A method for refining synthesis of valsartan

Abstract

The application belongs to the technical field of medicine synthesis, and particularly relates to a synthesis and refining method of valsartan. After L-valseril is used to prepare a crude valsartan product, ultrasonic-assisted crystallization is used to obtain high-purity valsartan. The synthesis and refining method significantly reduces the content of D-isomer, avoids multiple purification treatment steps, is simple in process and easy to operate, and provides a method for recovering L-valseril from a valsartan mother liquor, so as to further improve the utilization rate, reduce the cost, and be suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of medicine synthesis, and particularly relates to a synthesis and refining method of valsartan. BACKGROUND

[0002] Valsartan, chemical name N-(1-pentanoyl)-N-[4-[2-(1H-tetrazole-5-yl) phenyl] benzyl]-L-valine, is the second listed angiotensin II (Ang II) receptor antagonist, which avoids the adverse reactions of calcium antagonists and ACE inhibitors, and can be used for treating various types of hypertension, has the advantages of significant curative effect and good tolerance, and has become a first-line drug for treating hypertension. The chemical structural formula is as follows:

[0003]

[0004] Valsartan is a chiral drug, and its chiral center is easy to racemize in the preparation process to generate D-type isomers (impurity A in EP Pharmacopoeia), thereby reducing the optical purity of valsartan. According to the structural characteristics of valsartan, a hydrolysis reaction of the carboxyl group of valsartan ester is carried out under alkaline conditions in the last stage of the process. The hydrolysis reaction under alkaline conditions can cause partial racemization of the product to generate D-type isomers of valsartan.

[0005] For the removal of D-type isomers of valsartan, there are many literatures reported. For example, patents CN201110295707.6 and CN201210045388.8 dissolve the crude valsartan in an aqueous inorganic base solution to form a salt, then acidify with an aqueous inorganic acid solution, extract with ethyl acetate, concentrate to obtain a crude product, and then recrystallize to obtain high-purity valsartan; patent CN201110032265.6 dissolves the crude valsartan in a base or a strong base weak acid salt to form a salt, then adsorbs with activated carbon and macroporous adsorption resin, and finally acidifies to obtain a refined product; patent CN200910001859.3 uses butanone or a mixed solvent of butanone and ester and ether for refining; patent CN201310407962.4 uses an alcohol solvent-ester solvent system; patent CN201310047701.6 dissolves the crude product in an ester solvent, then adds an alkane solvent, stirs, and crystallizes by programmed cooling to obtain a pure product; and patent CN200810212026.7 dries the valsartan obtained by recrystallization, then washes in an aqueous alcohol solution, centrifuges, and dries, so that the purity of the obtained valsartan is greater than 99%, the single solvent residue is less than 5000 ppm, and the yield is about 53.9%.

[0006] The above preparation method repeatedly purifies valsartan by using multiple solutions, so that a large amount of waste liquid is generated in industrial production, the environment is seriously polluted, and the production cost is also increased; and a satisfactory quality can be obtained only after a series of treatment steps. In view of the problems existing in the prior art, it is necessary to develop a refining method of valsartan with high yield, good purification effect and simple process, so as to meet the needs of industrial production. SUMMARY

[0007] In view of the problems existing in the prior art, the present application provides a new synthesis and refining method of valsartan with high yield and high purity, which can significantly reduce the content of D-isomer, does not need multiple purification steps, is simple to operate, has low cost and is suitable for industrial application.

[0008] The specific technical scheme of the present application is as follows:

[0009] The present application provides a synthesis and refining method of valsartan, and the steps are as follows:

[0010] An alkali solution is added to a reaction kettle containing L-valseran ester, temperature control T1 is performed, and stirring reaction is performed for a time t1; after the reaction is completed, the aqueous phase is washed twice with an organic solvent, the aqueous phase is transferred into a reaction kettle, hydrochloric acid is slowly added dropwise at room temperature until the pH of the solution is 1-2, ethyl acetate is added, stirring is performed for a time t2, standing is performed, the organic phase is collected by liquid separation, the organic phase is dried, filtration is performed, ultrasonic stirring is performed for crystallization, centrifugal filtration is performed, and valsartan fine product is obtained.

