CN103435567A - Valsartan refining method - Google Patents

Abstract

The invention discloses a valsartan refining method, belonging to the technical field of medical chemistry. The method comprises the following steps: dissolving a valsartan crude product with isomer content of 1.0-10.0% in an alcohol solvent-ester solvent system; heating to 30-70 DEG C so as to completely dissolve the valsartan crude product; and slowly cooling, separating out crystals and filtering to obtain a valsartan refined product. The alcohol solvent is one of methanol, ethanol and isopropyl alcohol or the mixture of two or three of methanol, ethanol or isopropyl alcohol in any proportion; and the ester solvent is one of ethyl formate, ethyl acetate and methyl acetate or the mixture of two or three of ethyl formate, ethyl acetate and methyl acetate in any proportion. The mass ratio of the alcohol solvent to the ester solvent to the valsartan crude product is (0.05-1.0):(1.0-10.0):1. By adopting the method disclosed by the invention, the isomer content in the valsartan crude product is reduced to be hardly detected from 1.0-10.0%, and the quality of the finished product of valsartan is improved; the particle size of the finished product of valsartan is improved, thereby facilitating the product charge, centrifugation and drying; and the method is simple to operate, low in cost and suitable for industrial production.

Description

The process for purification of valsartan

Technical field

The invention belongs to the medical chemistry technical field, specifically, relate to a kind of process for purification of valsartan.

Background technology

Valsartan is the Angiotensin Ⅱ receptor antagonist of second listing, has become a line medicine for the treatment of hypertension drug at present, except treating hypertension, can also be used for the treatment of heart failure.Because step-down is steady, curative effect is strong, security is good, side effect is low, within 1st, to take 1 time, patient compliance good, valsartan has become fastest-rising hypertension agents.Nearly 2 years, valsartan became the leading kind on global abrupt antihypertensive therapy pharmaceutical market.

Valsartan is chiral drug, and in preparation process, the easy racemization of its chiral centre, generate D type isomer (impurity A in the EP pharmacopeia), causes the optical purity of valsartan to reduce.According to the constructional feature of valsartan, the technique final stage will be under alkaline condition to the reaction that is hydrolyzed of valsartan ester, carboxyl is wherein dissociated out.Hydrolysis reaction under alkaline condition can cause the racemization of product part, produces the D type isomer of valsartan.

Report and patent about the synthesis technique of valsartan have a lot, but few about refining correlation technique, especially few especially for the technology of isomer removal method.For the removal of isomer, prior art is to adopt simple ester solvent mostly, and valsartan is made with extra care repeatedly.The applicant also attempts adopting this method, experimental results show that simple ester solvent is very undesirable to the removal effect of isomer.

Patent CN102617497 and CN102391200, for removing the D type isomer in valsartan, are dissolved in the valsartan crude product aqueous solution of mineral alkali, are converted into the salt of valsartan, and then acidifying.Patent CN102093302, dissolve in the valsartan crude product in alkali or strong base-weak acid salt, is converted into the salt of valsartan, and then utilize gac, absorption with macroporous adsorbent resin, by acidifying, obtains elaboration.Due to valsartan easily racemization under alkaline condition, thus this type of scheme complex operation not only, and may continue racemization in treating processes, and do not reach the purpose of removing isomer, can make on the contrary content of isomer increase.

Patent CN101768128, for removing the D type isomer in valsartan, adopts the mixed solvent of butanone or butanone and other solvents to be made with extra care.The applicant also attempts adopting the process for purification in patent CN101768128, but that experimental result shows the method is unsatisfactory: the valsartan crude product that D type content of isomer is 5.9%, refining once after, D type content of isomer only is down to 4.2%, and yield is lower.The butanone price is also higher in addition, is not suitable for suitability for industrialized production.

Summary of the invention

For addressing the above problem, the invention provides a kind of simple to operate, product purity is high, cost is low, be applicable to the valsartan process for purification of suitability for industrialized production.

The process for purification of valsartan of the present invention, step is as follows: the valsartan crude product that is 1.0～10.0% by content of isomer is dissolved in alcoholic solvent-ester solvent system, intensification is all dissolved the valsartan crude product, more slowly cooling, crystallization, filtration, obtains the valsartan elaboration.

Valsartan is easily racemization under alkaline condition, and content of isomer is wherein increased.With existing patent CN102617497, with CN102391200, compare, the present invention, at refining step, does not use alkaline reagents, the possibility of having avoided the valsartan isomer to increase.The present invention, at refining step, adopts alcoholic solvent-ester solvent system in addition, with simple ester solvent, compares, and in effectively removing valsartan, in isomer, has guaranteed higher yield and low cost.

Wherein, the temperature of dissolving valsartan crude product is 30～70 ℃.

The mixture that described alcoholic solvent-ester solvent system is alcoholic solvent and ester solvent.

In described alcoholic solvent-ester solvent system, alcoholic solvent is that one or more in methyl alcohol, ethanol or Virahol mix with arbitrary proportion.

Described alcoholic solvent consumption is: the mass ratio of alcoholic solvent and valsartan crude product is 0.05～1.0:1.

In described alcoholic solvent-ester solvent system, ester solvent is that one or more in ethyl formate, ethyl acetate or methyl acetate mix with arbitrary proportion.

Described ester solvent consumption is: the mass ratio of ester solvent and valsartan crude product is 1.0～10.0:1.

Alcoholic solvent is larger to the solubleness of valsartan isomer, and also the solubleness to valsartan itself is larger simultaneously, so can not add too many alcoholic solvent.The ester solvent consumption is very little the time, and the system mobility after crystallization finishes is too poor, inconvenient blowing; When the ester solvent consumption is too many, bad for the removal effect of isomer.Adopt alcoholic solvent and the ester solvent of above-mentioned consumption, can effectively remove isomer, can guarantee higher yield again.

Compared with prior art, beneficial effect is in the present invention:

(1) the valsartan product purity made is high, the content of isomer in the valsartan crude product can be down to almost and be can't check by 1.0～10.0%, and the optical purity of products obtained is high;

(2) improve the granularity of valsartan finished product, be convenient to product blowing, centrifugal and dry, can obtain the finished product of better quality;

(3) adopt alcoholic solvent-ester solvent system to dissolve the valsartan crude product, then crystallization, filtration can obtain the valsartan highly finished product, simple to operate, easy control of process conditions, and the solvent cost that reaction adopts is low, is applicable to suitability for industrialized production.

Embodiment

Below in conjunction with embodiment, the present invention will be further described.

Embodiment 1

By valsartan 35g (D type content of isomer is 5.9%), be dissolved in the mixed solvent of ethanol 35ml and ethyl acetate 120ml, then be heated to 45 ± 2 ℃, make solid entirely molten.Slowly be down to room temperature, temperature-fall period can be separated out a large amount of white solids again.Suction filtration after 4 hours, obtain valsartan 28.2g, yield 80.6%, and D type content of isomer is 0.02%.

Embodiment 2

By valsartan 35g (D type content of isomer is 4.5%), be dissolved in the mixed solvent of methyl alcohol 16ml and ethyl formate 100ml, then be heated to 40 ± 2 ℃, make solid entirely molten.Slowly be down to room temperature, temperature-fall period can be separated out a large amount of white solids again.Suction filtration after 4 hours, obtain valsartan 30.2g, yield 86.3%, and D type content of isomer is 0.01%.

Embodiment 3

By valsartan 35g (D type content of isomer is 6.1%), be dissolved in the mixed solvent of Virahol 25ml and methyl acetate 100ml, then be heated to 65 ± 2 ℃, make solid entirely molten.Slowly be down to room temperature, temperature-fall period can be separated out a large amount of white solids again.Suction filtration after 4 hours, obtain valsartan 29.9g, yield 85.4%, and D type content of isomer is 0.07%.

Embodiment 4

By valsartan 35g (D type content of isomer is 8.6%), be dissolved in the mixed solvent of Virahol 35ml and methyl acetate 100ml, then be heated to 50 ± 2 ℃, make solid entirely molten.Slowly be down to room temperature, temperature-fall period can be separated out a large amount of white solids again.Suction filtration after 4 hours, obtain valsartan 28.3g, yield 80.9%, and D type content of isomer is 0.09%.

Embodiment 5

By valsartan 35g (D type content of isomer is 1.2%), be dissolved in the mixed solvent of methyl alcohol 2.0ml and ethyl acetate 35ml, then be heated to 54 ± 2 ℃, make solid entirely molten.Slowly be down to room temperature, temperature-fall period can be separated out a large amount of white solids again.Suction filtration after 4 hours, obtain valsartan 33.9g, and yield 96.9% does not detect D type isomer.

Embodiment 6

By valsartan 35g (D type content of isomer is 9.3%), be dissolved in the mixed solvent of ethanol 35ml and ethyl acetate 300ml, then be heated to 50 ± 2 ℃, make solid entirely molten.Slowly be down to room temperature, temperature-fall period can be separated out a large amount of white solids again.Suction filtration after 4 hours, obtain valsartan 20.6g, yield 71.1%, and D type content of isomer is 0.04%.

Claims (7)

1. the process for purification of a valsartan, it is characterized in that, step is as follows: the valsartan crude product that is 1.0～10.0% by content of isomer is dissolved in alcoholic solvent-ester solvent system, heats up the valsartan crude product is all dissolved, slowly cooling, crystallization, filtration again, obtain the valsartan elaboration.

2. the process for purification of valsartan according to claim 1, is characterized in that, the temperature of dissolving the valsartan crude product is 30～70 ℃.

3. the process for purification of valsartan according to claim 1, is characterized in that, the mixture that described alcoholic solvent-ester solvent system is alcoholic solvent and ester solvent.

4. according to the process for purification of claim 1,2 or 3 described valsartans, it is characterized in that, in described alcoholic solvent-ester solvent system, alcoholic solvent is that one or more in methyl alcohol, ethanol or Virahol mix with arbitrary proportion.

5. the process for purification of valsartan according to claim 4, is characterized in that, described alcoholic solvent consumption is: the mass ratio of alcoholic solvent and valsartan crude product is 0.05～1.0:1.

6. according to the process for purification of claim 1,2 or 3 described valsartans, it is characterized in that, in described alcoholic solvent-ester solvent system, ester solvent is that one or more in ethyl formate, ethyl acetate or methyl acetate mix with arbitrary proportion.

7. the process for purification of valsartan according to claim 6, is characterized in that, described ester solvent consumption is: the mass ratio of ester solvent and valsartan crude product is 1.0～10.0:1.