CN1800179A - Method for preparing candestartan - Google Patents
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- CN1800179A CN1800179A CN 200510131970 CN200510131970A CN1800179A CN 1800179 A CN1800179 A CN 1800179A CN 200510131970 CN200510131970 CN 200510131970 CN 200510131970 A CN200510131970 A CN 200510131970A CN 1800179 A CN1800179 A CN 1800179A
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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
It is synthetic to the invention belongs to medicine.Be specifically related to a kind of preparation method of Candesartan (Candesartan).
Background technology
Candesartan (Candesartan, 1) is the antagonist of a kind of long-acting Angiotensin II hypotype I acceptor (AT1), is non-peptide medicament molecule.For overcoming the shortcoming of the oral difficult absorption of Candesartan, its prodrug---candesartan Cilexetil (Candesartan cilexetil, 2) is gone on the market.The chemistry of Candesartan is called 2-oxyethyl group-1-[[2 '-(1H-tetrazolium-5-yl) [1,1 '-biphenyl]-4-yl] methyl]-1H-benzoglyoxaline-7-carboxylic acid.The chemistry of candesartan Cilexetil is called (±)-2-oxyethyl group-1-[[2 '-(1H-tetrazolium-5-yl) [1,1 '-biphenyl]-4-yl] methyl]-1H-benzoglyoxaline-7-carboxylic acid 1-(cyclohexyloxy carbonyl oxygen) ethyl ester.The chemical structure of Candesartan and candesartan Cilexetil is as follows respectively:
Candesartan (1) candesartan Cilexetil (2)
The visible patent EP 459136 of the synthetic method of existing Candesartan and candesartan Cilexetil, CN1204125C, CN 1207287C and J.Med.Chem.1993,36,2182-2196; J.Med.Chem.1993,36,2343-2349.
In Candesartan or candesartan Cilexetil preparation process, the difference of the synthetic method of tetrazyl, existing route can be divided into following two classes:
One, existing patent EP 459136 etc., the benzimidizole derivatives (3A) that replaces with cyanobiphenyl is a raw material, adopts trialkyl azide tin and cyano group under 100-120, to react and generates tetrazotized zole compound (4A), shown in reaction formula 1:
Reaction formula 1
Tetrazotized zole compound (4A) makes Candesartan (1) again through hydrolysis.Candesartan (1) is through protection, and esterification goes protection to make candesartan Cilexetil (2).
Chinese patent CN 1204125C improves aforesaid method.The benzimidizole derivatives (3B) that replaces with cyanobiphenyl is a raw material, adopts trialkyl tin chloride/sodiumazide and cyano group to be carried out to the tetrazolium reaction under 100-120 ℃, directly prepares candesartan Cilexetil (2).Shown in reaction formula 2:
3B candesartan Cilexetil (2)
Reaction formula 2
They are two years old; benzimidizole derivatives (5) and organic zinc reagent (6) raw material of existing patent CN 1207287C to replace adopts transition metal-catalyzed aryl linked reaction, directly introduces the tetrazyl of protection; prepare candesartan Cilexetil (2) through protective reaction, shown in reaction formula 3:
Candesartan Cilexetil (2)
Reaction formula 3
In the above-mentioned patent route, first kind route adopts organotin reagent and cyano group prepared in reaction tetrazole, need under high temperature (100-120 ℃) condition, to carry out, and long reaction time, the murder by poisoning reagent contamination is bigger; In the second class route, the no industrial goods of organic zinc reagent (6), reaction needs anhydrous and oxygen-free system, operational condition harshness.
Summary of the invention
The present invention relates to the preparation method of a kind of Candesartan (1), is that raw material can conveniently synthesize candesartan Cilexetil with it.
The objective of the invention is to seek the industrial process of preparation Candesartan easy, not harsh, the low contaminative of reaction conditions.
The preparation method's of a kind of Candesartan provided by the invention reactions steps is shown in reaction formula 4:
Reaction formula 4
In the reaction formula 4, with 2-t-butoxycarbonyl amino-3-nitrobenzoyl acid esters (I) and N-(trityl group)-5-(4 '-bromomethylbiphenyl-2-yl) tetrazole (II) is raw material, under alkaline condition, get 2-[N-(tertbutyloxycarbonyl)-N-[[(2 '-(N '-trityl)-tetrazole-5-yl through the N-alkylated reaction) [1,1 '-biphenyl]-the 4-yl] methyl] amino]-3-nitrobenzoyl acid esters (III).