[0011] Preferably, the L-valseran ester is one of L-valseran methyl ester, L-valseran ethyl ester and L-valseran benzyl ester, and preferably, the L-valseran ester is valsartan methyl ester.

[0012] Preferably, the alkali solution is one or a combination of 10% sodium hydroxide solution and 10% potassium hydroxide solution, and preferably, the alkali solution is 10% sodium hydroxide solution.

[0013] Preferably, the mass ratio of the valsartan ester to the alkali solution is 1:6-15, and preferably, the mass ratio is 1:8-10.

[0014] Preferably, the temperature control temperature T1 is 25-45°C, and preferably, the temperature control temperature T1 is 35-40°C.

[0015] Preferably, the stirring reaction time t1 is 8-12h, and preferably, the stirring reaction time t1 is 9-10h.

[0016] Preferably, the organic solvent is one of n-hexane, toluene and xylene, and preferably, the organic solvent is n-hexane.

[0017] Preferably, the mass ratio of the valsartan ester to ethyl acetate is 1:4-7, and preferably, the mass ratio is 1:5-6.

[0018] Preferably, the stirring time t2 is 10-30 min, preferably 15-20 min.

[0019] The drying is a common drying method in the art, such as drying with anhydrous sodium sulfate.

[0020] Preferably, the ultrasonic stirring crystallization time is 5-9 h, preferably 6-7 h.

[0021] Further, the present application provides a method for recovering L-val- sartan from a D-val sartan-containing val sartan mother liquor, comprising the following steps:

[0022] After the val sartan mother liquor is rotary evaporated to dryness, ethyl acetate is added, and the mixture is stirred at a temperature T2 for a time t3 under ultrasonic condition with slow cooling, and then filtered to obtain L-val sartan.

[0023] The val sartan mother liquor can be the mother liquor remaining after the val sartan mother liquor is centrifugally filtered to obtain val sartan, or can be the mother liquor remaining after the val sartan is refined or synthesized according to the common method in the art.

[0024] Preferably, the mass ratio of the ethyl acetate to the mother liquor after evaporation to dryness is 5-9:1, preferably 6-7:1.

[0025] Preferably, the temperature T2 is 40-60℃, preferably 50-55℃.

[0026] Preferably, the stirring time t3 is 25-50 min, preferably 30-40 min.

[0027] Preferably, the cooling temperature is -5-15℃, preferably 0-5℃.

[0028] The present application has the following advantages:

[0029] The present application provides a new method for synthesizing and refining val sartan, which uses ultrasonic assistance to obtain high-purity val sartan after obtaining val sartan crude product from L-val sartan ester, and the content of D-isomer is significantly reduced, and the method avoids multiple purification steps, is simple and easy to operate; and the present application also provides a method for further recovering L-val sartan from a val sartan mother liquor, thereby improving the utilization rate and reducing the cost, and being suitable for industrial production. BRIEF DESCRIPTION OF DRAWINGS

[0030] Figure 1 : Chiral chromatogram of val sartan obtained by synthesis and refinement in Example 4. DETAILED DESCRIPTION

[0031] The application is further illustrated by the following examples, it should be understood that the examples of the application are only used to illustrate the application, but not limit the application, so, the simple improvement of the application under the premise of the method of the application belongs to the scope of the application.

[0032] In the following examples, various processes and methods not described in detail are conventional methods known in the art, and the reagents used are commercially available and of analytical or chemical purity.

