CN102190652A - Preparation method of losartan metabolite EXP-3174 - Google Patents
Preparation method of losartan metabolite EXP-3174 Download PDFInfo
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- CN102190652A CN102190652A CN2011100483075A CN201110048307A CN102190652A CN 102190652 A CN102190652 A CN 102190652A CN 2011100483075 A CN2011100483075 A CN 2011100483075A CN 201110048307 A CN201110048307 A CN 201110048307A CN 102190652 A CN102190652 A CN 102190652A
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Abstract
The invention discloses a preparation method of a losartan metabolite EXP-3174. The chemical name of the EXP-3174 is 2-butyl-4-chloro-5-carboxy-1-{[2'-(1H-tetrazolyl-5-yl)-biphenyl-4]-methyl}imidazole. The preparation method is realized in a way that: 2-butyl-4-chloro-5-formacyl-1-{[2'-(1H-tetrazolyl-5-yl)-biphenyl-4]-methyl}imidazole is used as the raw material, a polar solvent is used as the solvent, and the pH value is regulated and controlled at 1-7 with a buffer solution; and in the presence of hydrogen peroxide, a sodium chlorite-antichlor system is used for oxidizing aldehyde to generate the corresponding carboxylic acid, and finally, the 2-butyl-4-chloro-5-carboxy-1-{[2'-(1H-tetrazolyl-5-yl)-biphenyl-4]-methyl}imidazole is generated. The preparation method has the advantages of mild reaction conditions, environment friendliness, high yield and purity, low cost for after-treatment and production, and the like, is simple to operate, and is applicable to industrial large-scale production.
Description
Technical field
It is synthetic to the invention belongs to medicine.Be specifically related to losartan meta-bolites 2-butyl-4-chloro-5-carboxyl-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4]-methyl } preparation method of imidazoles (EXP-3174).
Background technology
Losartan (Losartan, trade(brand)name losartan) is a kind of non-peptide class Angiotensin II (Ang II) receptor antagonist pharmaceuticals.Medical research finds that Ang II acceptor has two kinds of hypotype AT1 and AT2, and wherein the AT1 hypotype has clinical meaning most.Acceptor AT1 mainly is distributed in positions such as vascular smooth muscle, cardiac muscular tissue, brain, kidney and adrenal cortex glomerular zone cell, participates in cardiac muscle and smooth muscle contraction, regulates aldosterone secretion etc., and cardiovascular function stable had regulating effect.Losartan is first AT1 receptor antagonist with Orally active of selling on market, it also is the maximum antagonist of clinical experience accumulation, it has represented the prototype of highly selective AT1 receptor antagonist, derived from by the military field of 1-phenmethyl imidazoles-5-acetogenin (Takeda) series, this analog derivative is considered to the weak antagonist of Angiotensin II.Carry out metabolic conversion through enzymes such as Cytochrome P450s in vivo behind the oral losartan and be active stronger 2-butyl-4-chloro-5-carboxyl-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4]-methyl } imidazoles (EXP-3174), losartan and meta-bolites 2-butyl-4-chloro-5-carboxyl-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4]-methyl imidazoles (EXP-3174) only with the effect of AT1 receptors bind, and meta-bolites 2-butyl-4-chloro-5-carboxyl-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4]-methyl } imidazoles (EXP-3174) is 10 times of losartan to the restraining effect intensity of AT1, have higher pharmacologically active than parent, most of effectiveness of losartan is all from 2-butyl-4-chloro-5-carboxyl-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4]-methyl } imidazoles (EXP-3174).Losartan active metabolite 2-butyl-4-chloro-5-carboxyl-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4]-methyl } imidazoles (EXP-3174) energy selectivity and AT1 receptors bind, the effect of blocking-up Ang II produces hypotensive effect.In addition, the time that losartan sylvite peaks in blood was at 1.5～2.5 hours, and its meta-bolites 2-butyl-4-chloro-5-carboxyl-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4]-methyl } imidazoles (EXP-3174) time of peaking in blood, this also made its meta-bolites more help oral administration at 3～4 hours.
Losartan and losartan meta-bolites 2-butyl-4-chloro-5-carboxyl-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4]-methyl } chemical structural formula of imidazoles (EXP-3174) is respectively:
About preparing losartan meta-bolites 2-butyl-4-chloro-5-carboxyl-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4]-methyl the method for imidazoles (EXP-3174), bibliographical information is less, open report following six kinds of preparation methods are arranged.