Specifically, be to be acid binding agent with salt of wormwood, in second eyeball solvent, under 60-90 ℃, react preparation in 6-24 hour.
In above-mentioned reaction, raw material 2-t-butoxycarbonyl amino-3-nitrobenzoyl acid esters (I) can be methyl esters or ethyl ester.
In the reaction formula 4, compound (III) heats in containing organic mixed solvent of lower aliphatic alcohols, separates protection and makes compound (IV).For example, when separating protective reaction, compound (III) can be sloughed trityl and tertbutyloxycarbonyl protecting group simultaneously, 2-[N-[(2 '-(1H-tetrazole-5-yl) [1,1 '-biphenyl]-4-yl) methyl] amino]-3-nitrobenzoyl acid esters, i.e. compound (IV).Separate protective reaction and see reaction formula 5:
Reaction formula 5:
In the similar compound of existing document (as patent EP 459136, CN 1204125C and J.Med.Chem.1993,36,2182-2196 etc.) report, the method for removing of tertbutyloxycarbonyl is to slough under acidic conditions.Find that with this understanding, the trityl in the compound (III) can migrate on the amino in our test, generate compound (VII).See reaction formula 6:
Reaction formula 6
About the method for removing of tertbutyloxycarbonyl, bibliographical information (Rawal, V.H, J.Org.Chem.1987,52,19 are arranged; Wasserman, H.H.Tetrahedron Lett., 1982,23,465) but the 180-200 ℃ of tertbutyloxycarbonyl protecting group of descending on the deaminize.
Among the present invention, we find that in containing organic mixed solvent of lower aliphatic alcohols, compound (III) can be sloughed trityl and tertbutyloxycarbonyl protecting group simultaneously, obtains compound IV with high yield.
In above-mentioned reaction, the mixture that organic mixed solvent is made up of lower aliphatic alcohols and other organic solvent.The lower aliphatic alcohols here can be selected from any one in methyl alcohol or the ethanol; Other organic solvent here is meant the solvent that can dissolve each other with lower aliphatic alcohols; Can be selected from THF, glycol dimethyl ether, ethylene glycol monomethyl ether, dioxane, methylene dichloride, ethylene dichloride, toluene, dimethylbenzene, second eyeball, the N-Methyl pyrrolidone any one or a few.
In above-mentioned reaction, lower aliphatic alcohols is 1: 5 to 20: 1 with other volume of organic solvent ratio, and optimum condition was at 5: 5 to 10: 1.
In above-mentioned reaction, the temperature of reaction of separating protective reaction is at 30-140 ℃, and optimum condition is at 50-100 ℃.
In the reaction formula 4, the compound IV is in organic solvent, and metal catalyst exists down, the catalytic hydrogenating reduction nitro, 2-[N-[(2 '-(1H-tetrazole-5-yl) [1,1 '-biphenyl]-4-yl) methyl] amino]-3-Aminobenzoate (V).The reduction reaction of nitro in the compound IV can be carried out similarly by known general method.Reaction medium is ethyl acetate, tetrahydrofuran (THF), lower alcohol (as methyl alcohol, ethanol etc.), and metal catalyst is Pd-C, Raney's nickel etc., and reaction pressure is at 1-10atm, and the reaction times is 4-24 hour.Reaction intermediate compound V does not need purifying, can be directly used in the next step.
In the reaction formula 4, compound (V) and tetraethyl orthocarbonate are in organic solvent commonly used, with in the presence of organic acid, the heating cyclization makes 2-oxyethyl group-1-[[2 '-(1H-tetrazolium-5-yl) [1,1 '-biphenyl]-4-yl] methyl]-1H-benzimidazole-7-carboxylate (VI).
Reaction formula 7
Experiment shows, in above-mentioned reaction, and the consumption outbalance of tetraethyl orthocarbonate, when tetraethyl orthocarbonate far surpassed stoichiometry, by product VIII appearred in ring-closure reaction, influences reaction yield, shown in reaction formula 7.We find, in organic solvent, when the consumption of control tetraethyl orthocarbonate slightly surpasses stoichiometry, can effectively suppress side reaction.
