| JPS5498769 | MANUFACTURE OF 44OXOOBENZOPYRANE OR 44OXOONAPHTHOPYRANE DERIVATIVE |
| WO/2007/045369 | DIFLUOROPHENOL DERIVATIVES AND THEIR USE |
| JPS5832822 | ANTIULCER AGENT |
PANDEY ANAND KUMAR (IN)
LUTHRA PARVEN KUMAR (IN)
DESHPANDE PANDURANG BALWANT (IN)
PANDEY ANAND KUMAR (IN)
LUTHRA PARVEN KUMAR (IN)
| WO2004026847A1 | 2004-04-01 | |||
| WO2005049586A1 | 2005-06-02 | |||
| WO2004111018A1 | 2004-12-23 |
| US5399578A | 1995-03-21 |
CLAIMS
1. A process for preparation of Valsartan of formula (I) comprising hydrolysis of compound of formula (II)
Formula (II) Formula (I)
wherein Ri represents Ci-C 6 alkyl selected from methyl, ethyl, n-propyl, iso- propyl, n-butyl, tert-butyl or 2-methyl-propyl; substituted or unsubstituted phenyl group or like and P is hydrogen or a tetrazole protecting group, in presence of phase transfer catalyst.
2. A process as claimed in claim 1 , wherein hydrolysis is carried out with acid or base.
3. A process as claimed in claim 1 , wherein R 1 is methyl.
4. A process as claimed in claim 1 , wherein base is selected from group comprising alkali or alkaline earth metal hydroxides, carbonates or bicarbonates.
5. A process as claimed in claim 4, wherein the said alkali or alkaline earth metal hydroxides, carbonates or bicarbonates are selected from sodium hydroxide, potassium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate and like, preferably sodium hydroxide.
6. A process as claimed in claim 1 , wherein the said acid is selected from HCI, H 2 SO 4 , H 3 PO 4 , acetic acid, formic acid and the like, preferably HCI.
7. A process as claimed in claim 1 , wherein solvent is selected from water, chlorinated solvents, ethers, esters, aromatic hydrocarbons and mixtures thereof.
8. A process as claimed in claim 7, wherein solvent is selected from water, dichloro methane, dichloro ethane, chloroform, carbon tetrachloride, tetrahydrofuran, diethyl ether, diisopropyl ether, dimethyl ether, ethyl acetate, butyl acetate, methyl acetate, ethyl formate, methyl formate, benzene, toluene, xylene and like and mixtures thereof.
9. A process as claimed in claim 1 , wherein the said phase transfer catalyst is selected from crown ethers and quaternary ammonium salts.
10. A process as claimed in claim 9, wherein the said quaternary ammonium salt is selected from tetrabutyl ammonium chloride, tetrabutyl ammonium bromide, tetrabutyl ammonium fluoride, tetrabutyl ammonium iodide, cetyl trimethyl ammonium chloride and benzyl trialkyl ammonium chloride and mixtures thereof.
11. A process as claimed in claim 1 , wherein the said tetrazole protecting group is selected from trityl, monomethyoxytrityl, dimethoxytrityl, benzhydryl, acyl, benzyl which is unsubstituted or substituted, preferably by nitro, such as 4- nitrobenzyl, lower alkoxymethyl, such as methoxy- and ethόxymethyl, lower alkylthiomethyl, such as methylthiomethyl, silyl, such as tri-lower alkylsilyl, for example dimethyl-tert-butyl- and triisopropylsilyl, and 2-cyanoethyl, also lower alkoxy-lower alkoxymethyl, such as 2-methoxyethoxymethyl, benzyloxymethyl, phenacyl or like.
12. A process for preparing Valsartan of formula (I) such as herein described and illustrated by accompanying example ABSTRACT
An improved process for prepariang Valsartan of formula (I), by carrying out hydrolysis of Valsartan ester derivative of formula (II) in presence of phase transfer catalyst.
