CN110078640A - A kind of synthetic method of Valsartan intermediate - Google Patents
A kind of synthetic method of Valsartan intermediate Download PDFInfo
- Publication number
- CN110078640A CN110078640A CN201910249453.0A CN201910249453A CN110078640A CN 110078640 A CN110078640 A CN 110078640A CN 201910249453 A CN201910249453 A CN 201910249453A CN 110078640 A CN110078640 A CN 110078640A
- Authority
- CN
- China
- Prior art keywords
- chloride
- synthetic method
- formula
- compound
- valsartan
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/32—Separation; Purification; Stabilisation; Use of additives
- C07C253/34—Separation; Purification
Abstract
The present invention relates to a kind of synthetic methods of Valsartan intermediate, the following steps are included: Formula Il compound is first dissolved in organic solvent by (1), acid binding agent, sodium chloride or potassium chloride and water is added, stirs evenly, carries out insulation reaction after n-amyl chloride is added dropwise；(2) water quenching is added to go out after completion of the reaction, successively carry out alkali cleaning, pickling, again alkali cleaning, finally vacuum distillation obtains target product compounds of Formula I, i.e. N- [(2'- cyanobiphenyl -4- base) methyl]-N- (1- oxopentyl)-Valine methyl esters.The present invention is by the way that suitable sodium chloride or potassium chloride are added into reaction system, the generation of n-amyl chloride hydrolysis is inhibited using common-ion effect, to reduce the dosage of n-amyl chloride, be conducive to improve the purity and yield of product, reduce production cost, reduce the pollution to environment, is more suitable industrialized production.
Description
Technical field
The present invention relates to pharmacy preparation fields, refer specifically to a kind of synthetic method of Valsartan intermediate.
Background technique
Valsartan (Valsartan), chemical name: N- (1- oxygen amyl)-N- [4- [2- (1H-TETRAZOLE -5- base) phenyl] benzyl
Base]-Valine, it is a kind of angiotensin II receptor antagonist developed by Novartis Co., Ltd, has and be depressured steady, curative effect
By force, the features such as long action time, patient tolerability are good.
Compound N-[(2'- cyanobiphenyl -4- base) methyl]-N- (1- oxopentyl)-Valine methyl esters is synthesis figured silk fabrics
A key intermediate of Sha Tan, structure are shown in formula I.
Valsartan intermediate N [(2'- cyanobiphenyl -4- base) methyl]-N- (1- oxopentyl)-L- figured silk fabrics in the prior art
The preparation of propylhomoserin methyl esters is N- [(2'- cyanobiphenyl -4- base) methyl]-(L)-valine methyl ester hydrochloride (structure such as Formula II institute
Show) and n-amyl chloride in the presence of inorganic base aqueous solution and suitable solvent, obtain (N- [(2'- cyanobiphenyl -4- base)-first
Base]-N- valeryl-(L)-valine methyl ester (Formulas I), synthetic route is expressed as follows:
Due to the presence of water in reaction system, hydrolysis can occur for n-amyl chloride, this will lead to the increase of its dosage.And
In the molar ratio of prior art compound of formula H and n-amyl chloride, n-amyl chloride dosage is excessively high, increases miscellaneous in product
The residual of the positive valeric acid of matter needs to carry out multiple ammonia scrubbing, controls not only bad for the quality of product, leads to product purity and receipts
Rate is lower, also increases production cost and nitrogenous effluent discharge amount, environmental pollution are larger.
Therefore, it for the synthetic method of current above-mentioned Valsartan intermediate, is improved up for further.
Summary of the invention
Positive valeryl can effectively be inhibited the technical problem to be solved by the invention for the present situation of prior art is to provide a kind of
Chlorine water solution improves product purity and yield, the Valsartan intermediate for reducing environmental pollution to reduce n-amyl chloride dosage
Synthetic method.