[0033] Example 1

[0034] Into the reactor containing 100 g of L-valeryl methyl ester, 10% sodium hydroxide solution (900 g) was added, and the temperature was controlled at 35-40°C, and the reaction was stirred for 9-10 hours. After the reaction was completed, the aqueous phase was washed twice with n-hexane (250 mL x 2), and the aqueous phase was transferred into the reactor, and hydrochloric acid was slowly added dropwise at room temperature until the solution pH = 1-2, 500 g of ethyl acetate was added, stirred for 15-20 min, and the organic phase was collected by standing and partitioning, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and crystallized by ultrasonic stirring for 6-7 hours, and then centrifuged and filtered to obtain valeryl ester, with a yield of 91.8%, a chiral purity of 99.88%, and a chromatographic purity of 99.95%.

[0035] After the mother liquor was centrifuged and filtered, it was rotary evaporated to dryness to obtain an oil, 6 times the mass of ethyl acetate was added, and stirred at 50-55°C for 30-40 min, then slowly cooled to 0-5°C under ultrasonic conditions, and filtered to obtain L-valeryl ester, with a recovered chiral purity of 99.79% and a chromatographic purity of 99.89%. The total yield of the two steps of synthesis and mother liquor recovery was 96.1%.

[0036] Example 2

[0037] Into the reactor containing 100 g of L-valeryl methyl ester, 10% sodium hydroxide solution (800 g) was added, and the temperature was controlled at 40-45°C, and the reaction was stirred for 8-9 hours. After the reaction was completed, the aqueous phase was washed twice with n-hexane (250 mL x 2), and the aqueous phase was transferred into the reactor, and hydrochloric acid was slowly added dropwise at room temperature until the solution pH = 1-2, 500 g of ethyl acetate was added, stirred for 25-30 min, and the organic phase was collected by standing and partitioning, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and crystallized by ultrasonic stirring for 7-8 hours, and then centrifuged and filtered to obtain valeryl ester, with a yield of 90.2%, a chiral purity of 99.83%, and a chromatographic purity of 99.92%.

[0038] The mother liquor after centrifugal filtration was rotary evaporated to dryness to obtain an oil, 7 times the mass of ethyl acetate was added, stirred at 40-45 °C for 30-40 min, slowly cooled to -5-0 °C under ultrasonic condition, filtered to obtain L-valsartan fine product, the recovery chiral purity was 99.72%, the chromatographic purity was 99.85%. The total yield of two steps of synthesis and mother liquor recovery was 93.8%.

[0039] Example 3

[0040] 10% sodium hydroxide solution (1000 g) was added to the reaction kettle containing 100 g of L-valeryl methyl ester, temperature was controlled at 30-35 °C, stirred for 10-11 hours. After the reaction was completed, the aqueous phase was washed twice with n-hexane (250 mL x 2), the aqueous phase was transferred into the reaction kettle, hydrochloric acid was slowly added dropwise at room temperature until the solution pH = 1-2, 600 g of ethyl acetate was added, stirred for 10-15 min, and then allowed to stand, the organic phase was collected, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and then allowed to crystallize under ultrasonic stirring for 5-6 hours, centrifugal filtration was performed to obtain valsartan fine product, the yield was 91.0%, the chiral purity was 99.85%, and the chromatographic purity was 99.94%.

[0041] The mother liquor after centrifugal filtration was rotary evaporated to dryness to obtain an oil, 6 times the mass of ethyl acetate was added, stirred at 45-50 °C for 40-50 min, slowly cooled to 0-5 °C under ultrasonic condition, filtered to obtain L-valsartan fine product, the recovery chiral purity was 99.76%, the chromatographic purity was 99.88%, and the total yield of two steps of synthesis and mother liquor recovery was 95.0%.

[0042] Example 4

[0043] 10% potassium hydroxide solution (600 g) was added to the reaction kettle containing 100 g of L-valeryl methyl ester, temperature was controlled at 25-30 °C, stirred for 11-12 hours. After the reaction was completed, the aqueous phase was washed twice with toluene (250 mL x 2), the aqueous phase was transferred into the reaction kettle, hydrochloric acid was slowly added dropwise at room temperature until the solution pH = 1-2, 400 g of ethyl acetate was added, stirred for 20-25 min, and then allowed to stand, the organic phase was collected, dried with an appropriate amount of anhydrous sodium sulfate, filtered, and then allowed to crystallize under ultrasonic stirring for 8-9 hours, centrifugal filtration was performed to obtain valsartan fine product, the yield was 88.3%, the chiral purity was 99.80%, and the chromatographic purity was 99.87%.

