Method for removing trityl group of 1-trityl-5-(1,1'-biphenylyl-2 yl)-1H-tetrazole compound

An azole compound, trityl technology, applied in the field of pharmaceutical synthesis, can solve the problems of easy generation of impurities, high reaction temperature, long reaction time and the like

Active Publication Date: 2009-07-15
ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The main disadvantage of this method is that the reaction temperature is high, the reaction time is long, and it is easy to produce impurities.

Method used

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  • Method for removing trityl group of 1-trityl-5-(1,1'-biphenylyl-2 yl)-1H-tetrazole compound
  • Method for removing trityl group of 1-trityl-5-(1,1'-biphenylyl-2 yl)-1H-tetrazole compound
  • Method for removing trityl group of 1-trityl-5-(1,1'-biphenylyl-2 yl)-1H-tetrazole compound

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0046] 1-(cyclohexyloxycarbonyloxy)ethyl-2-ethoxy-1-[[2`-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzo Imidazole-7-carboxylate (candesartan cilexetil, VI)

[0047] Put 1-(cyclohexyloxycarbonyloxy)ethyl-2-ethoxy-1-[[2`-(N-triphenyl Methyl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate (trityl candesartan cilexetil, V) 10g, dichloromethane 20ml, methanol 40ml (moisture is 0.23%, KF detection, the same below), stir to dissolve. Acetyl chloride 1ml was added, and the reaction was stirred. After the reaction was finished, 10% potassium bicarbonate solution was added dropwise to adjust the pH value to neutral, and the mixture was left to stand and separated into layers. The aqueous layer was extracted once with 20 ml of dichloromethane. The dichloromethane layers were combined, dried over anhydrous magnesium sulfate, and concentrated to dryness under vacuum. Add 16ml of acetone and 32ml of n-hexane to the residue, stir to precipitate crystals, and filter with ...

example 2

[0049] 1-(cyclohexyloxycarbonyloxy)ethyl-2-ethoxy-1-[[2`-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzo Imidazole-7-carboxylate (candesartan cilexetil, VI)

[0050] Referring to Example 1, 1ml of acetyl chloride was replaced by 1ml of benzoyl chloride, yield 83.9%.

example 3

[0052] 1-(cyclohexyloxycarbonyloxy)ethyl-2-ethoxy-1-[[2`-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzo Imidazole-7-carboxylate (candesartan cilexetil, VI)

[0053] Referring to Example 1, 1ml of acetyl chloride was replaced by 1ml of chloroacetyl chloride, and the yield was 89.5%.

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PUM

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Abstract

The invention discloses a method for removing trityl from 1-trityl-5-(1,1'-biphenyl-2yl)-1H-tetrazole compound (I). The method is characterized by adding acyl halide in low-grade alcohol at low moisture condition to remove the trityl. The method has the advantages of rapid reaction speed, greatly shortened reaction time, higher product purity, and being fit for industrialized production. The method can be used for preparing related candesartan (VIII), losartan (X), irbesartan (XII), valsartan (XIV), olmesartan medoxomil (XVI) or olmesartan (XVIII).

Description

technical field [0001] The present invention relates to drug synthesis, in particular to a method for removing trityl from 1-trityl-5-(1,1`-biphenyl-2 base)-1H-tetrazolium compound (I) . Background technique [0002] 1-trityl-5-(1,1`-biphenyl-2 base)-1H-tetrazole compound (I) has the following structural formula: [0003] [0004] R in compound I can be: [0005] [0006] or [0007] where R 1 ,R 2 ,R 3 It can be H, halogen, straight-chain alkyl or substituted alkyl containing 1 to 5 carbon atoms, hydroxyalkyl containing 1 to 5 carbon atoms, alkoxy containing 1 to 5 carbon atoms , Alkoxymethyl or phenyl containing 1 to 5 carbon atoms. R 2 ,R 3 It can also be a five-membered, six-membered, seven-membered saturated or unsaturated ring, an aromatic ring or an aromatic ring with substituents. R in compound II is the same as R in compound I. [0008] Compound II, such as candesartan cilexetil, losartan potassium, irbesartan, valsartan, olmesartan medoxomil, e...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/10C07D405/14
Inventor 赵国标董鹏
Owner ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD
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