CN103012300A - Novel method for preparing valsartan - Google Patents
Novel method for preparing valsartan Download PDFInfo
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- CN103012300A CN103012300A CN2013100011389A CN201310001138A CN103012300A CN 103012300 A CN103012300 A CN 103012300A CN 2013100011389 A CN2013100011389 A CN 2013100011389A CN 201310001138 A CN201310001138 A CN 201310001138A CN 103012300 A CN103012300 A CN 103012300A
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Abstract
The invention discloses a novel method for preparing valsartan. The method comprises the following steps in sequence: carrying out cyclization reaction on N-(1-valeryl)-N-[4-[2-(5-cyan) phenyl] benzyl]-L-valine alkyl ester and sodium azide in the presence of ammonium salt, so as to obtain the valsartan methyl ester; mixing the cyclization reaction liquid of the prepared valsartan methyl ester with inorganic aqueous alkali I containing the sodium ion or potassium ion; stirring and reacting to obtain the salt; filtering again; washing; drying to obtain the pure valsartan methyl ester alkali metal salt; mixing and hydrolyzing the pure valsartan methyl ester alkali metal salt and the inorganic aqueous alkali II; acidifying again; extracting; recrystallizing at one time; and drying to obtain the valsartan, wherein the valsartan methyl ester alkali metal salt is provided with the following structural formula.
Description
Technical field
The invention belongs to organic and medicine synthetic field, the specifically preparation method of antihypertensive drug valsartan.
Background technology
Valsartan (Valsartan) is angiotensin II receptor antagonist (ARB); be used for the treatment of clinically hypertension; Chinese is: N-(1-pentanoyl)-N-[4-[2-(1H-tetrazole-5-yl) phenyl] benzyl]-Valine, structural formula is as follows:
US Patent No. 5399578A discloses the preparation method of valsartan bulk drug: N-(1-pentanoyl-N-[4-[2-(5-cyano group) phenyl] benzyl]-Valine benzyl ester and sodium azide carry out ring-closure reaction in the presence of organo-tin compound; obtain valsartan benzyl ester, the latter prepares valsartan through catalytic hydrogenolysis.
The method uses expensive, highly toxic organo-tin compound to participate in ring-closure reaction, final step need to be used the Pd catalytic hydrogenolysis, operational hazards not only, production cost is high, and inevitable residual organo-tin compound and the heavy metal palladium that trace is arranged in the valsartan bulk drug of producing.
In the disclosed method of Chinese patent CN101270096A, using instead at triethylamine hydrochloride replaces the tin compound that has of high poison to participate in reaction, avoided in the product highly toxic organo-tin compound residual, but the method is in the cyclization process, the product racemization is obvious, and the valsartan methyl ester intermediate does not have purification procedures yet, cause repeatedly recrystallization of the finished product valsartan needs, its chemical purity and optical purity just can reach standards of pharmacopoeia, complicated operation, yield is low, and cost is high.
Summary of the invention
Technical problem to be solved by this invention provides a kind of novel method for preparing valsartan, and the valsartan chemical purity that has Technology production now is low, optical purity is low to solve, and needs repeatedly recrystallization just can reach the problem of standards of pharmacopoeia.
For solving the problems of the technologies described above, the technical solution used in the present invention is as follows:
A kind of novel method for preparing valsartan, comprise the pentanoyl with N-(1-)-N-[4-[2-(5-cyano group) phenyl] benzyl]-Valine alkyl ester and sodium azide carry out ring-closure reaction and make the valsartan methyl esters in the presence of ammonium salt, the ring-closure reaction liquid of preparation valsartan methyl esters is mixed with the inorganic base aqueous solution I that contains sodium ion or potassium ion, the stirring reaction salify, refilter, wash, drying, obtain valsartan methyl esters an alkali metal salt sterling; Again with the hydrolysis of valsartan methyl esters an alkali metal salt sterling and inorganic base aqueous solution II Hybrid Heating, again acidifying, extraction, recrystallization, drying obtain valsartan;
Wherein said valsartan methyl esters an alkali metal salt, structural formula is as follows:
Valsartan methyl ester sodium salt valsartan methyl esters sylvite.