Specifically, organic solvent commonly used refers to aliphatic hydrocarbon (as normal hexane, sherwood oil), aromatic hydrocarbons (as benzene, toluene), ethyl acetate, tetrahydrofuran (THF), second eyeball etc. in the above-mentioned reaction.
In the above-mentioned reaction, organic acid refers to acetate, formic acid, methanesulfonic or tosic acid.Be preferably acetate, methanesulfonic.The consumption that organic acid calculates with equivalent is 2-[N-[(2 '-(1H-tetrazole-5-yl) [1,1 '-biphenyl]-4-yl) methyl] amino]-0.1-5.0 of 3-Aminobenzoate (V) doubly, optimum condition be 0.1-0.5 doubly.
The consumption that tetraethyl orthocarbonate calculates with equivalent is 2-[N-[(2 '-(1H-tetrazole-5-yl) [1,1 '-biphenyl]-4-yl) methyl] amino]-0.9-2 of 3-Aminobenzoate (V) doubly, optimum condition be 0.9-1.2 doubly.
In above-mentioned reaction, the scope of temperature of reaction is at 30-150 ℃, and optimum condition is at 50-100 ℃.
In the reaction formula 4, compound VI hydrolysis under alkaline condition, acidifying can make 2-oxyethyl group-1-[[2 '-(1H-tetrazolium-5-yl) [1,1 '-biphenyl]-4-yl easily] methyl]-1H-benzoglyoxaline-7-carboxylic acid (Candesartan, 1).
In last step reaction, the hydrolysis reaction of compound VI can be with reference to currently known methods, as document J.Med.Chem.1993,36,2182-2196; J.Med.Chem.1993,36,2343-2349 in the alkaline condition hydrolysis, can make Candesartan after the acidifying easily.
Compare with the synthetic method of existing Candesartan, the present invention has the following advantages:
1. be raw material with N-(trityl group)-5-(4 '-bromomethylbiphenyl-2-yl) tetrazole (II), directly introduce tetrazole ring, avoid using the dangerous raw material of poisoning such as triazo-compound, trialkyl azide tin or trialkyl tin chloride.
2. raw material is easy to get, and operating procedure is simple, is easy to suitability for industrialized production.
Embodiment
Below each embodiment further specify the present invention, but be not that the present invention is imposed any restrictions.
The preparation of reference example 1. 2-t-butoxycarbonyl amino-3-ethyl nitrobenzoate (I, R=ethyl)
Thermometer, reflux condensing tube, drying tube are being housed, and in the churned mechanically 1000mL four-hole bottle, are adding 2-carboxyl-3-ethyl nitrobenzoate (240g successively, 1.0mol), sulfur oxychloride (120mL), and exsiccant toluene 600mL, stir back flow reaction 3.5h down, concentrating under reduced pressure.Resistates is dissolved in the 200mL methylene dichloride, this solution is under agitation slowly splashed in DMF (200mL) solution of 96g sodiumazide stirring reaction 30min.After reaction finishes, with reaction solution impouring ether-normal hexane (3: 1,1L) and in the mixed solution of water (1L); Tell organic phase, behind deionized water wash, be evaporated to half volume, add the 600mL trimethyl carbinol, stir and slowly be heated to backflow down, decompression steams solvent behind the reaction 2h, promptly get 2-t-butoxycarbonyl amino-3-ethyl nitrobenzoate, be yellow paste, weight 300g, yield 94%, HPLC purity are 92%.These product are directly used in the next step.
The preparation of reference example 2. 2-t-butoxycarbonyl amino-3-nitrobenzoic acid methyl esters (I, R=methyl)
According to the method for reference example 1, the 2-carboxyl-3-nitrobenzoic acid methyl esters replacement 2-carboxyl-3-ethyl nitrobenzoate with 225g gets yellow paste 290g, i.e. target product 2-t-butoxycarbonyl amino-3-nitrobenzoic acid methyl esters.Yield 94%, HPLC purity are 93%.
