CN102060797A - High-purity valsartanmethyl ester crystal production process - Google Patents
High-purity valsartanmethyl ester crystal production process Download PDFInfo
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Abstract
The invention provides a clean, environmentally-friendly and high-purity valsartanmethyl ester crystal production process, which avoids using organic tin compounds which are very harmful to the human body and environment, such as azidotributyltin, chlorotributyltin and the like, and can obtain valsartanmethyl ester crystals with high chemical purity and high optical purity through crystallization and purification. The invention also provides a high-yield process for producing high-purity valsartan by using the valsartanmethyl ester crystals.
Description
Technical field
The invention belongs to the separation engineering technical field, be specifically related to a kind of high purity valsartan methyl esters crystalline production technique.
Background technology
Valsartan, English name Valsartan, Chinese N-(1-pentanoyl)-N-[4-[2-(1H-tetrazole-5-yl) phenyl] benzyl]-the L-Xie Ansuan, molecular formula: C
24H
29N
5O
3Molecular weight: 435.52, be the potent and specific angiotensin II receptor antagonists of a kind of non-peptide class, it has brand-new step-down mechanism, and step-down is steady, curative effect is strong, long action time, patient tolerability is good, can be used for treating hypertension, light moderate essential hypertension, especially secondary hypertension due to the suitable kidney damage, its structural formula is shown in 3:
The preparation method that U.S. Pat 5399578A proposes is: N-[(2 '-cyano group-1; 1 ' biphenyl-4-yl) alkyl]-L-valine methyl ester hydrochloride (compound 3) mixes with triethylamine with organic solvent; react with valeryl chloride then; obtain N-(1-pentanoyl)-N-[4-[2-(5-cyano group) phenyl] benzyl]-L-valine methyl ester (compound 1); then under the catalytic condition of tin compound; make compound 2 with the sodium azide reaction; this method is used tin compound catalyst; make the part tin compound remain in the middle of the product; and organo-tin compound toxicity is very strong; low-carbon alkyl tin dermal toxicity is also very strong simultaneously, and the healthy of production operation employee affected.
The method that Chinese patent CN1317485A proposes to prepare valsartan is: N-(1-pentanoyl)-N-[4-[2-(5-cyano group) phenyl] benzyl]-L-valine methyl ester (compound 4) is dissolved in aromatic solvents; the polyoxyethylene glycol that is silylated at the catalyzer terminal hydroxy group; under excessive a little the condition of nitrine trialkylated tin of stoichiometry; add the sodium azide reaction and make compound 5; this method has been used two kinds of catalyzer; do not avoid the use of organo-tin compound; the polyoxyethylene glycol production method complexity that the while terminal hydroxy group is silylated; adopt the method for shortening to slough benzyl protecting group; need hydrogenation unit, strengthened production cost.
Chinese patent CN101270096A has proposed to improve one's methods on above production basis; cancelled the tin compound catalyst of traditional use; use instead under the catalytic condition of triethylamine hydrochloride; compound (N-(1-pentanoyl)-N-[4-[2-(5-cyano group) phenyl] benzyl]-L-Xie Ansuan alkyl ester) and the hydrazoic acid reacting metal salt; this kind improved one's methods does not have tin compound catalysis toxicity, and needs use excessive a lot of hydrazoic acid metal-salt and amine salt or Lewis acid reaction but this kind improved one's methods.Trinitride also is highly toxic product, and excessive part need use the nitrite of severe toxicity to handle, energy consumption height not only, and waste gas is many, also causes very big wastes and pollution, and product purity is low, and particularly wherein the D-content of isomer is many, and yield is also low.
Valsartan methyl esters crystal is a kind of white solid, and is stable.Be easy to transportation, prevent to be isomerizated into D-valsartan methyl esters in the storage process in transportation.And valsartan methyl esters crystal only needs one-step hydrolysis reaction, just can obtain final bulk drug (valsartan).This provides very big convenience for the client, and the client can save the facility investment of de novo synthesis and unnecessary environmental pollution.