Formula (II) Formula (I) |
An improved process for preparation of (S)-N-(I -Carboxy-2-methyl-prop- 1-yl)-N-pentanoyl-N-r2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethv n-amine
FIELD OF INVENTION
The present invention relates to improved process for hydrolysis of N-[(2'-(1 H- Tetrazol-5-yl)biphenyl-4-yl)methyl]-N-valeryl-(L)-valine ester derivative of formula (II), henceforth referred as "Valsartan ester derivative" , which is penultimate intermediate for the preparation of Valsartan of formula (I), chemically known as (S)-N-(1-Carboxy-2-methyl-prop-1-yl)-N-pentanoyl-N-[2'-(1 H-tetrazol-5- yl)biphenyl-4-ylmethyl]-amine,
Formula (II) Formula (I)
wherein Ri represents Ci-Cβ alkyl selected from methyl, ethyl, n-propyl, iso- propyl, n-butyl, tert-butyl or 2-methyl-propyl; substituted or unsubstituted phenyl group or like and P is hydrogen or a tetrazole protecting group.
BACKGROUND OF INVENTION AND PRIOR ART
Valsartan belongs to group of angiotensin Il antagonists which are useful in the treatment of hypertension, anxiety, glaucoma and cardiac attacks. Valsartan is an orally active specific angiotensin Il antagonist acting on the AT1 receptor subtype. It is useful in regulating high blood pressure and cardiac insufficiency.
The process for preparing Valsartan is disclosed in US Patent No. 5,399,578 as shown by schematic diagram in Scheme-I:
Scheme-I:
The synthesis involves the conversion of 4-bromomethyl-2'-cyanobiphenyl of formula (A) to carbaldehyde of formula (C). Further, it is condensed with methyl ester of L-valine of formula (D) under reducing condition to give N-[(2'- cyanobiphenyl-4-yl)methyl-(L)-valine methyl ester of formula (E), which is purified by flash chromatography. Reaction of compound of formula (E) with n-Valeroyl chloride of formula (F) in presence of triethylamine gives N-valeryl-N-[(2'- cyanobiphenyl-4-yl)methyl-(L)-valine methyl ester or formula (G). After purification by flash chromatography, compound of formula (G) is cyclized in presence of tributyl tin azide in xylene and converted to Valsartan (I) in presence of sodium hydroxide.
The condensation of L-valine methyl ester and carbaldehyde requires reagent like sodium cyanoborohydride, which are costly. Also process involves
purification of intermediates by flash chromatography, which is lengthy and cumbersome and difficult to adopt at commercial scale.
According to another embodiment given in US Patent No. 5,399,578, the carbaldehyde compound (C) is condensed with Tosylate salt of L-valine benzyl ester in presence of sodium cyanoborohydride to give benzyl ester of formula (E). This compound is purified by converting it into its hydrochloride salt and then breaking the hydrochloride salt with sodium bicarbonate. The purified compound is then reacted with n-Valeroyl chloride and cyclized with tributyl tin azide in xylene. Further hydrogenation using Pd-C as catalyst gives Valsartan (I).
Another approach for the synthesis of Valsartan is disclosed in general description of Bioorganic and Medicinal Chemistry Letters, Vol. 4 (1), 1994 as shown below in Scheme-ll:
Scheme-ll:
Synthesis of Aminoacid-derived Ang Il antagonists
Diisopropylethylamine, H 3 C'
MDC I (F) ci
It is observed that hydrolysis using alkali metal hydroxides usually take longer reaction times like about 20 to about 30 hours, and hence it is not profitable at commercial scale.
Therefore, there is a need to have simple, easy to handle, cost effective process which has reduced reaction time, high yield and increased purity, for the preparation of Valsartan and its intermediates.
The inventors of the present invention have surprisingly found that hydrolysis of compound of formula (II) in presence of phase transfer catalysts reduces the reaction period to a considerable extent.
OBJECTS OF THE INVENTION
The object of the present invention is to provide an improved process for the preparation of Valsartan of formula (I).
Another object of the invention is to provide an improved process for the hydrolysis of compound of formula (II).
SUMMARY OF THE iNVENTION
According to the primary aspect of the present invention there is provided an improved process for preparation of Valsartan of formula (I), comprising carrying out hydrolysis of Valsartan ester derivative of formula (II) in presence of phase transfer catalyst.
Another aspect of the present invention provides an improved process for the hydrolysis of Valsartan ester derivative of formula (II) which has reduced reaction time and provides product with high yield and purity.