Embodiment 1.2-[N-(tertbutyloxycarbonyl)-N-[[(2 '-(N '-trityl)-tetrazole-5-yl) [1,1 '-biphenyl]-4-yl] methyl] amino]-preparation of 3-ethyl nitrobenzoate (III, R=ethyl)
Thermometer, reflux condensing tube, drying tube are being housed, and in the churned mechanically 1000mL four-hole bottle, (purity 92% 0.15mol) and second eyeball 500ml, stirs and adds salt of wormwood 32g (0.23mol) down to add 2-t-butoxycarbonyl amino-3-ethyl nitrobenzoate 51.4g.Mixture stirred after 30 minutes, add again N-(trityl group)-5-(4 '-bromomethylbiphenyl-2-yl) tetrazole (II) 89g (content 95%, 0.15mol), stirring and refluxing reaction 14 hours.Cold filtration, concentrating under reduced pressure reclaims the second eyeball.Resistates is dissolved in the methylene dichloride, the washing, organic phase with anhydrous sodium sulfate drying after, concentrating under reduced pressure gets faint yellow oily thing.This oily matter is intermediate III, weight 131g.These product can be directly used in the next step.Fusing point: 156-157 ℃.
Embodiment 2. 2-[N-[(2 '-(1H-tetrazole-5-yl) [1,1 '-biphenyl]-4-yl) methyl] amino]-preparation of 3-ethyl nitrobenzoate (IV, R=ethyl)
Thermometer, reflux condensing tube, drying tube are being housed, and in the churned mechanically 1000mL four-hole bottle, with 2-{N-(the tertbutyloxycarbonyl)-N-[(2 ' of gained of last step-(N '-trityl)-tetrazole-5-yl) biphenyl-4-yl] amino }-3-ethyl nitrobenzoate crude product is dissolved in the mixed solvent of 100ml ethyl acetate and 500ml methyl alcohol, reflux 24 hours concentrates.Resistates filters with methylene dichloride and sherwood oil crystallization, and a little petroleum ether of filter cake is drained, and vacuum-drying gets faint yellow solid 54.4g, is 2-[N-[(2 '-(1H-tetrazole-5-yl) biphenyl-4-yl) amino]-the 3-ethyl nitrobenzoate.In 2-t-butoxycarbonyl amino-3-ethyl nitrobenzoate, two step total recoverys are 81.5%.After the gained solid was used methylene dichloride and sherwood oil recrystallization, analytical results was as follows.Fusing point: 105-106 ℃, ultimate analysis: C23H20N6O4, calculated value (%): C, 62.16; H, 4.54; N, 18.91; O, 14.40, measured value (%): C, 62.21; H, 4.49; N, 14.48.1H-NMR(400MHz，DMSO-d6)1.27(t，J＝5.2Hz，3H)，4.14(d，J＝4.4Hz，2H)，4.26(q，J＝5.6Hz，2H)，6.83(t，J＝6.4Hz，1H)，7.07(d，J＝6.4Hz，2H)，7.24(d，J＝6.4Hz，2H)，7.53-7.58(m，2H)，7.64-7.67(m，2H)，8.05(d，J＝6Hz，2H)，8.56(brs，1H)。
Embodiment 3. 2-[N-[(2 '-(1H-tetrazole-5-yl) [1,1 '-biphenyl]-4-yl) methyl] amino]-preparation of 3-nitrobenzoic acid methyl esters (IV, R=methyl)
Thermometer, reflux condensing tube, drying tube are being housed, and in the churned mechanically 1000mL four-hole bottle, (purity 93% 0.15mol) and second eyeball 500ml, stirs and adds salt of wormwood 32g (0.23mol) down to add 2-t-butoxycarbonyl amino-3-nitrobenzoic acid methyl esters 47.7g.Mixture stirred after 30 minutes, add again N-(trityl group)-5-(4 '-bromomethylbiphenyl-2-yl) tetrazole (II) 89g (content 95%, 0.15mol), stirring and refluxing reaction 14 hours.Cold filtration, concentrating under reduced pressure reclaims the second eyeball.Add the 150ml acetic acid ethyl dissolution in the resistates, washing, organic layer with anhydrous sodium sulfate drying after, filter.Add 600ml methyl alcohol in the filtrate, reflux 24 hours concentrates.Resistates filters with methylene dichloride and sherwood oil crystallization, and a little petroleum ether of filter cake is drained, and vacuum-drying must solid 54.8g, is 2-[N-[(2 '-(1H-tetrazole-5-yl) [1,1 '-biphenyl]-4-yl) methyl] amino]-3-nitrobenzoic acid methyl esters.In 2-t-butoxycarbonyl amino-3-nitrobenzoic acid methyl esters, yield is 85.5%.