Duncia, J.V.; Carini, D.J.; Chiu, A.T.; Pierce, M.E.; Price, W.A.; Smith, R.D.; Wells, G.J.; Wong, P.C.; Wexler, R.R.; Johnson, A.L.; Timmermans, P.B.M.W.M. wait the people at Drugs of the Future, 1991, reported the potassium permanganate direct oxidation method in 16 (4), obtain its meta-bolites 2-butyl-4-chloro-5-carboxyl-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4 by the oxidation of losartan sylvite]-methyl } imidazoles (EXP-3174), reaction equation is as follows:
Prepare carboxylic acid derivative by losartan sylvite with the potassium permanganate direct oxidation, the oxidizing condition that need use is fierce, produces a large amount of by products, and crude product purity is low, the separation and purification difficulty.
Vincenzo Santagada; Ferdinando Fiorino; Elisa Perissutti; Beatrice Severino; Sara Terracciano; Cleber Evandro Teixeira; People such as Giuseppe Caliendo are at Tetrahedron Letters, propose in 2003 (44) to obtain its meta-bolites 2-butyl-4-chloro-5-carboxyl-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4 by the oxidation of losartan sylvite process microwave]-methyl } imidazoles (EXP-3174), reaction equation is as follows:
This method also can produce some by products; document report; have midbody product Losartan 5-carboxaldehyde (EXP-3179) can not be converted into meta-bolites 2-butyl-4-chloro-5-carboxyl-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4 fully in the reaction process]-methyl } imidazoles (EXP-3174), compound 2-butyl-4-chloro-5-formyl radical-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4]-methyl } imidazoles (EXP-3179) and 2-butyl-4-chloro-5-carboxyl-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4]-methyl } imidazoles (EXP-3174) warp all
1H NMR and MS spectrogram have carried out structural confirmation; these two compounds need carry out separation and purification through preparative chromatography; losartan meta-bolites 2-butyl-4-chloro-5-carboxyl-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4]-methyl } yield of imidazoles (EXP-3174) is 64%, large-scale production compound 2-butyl-4-chloro-5-carboxyl-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4]-methyl } imidazoles (EXP-3174) seriously is subjected to the restriction of plant and instrument.
Morteza Pirali-Hamedani, Alireza Aliabadi, M.Shekarchi, M.Amini, Mohammad Reza Rouini, people such as Abbas Shafiee and Alireza Foroumadi are at Asian Journal of Chemistry, 2009, proposed in 21 (6) to prepare its meta-bolites 2-butyl-4-chloro-5-carboxyl-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4 through four kinds of method for oxidation by Losartan 5-carboxa-ldehyde (EXP-3179)]-methyl } imidazoles (EXP-3174), reaction equation is as follows:
The used reagent of four kinds of above-mentioned different method for oxidation and yield etc. see the following form:
As can be seen from the table, the yield of above-mentioned four kinds of methods is also all between 51%-71%, and the document reports that also its raw material Losartan 5-carboxaldehyde (EXP-3179) can not be converted into meta-bolites 2-butyl-4-chloro-5-carboxyl-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4 fully]-methyl } imidazoles (EXP-3174), so yield is unsatisfactory.
Summary of the invention
The present invention for solve severe reaction conditions in the art methods, efficiency of pcr product and yield low, can not large-scale production etc. technical problem, seek a kind of industrial mass production high-purity compound 2-butyl-4-chloro-5-carboxyl-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4 of economical and convenient]-methyl the method for imidazoles (EXP-3174).
Technical scheme of the present invention
A kind of losartan meta-bolites 2-butyl-4-chloro-5-carboxyl-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4]-methyl } preparation method of imidazoles (EXP-3174); promptly adopt 2-butyl-4-chloro-5-formyl radical-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4]-methyl } imidazoles (EXP-3179) is raw material; make solvent with polar solvent; regulating and control the pH value with buffered soln is 1～7; be preferably 4.5; in the presence of hydrogen peroxide; controlled temperature is-10 ℃～30 ℃; be preferably 5 ℃; generate corresponding carboxylic acid by Textone-antichlor system oxidation aldehyde; finally generated losartan meta-bolites 2-butyl-4-chloro-5-carboxyl-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4]-methyl } imidazoles (EXP-3174), its chemical equation is as follows:
Used polar solvent is methyl alcohol, ethanol, Virahol, acetone, N, and one or more in dinethylformamide or the methyl-sulphoxide mix.