In the prior art with N-(1-pentanoyl)-N-[4-[2-(5-cyano group) phenyl] benzyl]-the L-valine methyl ester becomes tetrazole through ring-closure reaction; its product valsartan methyl esters is a thickness oily matter; be isomerizated into D-valsartan methyl esters easily, make quality product not guarantee.At present, find no and prepare valsartan methyl esters crystalline report.
Summary of the invention
Technical problem to be solved by this invention provides a kind of cleaning, environmental protection, highly purified valsartan methyl esters crystalline production technique.
For solving the problems of the technologies described above, the technical solution used in the present invention is as follows:
A kind of high purity valsartan methyl esters crystalline production technique, it comprises the steps:
(1) with N-(1-pentanoyl)-N-[4-[2-(5-cyano group) phenyl] benzyl]-L-valine methyl ester (1) is a raw material; under the effect of amine salt and other catalyzer such as Lewis acid or silicoorganic compound, in organic solvent, carry out ring-closure reaction and get valsartan methyl esters (2) with the metal-salt of hydrazoic acid.
(2) reaction solution that step (1) is obtained is cooled to room temperature, add alkaline solution, stir, standing demix, organic layer recycling, water layer mineral acid adjust pH to 1～2, again with methylene dichloride, ethyl acetate or toluene extraction, use the saturated common salt water washing to neutrality the organic solvent layer after the extraction,, obtain valsartan methyl esters crude product through concentrating under reduced pressure;
(3) the valsartan methyl esters dissolving crude product that step (2) is obtained was cooled to-20～10 ℃ of recrystallizations 2～5 hours again in alcoholic solvent, esters solvent or aromatic hydrocarbon solvent, filtered, and drying obtains valsartan methyl esters crystal.
In the step (1); described amine salt is the hydrochloride of organic amines such as triethylamine hydrochloride, trimethylamine hydrochloride, tripropyl amine hydrochloride, Tributylamine hydrochloride, diisopropylethylamine hydrochloride; or quaternary amine such as ammonium chloride, Tetrabutyl amonium bromide, benzyltriethylammoinium chloride; the amine salt molar weight is (1-pentanoyl)-N-[4-[2-(5-cyano group) phenyl] benzyl]-0.5～3.0 times of L-valine methyl ester (1) molar weight, preferred 1 times.
In the step (1); described Lewis acid is zinc chloride, aluminum chloride, iron trichloride or boron trifluoride; the Lewis acid molar weight is (1-pentanoyl)-N ([4-[2-5-cyano group) phenyl] benzyl]-0.1～1.0 times of L-valine methyl ester (1) molar weight, preferred 0.3 times.
In the step (1); described silicoorganic compound are trimethylchlorosilane or TERT-BUTYL DIMETHYL CHLORO SILANE; the silicoorganic compound molar weight is (1-pentanoyl)-N-[4-[2-(5-cyano group) phenyl] benzyl]-0.1～1.0 times of L-valine methyl ester (1) molar weight, preferred 0.3 times.
In the step (1), the metal-salt of described hydrazoic acid is sodiumazide, potassium azide or Lithium Azide.
In the step (1), described amine salt mole dosage is N-(1-pentanoyl)-N-[4-[2-(5-cyano group) phenyl] benzyl]-0.5～3.0 times of L-valine methyl ester (1) molar weight, preferred 1 times; The mole dosage of the metal-salt of described hydrazoic acid is N-[(2 '-cyanobiphenyl-4-yl) methyl]-0.5～3.0 times of N-pentanoyl-L-valine methyl ester (1) molar weight, preferred 1 times.
In the step (1), described organic solvent is inertia aromatic hydrocarbon, polar aprotic solvent or polar aprotic solvent.Described inertia aromatic hydrocarbon is benzene,toluene,xylene, trimethylbenzene, chlorobenzene or dichlorobenzene; Described polar aprotic solvent N, dinethylformamide, N,N-dimethylacetamide, N-Methyl pyrrolidone or dimethyl sulfoxide (DMSO); Described polar aprotic solvent is ethylene glycol, propylene glycol or glycerol.
In the step (1), the ring-closure reaction temperature is 80～200 ℃, preferred 100 ℃.Reaction times is 10～30 hours, preferred 20h.
In the step (2), described alkaline solution is sodium hydroxide or potassium hydroxide, and concentration is 500～1000g/L, and the adding quality of alkaline solution is 1～10 times of valsartan methyl esters quality, preferred 5 times.
In the step (2), described mineral acid is hydrochloric acid or sulfuric acid.
In the step (2), the amount of extraction solvent methylene dichloride, ethyl acetate or toluene is 1～5 times of valsartan methyl esters theoretical yield (being quality), preferred 1.5～2.5 times.Described valsartan methyl esters theoretical yield is in the step (1), N-(1-pentanoyl)-N-[4-[2-(5-cyano group) phenyl] benzyl]-L-valine methyl ester (1) is converted into the quality behind the valsartan methyl esters fully.
In the step (3), described alcoholic solvent is methyl alcohol, ethanol or Virahol; Described esters solvent is methyl acetate, ethyl acetate, butylacetate or isopropyl acetate; Described aromatic hydrocarbon solvent is benzene,toluene,xylene or chlorobenzene.
In the step (3), the weight of alcoholic solvent, esters solvent or aromatic hydrocarbon solvent is 1.0～10.0 times of valsartan methyl esters crude product weight.
Valsartan methyl esters crystal by the present invention's preparation only needs an one-step hydrolysis can obtain valsartan.Promptly under the effect of mineral alkali, valsartan methyl esters crystal is hydrolyzed in the mixture of water or organic solvent or water and organic solvent; Reaction extracts with organic solvent after finishing again, keeps water layer, and water layer is used mineral acid conditioned reaction liquid pH value to 1～2 such as hydrochloric acid, sulfuric acid or phosphoric acid; Use organic solvent extraction, washing, drying concentrates and obtains the valsartan crude product; Obtain the pure product of highly purified valsartan with the organic solvent recrystallization at last.
Wherein, the mineral alkali of hydrolysis reaction is lithium hydroxide, sodium hydroxide, potassium hydroxide, yellow soda ash or salt of wormwood.
Wherein, the organic solvent of hydrolysis reaction is alcoholic solvents such as methyl alcohol, ethanol, Virahol, ethylene glycol, or tetrahydrofuran (THF), acetone, 1, the solvents miscible with water such as 4-dioxane.
Wherein, the organic solvent that is used to extract is esters solvents such as methyl acetate, ethyl acetate, butylacetate, isopropyl acetate, or aromatic hydrocarbon solvents such as benzene,toluene,xylene, chlorobenzene, or halohydrocarbon such as methylene dichloride, ethylene dichloride, trichloromethane.
Wherein, the recrystallization organic solvent is alcoholic solvents such as methyl alcohol, ethanol, Virahol, or esters solvent such as methyl acetate, ethyl acetate, butylacetate, isopropyl acetate, or aromatic hydrocarbon solvents such as benzene,toluene,xylene, chlorobenzene.
Beneficial effect: by the valsartan methyl esters crystal of available high-optical-purity of the inventive method (99%) and high chemical purity (98%), only need an one-step hydrolysis can obtain valsartan by valsartan methyl esters crystal, and valsartan methyl esters crystalchecked is easy to transportation.This method is not used poisonous tin compound catalyst, and production technique is simple, cost is low, raw material is easy to get.
Description of drawings
Fig. 1 is the Electronic Speculum figure of the valsartan methyl esters of the inventive method preparation.