Embodiment 4. 2-[N-[(2 '-(1H-tetrazole-5-yl) [1,1 '-biphenyl]-4-yl) methyl] amino]-preparation of 3-Methyl anthranilate (V, R=methyl)
In 1 liter of autoclave, add 2-[N-[(2 '-(1H-tetrazole-5-yl) biphenyl-4-yl) amino]-3-nitrobenzoic acid methyl esters 43.1g (0.1mol), ethyl acetate 450ml, 10% palladium carbon 2.5g, 3atm hydrogenation is filtered, and concentrating under reduced pressure gets oily matter 40.5g.This oily matter is 2-[N-[(2 '-(1H-tetrazole-5-yl) [1,1 '-biphenyl]-4-yl) methyl] amino]-the 3-Methyl anthranilate, can be directly used in the next step.
Embodiment 5. 2-oxyethyl group-1-[[2 '-(1H-tetrazolium-5-yl) [1,1 '-biphenyl]-4-yl] methyl]-preparation of 1H-benzoglyoxaline-7-carboxylate methyl ester (VI, R=methyl)
Thermometer, reflux condensing tube, drying tube are being housed, are reaching in the churned mechanically 500mL four-hole bottle, add 2-[N-[(2 '-(1H-tetrazole-5-yl) [1 successively, 1 '-biphenyl]-the 4-yl) methyl] amino]-3-Methyl anthranilate 40g, tetraethyl orthocarbonate 16.3g (0.12mol), acetate 3g, and the 200ml ethyl acetate, stirring and refluxing reaction 1 hour.Cooling in ice-water bath, neutralizes with saturated sodium bicarbonate aqueous solution; Tell organic phase then, use saturated sodium-chloride, deionized water wash successively, anhydrous sodium sulfate drying.Concentrating under reduced pressure gets paste.Activated carbon decolorizing, ethyl acetate-chloroform recrystallization get 2-oxyethyl group-1-[[2 '-(1H-tetrazolium-5-yl) [1,1 '-biphenyl]-4-yl] methyl]-1H-benzoglyoxaline-7-carboxylate methyl ester 27.8g, yield is 61%, fusing point 191-192 ℃.
Embodiment 6. 2-[N-[(2 '-(1H-tetrazole-5-yl) [1,1 '-biphenyl]-4-yl) methyl] amino]-preparation of 3-subcutin (V, R=ethyl)
In 1 liter of autoclave, adding 2-[N-[(2 '-(1H-tetrazole-5-yl) [1,1 '-biphenyl]-the 4-yl) methyl] amino]-3-ethyl nitrobenzoate 44.4g (0.1mol), ethyl acetate 350ml, 5% palladium carbon 3.5g, 2atm hydrogenation, filter, concentrating under reduced pressure gets oily matter 42.5g.This oily matter is 2-[N-[(2 '-(1H-tetrazole-5-yl) [1,1 '-biphenyl]-4-yl) methyl] amino]-the 3-subcutin, can be directly used in the next step.
Embodiment 7. 2-oxyethyl group-1-[[2 '-(1H-tetrazolium-5-yl) [1,1 '-biphenyl]-4-yl] methyl]-preparation of 1H-benzoglyoxaline-7-carboxylic acid, ethyl ester (VI, R=ethyl)
Thermometer, dropping funnel, reflux condensing tube (drying tube) are being housed, and in the churned mechanically 500mL four-hole bottle, add 2-[N-[(2 '-(1H-tetrazole-5-yl) [1 successively, 1 '-biphenyl]-the 4-yl) methyl] amino]-3-subcutin 42g, acetate 2g, and 300ml benzene are heated to backflow, drip tetraethyl orthocarbonate 19.1g (0.14mol), stirring and refluxing reaction 1 hour.Cooling in ice-water bath, neutralizes with saturated sodium bicarbonate aqueous solution; Tell organic phase then, use saturated sodium-chloride, deionized water wash successively, anhydrous sodium sulfate drying.Concentrating under reduced pressure gets paste.Activated carbon decolorizing, ethyl acetate-benzene recrystallization, 2-oxyethyl group-1-[[2 '-(1H-tetrazolium-5-yl) [1,1 '-biphenyl]-4-yl] methyl]-1H-benzoglyoxaline-7-carboxylic acid, ethyl ester 25.4g, yield is 54.2%, fusing point 158-159 ℃.
