CN1137887C - Improved process for synthesizing Xieshatan - Google Patents
Improved process for synthesizing Xieshatan Download PDFInfo
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- 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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- chloro
- methyl
- reaction
- phenylbenzene
- valine ester
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Abstract
The present invention particularly relates to an improved process for synthesizing valsartan which belongs to the pharmaceutical synthesis. The improved process for synthesizing valsartan mainly improves the n-valerylizing reacttion step and tetrazazole reaction step of N-[[2'-cyano(1, 1'-diphenyl)-4-base]-methyl]-L-valine ester salt. The synthetic method of the present invention discloses in details.
Description
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.
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.
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, improving one's methods of a kind of synthesizing Xieshatan is characterized in that this method comprises the following steps:
(1) with N-[[2 '-cyanogen (1,1 '-phenylbenzene)-the 4-yl]-methyl]-aromatic solvents that L-L-valine ester hydrochloride IV and 3-8 doubly measure and the 4-dimethylamino pyridine of 0.5-2%, aqueous solution with carbonate, at 0-10 ℃, drip the n-amyl chloride that 0.4-0.8 doubly measures, 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 boils off partial solvent, makes N-(1-oxygen amyl group)-N-[[2 '-itrile group (1,1 '-phenylbenzene)-the 4-yl]-methyl]-L-L-valine ester V, promptly can be used for the next step without purifying;
(2) 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 aromatic solvents that 5-20 doubly measures, add Macrogol 200～1000VII that catalyzer terminal hydroxy group that 5-20% doubly measures is silylated, 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 tetrazole VI;
(3) below the reaction solution to 40 of cooling compound tetrazole VI ℃, adding concentration is the NaOH aqueous solution of 5%-10%, stirred 4-10 hour at 30-40 ℃, obtain the sodium-salt aqueous solution of valsartan I, be neutralized to PH＜2 with hydrochloric acid,, boil off solvent with methylbenzene extraction valsartan I, use re-crystallizing in ethyl acetate, obtain the valsartan white solid.
2, a kind of synthesizing Xieshatan according to claim 1 improves one's methods, the preparation method who it is characterized in that Macrogol 200～1000VII that wherein said terminal hydroxy group is silylated is to be chloro trimethyl silicane or the chloro tertiary butyl dimethyl-silicon that 200-1000 and 4-10 doubly measure with the polyoxyethylene glycol molecular-weight average, 30-35 ℃ of reaction 5 hours, steam solvent in decompression below 40 ℃, remove unreacted chlorosilane with aromatic hydrocarbon solvent at last.
3, a kind of synthesizing Xieshatan according to claim 1 improves one's methods, it is characterized in that the aromatic hydrocarbon solvent described in the wherein positive valeryl reaction is benzene, toluene, ethylbenzene or dimethylbenzene, usage quantity is N-[[2 '-cyanogen (1,1 '-phenylbenzene)-4-yl]-methyl]-3～8 times of L-L-valine ester hydrochloride IV; Carbonate is yellow soda ash, sodium bicarbonate, salt of wormwood or saleratus; The consumption of catalyzer 4-dimethylamino pyridine is N-[[2 '-cyanogen (1,1 '-phenylbenzene)-4-yl]-methyl]-L-L-valine ester hydrochloride IV 0.5～2%.
4, improving one's methods of a kind of synthesizing Xieshatan according to claim 1 is characterized in that wherein becoming the aromatic hydrocarbon solvent described in the tetrazole reaction is benzene, toluene, ethylbenzene or dimethylbenzene, and consumption is 5～20 times of L-L-valine ester V; The molecular-weight average of catalyst polyethylene glycol VII is 200～1000, and consumption is 5～20% of a L-Xie Ansuan; The end socket silylation of polyoxyethylene glycol VII is TMS or tertiary butyl dimethylsilyl; Chloro alkyl tin is chloro tin trimethyl, chloro tributyl tin or chloro triphenyltin.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB001153552A CN1137887C (en) | 2000-04-07 | 2000-04-07 | Improved process for synthesizing Xieshatan |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB001153552A CN1137887C (en) | 2000-04-07 | 2000-04-07 | Improved process for synthesizing Xieshatan |
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| CN1317485A CN1317485A (en) | 2001-10-17 |
| CN1137887C true CN1137887C (en) | 2004-02-11 |
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| CNB001153552A Expired - Lifetime CN1137887C (en) | 2000-04-07 | 2000-04-07 | Improved process for synthesizing Xieshatan |
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Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB0222056D0 (en) * | 2002-09-23 | 2002-10-30 | Novartis Ag | Process for the manufacture of organic compounds |
| TR200503396T1 (en) * | 2003-03-31 | 2006-08-21 | Hetero Drugs Limited | Valsartan in a new, amorphous form. |
| AU2003245037A1 (en) * | 2003-06-16 | 2005-01-04 | Hetero Drugs Limited | A novel 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 |
| KR20130139863A (en) * | 2010-08-03 | 2013-12-23 | 노파르티스 아게 | Highly crystalline valsartan |
| 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 |
-
2000
- 2000-04-07 CN CNB001153552A patent/CN1137887C/en not_active Expired - Lifetime
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| CN1317485A (en) | 2001-10-17 |
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Owner name: SHANGHAI INSTITUTE OF PHARMACEUTICAL INDUSTRY Effective date: 20130322 |
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Inventor after: Wang Xiaodong Inventor after: Shi Huilin Inventor after: Ge Jilong Inventor after: Tu Yongrui Inventor before: Wang Xiaodong Inventor before: Ge Jilong Inventor before: Tu Yongrui |
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Effective date of registration: 20130322 Address after: 213004 Jiangsu province Changzhou Lihua Village Patentee after: Pharmaceutical Co., Ltd., Changzhou Pharmaceutical Factory No.4 Patentee after: Shanghai Institute of pharmaceutical industry Address before: The southern city of Changzhou province Jiangsu 213004 Lihua Village Patentee before: Pharmaceutical Co., Ltd., Changzhou Pharmaceutical Factory No.4 |
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