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Silanization reaction catalyst

A silylation and catalyst technology, which is applied in the field of preparation of macrolide drug intermediates and other compounds, can solve the problems of high dosage of hexamethyldisilazane, no introduction of test data, and rising cost of auxiliary materials, etc. The effect of shortened reaction time, low production cost and less three wastes

Active Publication Date: 2010-01-13
ZHEJIANG GUOBANG PHARMA
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Problems solved by technology

[0012] In the product obtained by this method, there are many non-silanized impurities, and the content is relatively low, and the amount of hexamethyldisilazane is relatively large, which is 3.6 times the molar equivalent of erythromycin oxime, which makes the cost of auxiliary materials increase significantly, and redundant The hexamethyldisilazane forms trimethylsilanol, which increases environmental pollution
[0013] 4. Liang Jianhua mentioned in the literature introduced above that ammonium chloride salt was used to catalyze the silanization reaction of hexamethyldisilazane, but there was no specific test data introduction

Method used

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  • Silanization reaction catalyst

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Step 1: add 20.0 grams (0.0267mol) erythromycin A oxime, 200ml dichloromethane in the 500 milliliter four-necked reaction flask that stirrer, thermometer are equipped with, add 5.6 grams (0.0487mol) pyridine hydrochloride and 5.3 grams under stirring (0.0616mol) 2-ethoxypropene, reacted at 20-25°C for 15 minutes.

[0025] Step 2: Following step 1, add 5.7 g (0.0354 mol) of hexamethyldisilazane and react at 20-30° C. for 3 hours. After the reaction is over, add 60 ml of water to terminate, then adjust the pH to 9-10 with 20% sodium hydroxide solution, then wash with 60 ml of saturated brine and 60 ml of water successively, and concentrate and crystallize under reduced pressure to obtain 26.6 g, with a content of 75.8%. , of which the unsilanized content is 11.6%. Acetone was refined to obtain 21.2 grams of refined product, with a content of 92.6%, and a molar yield of 81.1%.

Embodiment 2

[0027] Step 1: Same as Step 1 in Embodiment 1.

[0028] Step 2: Following step 1, add 5.7 g (0.0354 mol) of hexamethyldisilazane, react for 5 minutes, add 0.8 g (0.005 mol) of pyridinium hydrobromide, and react at 20-30° C. for 2 hours. After the reaction is over, add 60 ml of water to terminate, then adjust the pH to 9-10 with sodium hydroxide solution, then wash with 60 ml of saturated brine and 60 ml of water successively, and concentrate and crystallize under reduced pressure to obtain 28.9 g, with a main content of 86.3%. , the non-silanized impurity was 0.7%. Acetone is refined to obtain 24.9 grams of fine product, the content is 96.0%, and the molar yield reaches 95.5%.

Embodiment 3

[0030] Step 1: Same as Step 1 in Embodiment 1.

[0031] Step 2: Following step 1, add 5.7 g (0.0354 mol) of hexamethyldisilazane, react for 5 minutes, add 0.04 g (0.00027 mol) of pyridinium hydrobromide, and react at 20-30° C. for 10 hours. After the reaction was finished, add 60 ml of water to terminate, then adjust the pH to 9-10 with sodium hydroxide solution, then wash with 60 ml of saturated brine and 60 ml of water successively, and distill and concentrate under reduced pressure to obtain 27.7 g of crystals with a main content of 84.3%. , the unsilanized impurity was 2.9%. Acetone is refined to obtain 23.6 grams of fine product, the content is 95.4%, and the molar yield reaches 90.4%.

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Abstract

The invention mainly discloses a silanization reaction catalyst. Etherate is obtained by erythromycin oxime through etherification, (2', 4'')-O-bis(trimethylsilyl)erythromycin A-9-O-(1-ethoxy-1-methylethyl) oxime of intermediate for synthesizing clarithromycin is prepared by the silanization reaction, the catalyst is added into the silanization reaction and is hydrobromide with a general formula being RHBr, wherein R is organic alkali, or the catalyst is strong acid and weak base salt with a general formula being XBr, wherein X is weak base cations. The consumption of the catalyst is 0.01-0.4 of the erythromycin oxime according to the mol, the temperature of the silanization catalysis reaction is 0-40 DEG C and the time of the silanization catalysis reaction is 1-10h. The invention enables the process for preparing the (2', 4'')-O-bis(trimethylsilyl)erythromycin A-9-O-(1-ethoxy-1-methylethyl) oxime to be stable, the yield to be high, the cost to be low and the three wastes to be less.

Description

technical field [0001] The invention relates to a catalyst used in the silanization reaction in the synthesis process of clarithromycin, and belongs to the technical field of preparation of macrolide drug intermediates and other compounds. Background technique [0002] (2',4")-Obistrimethylsilyl-erythromycin A-9[O-(1-ethoxy-1-methylethyl)]oxime (formula I) is an important compound for the synthesis of clarithromycin Intermediate, which is generally obtained from erythromycin oxime (formula III) through oxime etherification reaction to obtain etherified product (formula II), and then carried out silanization reaction. The reaction formula is as follows: [0003] [0004] 1. In US4990602: there are two ways of silanization reaction: [0005] 1) Use a mixed silylating agent of trimethylsilyl imidazole and trimethylchlorosilane for silylation protection. [0006] This method requires a large amount of high-priced trimethylsilyl imidazole as a silylating agent, and the react...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): B01J31/02B01J27/08C07H23/00C07H1/00
Inventor 陈林静金勇侯仲轲王兆刚田利焕邱家军
Owner ZHEJIANG GUOBANG PHARMA
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