CN109824661A - The preparation method of impurity in a kind of amyl ethyl quin ether hydrochloride - Google Patents
The preparation method of impurity in a kind of amyl ethyl quin ether hydrochloride Download PDFInfo
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Abstract
The present invention relates to technical field of organic synthesis, the preparation method of impurity in specifically a kind of amyl ethyl quin ether hydrochloride, step are as follows: using amyl ethyl quin ether and α-phenyl-α-cyclopenta-ethylene oxide be raw material under alkali compounds effect, reaction obtains 3- [2- cyclopenta -2- phenyl -2- (2- cyclopenta -2- hydroxyl -2- Phenyl-ethoxy) ethyoxyl] quinuclidine free alkali and hydrogen chloride into the hydrochloride for obtaining free alkali after salt.Preparation method of the invention has processing step simple, and side reaction is few, has the characteristics that easy to operate, post-processing is simple, raw material is cheap and easy to get, high income, is more suitable for being prepared on a large scale.
Description
Technical field
The present invention relates to technical field of organic synthesis, the preparation side of impurity in a kind of specifically following amyl ethyl quin ether hydrochloride
Method.
Background technique
Amyl ethyl quin ether hydrochloride (Penehyclidine Hydrochoride), the entitled 3- (2- cyclopenta -2- hydroxyl-of chemistry
2- phenyl ethoxy) quinuclidine hydrochloride, it is new selective anticholinergic agent, is acquisition national drug supervision and management in 1999
Office's approval (Military Medical Science Institute), treat and be poisoned for organophosphorus poison (pesticide) poisoning first-aid later period or cholinesterase
(ChE) atropinization is maintained after aging.
Impurity research is an important link in drug discovery process, while the foundation of quality standard needs a certain amount of mark
Quasi- product in all production lines of amyl ethyl quin ether hydrochloride being currently known, can all generate a kind of major impurity: 3- [2- through retrieving
Cyclopenta -2- phenyl -2- (2- cyclopenta -2- hydroxyl -2- Phenyl-ethoxy) ethyoxyl] quinuclidine hydrochloride.
Only patent CN106518862A carried out report to the synthesis of the impurity at present: the present invention is with α-phenyl-α-ring
Amyl-Alpha-hydroxy ethyl p-toluenesulfonate and 3- quinuclidinol are raw material, react certain time under alkaline condition, post-process to obtain 3-
[2- cyclopenta -2- phenyl -2- (2- cyclopenta -2- hydroxyl -2- Phenyl-ethoxy) ethyoxyl] quinuclidine hydrochloride is free
Alkali and hydrogen chloride are at the hydrochloride for being refining to obtain free alkali after salt.
This method continuously connects 2- cyclopenta -2- hydroxyl -2- Phenyl-ethoxy twice, instead by once feeding intake in the reaction
Should not exclusively, and side reaction is more, post-processing is chromatographed by column, and complicated for operation and yield is too low.
Summary of the invention
The present invention provides a kind of preparation methods of impurity in amyl ethyl quin ether hydrochloride.Present invention process step is simple, has
Easy to operate, the features such as post-processing is simple, raw material is cheap and easy to get, high income.
Reaction equation of the invention is as follows:
The preparation method of impurity in a kind of amyl ethyl quin ether hydrochloride of the present invention, comprising the following steps:
(1) after amyl ethyl quin ether dissolves in dimethyl sulfoxide, alkali is added, after being stirred to react, α-phenyl-α-cyclopenta-is added dropwise
After being stirred to react, purified water, methyl tertiary butyl ether(MTBE) extraction is added in ethylene oxide, and concentration obtains 3- [2- cyclopenta -2- phenyl -
2- (2- cyclopenta -2- hydroxyl -2- Phenyl-ethoxy) ethyoxyl] quinuclidine free alkali；
(2) by 3- [2- cyclopenta -2- phenyl -2- (2- cyclopenta -2- hydroxyl -2- Phenyl-ethoxy) ethyoxyl] quinine
Cycloalkanes free alkali is dissolved in organic solvent, is passed through hydrogen chloride gas, adjusts pH to 1~2, and cool down crystallization, obtains 3- [2- cyclopenta-
2- phenyl -2- (2- cyclopenta -2- hydroxyl -2- Phenyl-ethoxy) ethyoxyl] quinuclidine hydrochloride.