The technical scheme of the invention to solve the technical problem is: a kind of synthetic method of Valsartan intermediate,
It is characterized by comprising following steps
(1) first Formula Il compound is dissolved in organic solvent, acid binding agent, sodium chloride or potassium chloride and water is added, stirs
It mixes uniformly, carries out insulation reaction after n-amyl chloride is added dropwise；
(2) add water quenching to go out after completion of the reaction, successively carry out alkali cleaning, pickling, again alkali cleaning, finally vacuum distillation obtains target production
Object compounds of Formula I, i.e. N- [(2'- cyanobiphenyl -4- base) methyl]-N- (1- oxopentyl)-Valine methyl esters；
Preferably, organic solvent described in step (1) be toluene, it is dimethylbenzene, any in methylene chloride.
Preferably, acid binding agent described in step (1) is sodium carbonate or potassium carbonate.
Preferably, the molar ratio of the sodium carbonate or potassium carbonate and Formula II compound is 2.2~4:1.
Preferably, the mass ratio that feeds intake of sodium chloride described in step (1) or potassium chloride and Formula II compound is 0.3~1:1.
Using such feed ratio, sodium chloride or potassium chloride can be made preferably n-amyl chloride to be inhibited to hydrolyze.
Preferably, the mass ratio that feeds intake of water described in step (1) and Formula II compound is 3~5:1.
Preferably, the molar ratio of step (1) compound of formula H and n-amyl chloride is 1:1.05~1.2.Due to this
Invention uses sodium chloride or potassium chloride in step (1), the hydrolysis of n-amyl chloride is effectively reduced, so as to reduce positive valeryl
The dosage of chlorine is controlled in above-mentioned feed ratio.
Preferably, the temperature of insulation reaction described in step (1) is 15~35 DEG C.
Preferably, in step (2) solvent used by alkali cleaning be concentration 2.5% ammonia spirit, it is molten used by pickling
Agent is the aqueous hydrochloric acid solution of concentration 5%, then solvent used by alkali cleaning is the sodium bicarbonate solution of concentration 2%.
Compared with the prior art, the advantages of the present invention are as follows: the present invention is by the way that suitable chlorination is added into reaction system
Sodium or potassium chloride, the generation of n-amyl chloride hydrolysis is inhibited using common-ion effect, to reduce the use of n-amyl chloride
Amount is conducive to the purity and yield that improve product, reduces production cost, reduce the pollution to environment, be more suitable industry
Metaplasia produces.
Detailed description of the invention
Fig. 1 is the HPLC map of Valsartan intermediate shown in Formulas I in the embodiment of the present invention 1；
Fig. 2 is the HPLC map of Valsartan intermediate shown in Formulas I in the embodiment of the present invention 2；
Fig. 3 is the HPLC map of Valsartan intermediate shown in Formulas I in the embodiment of the present invention 3.
Specific embodiment
The present invention will be described in further detail below with reference to the embodiments of the drawings.
Embodiment 1:
The synthetic method of the present embodiment Valsartan intermediate the following steps are included:
(1) 30g Formula II compound and 200mL toluene are added into 500mL four-hole bottle, stirs evenly；By 21g sodium carbonate and
18g sodium chloride is added in 120mL water, is added drop-wise in above-mentioned four-hole bottle after stirring dissolved clarification；20~28 DEG C of temperature in control, slowly drips
Add 12g n-amyl chloride and 20mL toluene mixture liquid, drop finishes, insulated and stirred, and HPLC detects Formula II compound residual；
(2) after HPLC detects Formula II compound residual≤0.10%, 120mL water is added, branch vibration layer uses 120mL2.5%
Ammonia scrubbing organic phase, branch vibration layer；Organic phase, branch vibration layer are washed with 50mL5% aqueous hydrochloric acid solution；50mL2% carbon is used again
Sour hydrogen sodium washs organic phase, branch vibration layer；Organic layer vacuum distillation, obtains compound of formula I, yield: 99.0%, as shown in Figure 1, pure
It spends (HPLC): 99.76%.
