CN104496822A - Preparation method of 1-chloroethyl cyclohexyl propyl carbonate - Google Patents
Preparation method of 1-chloroethyl cyclohexyl propyl carbonate Download PDFInfo
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- CN104496822A CN104496822A CN201410766396.0A CN201410766396A CN104496822A CN 104496822 A CN104496822 A CN 104496822A CN 201410766396 A CN201410766396 A CN 201410766396A CN 104496822 A CN104496822 A CN 104496822A
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- pyridine
- chloroethyl
- triethylamine
- propyl carbonate
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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
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a preparation method of 1-chloroethyl cyclohexyl propyl carbonate and belongs to the field of chemicals. The preparation method of 1-chloroethyl cyclohexyl propyl carbonate comprises the following steps of: adding triethylamine or pyridine or N,N-dimethylaniline into trichloromethyl chloroformate at the temperature between 10 DEG C below zero and 0 DEG C, and dropwise adding paraldehyde to carry out reaction; adding triethylamine or pyridine or N,N-dimethylaniline after reaction, dropwise adding cyclohexanol under the condition that the temperature in a reactor is below 20 DEG C, and stirring to carry out reaction; taking a product of reaction, washing with water, and distilling by reducing pressure to obtain an organic phase which is 1-chloroethyl cyclohexyl propyl carbonate. The synthesized 1-chloroethyl cyclohexyl propyl carbonate is high in yield and purity and low in cost, and the preparation method of 1-chloroethyl cyclohexyl propyl carbonate is easy to control in the preparation process, is easy to operate, is low in risk and is particularly suitable for industrial production.
Description
Technical field
The present invention relates generally to chemical medicine field, particularly relates to a kind of preparation method of 1-chloroethyl Cyclohexylpropyl carbonic ether.
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 forms jointly, it is long that this medicine possesses onset cycle in the process of application, bioavailability is comparatively good, hypotensive effect is strong, the 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 the most common in medicine.Cefotiam hexetil is the ethyl esterified oral antibiotic of injection cefotiam.
Current 1-chloroethyl Cyclohexylpropyl carbonic ether synthetic method has:
Method one:
Method two:
Method one is owing to employing hypertoxic gas phosgene and acetaldehyde, so relatively stricter for process control requirements, and easily cause toxic gas to leak, danger is higher; The waste gas of sulfurous gas can be produced in method two building-up process, and because generate by product
, cause product yield to only have 40 ~ 50%, so both not environmentally also uneconomical.
Summary of the invention
The object of the invention is exactly to provide a kind of security higher, the preparation method of both economical 1-chloroethyl Cyclohexylpropyl carbonic ether.
The present invention includes following steps:
1) triethylamine or pyridine or DMA are dropped in the superpalite of-10 ~ 0 DEG C, and then drip paraldehyde and react;
2) after reaction terminates, then add triethylamine or pyridine or DMA, temperature in the kettle drips hexalin below 20 DEG C, and stirring reaction is to terminating;
3) get reaction product water to wash, rectification under vacuum, obtain organic phase, be i.e. 1-chloroethyl Cyclohexylpropyl carbonic ether.
Reaction formula of the present invention is as follows:
The present invention is by two-step reaction method, and the reaction of the first step: superpalite, under catalyst action, is decomposed into phosgene (boiling point is 8.2 DEG C), phosgene and paraldehyde continue reaction can obtain 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) under existent condition, generate the hydrochloride of 1-chloroethyl Cyclohexylpropyl carbonic ether and acid binding agent (triethylamine or pyridine or DMA).
Control at-10 ~ 0 DEG C in step 1), can make after input triethylamine or pyridine or DMA, decompose the phosgene (boiling point is 8.2 DEG C) produced and exist with liquid state, prevent its gasification and lose.
Step 2) in temperature in the kettle below 20 DEG C, drip hexalin, if temperature is higher than this temperature, then can produce be difficult to be separated impurity.
Advantage of the present invention is: the 1-chloroethyl Cyclohexylpropyl carbonic ether output of synthesis is high, and purity is high, and cost is low, is easy to control in production process, simple to operate, dangerous little, is specially adapted to suitability for industrialized production.
In addition, 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 superpalite, paraldehyde, preferably 0.01 ~ 0.015:1:0.44 ~ 0.45, can ensure under this ratio that superpalite reacts completely.
The time dripping described paraldehyde is 4 ~ 6h, causes the acute variation of temperature to prevent dropping too fast.
Described step 2) in, triethylamine or pyridine or DMA are 1.02 ~ 1.03:1 with the mol ratio that mixes of hexalin, if lower than this ratio, react and can not thoroughly carry out, if ratio is too high, raw material why can be made to remain, bring pressure to separation and purification.
In described step 3), during rectification under vacuum, temperature in the kettle is no more than 130 DEG C, if temperature is too high in rectifying, then can bring side reaction, cause productive rate step-down.