Embodiment 8. 2-oxyethyl group-1-[[2 '-(1H-tetrazolium-5-yl) [1,1 '-biphenyl]-4-yl] methyl]-preparation of 1H-benzoglyoxaline-7-carboxylic acid (Candesartan, 1)
Thermometer is being housed, reflux condensing tube, and in the churned mechanically 500mL there-necked flask, add successively and press prepared 2-oxyethyl group-1-[[2 '-(the 1H-tetrazolium-5-yl) [1 of example 5,1 '-biphenyl]-the 4-yl) methyl)-1H-benzoglyoxaline-7-carboxylate methyl ester 55g (0.12mol), methyl alcohol 300ml, and the NaOH aqueous solution 150ml of 1M, backflow stirring reaction 1 hour concentrates, enriched material adds deionized water 150ml, use ethyl acetate extraction, water layer is adjusted to pH3～4 with the hydrochloric acid of 1M and separates out crystal, with it at the ethyl acetate-ethanol recrystallization, get product Candesartan (1) 46g, fusing point, 181-183 ℃, yield is 86%.1H-NMR(400MHz，DMSO-d6)1.38(t，J＝7.0Hz，3H)，4.58(q，J＝7.0Hz，2H)，5.62(s，2H)，6.95(d，J＝8.5Hz，2H)，7.03(d，J＝8.5Hz，2H)，7.47-7.69(m，6H)。
Embodiment 9. 2-oxyethyl group-1-[[2 '-(1H-tetrazolium-5-yl) [1,1 '-biphenyl]-4-yl] methyl]-preparation of 1H-benzoglyoxaline-7-carboxylic acid (Candesartan, 1)
Thermometer is being housed, reflux condensing tube, and in the churned mechanically 500mL there-necked flask, add successively and press prepared 2-oxyethyl group-1-[[2 '-(the 1H-tetrazolium-5-yl) [1 of example 7,1 '-biphenyl]-the 4-yl] methyl]-1H-benzoglyoxaline-7-carboxylic acid, ethyl ester 48g (0.10mol), ethanol 300ml, and the NaOH aqueous solution 150ml of 1M, room temperature reaction is after 1 hour, reaction solution backflow stirring reaction 1 hour, concentrate, enriched material adds deionized water 150ml, uses ethyl acetate extraction, water layer is adjusted to pH3～4 with the hydrochloric acid of 1M and separates out crystal, it at the ethyl acetate-ethanol recrystallization, is got product Candesartan (1) 38.8g, fusing point, 181-183 ℃, yield is 88%.
Claims (11)
1, a kind of method for preparing Candesartan is characterized in that reactions steps is shown in reaction formula 4:
Reaction formula 4
In the reaction formula 4; with 2-t-butoxycarbonyl amino-3-nitrobenzoyl acid esters (I) and N-(trityl group)-5-(4 '-bromomethylbiphenyl-2-yl) tetrazole (II) is raw material; through the N-alkylated reaction; separate protective reaction; reduction reaction, ring-closure reaction and ester hydrolysis reaction make Candesartan (1).
2. method according to claim 1, it is characterized in that 2-[N-(tertbutyloxycarbonyl)-N-[[(2 '-(N '-trityl)-tetrazole-5-yl) [1,1 '-biphenyl]-4-yl] methyl] amino]-3-nitrobenzoyl acid esters (III) makes through the N-alkylated reaction by 2-t-butoxycarbonyl amino-3-nitrobenzoyl acid esters (I) and N-(trityl group)-5-(4 '-bromomethylbiphenyl-2-yl) tetrazole (II).
3. method according to claim 1; it is characterized in that described separating in the protective reaction; 2-[N-[(2 '-(1H-tetrazole-5-yl) [1; 1 '-biphenyl]-the 4-yl) methyl] amino]-3-nitrobenzoyl acid esters (IV) be by compound (III) in containing organic mixed solvent of lower aliphatic alcohols, slough trityl simultaneously and the tertbutyloxycarbonyl protecting group makes.