Embodiment 2:
The synthetic method of the present embodiment Valsartan intermediate the following steps are included:
(1) 30g Formula II compound and 200mL dimethylbenzene are added into 500mL four-hole bottle, stirs evenly；By 30g potassium carbonate
It is added in 150mL water with 20g sodium chloride, is added drop-wise in above-mentioned four-hole bottle after stirring dissolved clarification；20~28 DEG C of temperature in control, slowly
11g n-amyl chloride and 20mL dimethylbenzene mixed liquor is added dropwise, drop finishes, insulated and stirred, and HPLC detects Formula II compound residual；
(2) after HPLC detects Formula II compound residual≤0.10%, 120mL water, branch vibration layer is added；Use 120mL2.5%
Ammonia scrubbing organic phase, branch vibration layer；Organic phase, branch vibration layer are washed with 50mL5% aqueous hydrochloric acid solution；50mL2% carbon is used again
Sour hydrogen sodium washs organic phase, branch vibration layer；Organic layer vacuum distillation, obtains compound of formula I, yield: 99.2%, as shown in Fig. 2, pure
It spends (HPLC): 99.73%.
Embodiment 3:
The synthetic method of the present embodiment Valsartan intermediate the following steps are included:
(1) 50g Formula II compound and 335mL methylene chloride are added into 1000mL four-hole bottle, stirs evenly；By 35g carbon
Sour sodium and 39g potassium chloride are added in 200mL water, are added drop-wise in above-mentioned four-hole bottle after stirring dissolved clarification；20~28 DEG C of temperature in control,
20g n-amyl chloride and 33.5mL methylene chloride mixed liquor is slowly added dropwise, drop finishes, and insulated and stirred, it is residual that HPLC detects Formula II compound
It stays；
(2) after HPLC detects Formula II compound residual≤0.10%, 200mL water, branch vibration layer is added；Use 200mL2.5%
Ammonia scrubbing organic phase, branch vibration layer；Organic phase, branch vibration layer are washed with 85mL5% aqueous hydrochloric acid solution；85mL2% carbon is used again
Sour hydrogen sodium washs organic phase, branch vibration layer；Organic layer vacuum distillation, obtains compound of formula I, yield: 98.8%, as shown in figure 3, pure
It spends (HPLC): 99.81%.
Claims (9)
1. a kind of synthetic method of Valsartan intermediate, it is characterised in that: include the following steps
(1) first Formula Il compound is dissolved in organic solvent, acid binding agent, sodium chloride or potassium chloride and water is added, stirring is equal
It is even, insulation reaction is carried out after n-amyl chloride is added dropwise；
(2) add water quenching to go out after completion of the reaction, successively carry out alkali cleaning, pickling, again alkali cleaning, finally vacuum distillation obtains under target product
Compound of formula I, i.e. N- [(2'- cyanobiphenyl -4- base) methyl]-N- (1- oxopentyl)-Valine methyl esters；
2. the synthetic method of Valsartan intermediate according to claim 1, it is characterised in that: step has described in (1)
Solvent is toluene, dimethylbenzene, any in methylene chloride.
3. the synthetic method of Valsartan intermediate according to claim 1, it is characterised in that: step is tied up described in (1)
Sour agent is sodium carbonate or potassium carbonate.
4. the synthetic method of Valsartan intermediate according to claim 3, it is characterised in that: the sodium carbonate or potassium carbonate
Molar ratio with Formula II compound is 2.2~4:1.
5. the synthetic method of Valsartan intermediate according to claim 1, it is characterised in that: chlorination described in step (1)
The mass ratio that feeds intake of sodium or potassium chloride and Formula II compound is 0.3~1:1.
6. the synthetic method of Valsartan intermediate according to claim 1, it is characterised in that: water described in step (1) with
The mass ratio that feeds intake of Formula II compound is 3~5:1.
7. the synthetic method of Valsartan intermediate according to claim 1, it is characterised in that: Formula II chemical combination in step (1)
The molar ratio of object and n-amyl chloride is 1:1.05~1.2.
8. the synthetic method of Valsartan intermediate according to claim 1, it is characterised in that: kept the temperature described in step (1)
The temperature of reaction is 15~35 DEG C.
