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CN1137887C - A kind of improved method of synthesizing valsartan - Google Patents

A kind of improved method of synthesizing valsartan Download PDF

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Publication number
CN1137887C
CN1137887C CNB001153552A CN00115355A CN1137887C CN 1137887 C CN1137887 C CN 1137887C CN B001153552 A CNB001153552 A CN B001153552A CN 00115355 A CN00115355 A CN 00115355A CN 1137887 C CN1137887 C CN 1137887C
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valsartan
methyl
reaction
solvent
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CN1317485A (en
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王晓东
葛纪龙
屠永锐
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Pharmaceutical Co Ltd Changzhou Pharmaceutical Factory No4
Shanghai Institute of Pharmaceutical Industry
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Changzhou Siyao Pharmacy Co ltd
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Abstract

The present invention belongs to the field of medicine synthesis. In particular to an improved method for synthesizing valsartan. Mainly improves the reaction steps of N-valerylation and tetrazole formation of N- [ [2 '-cyano (1, 1' -diphenyl) -4-yl ] methyl ] -L-valine ester hydrochloride. The invention describes the synthesis method in detail.

Description

Improving one's methods of a kind of synthesizing Xieshatan
Technical field
It is synthetic to the invention belongs to medicine.Be specifically related to improving one's methods of a kind of synthesizing Xieshatan.
Background technology
Valsartan (Valsartan) is the hypertensive chemical synthetic drug of a kind of effective treatment, the chemistry of valsartan is called N1-(1-oxygen amyl group)-N-[[2 '-(1H-tetrazole-5-yl)-(1,1 '-phenylbenzene)-the 4-yl]-methyl]-L-Xie Ansuan (I), its synthetic method As patent US 5,399,578 and J.Med.Chem.1991, VOl.34, No.8,2525-2547).Main synthetic route has two: the first is a raw material with 2 '-cyano group-4-formyl biphenyl (II), generates Schiff's base with the L-Xie Ansuan condensation of the esterified protection of carboxyl, and again through hydrogenating reduction, positive valeryl changes into tetrazole, goes protecting group and obtains I.
Figure C0011535500042
It two is to be that raw material and III are condensed into secondary amine with 2 '-cyano group-4-bromomethylbiphenyl (III), through positive valerylization, becomes tetrazole again, goes protecting group and obtains I.The last three-step reaction of these two lines is the same.Wherein positive valerylization is difficult step with becoming the tetrazole reaction, and synthetic total recovery is had the greatest impact.
The positive valeryl reaction of bibliographical information is with N-[[2 '-cyano group (1,1 '-phenylbenzene)-4-yl]-methyl]-L-L-valine ester hydrochloride (IV) is dissolved in the methylene dichloride, adds diisopropyl ethyl amine, drips n-amyl chloride again about 30 ℃.
Wherein R is C 1-4Saturated alkyl or the shortcoming of this method of benzyl be: 1. use the more expensive diisopropyl ethyl amine of a large amount of prices with in and the hydrogenchloride that produces in the acylation process, and be difficult to reclaim and use again.2. when aftertreatment, a large amount of diisopropyl ethyl amines almost enters water entirely, has greater environmental impacts.3. because the methylene dichloride boiling point is low, loss was very big when a large amount of dichloromethane solvents reclaimed in distillation.
The synthetic tetrazole reaction of bibliographical information is with N-(1-oxygen amyl group)-N-[[2 '-itrile group (1,1 '-phenylbenzene)-the 4-yl]-methyl]-L-L-valine ester (V) is dissolved in the aprotic polar solvent (as N-N-methyl-2-2-pyrrolidone N-, DMF etc.), with nitrine trialkylated tin (methyl, normal-butyl or phenyl), reaction generates tetrazole (VI) about 140 ℃, but the price of nitrine trialkylated tin is very expensive, and is difficult to obtain.
Figure C0011535500061
VII R 1=R 2=R 3=CH 3Or R 1=R 2=CH 3R 3=t-Bu
Summary of the invention
The synthetic tetrazole method of improvement of the present invention is to be raw material with sodium azide, and the polyoxyethylene glycol (200-1000) that is silylated with terminal hydroxy group is a catalyzer (VII).In aromatic solvents, be carried out to the tetrazole reaction.
The objective of the invention is to overcome in the above-mentioned synthesizing Xieshatan shortcoming of positive valerylization and tetrazole reactions steps, improve reaction method, finally improve the total recovery of synthesizing Xieshatan.