Embodiment
Embodiment 1:
(1) in 1000ml reaction flask, drop into superpalite 198g, open and stir, when superpalite cool to-10 ~ 0 DEG C time add 2g triethylamine, drip 88g paraldehyde, 4 hours dropping process used times, after dropwising, continue stirring reaction 2h, and then add triethylamine 206g, temperature after to be mixed is drip hexalin 200g after 19 DEG C, dropwises, and continues stirring reaction 3h.
After reaction terminates, add water 100g, and separating organic phase is 1-chloroethyl Cyclohexylpropyl carbonic ether crude product.
(2) drop in rectification process bottle by the crude product of 1-chloroethyl Cyclohexylpropyl carbonic ether, controlling temperature in bottle is less than 130 DEG C, and vacuum decompression rectifying, namely obtain 1-chloroethyl Cyclohexylpropyl carbonic ether 380g, yield is 92%, and purity is greater than 99.5%.
Embodiment 2
(1) in 1000ml reaction flask, drop into superpalite 238g, open and stir, cool to-10 ~ 0 DEG C and add 2.4g pyridine, drip 106g paraldehyde, 6 hours dropping process used times, after dropwising, after continuing to stir 2h, add pyridine 247g, temperature after to be mixed is drip hexalin 240g after less than 20 DEG C, dropwises, and continues to stir 3h.
After reaction terminates, add water 120g, and separating organic phase is 1-chloroethyl Cyclohexylpropyl carbonic ether crude product.
(2) drop in rectification process bottle by the crude product of obtained 1-chloroethyl Cyclohexylpropyl carbonic ether, controlling temperature in bottle is less than 130 DEG C, and vacuum decompression rectifying, namely obtain 1-chloroethyl Cyclohexylpropyl carbonic ether 461g, yield is 93%, and purity is greater than 99.5%.
Embodiment 3:
(1) in 1000ml reaction flask, drop into superpalite 218g, open and stir, cool to-10 ~ 0 DEG C and add 2.4gN, accelerine, drip 116.6g paraldehyde, 6 hours dropping process used times, after dropwising, after continuing to stir 2h, add N, accelerine 272g, temperature after to be mixed is drip hexalin 220g after less than 20 DEG C, dropwises, and continues to stir 3h.
After reaction terminates, add water 110g, and separating organic phase is 1-chloroethyl Cyclohexylpropyl carbonic ether crude product.
(2) drop in rectification process bottle by the crude product of obtained 1-chloroethyl Cyclohexylpropyl carbonic ether, controlling temperature in bottle is less than 130 DEG C, and vacuum decompression rectifying, namely obtain 1-chloroethyl Cyclohexylpropyl carbonic ether 420g, yield is 92.5%, and purity is greater than 99.5%.
In the present invention, when step 1) adopt triethylamine or pyridine or DMA one of them time, step 2) can adopt the triethylamine different from step 1) or pyridine or DMA one of them.But from the simplification of raw material, the simplification angle of technique is set out, or be same substance in maintenance two step of trying one's best.
Claims (6)
1. a preparation method for 1-chloroethyl Cyclohexylpropyl carbonic ether, is characterized in that comprising the following steps:
1) triethylamine or pyridine or DMA are dropped in the superpalite of-10 ~ 0 DEG C, and then drip paraldehyde and react;
2) after reaction terminates, then add triethylamine or pyridine or DMA, temperature in the kettle drips hexalin below 20 DEG C, and stirring reaction is to terminating;
3) get reaction product water to wash, rectification under vacuum, obtain organic phase, be i.e. 1-chloroethyl Cyclohexylpropyl carbonic ether.
2. preparation method according to claim 1, is characterized in that in described step 1), and triethylamine or pyridine or DMA are 0.01 ~ 0.02:1:0.44 ~ 0.55 with the mixing quality ratio of superpalite, paraldehyde.
3. preparation method according to claim 2, is characterized in that in described step 1), and triethylamine or pyridine or DMA are 0.01 ~ 0.015:1:0.44 ~ 0.45 with the mixing quality ratio of superpalite, paraldehyde.
4. preparation method according to claim 1 or 2 or 3, the time that it is characterized in that dripping described paraldehyde is 4 ~ 6h.
5. preparation method according to claim 1, is characterized in that described step 2) in, triethylamine or pyridine or DMA are 1.02 ~ 1.03:1 with the mol ratio that mixes of hexalin.
6. preparation method according to claim 1, it is characterized in that in described step 3), during rectification under vacuum, temperature in the kettle is no more than 130 DEG C.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| 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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| CN104496822A true CN104496822A (en) | 2015-04-08 |
| CN104496822B CN104496822B (en) | 2016-10-26 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 (4)
| 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 |
| US20130244958A1 (en) * | 2012-03-15 | 2013-09-19 | Hoffmann-La Roche Inc. | Substituted pyrrolidine-2-carboxamides |
| 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 |
-
2014
- 2014-12-15 CN CN201410766396.0A patent/CN104496822B/en active Active
Patent Citations (4)
| 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 |
| US20130244958A1 (en) * | 2012-03-15 | 2013-09-19 | Hoffmann-La Roche Inc. | Substituted pyrrolidine-2-carboxamides |
| 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 |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
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