9. the synthetic method of Valsartan intermediate described in any claim according to claim 1~8, it is characterised in that:
Solvent used by alkali cleaning is the ammonia spirit of concentration 2.5% in step (2), and solvent used by pickling is the salt of concentration 5%
Solvent used by aqueous acid, then alkali cleaning is the sodium bicarbonate solution of concentration 2%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910249453.0A CN110078640B (en) | 2019-03-29 | 2019-03-29 | Synthesis method of valsartan intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910249453.0A CN110078640B (en) | 2019-03-29 | 2019-03-29 | Synthesis method of valsartan intermediate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110078640A true CN110078640A (en) | 2019-08-02 |
| CN110078640B CN110078640B (en) | 2022-04-05 |
Family
ID=67413866
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910249453.0A Active CN110078640B (en) | 2019-03-29 | 2019-03-29 | Synthesis method of valsartan intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110078640B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Citations (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1317485A (en) * | 2000-04-07 | 2001-10-17 | 常州四药制药有限公司 | Improved process for synthesizing Xieshatan |
| US20060149079A1 (en) * | 2005-01-03 | 2006-07-06 | Padi Pratap R | Process for preparing valsartan |
| EP1714963A1 (en) * | 2005-04-19 | 2006-10-25 | IPCA Laboratories Limited | Process for the Preparation of Valsartan and its Intermediates |
| CN100408035C (en) * | 2002-05-14 | 2008-08-06 | 诺瓦提斯公司 | Use of valsartan or its metabolite to inhibit platelet aggregation |
| EP2090567A2 (en) * | 2008-02-13 | 2009-08-19 | Ranbaxy Laboratories, Ltd. | Processes for the preparation of intermediates of valsartan |
| WO2009125416A2 (en) * | 2008-04-07 | 2009-10-15 | Hetero Research Foundation | Process for preparation of valsartan intermediate |
| CN101817795A (en) * | 2010-05-13 | 2010-09-01 | 浙江美诺华药物化学有限公司 | Improved method for synthesizing valsartan |
| WO2010133909A2 (en) * | 2009-05-20 | 2010-11-25 | Sms Pharmaceuticals Limited | Process for preparation of 5-substituted tetrazoles |
| KR20100132180A (en) * | 2009-06-09 | 2010-12-17 | 일동제약주식회사 | A novel process for the preparation of valsartan |
| CN102417486A (en) * | 2012-01-04 | 2012-04-18 | 合肥工业大学 | Method for synthesizing valsartan |
| WO2012056294A1 (en) * | 2010-10-29 | 2012-05-03 | Jubilant Life Sciences Ltd. | An improved process for the preparation of n-pentanoyl-n-[[2'-(1h-tetrazol-5-yi)[1,1'-biphenyl]-4-yi]methyl]-l-valine |
| CN102596899A (en) * | 2009-10-27 | 2012-07-18 | 诺瓦提斯公司 | Process for the manufacture of organic compounds |
| CN102911128A (en) * | 2012-09-25 | 2013-02-06 | 苏州天绿生物制药有限公司 | Synthetic method of valsartan |
| CN104045602A (en) * | 2014-06-28 | 2014-09-17 | 浙江华海药业股份有限公司 | Improved method for preparing tetrazole for valsartan |
| CN107056720A (en) * | 2016-12-30 | 2017-08-18 | 湖南千金湘江药业股份有限公司 | A kind of preparation and purification method of Valsartan |
-
2019
- 2019-03-29 CN CN201910249453.0A patent/CN110078640B/en active Active
Patent Citations (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1317485A (en) * | 2000-04-07 | 2001-10-17 | 常州四药制药有限公司 | Improved process for synthesizing Xieshatan |
| CN100408035C (en) * | 2002-05-14 | 2008-08-06 | 诺瓦提斯公司 | Use of valsartan or its metabolite to inhibit platelet aggregation |
| US20060149079A1 (en) * | 2005-01-03 | 2006-07-06 | Padi Pratap R | Process for preparing valsartan |
| EP1714963A1 (en) * | 2005-04-19 | 2006-10-25 | IPCA Laboratories Limited | Process for the Preparation of Valsartan and its Intermediates |
