CN102875485A - Method for controlling impurity VLSI-M in valsartan - Google Patents

Abstract

The invention discloses a method for controlling impurity VLSI-M in valsartan. Solvent for cyclization is limited by the method, DMF (dimethyl formamide) with formic acid content no larger than 200ppm is used as cyclization solvent to obtain valsartan, and the impurity VLSI-M content of the valsartan is no more than 0.015%. The method has the advantages that the method is simple, and since the cyclization solvent is limited, impurities are reduced as far as possible while productivity is guaranteed, and effectiveness in control of impurity content is achieved.

Description

The control method of impurity VLSI-M in the valsartan

Technical field

The present invention relates to technical field of pharmaceuticals, relate in particular to the control method of impurity VLSI-M in a kind of valsartan.

Background technology

Valsartan (valsartan, chemical formula see the formula I), chemical name: N-(1-oxygen amyl group)-N-[4-[2-(1H-TETRAZOLE-5-yl) phenyl] benzyl]-Valine, be a kind of 1 type (AT of angiotensinⅡ ₁) receptor antagonist, having brand-new Hypotensive Mechanism, step-down is steady, curative effect is strong, long action time, patient tolerability are good.

Document about valsartan is quite abundant, mainly concentrate on synthetic route and the crystal formation, such as the patent about the valsartan synthetic route US5399578, US7199144, WO2006067216, WO2008007391, WO2004026847, CN00115355 etc. are arranged; Patent about the valsartan crystal formation has US7105557, WO2003089417, WO2004087681, US20060270723 etc.; Aspect the Control of Impurities of valsartan, the open CN101367772 of Chinese patent has made following restriction to related substance: VLSI-A is no more than 1.0%; VLSI-B and VLSI-D must not distinguish above 0.2% and 0.1%, and other single unknown impuritie must not surpass 0.1%, and total impurities (not comprising VLSI-A) is no more than 0.3%, meets the requirement of American Pharmacopeia; The open CN200910085197.2 of Chinese patent is studied diovan foreign matter E, and the open CN200910242972.0 of Chinese patent is studied diovan foreign matter F.

In the research of valsartan amlodipine compound preparation, to have higher requirement for the quality of valsartan bulk drug, single impurity requires less than 0.02%, even less than 0.015%.Therefore, be necessary very much the unknown impuritie in the valsartan bulk drug is studied, find reason and the control method of generation.

By the research to the valsartan process for purification, find that the impurity of RRT value 0.5 is difficult to effectively remove by recrystallization, by the LC-MS analysis, the molecular weight of this impurity is [M+1] ⁺=380.Tentatively be judged as valsartan formylation impurity, chemical formula as shown in the formula:

Behind the directed synthetic VLSI-M, through the liquid phase location, confirm really VLSI-M of this impurity.

Summary of the invention

The control method that the purpose of this invention is to provide impurity VLSI-M in a kind of valsartan, by the research to VLSI-M in the valsartan product, determine the character of VLSI-M in the valsartan, restriction by cyclization solvent DMF in synthetic to valsartan, control the content of impurity, prepare highly purified valsartan product.

The technical scheme that realizes the object of the invention is as follows:

The control method of impurity VLSI-M in a kind of valsartan, the synthetic route of wherein said valsartan is as follows:

It is this synthetic purpose that the content of control VLSI-M is no more than 0.015% of end product weight, the present invention limits the cyclization solvent DMF for this reason, use the content of formic acid to be not more than the DMF of 200ppm as the cyclization solvent, synthesize according to said synthesis route, obtain valsartan, the weight content of its impurity VLSI-M is no more than 0.015%.

Further, the DMF that the weight content of formic acid is not more than 200ppm obtains by the following method: get technical grade DMF, measure its formic acid content; Formic acid content is during greater than 200ppm, and rectifying obtains the DMF that formic acid content is not more than 200ppm.

Beneficial effect of the present invention: the present invention DMF is that the cyclization solvent comes synthesizing Xieshatan, the difference of formic acid content is that the content produced of impurity VLSI-M is also different among the DMF, the present invention is according to the content of formic acid among the gate ring bonding solvent DMF, control the content of impurity, method is simple, in the situation that guarantee productivity, reduce the generation of impurity, reached foreign matter content has been accomplished effective control.

Description of drawings:

The below is described in further detail the present invention with reference to the accompanying drawings.

Fig. 1 is the liquid phase figure of valsartan;

Fig. 2 is the liquid phase figure of VLSI-M;

Fig. 3 is the liquid phase figure of valsartan and VLSI-M mixing sample introduction.

Embodiment

Further specify by the following examples the present invention, but not as restriction of the present invention

The preparation of example 1, valsartan

In the 1000ml there-necked flask, add 118g N-[(2 '-cyanobiphenyl-4-yl) methyl]-(L)-and valine methyl ester and 400ml toluene, 44g sodium bicarbonate, stirring is cooled to 0 ℃.Drip the 52ml valeryl chloride, keep temperature less than 10 ℃; Finish stirring at room 10 hours; TLC and HPLC show the reaction finish; Add 100ml * 2 water, stirred 0.5 hour, divide to walk water; Toluene is used 50ml 1N hydrochloric acid, 50ml 5% sodium bicarbonate and 50ml * 2 salt washing mutually, uses the 40g anhydrous sodium sulfate drying; Filter, filtrate is revolved to steam and is obtained light yellow oil, is N-[(2 '-cyanobiphenyl-4-yl) methyl]-the N-pentanoyl-(L)-valine methyl ester.

In the 2000ml there-necked flask, add triethylamine hydrochloride 135g, sodiumazide 40g, DMF400ml and N-[(2 '-cyanobiphenyl-4-yl) methyl]-the N-pentanoyl-(L)-valine methyl ester, be warming up to 140 ℃ of reactions 24～30 hours; The cooling room temperature adds 500ml toluene and 500ml sodium nitrite solution; Tell toluene layer, add 30～35 ℃ of lower stirrings 8～16 hours of potassium hydroxide solution of 560g10%, after reaction is finished, divide to walk toluene layer.It is 2～2.5 that water layer is slowly transferred PH with concentrated hydrochloric acid, stirs; With 500ml * 2 ethyl acetate extractions, combined ethyl acetate layer, with salt washing, decompression and solvent recovery behind the anhydrous sodium sulfate drying, obtain the yellow thickness oily matter of 115g, be the valsartan crude product.

Making with extra care of example 2, valsartan

The valsartan crude product that obtains is added in the 460ml ethyl acetate, is heated to fully dissolving; After being cooled to room temperature, continuing to be cooled to 0 ℃ and preserved 2 hours, filter, filter cake washs with a small amount of cold ethyl acetate; Oven dry obtains 80g valsartan primary crystallization product; Valsartan primary crystallization product is added in the 400ml ethyl acetate, is heated to dissolving, stir and be cooled to room temperature, filter, filter cake washs with a small amount of ethyl acetate, dries, and obtains 60g valsartan secondary crystal product, HPLC purity〉99.9%.

The preparation of example 3, VLSI-M

In the 500ml there-necked flask, add 60g N-[(2 '-cyanobiphenyl-4-yl) methyl]-(L)-and valine methyl ester and 100ml toluene, stir, be cooled to 0 ℃; Add 50ml acetic anhydride and 50ml formic acid, keep 20 ~ 30 ℃ of temperature.Stirred 10 hours; TLC and HPLC show the reaction finish; Add 100ml * 2 water, stirred 0.5 hour, divide to walk water; Toluene is through anhydrous sodium sulfate drying; Filter, filtrate is revolved to steam and is obtained light yellow oil, is N-[(2 '-cyanobiphenyl-4-yl) methyl]-the N-formyl radical-(L)-valine methyl ester.

In the 1000ml there-necked flask, add triethylamine hydrochloride 85g, sodiumazide 30g, DMF300ml and N-[(2 '-cyanobiphenyl-4-yl) methyl]-the N-formyl radical-(L)-valine methyl ester, be warming up to 140 ℃ of reactions 24～30 hours.The cooling room temperature adds 400ml toluene and 400ml sodium nitrite solution; Tell toluene layer, add 30～35 ℃ of lower stirrings 8～16 hours of potassium hydroxide solution of 500g10%, after reaction is finished, divide to walk toluene layer.It is 2～2.5 that water layer is slowly transferred PH with concentrated hydrochloric acid, stirs; With 500ml * 2 ethyl acetate extractions, combined ethyl acetate layer, with the salt washing, decompression and solvent recovery behind the anhydrous sodium sulfate drying obtains oily matter through re-crystallizing in ethyl acetate, is diovan foreign matter VLSI-M.

Fig. 1 is the liquid phase figure of valsartan; Fig. 2 is the liquid phase figure of VLSI-M; Fig. 3 is the liquid phase figure of valsartan and VLSI-M mixing sample introduction.VLSI-M is the formylation derivative of valsartan, in synthesis step, is caused by the formic acid in the cyclization solvent DMF, so the key of control impurity VLSI-M content is the content of formic acid among the gate ring bonding solvent DMF.Use the DMF of different formic acid contents as solvent, synthesizing Xieshatan, result data sees Table 1:

The content of formic acid table corresponding to the VLSI-M content results among table 1 DMF

Batch	Content/the ppm of formic acid among the DMF	Impurity VLSI-M content
			1	488	0.058%
2	405	0.035%
			3	317	0.021%
4	266	0.019%
			5	203	0.014%
6	152	0.011%

By upper table, can determine that the content of formic acid in the solvent DMF and the amount of valsartan lmpurities VLSI-M are corresponding relation.When the content of formic acid among the DMF during at 203ppm, the amount of the impurity VLSI-M in the valsartan is 0.014%; When the content of formic acid among the DMF during at 266ppm, the amount of the impurity VLSI-M in the valsartan is 0.019%.Therefore, the DMF that selects formic acid content to be not more than 200ppm prepares valsartan as the cyclization solvent.

Claims (1)

1. the control method of impurity VLSI-M in the valsartan, the synthetic route of wherein said valsartan is as follows:

It is characterized in that: use DMF that the weight content of formic acid is not more than 200ppm as the cyclization solvent, synthesize according to said synthesis route and obtain valsartan, impurity VLSI-M weight content is no more than 0.015%, and the chemical formula of described VLSI-M is as follows:

。

2.The control method of impurity VLSI-M in the valsartan according to claim 1, it is characterized in that, the DMF that the weight content of described formic acid is not more than 200ppm obtains by the following method: get technical grade DMF, measure its formic acid content, formic acid content is during greater than 200ppm, rectifying obtains the DMF that formic acid content is not more than 200ppm.

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