4. method according to claim 3 is characterized in that the mixture that described organic mixed solvent is made up of lower aliphatic alcohols and other organic solvent;
The lower aliphatic alcohols here can be selected from any one in methyl alcohol or the ethanol;
Other organic solvent here is the solvent that can dissolve each other with lower aliphatic alcohols; Can be selected from THF, glycol dimethyl ether, ethylene glycol monomethyl ether, dioxane, methylene dichloride, ethylene dichloride, toluene, dimethylbenzene, second eyeball, the N-Methyl pyrrolidone any one or a few.
5. method according to claim 3 is characterized in that described lower aliphatic alcohols and other volume of organic solvent ratio are 1: 5 to 20: 1, preferred 5: 5 to 10: 1.
6. method according to claim 3, the temperature of reaction that it is characterized in that separating protective reaction be at 30-140 ℃, preferred 50-100 ℃.
7. method according to claim 1, it is characterized in that 2-oxyethyl group-1-[[2 '-(1H-tetrazolium-5-yl) [1,1 '-biphenyl]-the 4-yl] methyl]-1H-benzimidazole-7-carboxylate (VI) be by compound (V) and tetraethyl orthocarbonate in organic solvent commonly used, with in the presence of organic acid, the heating cyclization makes.
8. method according to claim 7 is characterized in that the organic solvent of using always can be selected from as in the aliphatic hydrocarbon of normal hexane, sherwood oil any one; Also can be selected from as benzene any one in the aromatic hydrocarbons of toluene; Also can be selected from ethyl acetate, tetrahydrofuran (THF), any one in the second eyeball.
9. method according to claim 7 is characterized in that described organic acid can be selected from acetate, formic acid, methanesulfonic, any one in the tosic acid; Be preferably in acetate, the methanesulfonic any one; The consumption that organic acid calculates with equivalent is 0.1-5.0 a times of compound (V), and preferred 0.1-0.5 doubly.
10. method according to claim 7 is characterized in that the consumption that tetraethyl orthocarbonate calculates with equivalent, is 0.9-2 times of compound (V), and preferred 0.9-1.2 doubly.
11. method according to claim 1 is characterized in that compound VI hydrolysis under alkaline condition, acidifying can make Candesartan (1).
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| WO2008131582A1 (en) * | 2007-04-26 | 2008-11-06 | Topharman Shanghai Co., Ltd. | The method for making candixatan ester and intermediates thereof |
| WO2010067912A1 (en) * | 2008-12-12 | 2010-06-17 | Pharmacostech Co., Ltd. | Methods for preparing biphenyl benzoic acid derivatives |
| CN102702176A (en) * | 2012-06-05 | 2012-10-03 | 江西同和药业有限责任公司 | Preparation method for triphenyl candesartan |
| CN102850332A (en) * | 2011-06-29 | 2013-01-02 | 中国药科大学 | 1-(2,6-Dichlorophenyl)-3-n-butyl-1,4-dihydro-4-[4-[2-(1H-tetrazole-5-yl)-1H-pyrrole-1-yl]phenylmethyl]-5H-1,2,4-triazole-5-one with cardiovascular activity and synthesis process of medicinal salt thereof |
| CN101648918B (en) * | 2008-08-15 | 2013-01-09 | 联化科技股份有限公司 | Intermediate compound of candesartan cilexetil and synthesis method thereof |
| CN102952040A (en) * | 2012-11-20 | 2013-03-06 | 峨眉山天梁星制药有限公司 | Method for reducing nitro group of candesartan cilexetil intermediate into amino group |
| CN106699737A (en) * | 2016-12-07 | 2017-05-24 | 浙江华海药业股份有限公司 | Refining method of candesartan |
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| 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 |
| CN1207287C (en) * | 2002-12-23 | 2005-06-22 | 重庆圣华曦药业有限公司 | Ester compounds of bezimidazole and their preparations and uses in preparation of medicinal compound |
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| CN106699737A (en) * | 2016-12-07 | 2017-05-24 | 浙江华海药业股份有限公司 | Refining method of candesartan |
| CN114163391A (en) * | 2021-12-14 | 2022-03-11 | 迪嘉药业集团有限公司 | Candesartan intermediate and preparation method of candesartan |
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