[0044] The mother liquor after centrifugal filtration was rotary evaporated to dryness to obtain an oil, 5 times the mass of ethyl acetate was added, stirred at 55-60 °C for 25-30 min, slowly cooled to 10-15 °C under ultrasonic condition, filtered to obtain L-valsartan fine product, the recovery chiral purity was 99.70%, the chromatographic purity was 99.81%, and the total yield of two steps of synthesis and mother liquor recovery was 91.6%.

[0045] Example 5

[0046] Add 1500g of 10% sodium hydroxide solution to a reaction vessel containing 100g of L-valsartan methyl ester, and stir the reaction at 35-40℃ for 9-10 hours. After the reaction is complete, wash the aqueous phase twice with xylene (250mL×2), transfer the aqueous phase to the reaction vessel, slowly add hydrochloric acid dropwise to the solution pH=1-2 at room temperature, add 700g of ethyl acetate, stir for 15-20min, let stand, separate the organic phase, dry with an appropriate amount of anhydrous sodium sulfate, filter, sonicate and stir for 6-7 hours to crystallize, centrifuge and filter to obtain pure valsartan with a yield of 89.1%, chiral purity of 99.82%, and chromatographic purity of 99.90%.

[0047] After centrifugation and filtration, the mother liquor was rotary evaporated to dryness to obtain an oily substance. Nine times the weight of ethyl acetate was added, and the mixture was stirred at 50-55℃ for 30-40 min. The mixture was then slowly cooled to 5-10℃ under ultrasonic conditions and filtered to obtain pure L-valsartan. The chiral purity was 99.73%, the chromatographic purity was 99.82%, and the overall yield of the synthesis and mother liquor recovery was 93.0%.

[0048] Example 6

[0049] Add 900g of 10% sodium hydroxide solution to a reaction vessel containing 100g of L-valsartan ethyl ester, and stir the reaction at 35-40℃ for 9-10 hours. After the reaction is complete, wash the aqueous phase twice with n-hexane (250mL×2), transfer the aqueous phase to the reaction vessel, slowly add hydrochloric acid dropwise to the solution pH=1-2 at room temperature, add 500g of ethyl acetate, stir for 15-20min, let stand, separate the organic phase, dry with an appropriate amount of anhydrous sodium sulfate, filter, sonicate and stir for 6-7 hours to crystallize, centrifuge and filter to obtain pure valsartan with a yield of 90.9%, chiral purity of 99.85%, and chromatographic purity of 99.92%.

[0050] After centrifugation and filtration, the mother liquor was rotary evaporated to dryness to obtain an oily substance. Six times the weight of ethyl acetate was added, and the mixture was stirred at 50-55℃ for 30-40 min. The mixture was then slowly cooled to 0-5℃ under ultrasonic conditions and filtered to obtain pure L-valsartan. The chiral purity was 99.74%, the chromatographic purity was 99.88%, and the overall yield of the synthesis and mother liquor recovery was 94.7%.

[0051] Example 7

[0052] Add 900g of 10% sodium hydroxide solution to a reaction vessel containing 100g of L-valsartan benzyl ester, and stir the reaction at 35-40℃ for 9-10 hours. After the reaction is complete, wash the aqueous phase twice with n-hexane (250mL×2), transfer the aqueous phase to the reaction vessel, slowly add hydrochloric acid dropwise to the solution pH=1-2 at room temperature, add 500g of ethyl acetate, stir for 15-20min, let stand, separate the organic phase, dry with an appropriate amount of anhydrous sodium sulfate, filter, sonicate and stir for 6-7 hours to crystallize, centrifuge and filter to obtain pure valsartan with a yield of 91.2%, chiral purity of 99.84%, and chromatographic purity of 99.93%.

[0053] After centrifugation and filtration, the mother liquor was rotary evaporated to dryness to obtain an oily substance. Six times the weight of ethyl acetate was added, and the mixture was stirred at 50-55℃ for 30-40 min. The mixture was then slowly cooled to 0-5℃ under ultrasonic conditions and filtered to obtain pure L-valsartan. The chiral purity was 99.76%, the chromatographic purity was 99.90%, and the overall yield of the synthesis and mother liquor recovery was 95.1%.

[0054] Comparative Example 1

[0055] Add 900g of 10% sodium hydroxide solution to a reaction vessel containing 100g of L-valsartan methyl ester, and stir the reaction at 35-40℃ for 9-10 hours. After the reaction is complete, wash the aqueous phase twice with n-hexane (250mL×2), transfer the aqueous phase to the reaction vessel, slowly add hydrochloric acid dropwise to the solution pH=1-2 at room temperature, add 500g of ethyl acetate, stir for 15-20min, let stand, separate the organic phase, dry with an appropriate amount of anhydrous sodium sulfate, filter, stir to precipitate crystals for 6-7 hours, centrifuge and filter to obtain pure valsartan with a yield of 78.4%, chiral purity of 97.16%, and chromatographic purity of 98.35%.

[0056] After centrifugation and filtration, the mother liquor was rotary evaporated to dryness to obtain an oily substance. Six times the weight of ethyl acetate was added, and the mixture was stirred at 50-55℃ for 30-40 min. The mixture was then slowly cooled to 0-5℃ and filtered to obtain pure L-valsartan. The chiral purity was 94.84%, the chromatographic purity was 98.03%, and the overall yield of the synthesis and mother liquor recovery was 80.8%.

Claims

1. A method for synthesizing and purifying valsartan, characterized in that, The steps are as follows: An alkaline solution is added to the reaction vessel containing L-valsartan ester. The temperature is controlled at T1, and the reaction is stirred for t1. After the reaction is complete, the aqueous phase is washed twice with an organic solvent. The aqueous phase is transferred back to the reaction vessel, and hydrochloric acid is slowly added dropwise at room temperature until the solution pH = 1-2. Ethyl acetate is added, and the mixture is stirred for t2. After standing, the organic phase is collected by separation, dried, filtered, and crystallized by ultrasonic stirring. The crystals are then centrifuged and filtered to obtain pure valsartan. The alkaline solution is one or a combination of 10% sodium hydroxide solution and 10% potassium hydroxide solution. The mass ratio of valsartan ester to alkaline solution is 1:6-15; the temperature control temperature T1 is 25-45℃, and the stirring reaction time t1 is 8-12h; the mass ratio of valsartan ester to ethyl acetate is 1:4-7, and the stirring time t2 is 10-30min; the ultrasonic stirring crystallization time is 5-9h; the L-valsartan ester is one of L-valsartan methyl ester, L-valsartan ethyl ester, and L-valsartan benzyl ester; the organic solvent is selected from one of n-hexane, toluene, and xylene.

2. A method for recovering L-valsartan from a valsartan mother liquor containing D-valsartan, characterized in that, The steps are as follows: After the mother liquor is evaporated to dryness by rotary evaporation, ethyl acetate is added, the temperature is controlled at T2 and the stirring time is t3, the temperature is slowly reduced under ultrasonic conditions, and the mixture is filtered to obtain L-valsartan concentrate. The mother liquor is the remaining mother liquor after centrifugation and filtration to obtain valsartan concentrate according to claim 1.

3. The method according to claim 2, characterized in that, The mass ratio of ethyl acetate to the mother liquor after evaporation is 5-9:

1.

4. The method according to claim 2, characterized in that, The temperature control temperature T2 is 40-60℃, and the stirring time t3 is 25-50min.

5. The method according to claim 2, characterized in that, The cooling temperature is -5 to 15℃.

Images