WO2012056294A1 - An improved process for the preparation of n-pentanoyl-n-[[2'-(1h-tetrazol-5-yi)[1,1'-biphenyl]-4-yi]methyl]-l-valine - Google Patents

An improved process for the preparation of n-pentanoyl-n-[[2'-(1h-tetrazol-5-yi)[1,1'-biphenyl]-4-yi]methyl]-l-valine Download PDF

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WO2012056294A1
WO2012056294A1 PCT/IB2011/002538 IB2011002538W WO2012056294A1 WO 2012056294 A1 WO2012056294 A1 WO 2012056294A1 IB 2011002538 W IB2011002538 W IB 2011002538W WO 2012056294 A1 WO2012056294 A1 WO 2012056294A1
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formula
process according
methyl
valine
pentanoyl
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PCT/IB2011/002538
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WO2012056294A8 (en
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Jag Mohan Khanna
Anil Ganpatrao Holkar
Radheshyam Allugulasetty
Chandrashekhar Yelakanti
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Jubilant Life Sciences Ltd.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings

Definitions

  • the present invention relates to an improved process for the preparation of pure N- pentanoyl-N-[[2'-(lH-tetrazol-5-yl)[l, -biphenyl]-4-yl]methyl]-L-valine employing highly active carbon.
  • Valsartan, N-pentanoyl-N- [ [2 ' -( 1 H-tetrazol-5 -yl) [ 1 , ⁇ -biphenyl] -4-yl]methyl] -L- valine, is a known anti-hypertensive agent having the following formula I:
  • Valsartan its pharmaceutically acceptable salts, pharmaceutical compositions comprising Valsartan and their use in treating high blood pressure and cardiac insufficiency were first disclosed in U.S. Patent No. 5,399,578 along with its preparation.
  • Valsartan and/or its intermediates are disclosed in various references including U.S. Patent Nos. 5,399,578, 5,965,592, 5,260,325, 6,271,375, WO 02/006253, WO 01/082858, WO 99/67231 , WO 97/30036 and Peter Buhlmayer, et. al., Bioorganic & Medicinal Chemistry Letters, Vol. 4 (1), pp 29-34, 1994.
  • Valsartan as disclosed in U.S. Patent No. 5,399,578 is as depicted in scheme 1.
  • carbaldehyde of Formula II is reacted with L-valine methyl ester hydrochloride (Formula III), followed by treatment with valeryl chloride (Formula V) to produce N-[2'-cyanobiphenyl-4-yl-methyl] N-pentanoyl-L-valine methyl ester (Formula VI).
  • WO 2008/007391 discloses process for the preparation of valsartan by reacting compound of Formula XII
  • limit for heavy metals in valsartan is maximum 20 ppm, whereas according to official monograph of US Pharmacopoeia, limit for heavy metals in valsartan is 0.001% i.e. 10 ppm.
  • a process for producing N-pentanoyl-N-[[2'-(lH-tetrazol-5-yl)[l ,l '-biphenyl]-4-yl]methyl]- L-valine, acceptable for human consumption comprising treating crude N-pentanoyl-N-[[2'-(lH-tetrazoI-5-yl)[l ,l '-biphenyl]-4-yl]methyl]-L-valine with highly active carbon having pore volume of 0.8 to 1.8 cc/gm.
  • the highly active carbon used is having surface area of 1200 - 1800 m7gm.
  • X represents halogen selected from CI or Br
  • R ⁇ represents C 1 -C4 alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, 2-methyl propyl, or benzyl;
  • N-pentanoyl-N-[[2'-(lH-tetrazol-5-yl)[l,l '-biphenyl]-4-yl]methyl]-L-valine obtained is having tin content equal to or less than 5 ppm, preferably equal to or less than 1 ppm.
  • the disclosed embodiment of the present invention deals with a process for producing pure N-pentanoyl-N-[[2'-(lH-tetrazol-5-yl)[l, -biphenyl]-4-yl]methyl]-L- valine (valsartan) employing highly active carbon.
  • the present invention in its aspect is a new, improved, economically and industrially feasible method for preparing pure valsartan acceptable for human consumption.
  • the present invention provides an improved process for the preparation of N- pentanoyl-N-[[2'-(lH-tetrazol-5-yl)[l , -biphenyl]-4-yl]methyl]-L-valine (valsartan), wherein the process comprising treating crude N-pentanoyl-N-[[2'-(lH-tetrazol-5-yl)[l , l '- biphenyl]-4-yl]methyl]-L-valine with highly active carbon.
  • the highly active carbon used according to the invention is having pore volume in the range of 0.8 to 1.8 cc/gm, preferably 1.0 - 1.3 cc/gm and surface area between 1200 to 1800 m 2 /gm, preferably 1400 - 1600 m 2 /gm.
  • Pure valsartan obtained by the process of the invention is having tin content equal to or less than 5 ppm and preferably less than 1 ppm.
  • X represents halogen selected from CI or Br
