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Method for preparing candestartan

A candesartan and reaction technology, which is applied to a preparation field of candesartan, can solve the problems of harsh operating conditions, long reaction time, pollution of poisonous reagents and the like, and achieves the effect of simple operation process and easy industrial production.

Active Publication Date: 2006-07-12
LINHAI TIANYU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0019] Among the above-mentioned patent routes, the first type of route uses organotin reagents to react with cyano groups to prepare tetrazole, which needs to be carried out under high temperature (100-120°C) conditions, the reaction time is long, and the pollution of toxic reagents is relatively large; the second type of route , organozinc reagent (6) has no industrial products, the reaction requires anhydrous and oxygen-free system, and the operating conditions are harsh

Method used

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  • Method for preparing candestartan

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 12

[0058] Example 1.2-[N-(tert-butoxycarbonyl)-N-[[(2'-(N'-trityl)-tetrazol-5-yl)[1,1'-biphenyl]- Preparation of ethyl 4-yl]methyl]amino]-3-nitrobenzoate (III, R=ethyl)

[0059] In a 1000mL four-neck flask equipped with a thermometer, a reflux condenser, a drying tube, and a mechanical stirrer, add 51.4g of ethyl 2-tert-butoxycarbonylamino-3-nitrobenzoate (purity 92%, 0.15mol) and Acetonitrile 500ml, add potassium carbonate 32g (0.23mol) under stirring. After the mixture was stirred for 30 minutes, 89 g (content 95%, 0.15 mol) of N-(triphenylmethyl)-5-(4'-bromomethylbiphenyl-2-yl)tetrazolium (II) was added, The reaction was stirred at reflux for 14 hours. Cool and filter, concentrate under reduced pressure and recover acetonitrile. The residue was dissolved in dichloromethane, washed with water, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a pale yellow oil. The oil was Intermediate III, weighing 131 g. This pro...

Embodiment 2

[0060] Example 2. 2-[N-[(2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl)methyl]amino]-3-nitrobenzene Preparation of ethyl formate (IV, R = ethyl)

[0061] In a 1000mL four-neck flask equipped with a thermometer, reflux condenser, drying tube, and mechanical stirring, the 2-{N-(tert-butoxycarbonyl)-N-[(2'-(N'- Trityl)-tetrazolium-5-yl)biphenyl-4-yl]amino}-3-nitrobenzoic acid ethyl ester crude product was dissolved in the mixed solvent of 100ml ethyl acetate and 500ml methanol, heated to reflux for 24 hours, concentrated. The residue was crystallized with dichloromethane and petroleum ether, filtered, and the filter cake was washed with a little petroleum ether, sucked dry, and dried in vacuo to obtain 54.4 g of a light yellow solid, which was 2-[N-[(2'-(1H-tetraazole Azol-5-yl)biphenyl-4-yl)amino]-3-nitrobenzoic acid ethyl ester. Based on ethyl 2-tert-butoxycarbonylamino-3-nitrobenzoate, the two-step total yield was 81.5%. The resulting solid was recrystallized from dichlorometh...

Embodiment 3

[0062] Example 3. 2-[N-[(2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl)methyl]amino]-3-nitrobenzene Preparation of methyl formate (IV, R = methyl)

[0063] In a 1000mL four-necked flask equipped with a thermometer, a reflux condenser, a drying tube, and a mechanical stirrer, add 47.7 g of methyl 2-tert-butoxycarbonylamino-3-nitrobenzoate (purity 93%, 0.15 mol) and Acetonitrile 500ml, add potassium carbonate 32g (0.23mol) under stirring. After the mixture was stirred for 30 minutes, 89 g (content 95%, 0.15 mol) of N-(triphenylmethyl)-5-(4'-bromomethylbiphenyl-2-yl)tetrazolium (II) was added, The reaction was stirred at reflux for 14 hours. Cool and filter, concentrate under reduced pressure and recover acetonitrile. Add 150ml of ethyl acetate to the residue to dissolve, wash with water, dry the organic layer over anhydrous sodium sulfate, and filter. Add 600ml of methanol to the filtrate, heat to reflux for 24 hours, and concentrate. The residue was crystallized with dichlorom...

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Abstract

The invention relates to a method for synthesizing ridge sha tan, which uses the 2-tert-butyl ketonic oxygen amido-3-nitro benzoate (I) and N-(trityl )-5-(4'-morphine methylbiphenyll-2-group) tetrazolium (II) as raw material to do N-alkanisation reaction, protecting-released reaction, reduction reaction, ring-closed reaction and ester hydrolytic reaction. <0The protecting-released reaction can slough trityl and tert-butyl ketonic oxygen protect group in the lower aliphatic alcohol organic mixing solution.

Description

technical field [0001] The invention belongs to medicine synthesis. Specifically relates to a preparation method of candesartan (Candesartan). Background technique [0002] Candesartan (Candesartan, 1) is a long-acting antagonist of angiotensin II subtype I receptor (AT1), which is a non-peptide drug molecule. In order to overcome the shortcoming that candesartan is not easily absorbed orally, its prodrug - Candesartan cilexetil (2) has been listed. The chemical name of candesartan is 2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl]-1H -benzimidazole-7-carboxylic acid. The chemical name of candesartan cilexetil is (±)-2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl] 1-(cyclohexyloxycarbonyloxy)ethyl methyl]-1H-benzimidazole-7-carboxylate. The chemical structures of candesartan and candesartan cilexetil are shown below: [0003] [0004] Candesartan (1) Candesartan cilexetil (2) [0005] The synthetic methods of existing candesartan and candesar...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/10
Inventor 屠勇军张毅程荣德
Owner LINHAI TIANYU PHARMA
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