DETAILED DESCRIPTION OF THE INVENTION
The inventors of present invention have surprisingly found that reaction of Valsartan ester derivative of formula (II) with acid or base in presence of phase transfer catalysts gives Valsartan of formula (I) with high purity and yield in reduced reaction times.
Formula (II) Formula (I)
wherein Ri represents CrC 6 alkyl selected from methyl, ethyl, n-propyl, iso- propyl, n-butyl, tert-butyl or 2-methyl-propyl; substituted or unsubstituted phenyl group or like and P is hydrogen or a tetrazole protecting group.
The tetrazole protecting group is selected from trityl, monomethyoxytrityl, dimethoxytrityl, benzhydryl, acyl, benzyl which is unsubstituted or substituted, for example by nitro, such as 4-nitrobenzyl, lower alkoxymethyl, such as methoxy- and ethoxymethyl, lower alkylthiomethyl, such as methylthiomethyl, silyl, such as tri-lower alk ' ylsilyl, for example dimethyl-tert-butyl- and triisopropylsilyl, and 2- cyanoethyl, also lower alkoxy-lower alkoxymethyl, such as 2- methoxyethoxymethyl, benzyloxymethyl, phenacyl or like.
The reaction is generally carried out in presence of solvent selected from water, chlorinated solvents, ethers, esters, aromatic hydrocarbons and mixtures thereof, examples of which include dichloro methane, dichloro ethane, chloroform, carbon tetrachloride, tetrahydrofuran, diethyl ether, diisopropyl ether, dimethyl ether, ethyl acetate, butyl acetate, methyl acetate, ethyl formate, methyl formate, benzene, toluene, xylene and like.
The base is selected from group comprising of alkali or alkaline earth metal hydroxides, carbonates or bicarbonates selected from sodium hydroxide,
potassium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate and like, preferably sodium hydroxide.
The acid is selected from group comprising of HCI, H 2 SO 4 , H 3 PO 4 , acetic acid, formic acid or like.
The phase transfer catalyst is selected from crown ethers or quaternary ammonium salts. Quaternary ammonium salts can be aryl and aralkyl ammonium halide examples of which include tetrabutyl ammonium chloride, tetrabutyl ammonium bromide, tetrabutyl ammonium fluoride, tetrabutyl ammonium iodide, cetyl trimethyl ammonium chloride and benzyl trialkyl ammonium chloride or mixtures thereof.
The reaction takes place about 1 hour to about 20 hours, more preferably about 5 hours to 15 hours and most preferably about 10 hours to 12 hours. The reaction is carried out at temperature of about 0 0 C to reflux temperature of the solvent, preferably at ambient temperature.
The compound of formula (II) is prepared by method known perse of by any method know to person skilled in art.
According to the preferred embodiment, N-[(2'-(1 H-Tetrazol-5-yl)biphenyl-4- yl)methyl]-N-valeryl-(L)-valine methyl ester (compound of formula (II), wherein R- I = -CH 3 and P= H) is prepared from N-[(2'-cyanobiphenyl-4-yl) methyl] -N- pentanoyl - (L) valine methyl ester by using tributyl tin azide in xylene. Further the reaction mixture is cooled to ambient temperature and sodium hydroxide solution is added to it alongwith tetrabutyl ammonium bromide and is stirred at ambient temperatue till completion of reaction. The product is further isolated by conventional methods and purified by general methods know in art.
The process of the present invention is described by the following examples, which are illustrative only and should not be construed so as to limit the scope of the invention in any manner.
Examples:
Example 1: Preparation of (S)- N-( 1-carbonyl-2- methyl-prop -1-yl)-N- pentanoyl -N- [2'(1H - tetrazol-5-yl) biphenyl-4-yl methyl] (L) amine
The solution of N-[(2'-cyanobiphenyl-4-yl) methyl] -N- pentanoyl - (L) valine methyl ester as obtained above was treated with freshly prepared tributyltin azide (60 g,182 mmole) and refluxed for 12-20 hr. The reaction mixture is cooled and added sodium hydroxide solution and tetrabutyl ammonium bromide
(1.25 g) is added. The reaction mixture is stirred for 10-12 hr till the disappearance of starting ester derivative. After work-up the title compound is obtained as white solid. Yield: 20 g.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.