Above-mentioned a kind of losartan meta-bolites 2-butyl-4-chloro-5-carboxyl-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4]-methyl } preparation method of imidazoles (EXP-3174), specifically comprise being prepared as follows step:
(1), in container, add 2-butyl-4-chloro-5-formyl radical-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4]-methyl imidazoles, polar solvent, the control mixing speed is that 300rpm/min stirs, and forms clear solution;
The volumetric usage of used polar solvent is 2-butyl-4-chloro-5-formyl radical-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4]-methyl } 1.1～50 times of quality of imidazoles; Be preferably 8 times;
(2), add the biphosphate sodium water solution in the clear solution of gained in the step (1) or be 1.0～7.0 by the formulated buffered soln adjusting pH value of aqueous sodium acetate solution and acetic acid aqueous solution, add concentration again and be 10%～50% aqueous hydrogen peroxide solution; Under-10 ℃～30 ℃, slowly drip the sodium chlorite aqueous solution then, the control drop rate is 1mL/min, dropwises, and continues stirring reaction 3～5 hours;
In the said process by adding the biphosphate sodium water solution or being 1.0～7.0 by the pH value that the formulated buffered soln of aqueous sodium acetate solution and acetic acid aqueous solution is kept solution;
Aqueous hydrogen peroxide solution concentration in the reaction is preferably 30%, and its hydrogen peroxide consumption is the used 2-butyl of step (1)-4-chloro-5-formyl radical-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4]-methyl } 1.1～50 times of imidazoles amount of substance; Be preferably 1.5 times;
Textone consumption in the reaction is the used 2-butyl of step (1)-4-chloro-5-formyl radical-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4]-methyl } 1.1～50 times of imidazoles amount of substance; Be preferably 1.5 times;
Above-mentioned used SODIUM PHOSPHATE, MONOBASIC concentration of aqueous solution is preferably 8%, aqueous sodium acetate solution concentration is preferably 0.2mol/L in 1: 1 by volume formulated buffered soln of aqueous sodium acetate solution and acetic acid aqueous solution, acetic acid aqueous solution concentration is preferably 0.3mol/L;
(3), in the solution of step (2) gained, add S-WAT again to remove unreacted hydrogen peroxide oxidant;
Add S-WAT in (2) 1.1～50 times of the amount of substance of used hydrogen peroxide set by step of amounts; Be preferably 1.5 times;
(4), step (3) is removed solution behind the hydrogen peroxide oxidant;
If reaction system is used the lower solvents of boiling point such as methyl alcohol, ethanol, Virahol, acetone, remove through the Rotary Evaporators underpressure distillation and to desolvate, residual solution ethyl acetate extraction separatory, dry, concentrate, obtain white solid losartan meta-bolites 2-butyl-4-chloro-5-carboxyl-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4]-methyl } imidazoles (EXP-3174);
If reaction system is used N, the water miscible solvent of the high boiling point of dinethylformamide or methyl-sulphoxide, then will react in the water of 5-10 times of volume of feed liquid impouring with dispersion solvent, use the ethyl acetate extraction separatory again, dry, concentrate, obtain white solid losartan meta-bolites 2-butyl-4-chloro-5-carboxyl-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4] methyl } imidazoles (EXP-3174).
Beneficial effect of the present invention
A kind of losartan meta-bolites 2-butyl of the present invention-4-chloro-5-carboxyl-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4]-methyl } preparation method of imidazoles (EXP-3174), select for use Virahol or methyl-sulphoxide as solvent, SODIUM PHOSPHATE, MONOBASIC or acetate/sodium acetate are made buffer reagent, at 5 ℃, generate corresponding carboxylic acid by Textone-antichlor system oxidation aldehyde, final losartan metabolism 2-butyl-4-chloro-5-carboxyl-1-{[2 '-(1H-tetrazolium-5-the yl)-biphenyl-4 that gets]-methyl } imidazoles (EXP-3174), under preferred processing condition, losartan meta-bolites 2-butyl-4-chloro-5-carboxyl-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4]-methyl } imidazoles (EXP-3174) yield can reach more than 85%, purity detects through high performance liquid chromatography and reaches more than 99.0%, thereby have a productive rate height, the advantage that purity is high; Temperature of reaction is 5 ℃, thereby mild condition; The by product that oxygenant generates is a water, and excess oxide is also removed by S-WAT easily, thereby environmental friendliness, and postprocessing working procedures is simple, reduces the production cost of aftertreatment; There is not harsh complicated operations requirement yet.
Six kinds of prior art prepare losartan meta-bolites 2-butyl-4-chloro-5-carboxyl-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4]-methyl } in the method for imidazoles (EXP-3174), Duncia, J.V.; Carini, D.J.; Chiu, A.T.; Pierce, M.E.; Price, W.A.; Smith, R.D.; Wells, G.J.; Wong, P.C.; Wexler, R.R.; Johnson, A.L.; Timmermans, the potassium permanganate oxygen of people such as P.B.M.W.M. report is sent out the play-by-play that method is not seen yield and purity; Vincenzo Santagada; Ferdinando Fiorino; Elisa Perissutti; Beatrice Severino; Sara Terracciano; Cleber Evandro Teixeira; The microwave oxidation style yield of people such as Giuseppe Caliendo report is 64%, and its purity is not appeared in the newspapers.Morteza Pirali-Hamedani, Alireza Aliabadi, M.Shekarchi, M.Amini, Mohammad Reza Rouini, the yield of four kinds of methods of people such as Abbas Shafiee and Alireza Foroumadi report is between 51%-71%, and its purity is through thin-layer chromatography (Thin Layer Chromatography, TLC) detect, do not have explicit data.
The present invention compared with prior art adopts Textone-antichlor system oxidation aldehyde to generate corresponding carboxylic acid, than Duncia, and J.V.; Carini, D.J.; Chiu, A.T.; Pierce, M.E.; Price, W.A.; Smith, R.D.; Wells, G.J.; Wong, P.C.; Wexler, R.R.; Johnson, A.L.; Timmermans, the potassium permanganate direct oxidation method mild condition of people such as P.B.M.W.M. report, the crude product composition for preparing is single, purity height, easier recrystallization purifying;
The inventive method is than Vincenzo Santagada; Ferdinando Fiorino; Elisa Perissutti; Beatrice Severino; Sara Terracciano; Cleber Evandro Teixeira; It is about 20% that the microwave oxidation style yield that people such as Giuseppe Caliendo propose exceeds, and carries out scale operation also easilier, can carry out simply and easily feather weight or tonne industrial production and be not subjected to the influence and the restriction of plant and instrument;
The inventive method is than Morteza Pirali-Hamedani, Alireza Aliabadi, M.Shekarchi, M.Amini, Mohammad Reza Rouini, the yield of four kinds of methods of people such as Abbas Shafiee and Alireza Foroumadi report has improved more than the 12%-32%.
In sum, preparation method of the present invention in the prior art about losartan meta-bolites 2-butyl-4-chloro-5-carboxyl-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4]-methyl the preparation method of imidazoles (EXP-3174), the production cost of preparation method's reaction conditions gentleness of the present invention, environmental friendliness, aftertreatment is low, simple to operate, productive rate and the high synthetic method of purity, its productive rate reaches more than 85% under optimized technical scheme, purity reaches more than 99%, and is applicable to commercial scale production.
Embodiment
The present invention will be described in detail by means of the following examples, but the present invention is not limited to this.In analysis, use high performance liquid chromatography detection material purity.
As follows among the present invention for realizing reagent used in the present invention:
As follows among the present invention for realizing instrument used in the present invention:
Product losartan meta-bolites 2-butyl of the present invention-4-chloro-5-carboxyl-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4]-methyl } purity of imidazoles (EXP-3174) adopts high performance liquid chromatograph to detect, its detection method is referring to document Tetrahedron Letters, 2003 (44): 1149-1152.
Embodiment 1
In the 500mL four-hole boiling flask, add 2-butyl-4-chloro-5-formyl radical-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4]-methyl } imidazoles (42.1g), Virahol (200mL) stirs, and the control mixing speed is 300rpm/min, forms clear solution.Adding 8% biphosphate sodium water solution adjusting pH value again is 4.5.Add 30% hydrogen peroxide (14mL).Slowly drip the solution that Textone (17.1g) is dissolved in 100mL water in 5 ℃ of controlled temperature, the control drop rate is 1mL/min, keeps the pH value to be about 4.5, dropwises in about 2.5 hours.Continued stirring reaction 5 hours.Detection reaction is finished.Add S-WAT (6.3g) to destroy unreacted hydrogen peroxide oxidant.With the concentrated Virahol of removing of Rotary Evaporators, residual solution ethyl acetate extraction separatory, drying concentrates, and obtains white solid losartan meta-bolites 2-butyl-4-chloro-5-carboxyl-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4]-methyl } imidazoles (EXP-3174).Through recrystallizing and refining, be dried to constant weight, the 35.1g that weighs, yield 85.4%, purity 99.1%.