Wherein, the ring-closure reaction liquid of preparation valsartan methyl esters can adopt prior art to obtain, reference [Ceng Yuancai, the synthesising process research of valsartan, colloid and polymkeric substance, the 3rd phase of the 21st volume, in September, 2003, the 43rd page].
Wherein, the described inorganic base aqueous solution I that contains sodium ion or potassium ion is aqueous sodium hydroxide solution, potassium hydroxide aqueous solution, aqueous sodium carbonate, wet chemical, sodium bicarbonate aqueous solution or potassium bicarbonate aqueous solution; Preferred sodium bicarbonate aqueous solution.
Wherein, the reaction mol ratio of valsartan methyl esters and sodium ion or potassium ion is 1:(1 ~ 3), preferred 1:(1.3 ~ 1.6);
Wherein, the stirring reaction salt-forming condition is: 10 ~ 40 ℃ of temperature, preferred 15～30 ℃, 4 ~ 6 hours reaction times, preferred 2 ~ 4 hours.
Wherein, inorganic base aqueous solution II is aqueous sodium carbonate, wet chemical, lithium hydroxide aqueous solution, aqueous sodium hydroxide solution or potassium hydroxide aqueous solution; Preferred aqueous sodium hydroxide solution.
Wherein, the mol ratio of the mineral alkali among the inorganic base aqueous solution II and valsartan methyl esters an alkali metal salt is 1.5～5:1, preferred 3:1.
Wherein, hydrolysising reacting temperature is 0～60 ℃, preferred 25～30 ℃; Hydrolysis time is 4～12 hours, preferred 6 ~ 8 hours.
Wherein, described acidifying is for being acidified to pH1 ~ 3 with inorganic acid aqueous solution with reaction solution; Described mineral acid is hydrochloric acid, sulfuric acid or phosphoric acid etc., preferably uses hydrochloric acid.
Wherein, described extraction, extraction agent is ethyl acetate, propyl acetate, methylene dichloride, ethylene dichloride or toluene, ethyl acetate.
Wherein, a described recrystallization condition is: add in the crude product in the recrystallization solvent, for every 1g crude product, the adding volume of recrystallization solvent is 4 ~ 8mL, be heated to 40～60 ℃ of dissolvings, cool to again 0～5 ℃ of crystallization 1～5 hour, wherein, described recrystallization solvent is any one single solvent in ethyl acetate, propyl acetate and the methylene dichloride, or in any one solvent in ethyl acetate, propyl acetate and the methylene dichloride and normal hexane, normal heptane and the sherwood oil any one solvent mixed solvent.
Beneficial effect: the present invention has following advantage:
The valsartan yield is high, product purity is high, last handling process is simplified.
The valsartan that traditional technology is produced, because used valsartan methyl esters is not purified, its chemical purity is usually less than 90%, optical purity is usually less than 95%, the valsartan crude product that obtains after the hydrolysis, optical purity are usually less than 93%, optical purity behind the recrystallization usually about 96%, need the recrystallization more than at least twice, quality product just can reach standards of pharmacopoeia.
It is raw material that the present invention adopts valsartan methyl esters an alkali metal salt, and the valsartan crude product chemical purity after the hydrolysis is namely greater than 99%, and optical purity only needs a recrystallization just can reach standards of pharmacopoeia usually 97～98%.
Therefore, compare advantage simple to operate, that yield is high, product purity is higher that technique of the present invention has with traditional technology.
Embodiment
According to following embodiment, the present invention may be better understood.Yet, those skilled in the art will readily understand that the described concrete material proportion of embodiment, processing condition and result thereof only are used for explanation the present invention, and should also can not limit the present invention described in detail in claims.
Embodiment 1: the preparation of the ring-closure reaction liquid of valsartan methyl esters.