Further, the alkali being added in the step (1) is sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, one in sodium hydride
Kind, further, the alkali being added in the step (1) is sodium hydride.
Further, amyl ethyl quin ether and alkali and α-phenyl-α-cyclopenta-ethylene oxide molar ratio in the step (1)
For 1:1~2:1~2.Further, amyl ethyl quin ether rubs with alkali and α-phenyl-α-cyclopenta-ethylene oxide in step (1)
You are than being 1:1~1.05:1~1.1.
Further, reaction temperature is 40~100 DEG C in the step (1), and condensation reaction time is 3~15 hours；More
Further, reaction temperature is 60~80 DEG C, the reaction time 4~6 hours in step (1).
Further, the step (2) organic solvent is any one of methanol, ethyl alcohol, isopropanol, ethyl acetate
Or any two or more mixing.
Compared with prior art, the device have the advantages that are as follows: present invention process step is simple, and side reaction is few, tool
There is the features such as easy to operate, post-processing is simple, raw material is cheap and easy to get, high income, is more suitable for being prepared on a large scale.
Specific embodiment
The present invention is described further below with reference to embodiment, the following example is merely to illustrate the present invention, without answering
It is considered as and limits the scope of the invention.The person that is not specified actual conditions in embodiment, according to conventional conditions or manufacturer's recommended conditions
It carries out.Manufacturer person is not specified in agents useful for same or instrument, and being can be by the product of commercially available acquisition.
Embodiment 1:
The trip of 3- [2- cyclopenta -2- phenyl -2- (2- cyclopenta -2- hydroxyl -2- Phenyl-ethoxy) ethyoxyl] quinuclidine
From alkali
18.90g (0.06mol) amyl ethyl quin ether is added in 500ml there-necked flask, 150mLDMSO is added, is heated to 60 DEG C,
The NaH of 2.40g (0.06mol, 1eq) content 60% is added after to be dissolved, after continuing the heating of this temperature after adding reaction 1 hour,
11.80g (0.063mol, 1.05eq) α-phenyl-α-cyclopenta-ethylene oxide 40mLDMSO solution is added thereto, is continued
The heating of this temperature reaction 6 hours, 10 DEG C are cooled to, 100ml water is added, three times with methyl tertiary butyl ether(MTBE) extraction, merges organic phase,
Anhydrous sodium sulfate is dry, is concentrated to dryness, obtains faint yellow sticky oil object 27.41g.
3- [2- cyclopenta -2- phenyl -2- (2- cyclopenta -2- hydroxyl -2- Phenyl-ethoxy) ethyoxyl] quinuclidine salt
Hydrochlorate
By 27.00g 3- [2- cyclopenta -2- phenyl -2- (2- cyclopenta -2- hydroxyl -2- Phenyl-ethoxy) ethyoxyl]
Quinuclidine free alkali is added in 150ml ethyl acetate, is uniformly mixed, and is passed through hydrogen chloride gas to pH=1-2, stirring 2
Hour, it is cooled to 0 DEG C of crystallization 2 hours, filtration drying obtains white solid 3- [2- cyclopenta -2- phenyl -2- (2- cyclopenta -2-
Hydroxyl -2- Phenyl-ethoxy) ethyoxyl] quinuclidine 24.61g, yield 84.88%, purity 99.42%.
Embodiment 2:
The trip of 3- [2- cyclopenta -2- phenyl -2- (2- cyclopenta -2- hydroxyl -2- Phenyl-ethoxy) ethyoxyl] quinuclidine
From alkali
18.90g (0.06mol) amyl ethyl quin ether is added in 500ml there-necked flask, 150mLDMSO is added, is heated to 60 DEG C,
The NaH of 2.52g (0.063mol, 1.05eq) content 60% is added after to be dissolved, continues the heating of this temperature after adding reaction 1 hour
Afterwards, 11.80g (0.063mol, 1.05eq) α-phenyl-α-cyclopenta-ethylene oxide 40mLDMSO solution is added thereto, after
Continue the heating of this temperature reaction 4 hours, be cooled to 10 DEG C, 100ml water is added, three times with methyl tertiary butyl ether(MTBE) extraction, merges organic
Phase, anhydrous sodium sulfate is dry, is concentrated to dryness, obtains faint yellow sticky oil object 27.86g.
3- [2- cyclopenta -2- phenyl -2- (2- cyclopenta -2- hydroxyl -2- Phenyl-ethoxy) ethyoxyl] quinuclidine salt
Hydrochlorate
By 27.00g3- [2- cyclopenta -2- phenyl -2- (2- cyclopenta -2- hydroxyl -2- Phenyl-ethoxy) ethyoxyl] Kui
Peaceful cycloalkanes free alkali is added in 10ml isopropanol and 140ml ethyl acetate, is uniformly mixed, is passed through hydrogen chloride gas to pH=
1-2 stirs 2 hours, is cooled to 0 DEG C of crystallization 2 hours, filtration drying obtains white solid 3- [2- cyclopenta -2- phenyl -2- (2-
Cyclopenta -2- hydroxyl -2- Phenyl-ethoxy) ethyoxyl] quinuclidine 24.32g, yield 83.92%, purity 99.58%.
Embodiment 3:
18.90g (0.06mol) amyl ethyl quin ether is added in 500ml there-necked flask, 150mLDMSO is added, is heated to 60 DEG C,
The NaH of 2.52g (0.063mol, 1.05eq) content 60% is added after to be dissolved, continues the heating of this temperature after adding reaction 1 hour
Afterwards, 12.36g (0.066mol, 1.1eq) α-phenyl-α-cyclopenta-ethylene oxide 40mLDMSO solution is added thereto, after
Continue the heating of this temperature reaction 4 hours, be cooled to 10 DEG C, 100ml water is added, three times with methyl tertiary butyl ether(MTBE) extraction, merges organic
Phase, anhydrous sodium sulfate is dry, is concentrated to dryness, obtains faint yellow sticky oil object 28.12g.
3- [2- cyclopenta -2- phenyl -2- (2- cyclopenta -2- hydroxyl -2- Phenyl-ethoxy) ethyoxyl] quinuclidine salt
Hydrochlorate
By 27.50g3- [2- cyclopenta -2- phenyl -2- (2- cyclopenta -2- hydroxyl -2- Phenyl-ethoxy) ethyoxyl] Kui
Peaceful cycloalkanes free alkali is added in 15ml methanol and 135ml ethyl acetate, is uniformly mixed, is passed through hydrogen chloride gas to pH=1-
2, it stirs 2 hours, is cooled to 0 DEG C of crystallization 2 hours, filtration drying obtains white solid 3- [2- cyclopenta -2- phenyl -2- (2- ring
Amyl -2- hydroxyl -2- Phenyl-ethoxy) ethyoxyl] quinuclidine 24.54g, yield 83.14%, purity 99.68%.
It should be appreciated that the specific embodiments described herein are only used for understanding the present invention, it is not intended to limit the present invention,
Every other embodiment obtained by those of ordinary skill in the art without making creative efforts, belongs to this hair
The range of bright protection.