Embodiment 2
In the 250mL four-hole boiling flask, add 2-butyl-4-chloro-5-formyl radical-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4]-methyl } imidazoles (4.21g), acetone (35mL) stirs, and the control mixing speed is 300rpm/min, forms clear solution.Adding 8% biphosphate sodium water solution adjusting pH value again is 4.5.Add 30% hydrogen peroxide (1.4mL).Slowly drip the solution that Textone (1.71g) is dissolved in 15mL water in 5 ℃ of controlled temperature, the control drop rate is 1mL/min, keeps the pH value to be about 4.5.Dropwise the back and continued stirring reaction 5 hours, detection reaction is finished.Add S-WAT (0.63g) to destroy unreacted hydrogen peroxide oxidant.With the concentrated acetone of removing of Rotary Evaporators, residual solution ethyl acetate extraction separatory, drying concentrates, and obtains white solid losartan meta-bolites 2-butyl-4-chloro-5-carboxyl-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4]-methyl } imidazoles (EXP-3174).Through recrystallizing and refining, be dried to constant weight, the 3.5g that weighs, yield 85.5%, purity 99.0%.
Embodiment 3
In the 250mL four-hole boiling flask, add 2-butyl-4-chloro-5-formyl radical-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4]-methyl } imidazoles (4.21g), methyl-sulphoxide (35mL) stirs, and the control mixing speed is 300rpm/min, forms clear solution.Adding 8% biphosphate sodium water solution adjusting pH value again is 4.5.Add 30% hydrogen peroxide (1.4mL).Slowly drip the solution that Textone (1.71g) is dissolved in 15mL water in 5 ℃ of controlled temperature, the control drop rate is 1mL/min, keeps the pH value to be about 4.5.Dropwise the back and continued stirring reaction 4 hours, detection reaction is finished.Add S-WAT (0.63g) to destroy unreacted hydrogen peroxide oxidant.In the reaction feed liquid impouring 200mL water, use the ethyl acetate extraction separatory again, drying concentrates, and obtains white solid losartan meta-bolites 2-butyl-4-chloro-5-carboxyl-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4]-methyl } imidazoles (EXP-3174).Through recrystallizing and refining, be dried to constant weight, the 3.4g that weighs, yield 83.1%, purity 99.2%.
Embodiment 4
In the 250mL four-hole boiling flask, add 2-butyl-4-chloro-5-formyl radical-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4]-methyl } imidazoles (4.21g), methyl-sulphoxide (35mL) stirs, and the control mixing speed is 300rpm/min, forms clear solution.Adding 8% biphosphate sodium water solution adjusting pH value again is 4.5.Add 30% hydrogen peroxide (1.4mL).Slowly drip the solution that Textone (1.0g) is dissolved in 10mL water in 5 ℃ of controlled temperature, the control drop rate is 0.5mL/min, keeps the pH value to be about 4.5.Dropwise the back and continued stirring reaction 2 hours, detection reaction is finished.Add S-WAT (0.63g) to destroy unreacted hydrogen peroxide oxidant.In the reaction feed liquid impouring 200mL water, use the ethyl acetate extraction separatory again, drying concentrates, and obtains white solid losartan meta-bolites 2-butyl-4-chloro-5-carboxyl-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4]-methyl } imidazoles (EXP-3174).Through recrystallizing and refining, be dried to constant weight, the 3.4g that weighs, yield 83.1%, purity 98.5%.
Embodiment 5
In the 250mL four-hole boiling flask, add 2-butyl-4-chloro-5-formyl radical-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4]-methyl } imidazoles (4.21g), Virahol (35mL) stirs, and the control mixing speed is 300rpm/min, forms clear solution.Adding 8% biphosphate sodium water solution adjusting pH value again is 4.5.Add 30% hydrogen peroxide (1.0mL).Slowly drip the solution that Textone (1.71g) is dissolved in 15mL water in 5 ℃ of controlled temperature, the control drop rate is 1mL/min, keeps the pH value to be about 4.5.Dropwise the back and continued stirring reaction 4 hours, detection reaction is finished.Add S-WAT (0.46g) to destroy unreacted hydrogen peroxide oxidant.Virahol is removed in underpressure distillation, residual solution ethyl acetate extraction separatory, drying concentrates, and obtains white solid losartan meta-bolites 2-butyl-4-chloro-5-carboxyl-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4]-methyl } imidazoles (EXP-3174).Through recrystallizing and refining, be dried to constant weight, the 3.4g that weighs, yield 83.1%, purity 99.0%.