Fig. 2 is the XRD diffractogram of the valsartan methyl esters of the inventive method preparation.
Fig. 3 is differential scanning calorimetry (DSC) figure.
Fig. 4 is thermogravimetic analysis (TGA) (TG) figure.
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 to illustrate the present invention, and should also can not limit the present invention described in detail in claims.
Embodiment 1: valsartan methyl esters crude product synthetic.
In the 500ml four-hole boiling flask, add 50ml toluene; 40.65g (0.1mol) N-(1-pentanoyl)-N-[4-[2-(5-cyano group) phenyl] benzyl]-L-valine methyl ester (1); stir; heat up (about about 30 ℃) to compound (1-pentanoyl)-N-[4-[2-(5-cyano group) phenyl] benzyl]-dissolving of L-valine methyl ester is fully; after treating dissolving fully; 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 the sodium hydroxide alkaline solution that wherein adds 250ml 500g/L; layering; telling the upper strata organic solvent is recycled; to water layer dripping hydrochloric acid to pH value is 1-2; extract with methylene dichloride 100ml; leave standstill, divide and go upper aqueous layer, use twice of saturated common salt water washing organic layer; organic layer concentrates; get the valsartan methyl esters, HPLC follows the tracks of test sample, product purity＞90%; D-valsartan methyl esters isomer＜2% wherein, yield＞93%.
Embodiment 2: valsartan methyl esters crude product synthetic.
In the 500ml four-hole boiling flask, add the 50ml chlorobenzene; 40.65g (0.1mol) N-(1-pentanoyl)-N-[4-[2-(5-cyano group) phenyl] benzyl]-L-valine methyl ester (1); stir; be warming up to compound dissolution fully (about about 30 ℃), treat dissolving fully after, to wherein adding 6.5g (0.1mol) sodium azide and 9.6g (0.1mol) trimethylamine hydrochloride and 4.9g (0.03mol) iron trichloride; be warming up to about 110 ℃; back flow reaction 20 hours, HPLC follows the tracks of test sample, after reaction finishes; begin cooling; to wherein adding 250ml, the sodium hydroxide alkaline solution of 1000g/L, layering; telling lower floor's organic solvent is recycled; to water layer dripping hydrochloric acid to pH value is 1～2, with ethyl acetate 150ml extraction, leaves standstill; divide the sub-cloud water layer; with saturated common salt water washing organic layer twice, organic layer concentrates, and gets valsartan methyl esters crystal; HPLC follows the tracks of test sample; product purity＞90%, D-valsartan methyl esters isomer＜2% wherein, yield＞92%.
Embodiment 3: valsartan methyl esters refining.
The above-mentioned valsartan methyl esters crystal crude product that makes is added in the 100ml toluene, stirs and be warming up to 80 ℃, dissolve fully to solid, stop heating, naturally cool to room temperature, cool to 0 ℃ again, insulation 2～5h, filter the refining crystal of valsartan methyl esters.HPLC follows the tracks of test sample, product purity＞98%, wherein D-valsartan methyl esters isomer＜1%.Electronic Speculum figure sees Fig. 1.The XRD diffractogram is seen Fig. 2.DSC figure sees Fig. 3.TG figure sees Fig. 4.
Embodiment 4: the hydrolysis of valsartan methyl esters.
The above-mentioned valsartan methyl esters crystal that makes is put into the 500ml four-hole boiling flask,, keep 25 ℃ of temperature to the sodium hydroxide solution that wherein adds 200ml10%, isothermal reaction 12 hours, HPLC follows the tracks of test sample, after reaction finishes, add the toluene extraction, divide and remove organic layer, keep water, to dripping hydrochloric acid wherein, regulate PH to 1-2, add the 250ml ethyl acetate to water layer then and stir, aqueous phase extracted, branch vibration layer keeps organic layer, with saturated common salt water washing organic layer 2 times, organic layer concentrate valsartan.HPLC follows the tracks of test sample, product purity 95%,
Above-mentioned products obtained therefrom is put in the 250ml four-hole boiling flask, and to wherein adding the 100ml ethyl acetate, heating is dissolving fully, naturally cool to room temperature after, continue to be cooled to 0 ℃, preserve 2h, filter, dry the pure product of valsartan, HPLC follows the tracks of test sample, product purity 99%.
Embodiment 5:
Method with embodiment 1, different is after reaction finishes, begin cooling, to wherein adding 250ml, the sodium hydroxide alkaline solution of 800g/L, layering, telling lower floor's organic solvent is recycled, to water layer dripping hydrochloric acid to pH value is 1～2, with toluene 150ml extraction, leaves standstill, divide the sub-cloud water layer, with saturated common salt water washing organic layer twice, organic layer concentrates, and gets valsartan methyl esters crystal, HPLC follows the tracks of test sample, product purity＞90%, D-valsartan methyl esters isomer＜2% wherein, yield＞93%.
Embodiment 6:
With the method for embodiment 3, different is that the valsartan methyl esters crystal crude product that embodiment 5 makes is added in the 150ml ethanol.
Embodiment 7:
With the method for embodiment 3, different is that the valsartan methyl esters crystal crude product that embodiment 5 makes is added in the 150ml ethyl acetate.
Embodiment 8:
With the method for embodiment 3, different is that the valsartan methyl esters crystal crude product that embodiment 5 makes is added in the 150ml dimethylbenzene.
Claims (9)
1. a high purity valsartan methyl esters crystalline production technique is characterized in that it comprises the steps:
(1) with N-(1-pentanoyl)-N-[4-[2-(5-cyano group) phenyl] benzyl]-L-valine methyl ester (1) is a raw material, under the katalysis of amine salt and other catalyzer, in organic solvent, carries out ring-closure reaction and gets valsartan methyl esters (2) with the metal-salt of hydrazoic acid; Described other catalyzer is Lewis acid or silicoorganic compound;
(2) reaction solution that step (1) is obtained is cooled to room temperature, add alkaline solution, stir, standing demix, organic layer recycling, water layer mineral acid adjust pH to 1～2, again with methylene dichloride, ethyl acetate or toluene extraction, use the saturated common salt water washing to neutrality the organic solvent layer after the extraction,, obtain valsartan methyl esters crude product through concentrating under reduced pressure;
(3) the valsartan methyl esters dissolving crude product that step (2) is obtained is warming up to 60～90 ℃ again in alcoholic solvent, esters solvent or aromatic hydrocarbon solvent, and solid dissolves fully, stop heating, naturally cool to room temperature, cooling to 0 ℃ of insulation 2-5h,, to filter, drying obtains valsartan methyl esters crystal.
2. high purity valsartan methyl esters crystalline production technique according to claim 1, it is characterized in that in the step (1) that described amine salt mole dosage is N-(1-pentanoyl)-N-[4-[2-(5-cyano group) phenyl] benzyl]-0.5～3.0 times of L-valine methyl ester (1) molar weight; The mole dosage of the metal-salt of described hydrazoic acid is N-(1-pentanoyl)-N-[4-[2-(5-cyano group) phenyl] benzyl]-0.5～3.0 times of L-valine methyl ester (1) molar weight.
3. high purity valsartan methyl esters crystalline production technique according to claim 1 is characterized in that in the step (1), described organic solvent is inertia aromatic hydrocarbon, polar aprotic solvent or polar aprotic solvent.
4. high purity valsartan methyl esters crystalline production technique according to claim 1 is characterized in that in the step (1), the ring-closure reaction temperature is 80～200 ℃, and the reaction times is 10～30 hours.
5. high purity valsartan methyl esters crystalline production technique according to claim 1, it is characterized in that in the step (2), described alkaline solution is sodium hydroxide or potassium hydroxide, and concentration is 500～1000g/L, and the adding quality of alkaline solution is 1～10 times of valsartan methyl esters quality.
