CN105152925B - The synthetic method of ciprofibrate - Google Patents
The synthetic method of ciprofibrate Download PDFInfo
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- CN105152925B CN105152925B CN201510644979.0A CN201510644979A CN105152925B CN 105152925 B CN105152925 B CN 105152925B CN 201510644979 A CN201510644979 A CN 201510644979A CN 105152925 B CN105152925 B CN 105152925B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/01—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis
- C07C37/055—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis the substituted group being bound to oxygen, e.g. ether group
- C07C37/0555—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis the substituted group being bound to oxygen, e.g. ether group being esterified hydroxy groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form
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Abstract
The present invention relates to a kind of synthetic method of ciprofibrate, and with acetic acid 4 (2,2 dichloro cyclopropyl) phenyl ester for raw material, 2 [4 (2,2 dichloro cyclopropyl) phenoxy group] 2 methylpropanoic acids are obtained through alcoholysis, alkanisation and alkaline hydrolysis process.The beneficial effects of the invention are as follows：Entirely react raw materials used cheap and easy to get, mild condition, easy to operate, yield is good；The equal recoverable of solvent for use is reacted, environmental is low.
Description
Technical field
The present invention relates to a kind of synthetic method of ciprofibrate.
Background technology
Ciprofibrate is phenoxy acetic acid class hypolipidemic, entitled 2- [4- (2,2- dichloro cyclopropyl) the phenoxy group] -2- of chemistry
Methylpropanoic acid, researched and developed by French Synthelabo companies, be clinically used for failing through dietetic treatment II type and the high fat of IV type of control
Proteinemia.
Existing synthetic method is with the chlorcyclopropanes of 1- phenyl -2,2- two, the chlorcyclopropanes of 1- phenyl -2,2- two or 4- methoxyl groups
Styrene is initial action raw material, there is that the yield of key intermediate is relatively low, and the amplification production of nitration reaction has very big behaviour
Make security risk；The yield and quality of compound are low；Initiation material is expensive and market supply is rare, and its stability compared with
Difference, the problems such as easily polymerization.
Therefore, it is necessary to be improved to existing synthetic method and synthetic technology, the yield and quality of product are improved, simultaneously
Make reaction condition gentleer, operation is more controllable.
The content of the invention
The technical problem to be solved in the present invention is：Based on above mentioned problem, the present invention provides a kind of synthesis side of ciprofibrate
Method.
A technical scheme is used by the present invention solves its technical problem：A kind of synthetic method of ciprofibrate, with
Acetic acid -4- (2,2- dichloro cyclopropyl) phenyl ester is raw material, is comprised the following steps：
(1) alcoholysis reaction：In the basic conditions, alcoholysis reaction obtains for acetic acid -4- (2,2- dichloro cyclopropyl) phenyl esters and methanol
To 4- (2,2- dichloros cyclopropyl) phenol；
(2) alkylation reaction：With isobutyl ethyl bromide in the basic conditions, alkanisation is anti-for 4- (2,2- dichloro cyclopropyl) phenol
2- [4- (2,2- dichloros cyclopropyl) phenoxy group] -2 Methylpropionic acid ethyl ester should be obtained；
(3) Basic fluxing raction：2- [4- (2,2- dichloro cyclopropyl) phenoxy group] -2 Methylpropionic acid ethyl ester in the basic conditions,
Basic fluxing raction obtains 2- [4- (2,2- dichloros cyclopropyl) phenoxy group] -2 Methylpropionic acid.
Further, the mol ratio of acetic acid -4- (2,2- dichloro cyclopropyl) phenyl esters and alkali is 1 in step (1)：0.3~1：
0.6。
Further, the mol ratio of isobutyl ethyl bromide and alkali is (0.9~1.1) in step (2)：(1~1.5).
The beneficial effects of the invention are as follows：Entirely react raw materials used cheap and easy to get, mild condition, easy to operate, yield is good；
The equal recoverable of solvent for use is reacted, environmental is low.
Embodiment
Presently in connection with specific embodiment, the invention will be further described, following examples be intended to illustrate invention rather than
Limitation of the invention further.
Embodiment 1
Alcoholysis reaction：In 1L reaction bulbs put into 1mol acetic acid -4- (2,2- dichloros cyclopropyl) phenyl ester, 300g methanol,
0.3mol potassium carbonate, 20 DEG C are reacted 10 hours, and control is without raw material in HPLC, and be concentrated under reduced pressure to obtain grease 250g or so.
Alkylation reaction：1.8mol isobutyl ethyl bromides, 2mol potassium carbonate, 600g alcoholysis are put into 2L cleaning reaction bulbs
Product, temperature rising reflux are reacted 24 hours, and raw material is controlled in HPLC<1%, 50 DEG C are cooled to, water 900g is added, separates organic layer.
Basic fluxing raction：In organic layer plus 400g water, 400g30% liquid caustic soda is added dropwise, 15 DEG C of insulation reactions 1.5 hours, HPLC
Middle control 30 DEG C of dropwise addition dilute sulfuric acid 500g, adjusts PH=2.0, separates organic layer, be concentrated under reduced pressure, add petroleum ether 300g, analysis without raw material
Material, filter, centrifugation, dry to obtain 270g crude products, then final product 240g, HPLC are recrystallized to obtain with n-hexane>99%, fusing point 118-
119℃。
Embodiment 2
Alcoholysis reaction：In 1L reaction bulbs put into 1mol acetic acid -4- (2,2- dichloros cyclopropyl) phenyl ester, 300g methanol,
0.5mol potassium carbonate, 30 DEG C are reacted 11 hours, and control is without raw material in HPLC, and be concentrated under reduced pressure to obtain grease 255g or so.