In the 500ml four-hole boiling flask, add 150ml toluene; 40.65g(0.1mol) the N-(1-pentanoyl)-N-[4-[2-(5-cyano group) phenyl] benzyl]-Valine methyl esters (1); stir; heat up (about about 30 ℃) to compound (1-pentanoyl)-N-[4-[2-(5-cyano group) phenyl] benzyl]-Valine methyl esters dissolve complete; behind dissolve complete; to wherein adding 6.5g(0.1mol) sodium azide and 13.75g(0.1mol) triethylamine hydrochloride and 4g(0.03mol) zinc chloride; be warming up to about 100 ℃; back flow reaction 20 hours; HPLC follows the tracks of test sample; after reaction finishes; begin cooling; to wherein adding the 200ml water washing; divide the sub-cloud water layer, organic layer is used the water washing of 100ml saturated common salt again, divides to fall brine layer; obtaining organic layer is the toluene solution 160g of valsartan methyl esters crude product, contains valsartan methyl esters 22%.
Embodiment 2: the preparation of valsartan methyl ester sodium salt.
In the 3000ml four-hole boiling flask, add 1000g valsartan methyl esters toluene solution (the ring-closure reaction liquid that embodiment 1 makes, contain valsartan methyl esters 22%), add again the solution that 60g sodium bicarbonate and 540g water are made into, stirring at room salify 4 hours, filter, use the 100g toluene wash, again 100g water washing, 80 ℃ of vacuum-dryings obtain white valsartan methyl ester sodium salt 220g to constant weight.
HPLC detects, and chemical purity is 99.4%.
Chirality HPLC detects, and optical purity is 99.2%.
1HNMR analyzes, and does not have the peak corresponding to proton on the tetrazole ring.
Ultimate analysis: C, 63.49%, H, 6.45%, N, 14.80%, Na, 4.85%(theoretical value: C, 63.68%, H, 6.41%, N, 14.85%, Na, 4.88%)
Embodiment 3: the preparation of valsartan methyl esters sylvite.
In the 3000ml four-hole boiling flask, add 1000g valsartan methyl esters ethyl acetate solution (ring-closure reaction liquid, contain valsartan methyl esters 25%), add again the solution that 80g sodium bicarbonate and 600 water are made into, stirring at room salify 6 hours, filter, use the 100g toluene wash, again 100g water washing, 80 ℃ of vacuum-dryings obtain white valsartan methyl esters sylvite 260g to constant weight.
HPLC detects, and chemical purity is 99.5%.
Chirality HPLC detects, and optical purity is 99.1%.
1HNMR analyzes, and does not have the peak corresponding to proton on the tetrazole ring.
Ultimate analysis: C, 61.33%, H, 6.31%, N, 14.28%, K, 7.99%(theoretical value: C, 61.58%, H, 6.20%, N, 14.36%, K, 8.02%)
Embodiment 4: the preparation of valsartan.
In the 1000ml four-hole boiling flask, add 100g valsartan methyl ester sodium salt, add again the 250g10% sodium hydroxide solution, be incubated 25～30 ℃ of reactions 6 hours, with 10% dilute hydrochloric acid adjust pH to 2～3, use again the ethyl acetate extraction product three times, use 300ml at every turn.Merge organic layer, the 300ml water washing once, again the washing of 300ml saturated brine once, the 30g anhydrous magnesium sulfate drying filters, 60 ℃ of evaporated under reduced pressure obtain valsartan crude product 92.5g(HPLC and detect, chemical purity is 99.4%; Chirality HPLC detects, and optical purity is 97.8%).
Add the 500ml ethyl acetate in the crude product, be heated to 50 ℃ of dissolvings, cool to 0～5 ℃ of crystallization 2 hours again, filter, washing obtains valsartan 83g(HPLC and detects after the drying, and chemical purity is 99.8%; Chirality HPLC detects, and optical purity is 99.7%), hydrolysis crystallization total recovery 90%.
Embodiment 5: the preparation of valsartan.
