CN104496822B - A kind of preparation method of 1-chloroethyl Cyclohexylpropyl carbonic ester - Google Patents
A kind of preparation method of 1-chloroethyl Cyclohexylpropyl carbonic ester Download PDFInfo
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- CN104496822B CN104496822B CN201410766396.0A CN201410766396A CN104496822B CN 104496822 B CN104496822 B CN 104496822B CN 201410766396 A CN201410766396 A CN 201410766396A CN 104496822 B CN104496822 B CN 104496822B
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- cyclohexylpropyl
- chloroethyl
- carbonic ester
- pyridine
- triethylamine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C68/00—Preparation of esters of carbonic or haloformic acids
- C07C68/02—Preparation of esters of carbonic or haloformic acids from phosgene or haloformates
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C68/00—Preparation of esters of carbonic or haloformic acids
- C07C68/08—Purification; Separation; Stabilisation
Abstract
The preparation method of a kind of 1 chloroethyl Cyclohexylpropyl carbonic ester, relates to chemical medicine field, by the trichloromethyl chloroformate of triethylamine or pyridine or N, N dimethylaniline input 10～0 DEG C, drips paraldehydum the most again and reacts；After end, adding triethylamine or pyridine or N, N dimethylaniline, temperature in the kettle drips Hexalin below 20 DEG C, and stirring reaction is to terminating；Take product washing, rectification under vacuum, obtain organic facies, i.e. 1 chloroethyl Cyclohexylpropyl carbonic ester.1 chloroethyl Cyclohexylpropyl carbonic ester yield of synthesis is high, and purity is high, and low cost is easily controllable in production process, simple to operate, dangerous little, is particularly well-suited to industrialized production.
Description
Technical field
The invention mainly relates to chemical medicine field, particularly relate to the preparation method of a kind of 1-chloroethyl Cyclohexylpropyl carbonic ester.
Background technology
Chloromethyl butylperoxyisopropyl carbonate is synthesis candesartan Cilexetil, the intermediate of cefotiam hexetil, candesartan Cilexetil is a kind of a kind of medicine mechanism being applicable to essential hypertension, mainly angiotensin lI coordinate the hypertension of receptor antagonist (AT) class the to draw up comprehensive medicine of one that medicine collectively forms, it is long that this medicine possesses the onset cycle during application, bioavailability is the best, hypotensive effect is strong, advantage that side effect is little and receive attention and the concern of domestic and international people from all walks of life, become whole hypertension to draw up one most commonly seen in medicine.Cefotiam hexetil is to be the ethyl esterified oral antibiotic of injection cefotiam.
Current 1-chloroethyl Cyclohexylpropyl carbonic ester synthetic method has:
Method one:
Method two:
Method one is owing to employing severe toxicity gas phosgene and acetaldehyde, so relatively stricter for process control requirements, and easily causes toxic gas leakage, and danger is higher；Method two building-up process can produce the waste gas of sulfur dioxide, and because generate by-product
, cause product yield to only have 40～50%, thus the most uneconomical.
Summary of the invention
The object of the invention is contemplated to provide a kind of safety higher, the preparation method of both economical 1-chloroethyl Cyclohexylpropyl carbonic ester.
The present invention comprises the following steps:
1) by the trichloromethyl chloroformate of triethylamine or pyridine or DMA input-10～0 DEG C, drip paraldehydum the most again and react；
2) after reaction terminates, adding triethylamine or pyridine or DMA, temperature in the kettle drips Hexalin below 20 DEG C, and stirring reaction is to terminating；
3) take product washing, rectification under vacuum, obtain organic facies, i.e. 1-chloroethyl Cyclohexylpropyl carbonic ester.
The reaction equation of the present invention is as follows:
The present invention passes through two-step reaction method, the reaction of the first step: trichloromethyl chloroformate, under catalyst action, is decomposed into phosgene (boiling point is 8.2 DEG C), phosgene and paraldehydum continuation reaction and i.e. can get chloroformate-1-chloro-ethyl ester.
The reaction of second step: chloroformate-1-chloro-ethyl ester and Hexalin are at acid binding agent (triethylamine or pyridine or N, accelerine) exist under conditions of, generate 1-chloroethyl Cyclohexylpropyl carbonic ester and the hydrochlorate of acid binding agent (triethylamine or pyridine or DMA).
Step 1) controls at-10～0 DEG C, can make after putting into triethylamine or pyridine or DMA, decompose the phosgene (boiling point is 8.2 DEG C) produced and exist with liquid condition, prevent its gasification from losing.
Step 2) in temperature in the kettle below 20 DEG C, drip Hexalin, if temperature is higher than this temperature, then can produce the impurity being difficult to separate.
The invention have the advantage that the 1-chloroethyl Cyclohexylpropyl carbonic ester yield of synthesis is high, purity is high, and low cost is easily controllable in production process, simple to operate, dangerous little, is particularly well-suited to industrialized production.
Additionally, in step 1) of the present invention, triethylamine or pyridine or N, accelerine is 0.01～0.02:1:0.44～0.55 with the mixing quality ratio of trichloromethyl chloroformate, paraldehydum, preferably 0.01～0.015:1:0.44～0.45, can ensure that trichloromethyl chloroformate reaction under this ratio completely.
The time dripping described paraldehydum is 4～6h, causes the acute variation of temperature to prevent from dripping too fast.
Described step 2) in, the mixing mol ratio of triethylamine or pyridine or DMA and Hexalin is 1.02～1.03:1, if less than this ratio, reacting and can not thoroughly carry out, if ratio is too high, raw material why can be made to remain, bring pressure to isolated and purified.
In described step 3), during rectification under vacuum, temperature in the kettle is less than 130 DEG C, if temperature is too high in distillation process, then can bring side reaction, cause productivity step-down.
Detailed description of the invention
Embodiment 1:
(1) in 1000ml reaction bulb, put into trichloromethyl chloroformate 198g, open stirring, add 2g triethylamine when cooling to-10～0 DEG C when trichloromethyl chloroformate, dropping 88g paraldehydum, 4 hours dropping process used times, after dropping, continue stirring reaction 2h, then triethylamine 206g is added, temperature after to be mixed drips Hexalin 200g after being 19 DEG C, drips complete, continues stirring reaction 3h.
After reaction terminates, add water 100g, and separating organic facies is 1-chloroethyl Cyclohexylpropyl carbonic ester crude product.
(2) putting in rectification process bottle by the crude product of 1-chloroethyl Cyclohexylpropyl carbonic ester, in control bottle, temperature is less than 130 DEG C, and vacuum decompression rectification i.e. obtains 1-chloroethyl Cyclohexylpropyl carbonic ester 380g, and yield is 92%, and purity is more than 99.5%.
Embodiment 2
(1) in 1000ml reaction bulb, put into trichloromethyl chloroformate 238g, open stirring, cool to-10～0 DEG C and add 2.4g pyridine, dropping 106g paraldehydum, 6 hours dropping process used times, after dropping, after continuing stirring 2h, add pyridine 247g, temperature after to be mixed drips Hexalin 240g after being less than 20 DEG C, drips complete, continues stirring 3h.
After reaction terminates, add water 120g, and separating organic facies is 1-chloroethyl Cyclohexylpropyl carbonic ester crude product.
(2) putting in rectification process bottle by the crude product of prepared 1-chloroethyl Cyclohexylpropyl carbonic ester, in control bottle, temperature is less than 130 DEG C, and vacuum decompression rectification i.e. obtains 1-chloroethyl Cyclohexylpropyl carbonic ester 461g, and yield is 93%, and purity is more than 99.5%.
Embodiment 3:
(1) in 1000ml reaction bulb, put into trichloromethyl chloroformate 218g, open stirring, cool to-10～0 DEG C and add 2.4gN, accelerine, drip 116.6g paraldehydum, 6 hours dropping process used times, after dropping, after continuing stirring 2h, add N, accelerine 272g, temperature after to be mixed drips Hexalin 220g after being less than 20 DEG C, drips complete, continues stirring 3h.
After reaction terminates, add water 110g, and separating organic facies is 1-chloroethyl Cyclohexylpropyl carbonic ester crude product.
(2) putting in rectification process bottle by the crude product of prepared 1-chloroethyl Cyclohexylpropyl carbonic ester, in control bottle, temperature is less than 130 DEG C, and vacuum decompression rectification i.e. obtains 1-chloroethyl Cyclohexylpropyl carbonic ester 420g, and yield is 92.5%, and purity is more than 99.5%.
In the present invention, when step 1) use triethylamine or pyridine or DMA one of them time, step 2) can use the triethylamine different from step 1) or pyridine or DMA one of them.But from the unification of raw material, the simplification angle of technique is set out, also it is to try to keep in two steps for same substance.
Claims (5)
1. the preparation method of a 1-chloroethyl Cyclohexylpropyl carbonic ester, it is characterised in that comprise the following steps:
1) by the trichloromethyl chloroformate of triethylamine or pyridine or DMA input-10～0 DEG C, drip paraldehydum the most again and react；The time of dropping paraldehydum is 4～6h；
2) after reaction terminates, adding the one in the triethylamine identical with step 1) or pyridine or DMA, temperature in the kettle drips Hexalin below 20 DEG C, and stirring reaction is to terminating；
3) take product washing, rectification under vacuum, obtain organic facies, i.e. 1-chloroethyl Cyclohexylpropyl carbonic ester.
The most according to claim 1, preparation method, it is characterised in that in described step 1), triethylamine or pyridine or DMA are 0.01～0.02:1:0.44～0.55 with the mixing quality ratio of trichloromethyl chloroformate, paraldehydum.
The most according to claim 2, preparation method, it is characterised in that in described step 1), triethylamine or pyridine or DMA are 0.01～0.015:1:0.44～0.45 with the mixing quality ratio of trichloromethyl chloroformate, paraldehydum.
Preparation method the most according to claim 1, it is characterised in that described step 2) in, the mixing mol ratio of triethylamine or pyridine or DMA and Hexalin is 1.02～1.03:1.
The most according to claim 1, preparation method, it is characterised in that in described step 3), during rectification under vacuum, temperature in the kettle is less than 130 DEG C.
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| CN201410766396.0A CN104496822B (en) | 2014-12-15 | 2014-12-15 | A kind of preparation method of 1-chloroethyl Cyclohexylpropyl carbonic ester |
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| CN201410766396.0A CN104496822B (en) | 2014-12-15 | 2014-12-15 | A kind of preparation method of 1-chloroethyl Cyclohexylpropyl carbonic ester |
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| CN108358787A (en) * | 2017-06-14 | 2018-08-03 | 金溪斯普瑞药业有限公司 | The preparation method of 1- chloroethene butylcyclohexyl carbonic esters |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4614829A (en) * | 1983-08-26 | 1986-09-30 | Societe Nationale Des Poudres Et Explosifs | Process for the preparation of α-chlorinated chloroformates |
| CN1510031A (en) * | 2002-12-23 | 2004-07-07 | 重庆圣华曦药业有限公司 | Ester compounds of bezimidazole and their preparations and uses in preparation of medicinal compound |
| CN103626765A (en) * | 2012-08-27 | 2014-03-12 | 广东东阳光药业有限公司 | Substituted azaindole compound and salt, composition and application thereof |
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| US8993614B2 (en) * | 2012-03-15 | 2015-03-31 | F. Hoffmann-La Roche Ag | Substituted pyrrolidine-2-carboxamides |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4614829A (en) * | 1983-08-26 | 1986-09-30 | Societe Nationale Des Poudres Et Explosifs | Process for the preparation of α-chlorinated chloroformates |
| CN1510031A (en) * | 2002-12-23 | 2004-07-07 | 重庆圣华曦药业有限公司 | Ester compounds of bezimidazole and their preparations and uses in preparation of medicinal compound |
| CN103626765A (en) * | 2012-08-27 | 2014-03-12 | 广东东阳光药业有限公司 | Substituted azaindole compound and salt, composition and application thereof |
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