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Method for synthesizing ciprofibrate intermediate and the intermediate

A synthesis method and intermediate technology, applied in the synthesis method of ciprofibrate intermediate and the field of intermediates, can solve the problems of easy polymerization, difficulty in reagent transportation and storage, and easy decomposition, so as to improve yield and purity, Avoid the effect of high content of ortho by-products and H2O2

Inactive Publication Date: 2015-09-16
ZHEJIANG SANMEN HYGECON PHARMA CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

But when utilizing Friedel-Crafts reaction to synthesize compound (2) by compound (1), because the activity of acetyl chloride is bigger, easily produce the by-product of ortho isomer, thereby reduced the yield and the quality of compound (4) , is also unfavorable for the purification of follow-up reaction product simultaneously; In addition, in compound (4) synthetic compound (5) process, adopts 40% hydrogen peroxide, there is certain potential safety hazard in production, hydrogen peroxide stability is relatively poor simultaneously, easily decomposes, gives Transportation and storage of reagents pose certain difficulties
[0012] 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

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  • Method for synthesizing ciprofibrate intermediate and the intermediate
  • Method for synthesizing ciprofibrate intermediate and the intermediate
  • Method for synthesizing ciprofibrate intermediate and the intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Embodiment 1: the preparation of 2,2-dichlorocyclopropylbenzene

[0044]

[0045] 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 react under 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 a commercially available standard sample (purchased from Energy Chemical).

Embodiment 2

[0046] Example 2: Preparation of 1-[4-(2,2-dichlorocyclopropyl)phenyl]-1-hexanone

[0047]

[0048] 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%.

[0049] end product from 1 H-NMR, mass spectrometry and HPLC characterization.

[0050] HPLC purity: 98.3%, wherein the...

Embodiment 3

[0055] Embodiment 3: Preparation of 4-(2,2-dichlorocyclopropyl)phenol

[0056]

[0057] Add 520ml of acetic acid into 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.

[0058] 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 t...

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Abstract

The invention discloses a method for synthesizing ciprofibrate intermediate. The method comprises: conducting cyclization reaction on styrene to obtain 2,2-dichloro-cyclopropylmethyl phenyl; conducting Friedel-Crafts acylation reaction on 2,2-dichloro-cyclopropylbenzene to obtain a compound (III), wherein an acylating agent is R1COCl, and R1 is C4-C12 alkyl group; and conducting Baeyer-Villiger oxidation reaction on the compound (III) to obtain a compound (IV). The invention employs fatty acyl chloride with long chain hydrocarbyl structure in the acylation reaction to increase steric hindrance and reduce the reaction activity of the acyl chloride; the content of the produced ortho isomer is less than 0.2%; and the method improves the yield and purity of the product, is superior to the reaction of acetyl chloride (the content of ortho isomer is 0.5-1%), and the utilization of room temperature conditions reduces energy consumption for production.

Description

[0001] This application is a divisional application with the application number 201310590127.9, the filing date is November 20, 2013, and the invention name is "Synthetic method of ciprofibrate". technical field [0002] The invention belongs to the technical field of pharmaceutical synthesis, and in particular relates to a synthesis method and an intermediate of a ciprofibrate intermediate. Background technique [0003] 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. [0004] 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: [0005] [0006] Method A: In the patent document US405363...

Claims

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Application Information

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IPC IPC(8): C07C39/42C07C37/055C07C49/813
CPCC07C37/0555C07C45/46C07C49/813C07C2601/02
Inventor 贾春祥陈文斌黄锋王涛
Owner ZHEJIANG SANMEN HYGECON PHARMA CO LTD
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