Embodiment 6
In the 250mL four-hole boiling flask, add 2-butyl-4-chloro-5-formyl radical-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4]-methyl } imidazoles (4.21g), methyl-sulphoxide (35mL) stirs, and the control mixing speed is 300rpm/min, forms clear solution.Add again that to regulate the pH value by the aqueous sodium acetate solution (0.75mL) of 0.2mol/L with the buffered soln of acetic acid aqueous solution (16.3mL) preparation of 0.3mol/L be 1.0.Add 30% hydrogen peroxide (1.4mL).Slowly drip the solution that Textone (1.71g) is dissolved in 15mL water in 5 ℃ of controlled temperature, the control drop rate is 0.5mL/min, keeps the pH value to be about 1.0.Dropwise the back and continued stirring reaction 4 hours, add 30% hydrogen peroxide (0.5mL), detection reaction is finished.Add S-WAT (0.90g) to destroy unreacted hydrogen peroxide oxidant.In the reaction feed liquid impouring 200mL water (high degree of agitation), use the ethyl acetate extraction separatory, drying concentrates, and obtains white solid losartan meta-bolites 2-butyl-4-chloro-5-carboxyl-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4]-methyl } imidazoles (EXP-3174).Through recrystallizing and refining, be dried to constant weight, the 3.2g that weighs, yield 78.3%, purity 98.4%.
Embodiment 7
In the 500mL four-hole boiling flask, add 2-butyl-4-chloro-5-formyl radical-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4]-methyl } imidazoles (14.5g), methyl-sulphoxide (100mL) stirs, and the control mixing speed is 300rpm/min, forms clear solution.Add again and regulate the pH value by the aqueous sodium acetate solution (3.7mL) of 0.2mol/L with the buffered soln of acetic acid aqueous solution (6.3mL) preparation of 0.3mol/L and be about 4.5.Add 30% hydrogen peroxide (5mL).Slowly drip the solution that Textone (5.8g) is dissolved in 40mL water in 5 ℃ of controlled temperature, the control drop rate is 1mL/min, keeps the pH value to be about 4.5, dropwises the back and continues stirring reaction 3 hours, and detection reaction is finished.Add S-WAT (2.2g) to destroy unreacted hydrogen peroxide oxidant.The reaction feed liquid is scattered in the 500mL water, uses the ethyl acetate extraction separatory, and drying concentrates, and obtains white solid losartan meta-bolites 2-butyl-4-chloro-5-carboxyl-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4]-methyl } imidazoles (EXP-3174).Through recrystallizing and refining, be dried to constant weight, the 12.5g that weighs, yield 83.4%, purity 98.9%.
Embodiment 8
In the 500mL four-hole boiling flask, add 2-butyl-4-chloro-5-formyl radical-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4]-methyl } imidazoles (14.5g), methyl-sulphoxide (100mL) stirs, and the control mixing speed is 300rpm/min, forms clear solution.Add again and regulate the pH value by the aqueous sodium acetate solution (3.7mL) of 0.2mol/L with the buffered soln of acetic acid aqueous solution (6.3mL) preparation of 0.3mol/L and be about 4.5.Add 10% hydrogen peroxide (15mL).Slowly drip the solution that Textone (5.8g) is dissolved in 40mL water in 5 ℃ of controlled temperature, the control drop rate is 1mL/min, and keeping the pH value is 4.5, dropwises in about 1.5 hours.Continued stirring reaction 3 hours.Detection reaction is finished.Add S-WAT (2.2g) to destroy unreacted hydrogen peroxide oxidant.The reaction feed liquid is scattered in the 500mL water, uses the ethyl acetate extraction separatory, and drying concentrates, and obtains white solid losartan meta-bolites 2-butyl-4-chloro-5-carboxyl-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4]-methyl } imidazoles (EXP-3174).Through recrystallizing and refining, be dried to constant weight, the 12.0g that weighs, yield 80.0%, purity 98.4%.