The invention discloses improving one's methods of a kind of synthesizing Xieshatan; it is characterized in that having improved N-[[2 '-cyano group (1; 1 '-phenylbenzene)-the 4-yl]-methyl]-the positive valerylization of L-L-valine ester hydrochloride (IV) and become the tetrazole reaction to generate the step of VII; go at last protecting group to obtain valsartan (I); specifically be aromatic solvents that IV and 3-8 are doubly measured and the 4-dimethylamino pyridine of 0.5-2%; aqueous solution with carbonate; drip the n-amyl chloride that 0.4-0.8 doubly measures 0-10 ℃ (the best is 5 ℃), and stirring more than 2 hours under this temperature.Stirred several hours at 40-50 ℃ more at last, excessive n-amyl chloride hydrolysis is fallen, be cooled to room temperature, the layering phase of anhydrating, organic phase is removed catalyzer 4-dimethylamino pyridine through the dilute hydrochloric acid washing, again through being washed to neutrality, drying, boil off partial solvent, make V, promptly can be used for the next step without purifying; V is dissolved in the aromatic solvents that 5-20 doubly measures, add polyoxyethylene glycol (200～1000) that the catalyzer terminal hydroxy group of 5-20% amount is silylated (VII), add the chloro trialkylated tin of doubly measuring than the excessive 10%-50% of stoichiometry, add the sodium azide that 0.2-0.6 doubly measures, heating reflux reaction 10-20 hour, obtain compound VI; Below the cooling reaction solution to 40 ℃.Adding concentration is the NaOH aqueous solution of 5%-10%, stirs 4-10 hour at 30-40 ℃, obtains the sodium-salt aqueous solution of valsartan I, is neutralized to PH＜2 with hydrochloric acid, uses methylbenzene extraction I, boils off solvent, uses re-crystallizing in ethyl acetate, obtains the valsartan white solid.
In the method for the present invention, the preparation method of the polyoxyethylene glycol that wherein said terminal hydroxy group is silylated (200-1000) VII doubly measures polyoxyethylene glycol (molecular-weight average is 200-1000) with 4-10 the chloro trimethyl silicane or the chloro tertiary butyl dimethyl-silicon of (best 6 times of amounts), 30-35 ℃ of reaction 5 hours, steam solvent in decompression below 40 ℃, remove unreacted chlorosilane with aromatic hydrocarbon solvent at last.
Aromatic hydrocarbon solvent described in the positive valeryl reaction of method of the present invention is benzene, toluene, ethylbenzene or dimethylbenzene, and usage quantity is 3～8 times of IV, and the best is 5 times; Carbonate is yellow soda ash, sodium bicarbonate, salt of wormwood or saleratus; The consumption of catalyzer 4-dimethylamino pyridine is 0.5～2% of IV, and the best is 1%.
It is benzene, toluene, ethylbenzene or dimethylbenzene that method of the present invention becomes the aromatic hydrocarbon solvent described in the tetrazole reaction, and consumption is 5～20 times of L-Xie Ansuan, and the best is 10 times; The molecular-weight average of catalyst polyethylene glycol VII is 200～1000, and the best is 400, and consumption is 5～20% of L-L-valine ester V; The end socket silylation of VII is TMS or tertiary butyl dimethylsilyl; Chloro alkyl tin is chloro tin trimethyl, chloro tributyl tin or chloro triphenyltin.
Method yield height of the present invention, wherein positive valeryl yield＞99% becomes the tetrazole total recovery to reach 55～78%, and has following significant advantage:
1, in positive valeryl reaction, uses the reaction of 4-dimethylamino pyridine catalytie esterification, reaction is carried out at a lower temperature, avoided the reaction of valeryl chloride and water; Use aromatic solvents, almost all can recovery set usefulness, production cost is low, and is little to environmental influence; The reaction yield height, also no coupling product generates; Aftertreatment is simple, does not need purifying, and steaming to the greatest extent, solvent promptly can be used for the next step.
2, use new catalyst VII in becoming the tetrazole reaction, use new catalyst, make temperature of reaction reduce to 110 ℃ by 140 ℃, byproduct of reaction obviously reduces, and has reduced the danger of triazo-compound blast; Speed of response is accelerated, and reduces to tens hours by original more than 30 hour; Use aromatic hydrocarbon solvent at a low price and be easy to and reclaim; Use cheap sodium azide to replace expensive nitrine trialkylated tin; Catalyst V II not only is catalyzed into tetrazole reaction, and catalyzer is converted into corresponding polyoxyethylene glycol when hydrolysis, its again catalysis hydrolysis reaction, and be easy to separate.