Claims (8)
1. the preparation method of impurity in a kind of amyl ethyl quin ether hydrochloride, which is characterized in that reaction step is as follows:
Specifically, comprising the following steps:
(1) after amyl ethyl quin ether dissolves in dimethyl sulfoxide, alkali is added, after being stirred to react, α-phenyl-α-cyclopenta-epoxy is added dropwise
After being stirred to react, purified water, methyl tertiary butyl ether(MTBE) extraction is added in ethane, and concentration obtains 3- [2- cyclopenta -2- phenyl -2- (2-
Cyclopenta -2- hydroxyl -2- Phenyl-ethoxy) ethyoxyl] quinuclidine free alkali；
(2) by 3- [2- cyclopenta -2- phenyl -2- (2- cyclopenta -2- hydroxyl -2- Phenyl-ethoxy) ethyoxyl] quinuclidine
Free alkali is dissolved in organic solvent, is passed through hydrogen chloride gas, adjusts pH to 1~2, and cool down crystallization, obtains 3- [2- cyclopenta -2- benzene
Base -2- (2- cyclopenta -2- hydroxyl -2- Phenyl-ethoxy) ethyoxyl] quinuclidine hydrochloride.
2. the preparation method of impurity in a kind of amyl ethyl quin ether hydrochloride according to claim 1, which is characterized in that the step
(1) alkali being added in is one of sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride.
3. the preparation method of impurity in a kind of amyl ethyl quin ether hydrochloride according to claim 2, which is characterized in that the step
(1) alkali being added in is sodium hydride.
4. the preparation method of impurity in a kind of amyl ethyl quin ether hydrochloride according to claim 1, which is characterized in that the step
(1) amyl ethyl quin ether and alkali and α-phenyl-α-cyclopenta-ethylene oxide molar ratio are 1:1~2:1~2 in.
5. the preparation method of impurity in a kind of amyl ethyl quin ether hydrochloride according to claim 4, which is characterized in that the step
(1) amyl ethyl quin ether and alkali and α-phenyl-α-cyclopenta-ethylene oxide molar ratio are 1:1~1.05:1~1.1 in.
6. the preparation method of impurity in a kind of amyl ethyl quin ether hydrochloride according to claim 1, which is characterized in that the step
(1) reaction temperature is 40~100 DEG C in, and the reaction time is 3~15 hours.
7. the preparation method of impurity in a kind of amyl ethyl quin ether hydrochloride according to claim 6, which is characterized in that the step
(1) reaction temperature is 60~80 DEG C in, and the reaction time is 4~6 hours.
8. the preparation method of impurity in a kind of amyl ethyl quin ether hydrochloride according to claim 1, which is characterized in that the step
(2) solvent is any one of methanol, ethyl alcohol, isopropanol, ethyl acetate or any two or more mixing.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112028887A (en) * | 2020-09-04 | 2020-12-04 | 江苏恩华药业股份有限公司 | Penehyclidine hydrochloride impurity and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20160244439A1 (en) * | 2013-07-13 | 2016-08-25 | Beijing Fswelcome Technology Development Co., Ltd | Quinine compounds, and optical isomers, preparation method and medical use thereof |
| CN106518862A (en) * | 2016-09-27 | 2017-03-22 | 海口南陆医药科技股份有限公司 | Preparation method of impurity in penehyclidine hydrochloride |
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2019
- 2019-03-30 CN CN201910253766.3A patent/CN109824661B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20160244439A1 (en) * | 2013-07-13 | 2016-08-25 | Beijing Fswelcome Technology Development Co., Ltd | Quinine compounds, and optical isomers, preparation method and medical use thereof |
| CN106518862A (en) * | 2016-09-27 | 2017-03-22 | 海口南陆医药科技股份有限公司 | Preparation method of impurity in penehyclidine hydrochloride |
Non-Patent Citations (1)
| Title |
|---|
| 钟霞等: "盐酸戊乙奎醚工艺杂质的合成研究", 《化学研究与应用》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112028887A (en) * | 2020-09-04 | 2020-12-04 | 江苏恩华药业股份有限公司 | Penehyclidine hydrochloride impurity and preparation method thereof |
| CN112028887B (en) * | 2020-09-04 | 2022-06-28 | 江苏恩华药业股份有限公司 | Penehyclidine hydrochloride impurity and preparation method thereof |
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