In the 1000ml four-hole boiling flask, add 100g valsartan methyl esters sylvite, add again the 250g10% potassium hydroxide solution, be incubated 25～30 ℃ of reactions 8 hours, with 10% dilute hydrochloric acid adjust pH to 2～3, use again the ethyl acetate extraction product three times, use 300ml at every turn.Merge organic layer, the 300ml water washing once, again the washing of 300ml saturated brine once, the 30g anhydrous magnesium sulfate drying filters, 60 ℃ of evaporated under reduced pressure obtain valsartan crude product 88.5g(HPLC and detect, chemical purity is 99.2%; Chirality HPLC detects, and optical purity is 97.5%).
Add the 500ml ethyl acetate in the crude product, be heated to 50 ℃ of dissolvings, cool to 0～5 ℃ of crystallization 3 hours again, filter, washing obtains valsartan 79.5g(HPLC and detects after the drying, and chemical purity is 99.8%; Chirality HPLC detects, and optical purity is 99.7%), hydrolysis crystallization total recovery 89%.
Comparative example: the preparation of valsartan.
In the 3000ml four-hole boiling flask, add 1000g valsartan methyl esters toluene solution (ring-closure reaction liquid, contain valsartan methyl esters 22%), add again the 600g10% sodium hydroxide solution, be incubated 25～30 ℃ of reactions 8 hours, divide to fall toluene layer, water layer again with the extraction of 300ml toluene once.Water layer is used the ethyl acetate extraction product three times again with 10% dilute hydrochloric acid adjust pH to 2～3, uses 500ml at every turn.Merge organic layer, the 500ml water washing once, again the washing of 500ml saturated brine once, the 50g anhydrous magnesium sulfate drying filters, 60 ℃ of evaporated under reduced pressure obtain valsartan crude product 205g(HPLC and detect, chemical purity is 98.1%; Chirality HPLC detects, and optical purity is 92.6%).
Add the 1200ml ethyl acetate in the crude product, be heated to 50 ℃ of dissolvings, cool to 0～5 ℃ of crystallization 2 hours again, filter, washing obtains valsartan primary crystallization product 182g(HPLC and detects after the drying, and chemical purity is 99.3%; Chirality HPLC detects, and optical purity is 96.2%).
Add the 1000ml ethyl acetate among the valsartan primary crystallization product 182g, be heated to 50 ℃ of dissolvings, cool to 0～5 ℃ of crystallization 2 hours again, filter, washing obtains valsartan 160g(HPLC and detects after the drying, and chemical purity is 99.7%; Chirality HPLC detects, and optical purity is 99.4%), hydrolysis crystallization total recovery 75%.
Claims (10)
1. novel method for preparing valsartan, comprise the pentanoyl with N-(1-)-N-[4-[2-(5-cyano group) phenyl] benzyl]-Valine alkyl ester and sodium azide carry out ring-closure reaction and make the valsartan methyl esters in the presence of ammonium salt, it is characterized in that, the ring-closure reaction liquid of preparation valsartan methyl esters is mixed with the inorganic base aqueous solution I that contains sodium ion or potassium ion, the stirring reaction salify, refilter, wash, drying, obtain valsartan methyl esters an alkali metal salt sterling; Again with valsartan methyl esters an alkali metal salt sterling and inorganic base aqueous solution II mixed hydrolysis, again acidifying, extraction, recrystallization, drying obtain valsartan;
Wherein said valsartan methyl esters an alkali metal salt, structural formula is as follows:
2. the novel method of preparation valsartan according to claim 1, it is characterized in that the described inorganic base aqueous solution I that contains sodium ion or potassium ion is aqueous sodium hydroxide solution, potassium hydroxide aqueous solution, aqueous sodium carbonate, wet chemical, sodium bicarbonate aqueous solution or potassium bicarbonate aqueous solution.
3. the novel method of preparation valsartan according to claim 1 is characterized in that, the reaction mol ratio of valsartan methyl esters and sodium ion or potassium ion is 1:(1 ~ 3).
4. the novel method of preparation valsartan according to claim 1 is characterized in that, the stirring reaction salt-forming condition is: 10 ~ 40 ℃ of temperature, 4 ~ 6 hours reaction times.