Specific embodimentsExample 1. N-(1-oxygen amyl group)-N-[[2 '-cyano group (1,1 '-phenylbenzene)-4-yl]
The preparation of-methyl-L-valine methyl ester
Reflux condensing tube is being housed, and thermometer is in the 500ml four-hole boiling flask of dropping funnel and mechanical stirring slurry, add N-[[2 '-cyano group (1,1 '-phenylbenzene)-and the 4-yl] methyl] L-valine methyl ester hydrochloride 35.8 grams (0.100mol), 180 milliliters of toluene, 10% Na 2CO 3The aqueous solution 200 grams (0.189mol), 4-dimethylamino pyridine 0.4 gram stirs, and frozen water is cooled to 5 ℃.Drip n-amyl chloride 18.1 grams (0.15mol), finish and continue to stir 3 hours.Be warming up to 45 ℃ of restir 1.5 hours.Be cooled to room temperature, branch vibration layer, organic layer are used the hydrochloric acid of 1N, 5%NaHCO respectively 3The aqueous solution, deionized water wash.Na 2SO 4Drying is steamed toluene, gets syrupy shape material N-(1-oxygen amyl group)-N-[[2 '-cyano group (1,1 '-phenylbenzene)-4-yl]-methyl]-L-valine methyl ester 40 grams, yield 98.0%.
Example 2.N-(1-oxygen amyl group)-N-[[2 '-cyano group (1,1 '-phenylbenzene)-4-yl]-
Methyl]-preparation of L-Xie Ansuan benzyl ester
Reflux condensing tube is being housed, thermometer, in the 500ml four-hole glass flask of dropping funnel and mechanical stirring slurry, add N-(1-oxygen amyl group)-N-[[2 '-cyano group (1,1,-phenylbenzene)-the 4-yl]-methyl]-L-Xie Ansuan benzyl ester 43.5 grams (0.100mol), 4-dimethylamino pyridine 0.5 gram, other raw material consumption and operating method are identical with example 1.Obtain syrupy shape material N-(1-oxygen amyl group)-N-[[2 '-cyano group (1,1 '-phenylbenzene-4-yl) methyl]-L-Xie Ansuan benzyl ester 48.1 grams, yield 99.4%.
The preparation of 3. pairs-trimethyl silicone hydride of example poly(oxyethylene glycol) 400
Reflux condensing tube is being housed, and thermometer in the 250ml glass flask of magnetic stirring apparatus, adds 20 gram poly(oxyethylene glycol) 400, chloro trimethyl silicane 120ml, and 30-35 ℃ was stirred 5 hours.Steam chloro trimethyl silicane solvent in decompression below 40 ℃, carrying secretly with small amount of toluene for chloro trimethyl silicane three times, viscous liquid two-trimethyl silane polyethylene glycol 24 grams.
The preparation of example 4. valsartans
Reflux condensing tube is being housed, thermometer, in the 1000ml four-hole boiling flask of mechanical stirring slurry, add N-(1-oxygen amyl group)-N-[[2 '-cyano group (1,1 ' phenylbenzene)-4-yl]-methyl]-L-valine methyl ester 61.2 grams (0.15mol), toluene 500ml, two-trimethyl silicone hydride poly(oxyethylene glycol) 400 catalyzer 6 grams, chloro tributyl tin 65.1 grams (0.200ml), sodium azide 12 grams (0.185ml), heating was flowed back to 18 hours.Be cooled to room temperature, add 5% NaOH aqueous solution 300ml again, stirred 6 hours at 30-40 ℃.The water intaking phase is transferred PH=1 with concentrated hydrochloric acid, divides with 600ml toluene and extracts the organism of separating out from aqueous phase three times.Boil off toluene, use the 300ml re-crystallizing in ethyl acetate, get white crystalline solid valsartan 49.6 grams, yield 76%, fusing point 105-106 ℃, [α] D=-68 ° (C=1, methyl alcohol).