6. high purity valsartan methyl esters crystalline production technique according to claim 1 is characterized in that in the step (2), described mineral acid is hydrochloric acid or sulfuric acid.
7. high purity valsartan methyl esters crystalline production technique according to claim 1 is characterized in that in the step (2) that the quality of extraction solvent methylene dichloride, ethyl acetate or toluene is 1～5 times of valsartan methyl esters Theoretical Mass.
8. high purity valsartan methyl esters crystalline production technique according to claim 1 is characterized in that in the step (3), described alcoholic solvent is methyl alcohol, ethanol or Virahol; Described esters solvent is methyl acetate, ethyl acetate, butylacetate or isopropyl acetate; Described aromatic hydrocarbon solvent is benzene,toluene,xylene or chlorobenzene.
9. high purity valsartan methyl esters crystalline production technique according to claim 1 is characterized in that in the step (3) that the weight of alcoholic solvent, esters solvent or aromatic hydrocarbon solvent is 1.0～10.0 times of valsartan methyl esters crude product weight.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102321038A (en) * | 2011-07-11 | 2012-01-18 | 安徽省虹升生物科技有限公司 | Improved valsartan preparation method |
| CN102391200A (en) * | 2011-09-30 | 2012-03-28 | 浙江新赛科药业有限公司 | Preparation method of high purity valsartan |
| CN103739564A (en) * | 2012-02-20 | 2014-04-23 | 中国科学院上海药物研究所 | Multiple crystal forms of valsartan and preparation method thereof |
| CN103923028A (en) * | 2014-05-04 | 2014-07-16 | 青岛雪洁助剂有限公司 | Preparation method of valsartan |
| CN104744389A (en) * | 2015-03-12 | 2015-07-01 | 常州康丽制药有限公司 | Method for recycling valsartan methyl ester from valsartan crystallization mother solution |
| CN112079788A (en) * | 2019-06-13 | 2020-12-15 | 安徽美诺华药物化学有限公司 | Preparation method of valsartan |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060149079A1 (en) * | 2005-01-03 | 2006-07-06 | Padi Pratap R | Process for preparing valsartan |
| CN101270096A (en) * | 2007-03-22 | 2008-09-24 | 浙江华海药业股份有限公司 | Method for synthesizing diovan |
-
2010
- 2010-12-31 CN CN 201010617085 patent/CN102060797A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060149079A1 (en) * | 2005-01-03 | 2006-07-06 | Padi Pratap R | Process for preparing valsartan |
| CN101270096A (en) * | 2007-03-22 | 2008-09-24 | 浙江华海药业股份有限公司 | Method for synthesizing diovan |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102321038A (en) * | 2011-07-11 | 2012-01-18 | 安徽省虹升生物科技有限公司 | Improved valsartan preparation method |
| CN102321038B (en) * | 2011-07-11 | 2014-03-26 | 安徽省虹升生物科技有限公司 | Improved valsartan preparation method |
| CN102391200A (en) * | 2011-09-30 | 2012-03-28 | 浙江新赛科药业有限公司 | Preparation method of high purity valsartan |
| CN102391200B (en) * | 2011-09-30 | 2014-06-18 | 浙江新赛科药业有限公司 | Preparation method of high purity valsartan |
| CN103739564A (en) * | 2012-02-20 | 2014-04-23 | 中国科学院上海药物研究所 | Multiple crystal forms of valsartan and preparation method thereof |
| 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 |
| CN104744389A (en) * | 2015-03-12 | 2015-07-01 | 常州康丽制药有限公司 | Method for recycling valsartan methyl ester from valsartan crystallization mother solution |
| CN112079788A (en) * | 2019-06-13 | 2020-12-15 | 安徽美诺华药物化学有限公司 | Preparation 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 |
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Application publication date: 20110518 |