Embodiment 9
In the 500mL four-hole boiling flask, add 2-butyl-4-chloro-5-formyl radical-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4]-methyl } imidazoles (14.5g), methyl-sulphoxide (100mL) stirs, and the control mixing speed is 300rpm/min, forms clear solution.Add again that to regulate the pH value by the aqueous sodium acetate solution (3.7mL) of 0.2mol/L with the buffered soln of acetic acid aqueous solution (6.3mL) preparation of 0.3mol/L be 4.5.Add 30% hydrogen peroxide (5mL).Slowly drip the solution that Textone (5.8g) is dissolved in 40mL water in-10 ℃ of controlled temperature, the control drop rate is 1mL/min, keeps the pH value to be about 4.5, dropwises the back and continues stirring reaction 16 hours, and detection reaction is finished.Add S-WAT (2.2g) to destroy unreacted hydrogen peroxide oxidant.The reaction feed liquid is scattered in the 500mL water, uses the ethyl acetate extraction separatory, and drying concentrates, and obtains white solid losartan meta-bolites 2-butyl-4-chloro-5-carboxyl-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4]-methyl } imidazoles (EXP-3174).Through recrystallizing and refining, be dried to constant weight, the 12.4g that weighs, yield 83.1%, purity 98.7%.
Embodiment 10
In the 500mL four-hole boiling flask, add 2-butyl-4-chloro-5-formyl radical-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4]-methyl } imidazoles (14.5g), methyl-sulphoxide (100mL) stirs, and the control mixing speed is 300rpm/min, forms clear solution.Add again that to regulate the pH value by the aqueous sodium acetate solution (3.7mL) of 0.2mol/L with the buffered soln of acetic acid aqueous solution (6.3mL) preparation of 0.3mol/L be 4.5.Add 30% hydrogen peroxide (5mL).Slowly drip the solution that Textone (5.8g) is dissolved in 40mL water in 30 ℃ of controlled temperature, the control drop rate is 1mL/min, keeps the pH value to be about 4.5, dropwises the back and continues stirring reaction 10 hours, add 30% hydrogen peroxide (5mL) during this time, detection reaction is finished.Add S-WAT (3.3g) to destroy unreacted hydrogen peroxide oxidant.The reaction feed liquid is scattered in the 500mL water, uses the ethyl acetate extraction separatory, and drying concentrates, and obtains white solid losartan meta-bolites 2-butyl-4-chloro-5-carboxyl-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4]-methyl } imidazoles (EXP-3174).Through recrystallizing and refining, be dried to constant weight, the 12.4g that weighs, yield 83.1%, purity 98.7%.
Above said content only is the basic explanation of the present invention under conceiving, and according to any equivalent transformation that technical scheme of the present invention is done, all should belong to protection scope of the present invention.
Claims (6)
1. losartan meta-bolites 2-butyl-4-chloro-5-carboxyl-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4]-methyl } preparation method of imidazoles; it is characterized in that adopting 2-butyl-4-chloro-5-formyl radical-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4]-methyl } imidazoles is raw material; make solvent with polar solvent; regulating and control the pH value with buffered soln is 1～7; in the presence of hydrogen peroxide; in-10 ℃～30 ℃; generate corresponding carboxylic acid by Textone-antichlor system oxidation aldehyde, finally obtain losartan meta-bolites 2-butyl-4-chloro-5-carboxyl-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4]-methyl } imidazoles.
2. a kind of losartan meta-bolites 2-butyl as claimed in claim 1-4-chloro-5-carboxyl-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4]-methyl } preparation method of imidazoles; it is characterized in that preferably adopting 2-butyl-4-chloro-5-formyl radical-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4]-methyl } imidazoles is raw material; make solvent with polar solvent; regulating control pH value with buffered soln is 4.5; in the presence of hydrogen peroxide; in 5 ℃; generate corresponding carboxylic acid by Textone-antichlor system oxidation aldehyde, finally obtain losartan meta-bolites 2-butyl-4-chloro-5-carboxyl-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4]-methyl } imidazoles.
3. losartan meta-bolites 2-butyl as claimed in claim 1 or 2-4-chloro-5-carboxyl-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4]-methyl } preparation method of imidazoles (EXP-3174), it is characterized in that described polar solvent is methyl alcohol, ethanol, Virahol, acetone, N, one or more in dinethylformamide or the methyl-sulphoxide mix.