5. the novel method of preparation valsartan according to claim 1 is characterized in that, inorganic base aqueous solution II is aqueous sodium carbonate, wet chemical, lithium hydroxide aqueous solution, aqueous sodium hydroxide solution or potassium hydroxide aqueous solution.
6. the novel method of preparation valsartan according to claim 1 is characterized in that, the mol ratio of the mineral alkali among the inorganic base aqueous solution II and valsartan methyl esters an alkali metal salt is 1.5～5:1.
7. the novel method of preparation valsartan according to claim 1 is characterized in that, hydrolysising reacting temperature is 0～60 ℃, and hydrolysis time is 4～12 hours.
8. the novel method of preparation valsartan according to claim 1 is characterized in that, described acidifying is for being acidified to pH1 ~ 3 with inorganic acid aqueous solution with reaction solution.
9. the novel method of preparation valsartan according to claim 1 is characterized in that, described extraction, and extraction agent is ethyl acetate, propyl acetate, methylene dichloride, ethylene dichloride or toluene.
10. the novel method of preparation valsartan according to claim 1, it is characterized in that, a described recrystallization condition is: add in the crude product in the recrystallization solvent, for every 1g crude product, the adding volume of recrystallization solvent is 4 ~ 8mL, be heated to 40～60 ℃ of dissolvings, cool to again 0～5 ℃ of crystallization 1～5 hour, wherein, described recrystallization solvent is ethyl acetate, any one single solvent in propyl acetate and the methylene dichloride, or ethyl acetate, any one solvent and normal hexane in propyl acetate and the methylene dichloride, in normal heptane and the sherwood oil any one solvent mixed solvent.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103923028A (en) * | 2014-05-04 | 2014-07-16 | 青岛雪洁助剂有限公司 | Preparation method of valsartan |
| WO2020010643A1 (en) * | 2018-07-13 | 2020-01-16 | 浙江华海药业股份有限公司 | Method for synthesizing valsartan |
| WO2020248341A1 (en) * | 2019-06-13 | 2020-12-17 | 宁波美诺华药业股份有限公司 | Method for preparing valsartan |
| CN112457266A (en) * | 2020-12-24 | 2021-03-09 | 江苏新瑞药业有限公司 | Valsartan mother liquor recovery method |
| CN113264891A (en) * | 2021-05-26 | 2021-08-17 | 珠海润都制药股份有限公司 | Method for recovering L-valsartan from valsartan mother liquor containing D-valsartan |
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103923028A (en) * | 2014-05-04 | 2014-07-16 | 青岛雪洁助剂有限公司 | Preparation method of valsartan |
| CN103923028B (en) * | 2014-05-04 | 2017-05-24 | 青岛雪洁助剂有限公司 | Preparation method of valsartan methyl ester |
| WO2020010643A1 (en) * | 2018-07-13 | 2020-01-16 | 浙江华海药业股份有限公司 | Method for synthesizing valsartan |
| CN112638885A (en) * | 2018-07-13 | 2021-04-09 | 浙江华海药业股份有限公司 | Synthesis method of valsartan |
| US11434210B2 (en) | 2018-07-13 | 2022-09-06 | Zhejiang Huahai Pharmaceutical Co., Ltd | Method for synthesizing valsartan |
| CN112638885B (en) * | 2018-07-13 | 2024-06-11 | 浙江华海药业股份有限公司 | Synthesis method of valsartan |
| WO2020248341A1 (en) * | 2019-06-13 | 2020-12-17 | 宁波美诺华药业股份有限公司 | Method for preparing valsartan |
| CN112457266A (en) * | 2020-12-24 | 2021-03-09 | 江苏新瑞药业有限公司 | Valsartan mother liquor recovery method |
| CN113264891A (en) * | 2021-05-26 | 2021-08-17 | 珠海润都制药股份有限公司 | Method for recovering L-valsartan from valsartan mother liquor containing D-valsartan |
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Application publication date: 20130403 |