The preparation of example 5-8 valsartan
Operating process is with example 4.The use of raw material is except that catalyzer, and other is also with example 4.Its reaction yield and valsartan quality such as table 1:
Numbering Catalyst type Catalyst levels (gram) Yield mp(℃) [α] D(C=1) methyl alcohol
5 Two trimethyl silicone hydride Macrogol 200s 6 55％ 103 -63
6 Two-the trimethyl silicone hydride Polyethylene Glycol-600 6 63％ 104 -66
7 Two-the trimethyl silicone hydride cetomacrogol 1000 10 69％ 105 -65
8 Two-tertiary butyl dimethylsilane polyethylene glycol 400 6 78％ 105 -68

Claims (4)

1、一种合成缬沙坦的改进方法，其特征在于该方法包括下列步骤：1. An improved method for synthesizing valsartan, characterized in that the method comprises the following steps: (1)将N-[[2’-氰(1，1’-二苯基)-4-基]-甲基]-L-缬氨酸酯盐酸盐IV与3-8倍量的芳香类溶剂与0.5-2％的4-二甲胺基吡啶，与碳酸盐的水溶液混合，在0-10℃，滴加0.4-0.8倍量的正戊酰氯，并在此温度下搅拌2小时以上；最后再在40-50℃搅拌几小时，使过量的正戊酰氯水解掉，冷却至室温，分层去水相，有机相经稀盐酸洗涤去催化剂4-二甲胺基吡啶，再经水洗至中性，干燥，蒸去部分溶剂，制得N-(1-氧戊基)-N-[[2’-腈基(1，1’-二苯基)-4-基]-甲基]-L-缬氨酸酯V，不经提纯即可用于下步反应；(1) N-[[2'-cyano(1,1'-diphenyl)-4-yl]-methyl]-L-valine ester hydrochloride IV and 3-8 times the amount of aromatic Mix solvent-like solvent with 0.5-2% 4-dimethylaminopyridine and carbonate aqueous solution, add 0.4-0.8 times the amount of n-pentanoyl chloride dropwise at 0-10°C, and stir at this temperature for 2 hours above; finally, stir at 40-50°C for several hours to hydrolyze excess n-valeryl chloride, cool to room temperature, separate the water phase, and wash the organic phase with dilute hydrochloric acid to remove the catalyst 4-dimethylaminopyridine, and then Wash with water until neutral, dry, and evaporate part of the solvent to obtain N-(1-oxopentyl)-N-[[2'-cyano(1,1'-diphenyl)-4-yl]-methanol Base]-L-valine ester V can be used for the next step reaction without purification; (2)将N-(1-氧戊基)-N-[[2’-腈基(1，1’-二苯基)-4-基]-甲基]-L-缬氨酸酯V溶于5-20倍量的芳香类溶剂，加5-20％倍量的催化剂端羟基被硅烷化的聚乙二醇200～1000VII，加比化学计量过量10％-50％倍量的氯代三烃基锡，加0.2-0.6倍量的叠氮钠，加热回流反应10-20小时，得到化合物四氮唑VI； (2) N-(1-oxopentyl)-N-[[2'-nitrile (1,1'-diphenyl)-4-yl]-methyl]-L-valine ester V Soluble in 5-20 times the amount of aromatic solvents, add 5-20% times the amount of polyethylene glycol 200-1000VII with silanized catalyst terminal hydroxyl groups, add 10%-50% times the amount of chlorination Trihydrocarbyl tin, add 0.2-0.6 times the amount of sodium azide, heat and reflux for 10-20 hours to obtain compound tetrazole VI; (3)冷却化合物四氮唑VI的反应液至40℃以下，加入浓度为5％-10％的NaOH水溶液，在30-40℃搅拌4-10小时，得到缬沙坦I的钠盐水溶液，用盐酸中和至PH＜2，用甲苯提取缬沙坦I，蒸去溶剂，用乙酸乙酯重结晶，得到缬沙坦白色固体。(3) cooling the reaction solution of the compound tetrazolium VI to below 40°C, adding a concentration of 5%-10% NaOH aqueous solution, and stirring at 30-40°C for 4-10 hours to obtain the sodium salt solution of valsartan I, Neutralize with hydrochloric acid to pH<2, extract valsartan I with toluene, evaporate the solvent, and recrystallize with ethyl acetate to obtain valsartan as a white solid. 2、根据权利要求1所述的一种合成缬沙坦的改进方法，其特征在于其中所述的端羟基被硅烷化的聚乙二醇200～1000VII的制备方法是将聚乙二醇平均分子量为200-1000与4-10倍量的氯代三甲基硅或氯代叔丁基二甲基硅，在30-35℃反应5小时，在40℃以下减压蒸出溶剂，最后用芳香烃类溶剂除去未反应的氯代硅烷。2. An improved method for synthesizing valsartan according to claim 1, characterized in that the preparation method of polyethylene glycol 200-1000VII wherein the terminal hydroxyl group is silanized is to obtain the average molecular weight of polyethylene glycol 200-1000 and 4-10 times the amount of chlorotrimethylsilane or chlorotert-butyldimethylsilane, react at 30-35°C for 5 hours, evaporate the solvent under reduced pressure below 40°C, and finally use aromatic Hydrocarbon solvents remove unreacted chlorosilanes. 3、根据权利要求1所述的一种合成缬沙坦的改进方法，其特征在于其中正戊酰化反应中所述的芳香烃类溶剂为苯、甲苯、乙苯或二甲苯，使用量为N-[[2’-氰(1，1’-二苯基)-4-基]-甲基]-L-缬氨酸酯盐酸盐IV的3～8倍；碳酸盐为碳酸钠、碳酸氢钠、碳酸钾或碳酸氢钾；催化剂4-二甲胺基吡啶的用量为N-[[2’-氰(1，1’-二苯基)-4-基]-甲基]-L-缬氨酸酯盐酸盐IV的0.5～2％。3. An improved method for synthesizing valsartan according to claim 1, characterized in that the aromatic hydrocarbon solvent described in the n-valerylation reaction is benzene, toluene, ethylbenzene or xylene, and the usage amount is 3-8 times of N-[[2'-cyano(1,1'-diphenyl)-4-yl]-methyl]-L-valine ester hydrochloride IV; carbonate is sodium carbonate , sodium bicarbonate, potassium carbonate or potassium bicarbonate; the amount of catalyst 4-dimethylaminopyridine is N-[[2'-cyano(1,1'-diphenyl)-4-yl]-methyl] - 0.5-2% of L-valine ester hydrochloride IV. 4、根据权利要求1所述的一种合成缬沙坦的改进方法，其特征在于其中成四氮唑反应中所述的芳香烃类溶剂为苯、甲苯、乙苯或二甲苯，用量为L-缬氨酸酯V的5～20倍；催化剂聚乙二醇VII的平均分子量为200～1000，用量为L-缬氨酸的5～20％；聚乙二醇VII的封头硅烷基为三甲基硅烷基或叔丁基二甲基硅烷基；氯代烃基锡为氯代三甲基锡、氯代三丁基锡或氯代三苯基锡。4. An improved method for synthesizing valsartan according to claim 1, wherein the aromatic hydrocarbon solvent described in the tetrazolium-forming reaction is benzene, toluene, ethylbenzene or xylene, and the consumption is L -5～20 times of valine ester V; the average molecular weight of the catalyst polyethylene glycol VII is 200～1000, and the dosage is 5～20% of L-valine; the head silyl group of polyethylene glycol VII is Trimethylsilyl or tert-butyldimethylsilyl; hydrocarbyltin chloride is trimethyltin chloride, tributyltin chloride or triphenyltin chloride.
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GB0222056D0 (en) * 2002-09-23 2002-10-30 Novartis Ag Process for the manufacture of organic compounds
WO2004087681A1 (en) * 2003-03-31 2004-10-14 Hetero Drugs Limited A novel amorphous form of valsartan
US7361770B2 (en) * 2003-06-16 2008-04-22 Hetero Drugs Limited Process for preparation of valsartan
CN101362728B (en) * 2008-08-22 2011-07-20 北京赛科药业有限责任公司 Valsartan synthesis method
CN101475540B (en) * 2009-01-22 2011-05-11 江苏德峰药业有限公司 Preparation of Valsartan
CN102010381B (en) * 2009-09-05 2012-02-08 山东新时代药业有限公司 Improved preparation method of valsartan
WO2011124655A1 (en) * 2010-04-07 2011-10-13 Krka, D.D., Novo Mesto Improved process for preparing valsartan
BR112013002589A2 (en) * 2010-08-03 2019-09-24 Novartis Ag highly crystalline valsatana
CN102093302B (en) * 2011-01-28 2013-03-20 海南美兰史克制药有限公司 Valsartan compound and new manufacturing method thereof
CN102329276B (en) * 2011-09-30 2013-09-25 浙江新赛科药业有限公司 Method for recovering valsartan mother liquid
CN110078640B (en) * 2019-03-29 2022-04-05 浙江美诺华药物化学有限公司 Synthesis method of valsartan intermediate
EP3939967A1 (en) 2020-07-15 2022-01-19 KRKA, d.d., Novo mesto A continuous process for the preparation of (s)-methyl n-((2'-cyano-[1,1'-biphenyl]-4-yl)methyl)-n-pentanoylvalinate in a flow reactor

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