Preparation method of 5-losartan carbonate

Abstract

The invention provides a method for preparing a losartan derivative 5-losartan carbonate from 2-butyl-4-chloro-5-formoxyl-1-{[2'-2(1-H-tetrazole-5-yl)-biphenyl-4]-methyl} imidazole. According to the invention, the total yield of 5-losartan carbonate is 75.6%; and on the existing technology basis, the yield is further improved, cost is reduced, product purity is improved, maneuverability is increased. Thus, the method provided by the invention is suitable for industrial production.

Description

Technical field:

[0001] The invention relates to a preparation method of losartan 5-carboxylate, a derivative of antihypertensive drug losartan. Background technique:

[0002] 5-Carboxylic acid losartan English name: 5-carboxylic acid metabolite, CAS#: 124750-92-1; molecular weight: 436.89, molecular formula: C 22 h 21 ClN 6 o 2 ; The chemical name is: The chemical name is 2-butyl-4-chloro-1-[2'-(1H-tetrazol-5-yl)1,1'-biphenyl-methyl]imidazole-5-carboxylate Acid; referred to as EXP-3174. 5-Carboxylate losartan is the active metabolite of the high blood pressure drug losartan in the human body, its activity is 10-40 times that of losartan, and the half-life of losartan is 1 hour, while The half-life of EXP-3174 is as long as 6-9 hours.

[0003] DuPont disclosed a series of imidazole derivatives in patent EP0253310, in which the compound code-named DUP753 showed good blood pressure-lowering activity, and was officially approved by the U.S. Food and Drug Administration (FD...

Examples

Embodiment 1

[0014] Preparation of 2-butyl-4-chloro-5-formyl-1-{[2'-2(1-H-tetrazol-5-yl)-biphenyl-4]-methyl}imidazole

[0015]

[0016] Add formula (3) compound (22.5g, 34.2mmol) and isopropanol (150ml) in the 250ml three-neck flask equipped with reflux condenser and dropping funnel, stir mechanically, heat up to 50 ℃, solid does not dissolve, 0.5 h Add 3.4N hydrochloric acid (24ml) dropwise, the solid dissolves, the solution is yellow-green, keep the temperature at 50°C and stir the reaction, TLC (PE:EA=2:1) ​​tracks the reaction progress, after 5h it shows that the basic reaction of the raw materials is complete. Stop heating and stirring, cool and stand overnight. There were colorless transparent particles precipitated at the bottom of the bottle, filtered, and the solid particles were confirmed to be trityl alcohol by comparing with the HPLC spectrum of the standard sample. The filtrate was poured into 500ml of water, stirred for 0.5h, and a white solid was precipitated. After filt...

Embodiment 2

[0019] Preparation of 5-carboxylate losartan

[0020]

[0021] Add compound 4 (3.0 g, 6.93 mmol) and 50 ml of isopropanol to a 100 mL three-necked flask, heat to 40° C. and stir to dissolve the compound 4 solid, then cool down to 5° C., and add 30% hydrogen peroxide (1.17 ml). In addition, sodium chlorite (1.84g) was dissolved in water (14.12ml), and the prepared sodium chlorite solution was added to the three-necked flask in batches within 2 hours at 5°C, and TLC (DCM:MeOH=10:1) Following the progress of the reaction, after 5 hours, it was shown that there was basically no raw material in the reaction. Stop stirring and let stand overnight. Pour the reaction solution into 500ml of water, stir to precipitate white solids, add 10N / L sodium hydroxide solution to the suspension, when the pH is 13, the liquid becomes clear, filter to remove insoluble impurities, pour the filtrate back into the beaker, and quickly Add concentrated hydrochloric acid dropwise under stirring cond...

Technical field:

[0001] The invention relates to a preparation method of losartan 5-carboxylate, a derivative of antihypertensive drug losartan. Background technique:

[0002] 5-Carboxylic acid losartan English name: 5-carboxylic acid metabolite, CAS#: 124750-92-1; molecular weight: 436.89, molecular formula: C 22 h 21 ClN 6 o 2 ; The chemical name is: The chemical name is 2-butyl-4-chloro-1-[2'-(1H-tetrazol-5-yl)1,1'-biphenyl-methyl]imidazole-5-carboxylate Acid; referred to as EXP-3174. 5-Carboxylate losartan is the active metabolite of the high blood pressure drug losartan in the human body, its activity is 10-40 times that of losartan, and the half-life of losartan is 1 hour, while The half-life of EXP-3174 is as long as 6-9 hours.

[0003] DuPont disclosed a series of imidazole derivatives in patent EP0253310, in which the compound code-named DUP753 showed good blood pressure-lowering activity, and was officially approved by the U.S. Food and Drug Administration (FD...

Examples

Embodiment 1

[0014] Preparation of 2-butyl-4-chloro-5-formyl-1-{[2'-2(1-H-tetrazol-5-yl)-biphenyl-4]-methyl}imidazole

[0015]

[0016] Add formula (3) compound (22.5g, 34.2mmol) and isopropanol (150ml) in the 250ml three-neck flask equipped with reflux condenser and dropping funnel, stir mechanically, heat up to 50 ℃, solid does not dissolve, 0.5 h Add 3.4N hydrochloric acid (24ml) dropwise, the solid dissolves, the solution is yellow-green, keep the temperature at 50°C and stir the reaction, TLC (PE:EA=2:1) ​​tracks the reaction progress, after 5h it shows that the basic reaction of the raw materials is complete. Stop heating and stirring, cool and stand overnight. There were colorless transparent particles precipitated at the bottom of the bottle, filtered, and the solid particles were confirmed to be trityl alcohol by comparing with the HPLC spectrum of the standard sample. The filtrate was poured into 500ml of water, stirred for 0.5h, and a white solid was precipitated. After filt...

Embodiment 2

[0019] Preparation of 5-carboxylate losartan

[0020]

[0021] Add compound 4 (3.0 g, 6.93 mmol) and 50 ml of isopropanol to a 100 mL three-necked flask, heat to 40° C. and stir to dissolve the compound 4 solid, then cool down to 5° C., and add 30% hydrogen peroxide (1.17 ml). In addition, sodium chlorite (1.84g) was dissolved in water (14.12ml), and the prepared sodium chlorite solution was added to the three-necked flask in batches within 2 hours at 5°C, and TLC (DCM:MeOH=10:1) Following the progress of the reaction, after 5 hours, it was shown that there was basically no raw material in the reaction. Stop stirring and let stand overnight. Pour the reaction solution into 500ml of water, stir to precipitate white solids, add 10N / L sodium hydroxide solution to the suspension, when the pH is 13, the liquid becomes clear, filter to remove insoluble impurities, pour the filtrate back into the beaker, and quickly Add concentrated hydrochloric acid dropwise under stirring cond...

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