Synthetic method of ciprofibrate

A synthesis method and technology of dichlorocyclopropyl, applied in the synthesis field of cycloprofibrate, can solve the problems of difficult transportation and storage of reagents, easy polymerization, easy decomposition, etc., avoid vicinal by-products, and improve yield and the effect of high purity and H2O2 content

Active Publication Date: 2014-03-05
ZHEJIANG SANMEN HYGECON PHARMA CO LTD
View PDF4 Cites 14 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, when using the Friedel-Crafts reaction to synthesize compound (2) from compound (1), due to the high activity of acetyl chloride, it is easy to produce by-products of ortho isomers, thereby reducing the yield and quality of compound (4) , and it is also not conducive to the purification of subsequent reaction products; in addition, in the process of synthesizing compound (5) from compound (4), 40% hydrogen peroxide is used, which has certain safety hazards in production. At the same time, hydrogen peroxide has poor stability and is easy to decompose. Transport and storage of reagents pose certain difficulties
[0011] Synthetic route C: The starting material (6) is expensive and rarely available in the market, and its stability is poor, it is prone to polymerization, and it is difficult to store for a long time, so the production cost of this route is relatively high

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Synthetic method of ciprofibrate
  • Synthetic method of ciprofibrate
  • Synthetic method of ciprofibrate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Embodiment 1: the preparation of 2,2-dichlorocyclopropylbenzene

[0043]

[0044] Add 30g of styrene, 30ml of dichloromethane, 43.5g of chloroform and 1.2g of TEBA (benzyltriethylammonium chloride) into a 250ml four-necked flask. Raise the temperature to reflux, add dropwise lye (28.5g NaOH + 28.5ml water), and reflux for 8 hours. Cool to room temperature, add 60ml of water, stir for 10 minutes, let stand to separate layers, extract the water layer with petroleum ether, combine the organic layers, dry over anhydrous sodium sulfate, filter, and distill the filtrate under high vacuum with an oil pump, slowly heat up to distillate After stabilization, control the temperature at about 95-100°C for distillation to obtain a colorless liquid. Yield: 88.6%; HPLC purity: 99.2%. The HPLC peak time of the product is consistent with that of the commercial standard sample (purchased from Energy Chemical).

Embodiment 2

[0045] Example 2: Preparation of 1-[4-(2,2-dichlorocyclopropyl)phenyl]-1-hexanone

[0046]

[0047] Add 210ml of dichloromethane, 60g of AlCl to a dry 500ml four-neck flask 3 , control the temperature at 20°C, slowly add 75.4g of n-hexanoyl chloride dropwise under stirring, control the temperature below 30°C, continue stirring until AlCl 3 completely dissolved. Cool to 20-25°C, slowly add 70g of 2,2-dichlorocyclopropylbenzene dropwise, raise the temperature to 30-35°C after the dropwise addition, and keep the reaction for 3 hours. After the reaction, the reaction solution was added dropwise to 370 g of ice water, the organic phase was separated, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 1-[4-(2,2-dichlorocyclo Propyl)phenyl]-1-hexanone. Yield: 98%.

[0048] end product from 1 H-NMR, mass spectrometry and HPLC characterization.

[0049] HPLC purity: 98.3%, the content...

Embodiment 3

[0054] Embodiment 3: Preparation of 4-(2,2-dichlorocyclopropyl)phenol

[0055]

[0056] Add 520ml of acetic acid to a 1000ml four-neck flask, cool to 10-15°C, add 138g of carbamide peroxide (UHP), add 118g of maleic anhydride, and keep stirring at 15-20°C for 3 hours. Raise the temperature to 35-40°C, add 86.1g of 1-[4-(2,2-dichlorocyclopropyl)phenyl]-1-hexanone dropwise, raise the temperature to 45-50°C after dropping, and keep the reaction for 5 hours. Cool to room temperature, wash with water, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a brown-yellow liquid.

[0057] Add 100ml of methanol and 2.6g of potassium carbonate, heat up to 35-40°C with stirring, keep the reaction for 4 hours, and concentrate under reduced pressure to remove methanol. The concentrate was dissolved in dichloromethane, washed with water, adjusted to pH 9-10 with dilute lye, the aqueous layer was separated, acidified with dilute hydrochloric acid to ...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

No PUM Login to view more

Abstract

The invention discloses a synthetic method of ciprofibrate. The method comprises the following steps: taking styrene as a starting material; obtaining the ciprofibrate by the processes of cyclization, acylation, Baeyer-Villiger oxidation, alcoholysis, alkylation and hydrolysis, wherein an acylation reagent adopted in the acylation process is R1COCl; the R1 is C4-C12 alkyl. Fatty acyl chloride of which a hydrocarbyl structure is a long chain is adopted in acylation reaction, so that the steric hindrance is increased, the reaction activity of acyl chloride is reduced, the content of the produced ortho-position isomer is smaller than 0.2% and superior to that of acetyl chloride reaction (the content of the ortho-position isomer is 0.5-1%), the yield and the purity of the product are improved, and meanwhile, a room-temperature reaction condition is adopted, so that the energy consumption of production is reduced. Urea peroxide instead of hydrogen peroxide is used as an oxidant in the Baeyer-Villiger oxidation, and acetic acid is used instead of acetic anhydride, so that the reaction condition is milder, and the operation is more controllable.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical synthesis, and in particular relates to a synthesis method of ciprofibrate. Background technique [0002] Ciprofibrate is a phenoxyacetic acid hypolipidemic drug with a chemical name of 2-[4-(2,2-dichlorocyclopropyl)phenoxy]-2-methylpropionic acid, developed by Synthelabo in France. It is clinically used for type Ⅱ and type Ⅳ hyperlipoproteinemia that cannot be controlled by diet therapy. [0003] There are few reports on its synthetic methods in the literature. This article summarizes its existing synthetic routes according to the different construction sequences, as shown in the following formula: [0004] [0005] Method A: In the patent document US4053636, 1-phenyl-2,2-dichlorocyclopropane (1) is used as raw material, and compound (2) is obtained through nitration reaction, and then the nitro group is reduced by 10% palladium carbon to obtain 4-(2 ,2-Dichlorocyclopropyl)aniline (3)...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
Patent Type & Authority Applications(China)
IPC IPC(8): C07C59/72C07C27/02
CPCC07C17/275C07C37/0555C07C45/46C07C49/813C07C51/09C07C67/31C07C67/42C07C69/63C07C69/712C07C2601/02C07C59/72C07C39/42C07C23/18
Inventor 贾春祥陈文斌黄锋王涛
Owner ZHEJIANG SANMEN HYGECON PHARMA CO LTD
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap