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A kind of technology of valsartan and impurity, applied in N-methyl)-N-nitroso-L-valine and preparation field thereof
Pending Publication Date: 2019-07-19
ZHEJIANG HUAHAI ZHICHENG PHARMA CO LTD +2
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At present, there is no literature reporting the structure and preparation method of the impurity, so the directional synthesis of the impuri...
Method used
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Embodiment 1
[0021] Synthesis of N-((2'-cyano-[1,1'-biphenyl]-4-yl)methyl)-L-valine (compound of formula II):
[0022] Into a 1000mL three-neck flask, add 35.8g (0.1mol) N-((2'-cyano-[1,1'-biphenyl]-4-yl)methyl)-L-valine methyl ester successively Hydrochloride, 300g of methanol, stirred for 10 minutes, added a solution prepared by 40g (1.0mol) NaOH and 200mL of water, kept at 30-40°C, and stirred for 5h. Hydrochloric acid was added dropwise to pH = 5-6, and stirring was continued for 15 minutes after the dropwise addition was completed. The filtrate was filtered off and the filter cake was retained. The filter cake was washed with 100 g of water. Dry in a vacuum oven to obtain the compound of formula II, 28.9 g of white solid, HPLC purity: 98%, yield 94%.
Embodiment 2
[0024] Synthesis of N-((2'-cyano-[1,1'-biphenyl]-4-yl)methyl)-L-valine (compound of formula II):
[0025] Into a 1000mL three-necked flask, add 35.8g (0.04mol) N-((2'-cyano-[1,1'-biphenyl]-4-yl)methyl)-L-valine methyl ester successively Hydrochloride, 200g of ethanol, stir for 10 minutes, add a solution prepared by 44.8g (0.8mol) KOH and 200mL of water, keep warm at 40-45°C, and react for 20h. Hydrochloric acid was added dropwise to pH = 5-6, and stirring was continued for 15 minutes after the dropwise addition was completed. The filtrate was filtered off and the filter cake was retained. The filter cake was washed with 100 g of water. Dry in a vacuum oven to obtain the compound of formula II, 28.3 g of white solid, HPLC purity: 99%, yield 92%.
Embodiment 3
[0027] Synthesis of N-((2'-cyano-[1,1'-biphenyl]-4-yl)methyl)-N-nitroso-L-valine (formula I valsartan impurity):
[0028] In the there-necked flask of 500mL, add 30.8g (0.1mol) formula II compound successively, the methanol of 150g, the dichloromethane of 150g, 14.4g (0.15mol) methanesulfonic acid, after stirring for 10 minutes, slowly dropwise add 10.3g ( 0.15mol) NaNO 2 Prepare the solution with 20mL of water, react for 1-2 hours, filter, and dry the filter cake to obtain the impurity of formula I valsartan, 26.3g of off-white powder, HPLC purity: 95%, yield 78%. MS-ESI(m / z):[M+H]+338.4.
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Abstract
The invention discloses a valsartan impurity and a preparation method of the valsartan impurity. The valsartan impurity has a structure shown as formula I as shown in the specification. The preparation method of the valsartan impurity comprises the following steps: a) allowing a compound, N-((2'-cyan-[1,1'-biphenyl]-4) methyl)-L-valine methyl ester hydrochloride as a starting material and alkali to give an esterification reaction in a solvent and then performing acidification to prepare a compound shown as formula II as shown in the specification, and b) allowing the compound shown as the formula II and sodium nitrite in an organic solvent to be subjected to nitrosation under an acidic condition to form the valsartan impurity shown as the formula I. The preparation method is mild in reaction condition, simple in technology, short in reaction time and good in yield; the high-purity valsartan impurity shown as the formula I is obtained; a reliable impurity control is provided for qualitycontrol research of a valsartan product; and the valsartan impurity has very important significance.
Description
technical field [0001] The present invention relates to the field of medicinal chemistry, in particular to N-((2'-cyano-[1,1'-biphenyl]-4-yl)methyl)-N-nitroso-L-valine (a A kind of valsartan impurity) and preparation method thereof. [0002] Background of the invention [0003] Valsartan (English name Valsartan), the chemical name is N-(1-pentanoyl)-N-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]- 4-base] methyl]-L-valine, its structural formula is as follows: [0004] [0005] Valsartan is an antihypertensive drug developed by Novartis. It is an angiotensin receptor antagonist, which can be used for various types of hypertension and has a good protective effect on the heart, brain and kidney. [0006] During the synthesis of valsartan, the inventors found that the impurity of formula I (N-((2'-cyano-[1,1'-biphenyl]-4-yl)methyl)-N-nitroso -L-valine) is a potential genotoxic impurity, and its structural formula is as follows: [0007] [0008] The impurity has a genotoxicit...
Claims
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