| EP2090567A2 (en) * | 2008-02-13 | 2009-08-19 | Ranbaxy Laboratories, Ltd. | Processes for the preparation of intermediates of valsartan |
| WO2009125416A2 (en) * | 2008-04-07 | 2009-10-15 | Hetero Research Foundation | Process for preparation of valsartan intermediate |
| WO2010133909A2 (en) * | 2009-05-20 | 2010-11-25 | Sms Pharmaceuticals Limited | Process for preparation of 5-substituted tetrazoles |
| KR20100132180A (en) * | 2009-06-09 | 2010-12-17 | 일동제약주식회사 | A novel process for the preparation of valsartan |
| CN102596899A (en) * | 2009-10-27 | 2012-07-18 | 诺瓦提斯公司 | Process for the manufacture of organic compounds |
| CN101817795A (en) * | 2010-05-13 | 2010-09-01 | 浙江美诺华药物化学有限公司 | Improved method for synthesizing valsartan |
| WO2012056294A1 (en) * | 2010-10-29 | 2012-05-03 | Jubilant Life Sciences Ltd. | An improved process for the preparation of n-pentanoyl-n-[[2'-(1h-tetrazol-5-yi)[1,1'-biphenyl]-4-yi]methyl]-l-valine |
| CN102417486A (en) * | 2012-01-04 | 2012-04-18 | 合肥工业大学 | Method for synthesizing valsartan |
| CN102911128A (en) * | 2012-09-25 | 2013-02-06 | 苏州天绿生物制药有限公司 | Synthetic method of valsartan |
| CN104045602A (en) * | 2014-06-28 | 2014-09-17 | 浙江华海药业股份有限公司 | Improved method for preparing tetrazole for valsartan |
| CN107056720A (en) * | 2016-12-30 | 2017-08-18 | 湖南千金湘江药业股份有限公司 | A kind of preparation and purification method of Valsartan |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN110078640B (en) | 2022-04-05 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105753888B (en) | A kind of free state Yi Dushaban preparation method | |
| CN104672238B (en) | A kind of Li Gelieting preparation method | |
| CN110078640A (en) | A kind of synthetic method of Valsartan intermediate | |
| EP2044021B1 (en) | Process for preparing remifentanil, intermediates thereof, use of said intermediates and processes for their preparation | |
| CN103923028B (en) | Preparation method of valsartan methyl ester | |
| Pandey et al. | A facile procedure for tert-butoxycarbonylation of amines promoted by yttria-zirconia based strong Lewis acid catalyst | |
| CN105111103B (en) | The preparation method of salicylonitrile and its derivative | |
| EP3786152A1 (en) | Method for manufacturing aromatic nitrile compound | |
| CN105712919A (en) | Application of amide condensing agent in vildagliptin synthetic method | |
| CN107935997A (en) | A kind of difficult to understand this replaces the synthetic method of Buddhist nun | |
| CN108276356B (en) | Preparation method of 3, 5-disubstituted thiazolidine-2-thioketone compound | |
| CN101591328A (en) | The chemical synthesis process of a kind of 2-bromothiophene and derivative thereof | |
| ZA200700131B (en) | Method for producing 2-oxo-1-phenyl-3-oxabicyclo(3.1.0) hexane | |
| CN111925317B (en) | Ropivacaine hydrochloride impurity and preparation method thereof | |
| CN104327107A (en) | Preparation method of fluoroquinolone antibiosis medicine | |
| CN106045870B (en) | A kind of method for preparing amide | |
| WO2018187717A1 (en) | Continuous flow synthesis of ibuprofen | |
| CN103880756A (en) | Preparation method of azilsartan intermediate | |
| CN105399668B (en) | A kind of method that " one kettle way " prepares Sorafenib | |
| CN107513047A (en) | Microwave assisting method synthesizes the friendly process of BPTA | |
| CN113620855A (en) | Yiwan kasai intermediate II and synthetic method thereof | |
| US20220411369A1 (en) | Method for producing pyrrolidine compound | |
| CN104098556B (en) | A kind of synthesis technology of razaxaban | |
| CN107759565A (en) | A kind of preparation method of the butanol derivs thing of 1 triazole 2 | |
| CN106674085A (en) | Synthetic method for N-1,3-difluoro isopropyl-4-aminopiperidine compounds |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |