preparation method of a Benzhexol HCL, its processing step is: the intermediate Propiophenone piperidine hydrochlorate for preparing Benzhexol HCL earlier, refabrication Benzhexol HCL crude product, again the Benzhexol HCL crude product refining is got the Benzhexol HCL finished product, it is characterized in that the step of preparation process of described Benzhexol HCL crude product is as follows:
Magnesium sheet, anhydrous methyl tertiary butyl ether, chlorocyclohexane and the crystalline flake of iodine are mixed to reaction to be caused, under reflux state, drip chlorocyclohexane and methyl tertiary butyl ether mixed solution, drip off, insulation back flow reaction 60～90 minutes, temperature is controlled at 55～65 ℃, again to wherein slowly dripping the Propiophenone piperidine hydrochlorate, dripped complete insulation reaction 2～2.5 hours, temperature is controlled at 55～65 ℃, and insulation is finished, add band water beetle base tertbutyl ether, play hydrolytic action; Heating in water bath slowly is warming up to 55～65 ℃, reclaims methyl tertiary butyl ether, and methyl tertiary butyl ether reclaims when finishing postcooling to 30 ℃, drips water and hydrochloric acid, drips under reflux state, drips off between 30～40 minutes, reclaims methyl tertiary butyl ether simultaneously; Drip and finish, continue the recovery methyl tertiary butyl ether, treat can stop when temperature reaches 65 ℃ to reclaim, be cooled to 15～25 ℃ again, filter, water flushing 2～3 times dries, and discharging gets the Benzhexol HCL crude product.
2. the preparation method of Benzhexol HCL according to claim 1 is characterized in that: used each raw material mass mixture ratio in the preparation of described Benzhexol HCL crude product:
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| CN2010105664388A CN102030723B (en) | 2010-11-02 | 2010-12-01 | Preparation method of trihexyphenidyl hydrochloride |
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| CN2010105664388A CN102030723B (en) | 2010-11-02 | 2010-12-01 | Preparation method of trihexyphenidyl hydrochloride |
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| CN102030723A true CN102030723A (en) | 2011-04-27 |
| CN102030723B CN102030723B (en) | 2012-07-04 |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103204828A (en) * | 2013-04-19 | 2013-07-17 | 苏州园方化工有限公司 | Preparation method of 1-cyclohexyl-1-phenyl-3-piperidinepropanol hydrochloride |
| CN105218481A (en) * | 2014-07-01 | 2016-01-06 | 江苏天士力帝益药业有限公司 | A kind of preparation method of Benzhexol HCL |
| CN110003094A (en) * | 2019-05-04 | 2019-07-12 | 上海葆隆生物科技有限公司 | A kind of preparation method of benzhexol oxidation impurities |
| CN111909115A (en) * | 2020-09-18 | 2020-11-10 | 天津力生制药股份有限公司 | Synthesis method of diphenhydrasol hydrochloride |
| CN112480037A (en) * | 2020-12-14 | 2021-03-12 | 常州康普药业有限公司 | Synthesis method of diphenhydrasol hydrochloride |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2716121A (en) * | 1949-11-03 | 1955-08-23 | American Cyanamid Co | Basic tertiary piperidino alcohols |
| CN1582929A (en) * | 2004-05-21 | 2005-02-23 | 南昌弘益科技有限公司 | Aparkan drops and their preparation |
-
2010
- 2010-12-01 CN CN2010105664388A patent/CN102030723B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2716121A (en) * | 1949-11-03 | 1955-08-23 | American Cyanamid Co | Basic tertiary piperidino alcohols |
| CN1582929A (en) * | 2004-05-21 | 2005-02-23 | 南昌弘益科技有限公司 | Aparkan drops and their preparation |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103204828A (en) * | 2013-04-19 | 2013-07-17 | 苏州园方化工有限公司 | Preparation method of 1-cyclohexyl-1-phenyl-3-piperidinepropanol hydrochloride |
| CN103204828B (en) * | 2013-04-19 | 2015-07-22 | 苏州园方化工有限公司 | Preparation method of 1-cyclohexyl-1-phenyl-3-piperidinepropanol hydrochloride |
| CN105218481A (en) * | 2014-07-01 | 2016-01-06 | 江苏天士力帝益药业有限公司 | A kind of preparation method of Benzhexol HCL |
| CN105218481B (en) * | 2014-07-01 | 2019-01-25 | 江苏天士力帝益药业有限公司 | A kind of preparation method of benzhexol hydrochloride |
| CN110003094A (en) * | 2019-05-04 | 2019-07-12 | 上海葆隆生物科技有限公司 | A kind of preparation method of benzhexol oxidation impurities |
| CN111909115A (en) * | 2020-09-18 | 2020-11-10 | 天津力生制药股份有限公司 | Synthesis method of diphenhydrasol hydrochloride |
| CN112480037A (en) * | 2020-12-14 | 2021-03-12 | 常州康普药业有限公司 | Synthesis method of diphenhydrasol hydrochloride |
| CN112480037B (en) * | 2020-12-14 | 2022-03-01 | 常州康普药业有限公司 | Synthesis method of diphenhydrasol hydrochloride |
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| CN102030723B (en) | 2012-07-04 |
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