CN103304543A - Preparation method of candesartan cilexetil - Google Patents
Preparation method of candesartan cilexetil Download PDFInfo
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- CN103304543A CN103304543A CN2012100633575A CN201210063357A CN103304543A CN 103304543 A CN103304543 A CN 103304543A CN 2012100633575 A CN2012100633575 A CN 2012100633575A CN 201210063357 A CN201210063357 A CN 201210063357A CN 103304543 A CN103304543 A CN 103304543A
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Abstract
The invention discloses a preparation method of candesartan cilexetil. The method includes: taking 2-amino-3-nitromethylbenzoate and 4-formyl-2-biphenylcarbonitrile as starting materials, carrying out condensation, reduction and cyclization reactions so as to obtain a compound (III), then adding a tetrazole ring, and carrying out hydrolysis, N-protection, esterification and deprotection so as to obtain a final product (VIII). The method has the advantages of low cost, strong reaction controllability, small environmental pollution, and greatly improved product yield and quality, thus being suitable for mass production.
Description
Technical field
The invention belongs to technical field of medicine synthesis, specifically, relate to the preparation method of the smooth class hypertension drug of a kind of sand candesartan Cilexetil.
Background technology
The chemical name of candesartan Cilexetil is: (±)-1-[[(hexamethylene oxo) carbonyl] oxo] ethyl-2-oxyethyl group-1-[[2'-(1H-tetrazole base-5)-[1, the 1'-xenyl]-the 4-yl] methyl]-the 1H-benzimidazole-7-carboxylate, its structural formula is:
Candesartan Cilexetil is as the prodrug of Candesartan, and in gi tract, it can be hydrolyzed to Candesartan quick and completely.Candesartan is Angiotensin II AT1 receptor antagonist, by the vasoconstrictor effects of antagonizing vessel Angiotensin Converting Enzyme II with vascular smooth muscle AT1 receptors bind, thereby reduces peripheral vascular resistance, is a kind of long-acting receptor antagonist.
Document US 5,196,144, among the EP 688,272, the synthetic route of candesartan Cilexetil is long, has comprised the preparation of monoesters thing; The preparation of 2-tertiary butyl oxygen base-3-ethyl nitrobenzoate; The benzyl reaction; Deprotection; The reduction of nitro; The preparation of imidazoles thing; Prepare four ammonia azoles things; Hydrolysis reaction; Protective reaction; Esterification, Deprotection get the candesartan Cilexetil product.
Some reference disclose the technology of preparing of candesartan Cilexetil, for example US2010210852, US2010197933, US5196444A, W02008012371A, JP2010116409, CN200510000109.6, CN200510022136.3, CN101781286A etc. have all reported the method for preparing candesartan Cilexetil, but there is a common problem in the candesartan Cilexetil of these method preparations, owing to still having impurity, obtains candesartan Cilexetil purity not high exactly.When being used in the preparation candesartan cilexetil, it is difficult to purifying and processing, the candesartan cilexetil that is still oily of gained.
CN101781286A is to the crude product recrystallizing methanol, and purity is 90～91%.CN200510022136.3 relates to a kind of novel preparation process of candesartan Cilexetil, and its synthesis step comprises: 1. the preparation method of triphenylmethyl tetrazole intermediate; 2. cyclohexyl chloroethane carbonate preparation method; 3. synthesize candesartan Cilexetil with cyclohexyl chloroethane carbonate as esterifying reagent, crude product is through silica gel column chromatography separating purification, and yield 89% gets product, then product is used aqueous ethanolic solution crystallization, yield 92%.The method total recovery is low, and is not suitable for industrial needs.
In addition, deposit improper or shelf-time when long in candesartan Cilexetil, can lead diligent active constituents of medicine content, color and luster is deepened, and its related substances raises.In some cases, because controlling of production process is improper, cause pharmaceutical purity also undesirable.Therefore be necessary underproof product is further carried out purifying, provide highly purified candesartan Cilexetil with high yield.