Alkylation reaction：2mol isobutyl ethyl bromides, 2.5mol potassium carbonate, 600g alcoholysis are put into 2L cleaning reaction bulbs
Product, temperature rising reflux are reacted 24 hours, and raw material is controlled in HPLC<1%, 50 DEG C are cooled to, water 900g is added, separates organic layer.
Basic fluxing raction：In organic layer plus 400g water, 400g30% liquid caustic soda is added dropwise, 25 DEG C of insulation reactions 2 hours, in HPLC
Control 40 DEG C of dropwise addition dilute sulfuric acid 500g, adjusts PH=2.0, separates organic layer, be concentrated under reduced pressure, add petroleum ether 300g, analysis without raw material
Material, filter, centrifugation, dry to obtain 280g crude products, then final product 250g, HPLC are recrystallized to obtain with n-hexane>99%, fusing point 118-
119℃。
Embodiment 3
Alcoholysis reaction：In 1L reaction bulbs put into 1mol acetic acid -4- (2,2- dichloros cyclopropyl) phenyl ester, 300g methanol,
0.6mol potassium carbonate, 40 DEG C are reacted 12 hours, and control is without raw material in HPLC, and be concentrated under reduced pressure to obtain grease 250g or so.
Alkylation reaction：2.2mol isobutyl ethyl bromides, 3mol potassium carbonate, 600g alcoholysis are put into 2L cleaning reaction bulbs
Product, temperature rising reflux are reacted 24 hours, and raw material is controlled in HPLC<1%, 50 DEG C are cooled to, water 900g is added, separates organic layer.
Basic fluxing raction：In organic layer plus 400g water, 400g30% liquid caustic soda is added dropwise, 30 DEG C of insulation reactions 3 hours, in HPLC
Control 50 DEG C of dropwise addition dilute sulfuric acid 500g, adjusts PH=2.0, separates organic layer, be concentrated under reduced pressure, add petroleum ether 300g, analysis without raw material
Material, filter, centrifugation, dry to obtain 275g crude products, then final product 243g, HPLC are recrystallized to obtain with n-hexane>99%, fusing point 118-
119℃。
It is complete by above-mentioned description, relevant staff using the above-mentioned desirable embodiment according to the present invention as enlightenment
Various changes and amendments can be carried out without departing from the scope of the technological thought of the present invention' entirely.The technology of this invention
Property scope is not limited to the content on specification, it is necessary to determines its technical scope according to right.
Claims (1)
1. a kind of synthetic method of ciprofibrate, it is characterized in that：, for raw material, pressed with acetic acid -4- (2,2- dichloro cyclopropyl) phenyl ester
Following steps are carried out,
(1) alcoholysis reaction：In 1L reaction bulbs put into 1mol acetic acid -4- (2,2- dichloros cyclopropyl) phenyl ester, 300g methanol,
0.5mol potassium carbonate, 30 DEG C are reacted 11 hours, and control is without raw material in HPLC, and be concentrated under reduced pressure to obtain grease 255g；
(2) alkylation reaction：2mol isobutyl ethyl bromides, 2.5mol potassium carbonate, 600g alcoholysis are put into 2L cleaning reaction bulbs
Product, temperature rising reflux are reacted 24 hours, and raw material is controlled in HPLC<1%, 50 DEG C are cooled to, water 900g is added, separates organic layer；
(3) Basic fluxing raction：In organic layer plus 400g water, 400g30% liquid caustic soda is added dropwise, 25 DEG C of insulation reactions 2 hours, in HPLC
Control 40 DEG C of dropwise addition dilute sulfuric acid 500g, adjusts pH=2.0, separates organic layer, be concentrated under reduced pressure, add petroleum ether 300g, analysis without raw material
Material, filter, centrifugation, dry to obtain 280g crude products, then final product 250g is recrystallized to obtain with n-hexane.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3948973A (en) * | 1972-08-29 | 1976-04-06 | Sterling Drug Inc. | Halocyclopropyl substituted phenoxyalkanoic acids |
| CN1514819A (en) * | 2001-05-08 | 2004-07-21 | ���ʻ�ѧʵ��������˾ | 2-[4-2,2-dihalocyclopropyl)phenoxy]-alkanoic acids and exters thereof production process |
| CN103613498A (en) * | 2013-11-20 | 2014-03-05 | 浙江三门恒康制药有限公司 | Synthetic method of ciprofibrate |
-
2015
- 2015-10-08 CN CN201510644979.0A patent/CN105152925B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3948973A (en) * | 1972-08-29 | 1976-04-06 | Sterling Drug Inc. | Halocyclopropyl substituted phenoxyalkanoic acids |
| CN1514819A (en) * | 2001-05-08 | 2004-07-21 | ���ʻ�ѧʵ��������˾ | 2-[4-2,2-dihalocyclopropyl)phenoxy]-alkanoic acids and exters thereof production process |
| CN103613498A (en) * | 2013-11-20 | 2014-03-05 | 浙江三门恒康制药有限公司 | Synthetic method of ciprofibrate |
Non-Patent Citations (1)
| Title |
|---|
| 环丙贝特的合成;李景锋等;《沈阳药科大学学报》;20081231;第25卷(第12期);954-955，991 * |
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