4. losartan meta-bolites 2-butyl as claimed in claim 3-4-chloro-5-carboxyl-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4]-methyl } preparation method of imidazoles (EXP-3174), it is characterized in that it specifically comprises to be prepared as follows step:
(1), in container, add 2-butyl-4-chloro-5-formyl radical-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4]-methyl the imidazoles raw material, polar solvent, the control mixing speed is that 300rpm/min stirs, and forms clear solution;
The volumetric usage of used polar solvent is 2-butyl-4-chloro-5-formyl radical-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4]-methyl } 1.1～50 times of quality of imidazoles;
(2), add the biphosphate sodium water solution in the step (1) in the clear solution of gained or be 1.0～7.0 by the buffered soln adjusting pH value of aqueous sodium acetate solution and acetic acid aqueous solution preparation, add concentration again and be 10%～50% aqueous hydrogen peroxide solution; Under-10 ℃～30 ℃, slowly drip the sodium chlorite aqueous solution then, the control drop rate is 1mL/min, dropwises, and continues stirring reaction 3～5 hours;
In the said process by adding the biphosphate sodium water solution or being 1.0～7.0 by the pH value that the formulated buffered soln of aqueous sodium acetate solution and acetic acid aqueous solution is kept solution;
Hydrogen peroxide consumption in the reaction is the used 2-butyl of step (1)-4-chloro-5-formyl radical-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4]-methyl } 1.1～50 times of amount of substance of imidazoles raw material;
Textone consumption in the reaction is the used 2-butyl of step (1)-4-chloro-5-formyl radical-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4]-methyl } 1.1～50 times of amount of imidazoles raw material;
(3), in the solution of step (2) gained, add S-WAT again to remove unreacted hydrogen peroxide oxidant;
Add S-WAT in (2) 1.1～50 times of the amount of substance of used hydrogen peroxide set by step of amounts;
(4), step (3) is removed solution behind the hydrogen peroxide oxidant;
If reaction system is used the lower solvents of boiling point such as methyl alcohol, ethanol, Virahol, acetone, remove through the Rotary Evaporators underpressure distillation and to desolvate, residual solution ethyl acetate extraction separatory, dry, concentrate, obtain white solid losartan meta-bolites 2-butyl-4-chloro-5-carboxyl-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4]-methyl } imidazoles;
If reaction system is used N, the water miscible solvent of the high boiling point of dinethylformamide or methyl-sulphoxide, then will react in the water of 5～10 times of volumes of feed liquid impouring with dispersion solvent, use the ethyl acetate extraction separatory again, dry, concentrate, obtain white solid losartan meta-bolites 2-butyl-4-chloro-5-carboxyl-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4]-methyl } imidazoles.
5. losartan meta-bolites 2-butyl as claimed in claim 4-4-chloro-5-carboxyl-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4]-methyl } preparation method of imidazoles (EXP-3174), it is characterized in that: used SODIUM PHOSPHATE, MONOBASIC concentration of aqueous solution is preferably 8% in the step (2), aqueous sodium acetate solution concentration is preferably 0.2mol/L in 1: 1 by volume formulated buffered soln of aqueous sodium acetate solution and acetic acid aqueous solution, acetic acid aqueous solution concentration is preferably 0.3mol/L.
6. losartan meta-bolites 2-butyl as claimed in claim 4-4-chloro-5-carboxyl-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4]-methyl } preparation method of imidazoles (EXP-3174), it is characterized in that:
The volumetric usage of used polar solvent is 2-butyl-4-chloro-5-formyl radical-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4 in the step (1)]-methyl } 8 times of quality of imidazoles;
Regulate the pH value in the step (2) and be preferably 4.5, used aqueous hydrogen peroxide solution concentration is preferably 30%, preferred 5 ℃ of temperature; The amount of used hydrogen peroxide is preferably pressed 2-butyl-4-chloro-5-formyl radical-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4]-methyl } 1.5 times of amount of substance amounts of imidazoles calculate; Textone consumption in the reaction is preferably 2-butyl-4-chloro-5-formyl radical-1-{[2 '-(1H-tetrazolium-5-yl)-biphenyl-4]-methyl } 1.5 times of imidazoles amount of substance.
The amount that adds S-WAT in the step (3) 1.5 times of calculating of the amount of substance of used hydrogen peroxide in (2) preferably set by step.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103965171A (en) * | 2014-04-30 | 2014-08-06 | 上海艾力斯医药科技有限公司 | Preparation method for Allisartan Isoproxil |
| CN105218527A (en) * | 2015-10-10 | 2016-01-06 | 江苏宝众宝达药业有限公司 | The preparation method of a kind of EXP-3174 |
-
2011
- 2011-02-28 CN CN2011100483075A patent/CN102190652A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103965171A (en) * | 2014-04-30 | 2014-08-06 | 上海艾力斯医药科技有限公司 | Preparation method for Allisartan Isoproxil |
| CN105218527A (en) * | 2015-10-10 | 2016-01-06 | 江苏宝众宝达药业有限公司 | The preparation method of a kind of EXP-3174 |
| CN105218527B (en) * | 2015-10-10 | 2018-04-24 | 江苏宝众宝达药业有限公司 | A kind of preparation method of EXP-3174 |
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