Summary of the invention
The invention provides a kind of preparation method of candesartan Cilexetil, can solve the problem that reaction efficiency is not high and yield is on the low side that prior art exists, reduced pollution and the waste of toxic reagent, improved product yield, be with a wide range of applications.
The present invention implements by following reactions steps:
The present invention includes the following step:
(1) by 2-amino-3-nitrobenzene methyl and 4-aldehyde radical-2-biphenylcarbonitriles in organic solvent, temperature is controlled under 0 ~ 5 ℃ the condition, generates 2-[[2 '-cyanobiphenyl-4-yl through condensation reaction] methylene amino]-the 3-nitrobenzene methyl (
I);
(2) compound (
I) react in autoclave with 10% palladium carbon, with nitrogen replacement air 3 times, use hydrogen exchange nitrogen 5 times, logical hydrogen to 0.20 ~ 0.25MPa is warming up to 40 ~ 45 ℃ of reactions and reduces to get 2-[[2 '-cyanobiphenyl-4-yl again] methyl] amino]-the 3-Methyl anthranilate (
II);
(3) compound (II) is heated to 80 ℃ with tetraethyl orthocarbonate, reacts cyclization in 1 hour and gets 1-[(2 '-cyanobiphenyl-4-yl) methyl]-2-oxyethyl group-1H-benzoglyoxaline-7-carboxylate methyl ester (
III);
(4) compound (
III) with change nitrogenize tin reaction of tributyl, cyano group changes the tetrazole ring into, gets 2-oxyethyl group-1-[[2 '-(1H-tetrazolium-5-yl) xenyl-4-yl] methyl] benzoglyoxaline-7-carboxylic acid, ethyl ester (
IV);
(5) compound (
IV)Hydrolysis generates 2-oxyethyl group-1-[[2 '-(1H-tetrazolium-5-yl) xenyl-4-yl under alkaline condition] methyl] benzoglyoxaline-7-carboxylic acid (
V);
(6) compound (
V) react with triphenylmethyl chloride and triethylamine hydrochloride, through the N-protected reaction, obtain compound 2-oxyethyl group-1-[[2 ,-(1-trityl tetrazole-5-yl) xenyl-4 base] methyl] benzoglyoxaline-7-carboxylic acid (
VI);
(7) compound (
VI) through esterification, generate compound 2-oxyethyl group-1-[[2 ,-(1-trityl tetrazole-5-yl) xenyl-4 base] methyl] benzoglyoxaline-7-carboxylic acid, 1-[[cyclohexyl oxygen base] carbonyl] the oxygen base] ethyl ester (
VII);
(8) compound (
VII) deprotection obtains compound (±)-2-oxyethyl group-1-[[2 '-(1H-tetrazole-5-yl) [1, l '-biphenyl l-4-yl] methyl]-1H-benzoglyoxaline-7-carboxylic acid, 1-[[cyclohexyl oxygen base] carbonyl] the oxygen base] ethyl ester (VIII).
The advantage of this reaction is: having selected 2-amino-3-nitrobenzene methyl and 4-aldehyde radical-2-biphenylcarbonitriles is starting raw material, make 2-[[2 '-cyanobiphenyl-4-yl] methylene amino]-the 3-nitrobenzene methyl, select again 10% palladium carbon to reduce to get 2-[[2 '-cyanobiphenyl-4-yl] methyl] amino]-the 3-Methyl anthranilate, the reaction controllability is strong, and product yield is high, and reduced synthesis step, so that reaction is simple more, energy consumption reduces.
In sum, synthetic route of the present invention is shorter, and cost reduces greatly, and environmental pollution is little, and is easy and simple to handle, is fit to industrialized production.
Embodiment
The embodiment of the indefiniteness that the below provides only is used for illustrating preferred embodiment of the present invention, should not be used for limiting the present invention, and scope of the present invention is determined by additional claim.
Synthesizing of embodiment 1 chemical compounds I:
In the 100ml there-necked flask, add 4-aldehyde radical-2-biphenylcarbonitriles 2.07g, methylene dichloride 50ml, start stirring, ice-water bath is cooled to 0 ~ 5 ℃, drip the solution of 2-amino-3-nitrobenzene methyl 1.95g/8ml methylene dichloride, finish, insulation reaction 30min adds the 5g anhydrous magnesium sulfate, remove ice-water bath, be back to room temperature reaction 2h.TLC detection reaction complete, with the system suction filtration, filter cake 10ml eluent methylene chloride, mother liquor is concentrated, enriched material Virahol recrystallization gets chemical compounds I faint yellow solid 3.11g, yield 80%.
Synthesizing of embodiment 2 compound iis:
With chemical compounds I 10g, 10% palladium carbon 0.05g, tetrahydrofuran (THF) 100ml joins the 250ml autoclave, uses nitrogen replacement air 3 times, uses hydrogen exchange nitrogen 5 times again, and logical hydrogen to 0.20 ~ 0.25MPa is warming up to 40 ~ 45 ℃ of reactions.React approximately 4h, the TLC detection reaction is complete.With the system suction filtration, filter cake is drained with the drip washing of 20ml tetrahydrofuran (THF).Mother liquor concentrates to get compound ii faint yellow solid 8.62g, yield 93%.
Synthesizing of embodiment 3 compound III:
With the 1.68kg compound ii, tetraethyl orthocarbonate 1.55kg, Glacial acetic acid 0.2kg drops in the tank and mixes, be heated to 80 ℃, reacted 1 hour, through the complete (developping agent: sherwood oil: ethyl acetate=4:1 of TCL detection reaction, Rf=0.55), remove 0.16kg acetic acid under reduced pressure, obtain the light brown solid, add methyl alcohol 2.4kg and stir, centrifugal, obtain solid, with ethyl acetate 6kg recrystallization, obtain solid, with the ether washing, resistates adds acetic acid ethyl dissolution, organic layer washs with saturated sodium bicarbonate, wash once, water layer is carried once with ethyl acetate is counter, merges organic layer, the saturated sodium bicarbonate washing, washing, saturated sodium-chloride is washed, the organic layer anhydrous sodium sulfate drying, the distillation organic layer, the stirring that adds diethyl ether after having steamed, centrifugal compound III 1.56kg, the yield 81.3% of obtaining.
Synthesizing of embodiment 4 compounds Ⅳs:
With 1.56kg compound III, the nitrogenize tin 2.58kg tributyl changes, 4.8kg dimethylbenzene drops in the retort, be heated to back flow reaction 24 hours, through the complete (developping agent: chloroform: ethyl acetate: methyl alcohol=4:2:1 of TCL detection reaction, Rf=0.5), be cooled to normal temperature, add the 2.4kg ether in tank, wash to organic layer colourlessly with 3N aqueous sodium hydroxide solution 2.4kg, the water layer of telling is carried once with ether 0.8kg is counter, icy salt solution is cooled to 0 ℃, regulate pH=3 with 6N hydrochloric acid 0.4kg, separate out a large amount of white solids, centrifuging, filter cake water 4kg fully washes away inorganic salt, with a small amount of ethyl acetate 2kg washing, obtain compounds Ⅳ 1.51kg, yield 93.8% again.
Synthesizing of embodiment 5 compound V:
1.48kg compounds Ⅳ, methyl alcohol 12kg are dropped in the retort, add 1N aqueous sodium hydroxide solution 4.4kg, be warming up to 65 ℃, stir 5h, through the complete (developping agent: sherwood oil: ethyl acetate=7:3), remove methyl alcohol under reduced pressure of TCL detection reaction, residual solution adds water 2.4kg dissolving, with the washing of 1.2kg ethyl acetate, minute water-yielding stratum is regulated pH=3, crystallize out with 1mol/L hydrochloric acid 4kg, centrifuging, filter cake water 2kg washing, dry compound V 1.26kg, the yield 91.3% of getting.
Synthesizing of embodiment 6 compound VI:
1.24kg compound V is dissolved in the 8kg methylene dichloride, after 0.96kg triphenylmethyl chloride and 0.4kg triethylamine are dropped in the retort, temperature control is at 0 ℃, stirring reaction 1h, and reaction solution water 4kg washs once, use anhydrous sodium sulphate 0.8kg dry after telling organic layer, remove solvent under reduced pressure, residue is through behind the column purification, with ethyl acetate 6.4kg recrystallization, obtain compound VI 1.38kg, yield 72.1%.
Synthesizing of embodiment 7 compound VIII:
1.36kg compound VI is dissolved in 7.2kg N, dinethylformamide, rear and 0.38kg salt of wormwood, 0.54kg1-chloroethyl cyclohexyl carbonic ether drops in the retort, reaction is 3 hours under stirring at room, through the complete (developping agent: sherwood oil: ethyl acetate=7:3 of TCL detection reaction, Rf=0.5), add entry 0.8kg in the reaction solution and make dissolution of solid, rear with ethyl acetate 3.2kg extraction, organic layer water 3.2kg washing once, dry with anhydrous sodium sulphate 0.8kg, remove solvent under reduced pressure, get the compound VII, the compound VII is dissolved with 1.84kg methyl alcohol and 4.8kg methylene dichloride, drip HCL-methyl alcohol (1:10) solution 0.96kg, drip rear stirring 6h, through the complete (developping agent: PE/EA/ methyl alcohol=6:3:1 of TCL detection reaction, Rf=0.6) adding ethyl acetate 2.4kg and water 2.4kg stirs, regulate pH=6～7 with saturated sodium bicarbonate solution 2kg, tell organic phase behind the standing demix, water 2.4kg washing once, and is with saturated aqueous common salt 2.4kg washing once, dry with anhydrous sodium sulphate 0.8kg, remove solvent under reduced pressure, resistates adds 3.2kg acetone, heating for dissolving, and insolubles is fallen in centrifuging, added 0.8kg normal hexane stirring and crystallizing 3 hours, icy salt solution is cooled to 0 ℃, and stirring and crystallizing 8h has a large amount of white crystals bodies, centrifugal, filter cake fully washs with acetone and normal hexane (1:9) mixed solvent 6.4kg, and is centrifugal, the dry whitening compound VIII 385g that gets, check mp:103～106 ℃, yield 32.0%.
Claims (5)
1. the preparation method of a candesartan Cilexetil is characterized in that may further comprise the steps:
(1) by 2-amino-3-nitrobenzene methyl and 4-aldehyde radical-2-biphenylcarbonitriles in organic solvent, temperature is controlled under 0 ~ 5 ℃ the condition, generates 2-[[2 '-cyanobiphenyl-4-yl through condensation reaction] methylene amino]-the 3-nitrobenzene methyl (
I);
(2) compound (
I) react with reductive agent, get 2-[[2 '-cyanobiphenyl-4-yl] methyl] amino]-the 3-Methyl anthranilate (
II);
(3) compound (II) gets 1-[(2 '-cyanobiphenyl-4-yl with tetraethyl orthocarbonate heating cyclization) methyl]-2-oxyethyl group-1H-benzoglyoxaline-7-carboxylate methyl ester (
III);
(4) compound (
III) with change nitrogenize tin reaction of tributyl, cyano group changes the tetrazole ring into, gets 2-oxyethyl group-1-[[2 '-(1H-tetrazolium-5-yl) xenyl-4-yl] methyl] benzoglyoxaline-7-carboxylic acid, ethyl ester (
IV);
(5) compound (
IV)Hydrolysis generates 2-oxyethyl group-1-[[2 '-(1H-tetrazolium-5-yl) xenyl-4-yl under alkaline condition] methyl] benzoglyoxaline-7-carboxylic acid (
V);
(6) compound (
V) react with triphenylmethyl chloride and triethylamine hydrochloride, through the N-protected reaction, obtain compound 2-oxyethyl group-1-[[2 ,-(1-trityl tetrazole-5-yl) xenyl-4 base] methyl] benzoglyoxaline-7-carboxylic acid (
VI);
(7) compound (
VI) through esterification, generate compound 2-oxyethyl group-1-[[2 ,-(1-trityl tetrazole-5-yl) xenyl-4 base] methyl] benzoglyoxaline-7-carboxylic acid, 1-[[cyclohexyl oxygen base] carbonyl] the oxygen base] ethyl ester (
VII);
(8) compound (
VII) deprotection obtains compound (±)-2-oxyethyl group-1-[[2 '-(1H-tetrazole-5-yl) [1,1 '-biphenyl]-4-yl] methyl]-1H-benzoglyoxaline-7-carboxylic acid, 1-[[cyclohexyl oxygen base] carbonyl] the oxygen base] ethyl ester (VIII).
2. the preparation method of described candesartan Cilexetil according to claim 1, it is characterized in that: the organic solvent in the step (1) be selected from acetonitrile, methyl alcohol, ethanol, Virahol, acetone, tetrahydrofuran (THF), two uh one or more in alkane, dimethyl formamide, N,N-DIMETHYLACETAMIDE, the dimethyl sulfoxide (DMSO), be preferably methylene dichloride.
3. the preparation method of described candesartan Cilexetil according to claim 1, it is characterized in that: the reductive agent in the step (2) is lithium aluminium hydride, sodium borohydride, palladium carbon (10%), is preferably palladium carbon (10%).
4. the preparation method of described candesartan Cilexetil according to claim 1, it is characterized in that: the heating cyclization temperature in the step (3) is controlled at 60-100 ℃, is preferably 80 ℃.
5. the preparation method of described candesartan Cilexetil according to claim 1, it is characterized in that: the alkaline solution under the alkaline condition in the step (5) refers to NaOH, KOH, CsOH, Ba (OH)
2, Mg (OH)
2, Ca (OH)
2, Sr (OH)
2, KH CO
3, K
2CO
3, NaH CO
3, Na
2CO
3, Cs
2CO
3In one or more mixed ammonium/alkali solutions.
?
?
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| CN2012100633575A CN103304543A (en) | 2012-03-12 | 2012-03-12 | Preparation method of candesartan cilexetil |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106032377A (en) * | 2015-03-12 | 2016-10-19 | 天津药物研究院有限公司 | Tetrazole type URAT1 inhibitors, preparing method, and uses of the inhibitors in treatment of hyperuricemia and gout |
| WO2016192099A1 (en) * | 2015-06-05 | 2016-12-08 | 浙江华海药业股份有限公司 | Method for preparing trityl candesartan |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1055927A (en) * | 1990-04-27 | 1991-11-06 | 武田药品工业株式会社 | Benzimidizole derivatives and preparation thereof and purposes |
| WO2011145100A1 (en) * | 2010-05-20 | 2011-11-24 | Hetero Research Foundation | Process for preparation of candesart an cilexetil substantially free of des-candesartan cilexetil impurity |
-
2012
- 2012-03-12 CN CN2012100633575A patent/CN103304543A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1055927A (en) * | 1990-04-27 | 1991-11-06 | 武田药品工业株式会社 | Benzimidizole derivatives and preparation thereof and purposes |
| US5196444A (en) * | 1990-04-27 | 1993-03-23 | Takeda Chemical Industries, Ltd. | 1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate and compositions and methods of pharmaceutical use thereof |
| WO2011145100A1 (en) * | 2010-05-20 | 2011-11-24 | Hetero Research Foundation | Process for preparation of candesart an cilexetil substantially free of des-candesartan cilexetil impurity |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106032377A (en) * | 2015-03-12 | 2016-10-19 | 天津药物研究院有限公司 | Tetrazole type URAT1 inhibitors, preparing method, and uses of the inhibitors in treatment of hyperuricemia and gout |
| WO2016192099A1 (en) * | 2015-06-05 | 2016-12-08 | 浙江华海药业股份有限公司 | Method for preparing trityl candesartan |
| CN107709313A (en) * | 2015-06-05 | 2018-02-16 | 浙江华海药业股份有限公司 | A kind of method for preparing trityl candesartan |
| CN107709313B (en) * | 2015-06-05 | 2020-10-23 | 浙江华海药业股份有限公司 | Method for preparing trityl candesartan |
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Application publication date: 20130918 |