  • R ⁇ represents C 1 -C4 alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, 2-methyl propyl, or benzyl;
  • the acid addition salt employed herein is hydrochloride or hydrobromide and preferably hydrochloride.
  • the base used in step (a) is selected from organic or inorganic base.
  • the inorganic base is selected from hydroxides, hydrides, carbonates, bicarbonates or alkoxides salt of alkali or alkaline earth metal, wherein alkali and alkaline earth metal is selected from Li, Na, K, Mg, Ca and the like.
  • the organic base is amine.
  • the preferred base is selected from sodium hydroxide, potassium hydroxide, sodium hydride, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium methoxide, sodium ethoxide, potassium t-butoxide, triethylamine, ethylamine, di-isopropyl ethylamine, tributylamine, dicyclohexyl amine, pyridine and the like.
  • the more preferred base is potassium carbonate or sodium carbonate.
  • the solvent used in step (a) is selected from amides, sulfoxides, ketones, hydrocarbons, ethers, esters, halogenated hydrocarbons or mixture thereof.
  • the preferred solvent is dimethyl formamide, dimethyl acetamide, dimethyl sulfoxides, acetonitrile, propionitrile, acetone, methyl ethyl ketone, methyl isobutyl ketone, toluene, o-xylene, m- xylene, ⁇ -xylene, cyclohexane, cycloheptane, tetrahydrofuran, diethyl ether, di-isopropyl ether, dioxane, 2-methyl tetrahydrofuran, ethyl acetate, propyl acetate, butyl acetate, methylene dichloride, ethylene dichloride, chloroform or mixture thereof.
  • the more preferred solvent is dimethyl formamide.
  • the base used in step (b) is selected from organic or inorganic base.
  • the inorganic base is selected from hydroxides, carbonates, bicarbonates or alkoxides salts of alkali or alkaline earth metal, wherein alkali and alkaline earth metal is selected from Li, Na, , Mg, Ca and the like.
  • the organic base is amine.
  • the preferred base is selected from sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium methoxide, sodium ethoxide, potassium t-butoxide, triethylamine, ethylamine, di-isopropyl ethylamine, tributylamine, dicyclohexylamine, pyridine and the like.
  • the more preferred base is triethyl amine.
  • the solvent used in step (b) is selected from amides, sulfoxides, ketones, hydrocarbons, ethers, esters, halogenated hydrocarbons or mixture thereof.
  • the preferred solvent is dimethyl formamide, dimethyl acetamide, dimethyl sulfoxides, acetonitrile, propionitrile, acetone, methyl ethyl ketone, methyl isobutyl ketone, toluene, o-xylene, m- xylene, ⁇ -xylene, cyclohexane, cycloheptane, tetrahydrofuran, diethyl ether, di-isopropyl ether, dioxane, 2-methyl tetrahydrofuran, ethyl acetate, propyl acetate, butyl acetate, methylene dichloride, ethylene dichloride, chloroform or mixture thereof.
  • the more preferred solvent is methylene dichloride.
  • Reaction of step (b) is carried out at temperature range of 0-50°C, preferably at 0- 5°C.
  • the alkali metal azide used in step (c) is sodium azide.
  • the solvent used in step (c) is selected from amides, sulfoxides, hydrocarbons or mixture thereof.
  • the preferred solvent is dimethyl formamide, dimethyl acetamide, N- methyl pyrrolidone, dimethyl sulfoxides, toluene, o-xylene, w-xylene, / ⁇ -xylene, cyclohexane, cycloheptane or mixture thereof.
  • the more preferred solvent is o-xylene.
  • Reaction of step (c) is carried out at temperature range of 80-180°C, preferably at 145-150°C.
  • the base used in step (c) is inorganic base, which is selected from hydroxides, carbonates or bicarbonates salts of alkali or alkaline earth metal, wherein alkali and alkaline earth metal is selected from Li, Na, K, Mg, Ca and the like.
  • the preferred base is selected from sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogen carbonate or potassium hydrogen carbonate.
  • the more preferred base is sodium hydroxide.
  • the reaction mixture is heated to 55-60°C and extracted with water. Then the pH of aqueous layer is adjusted to 9-1 1 and preferably to 10-10.5, with use of acid.
  • the role of pH is important in lowering the metal content, especially tin content.
  • the pH is found to be suitable in the range of 9-1 1.
  • step (c) The resulting valsartan as obtained in step (c) is converted into pure valsartan with or without isolation.
  • the active carbon used is of grade PF 51 1 SPL, having details as given below. Drastic tin content reduction is observed with highly active carbon and it is due to its macro porosity i.e. large pore volume and high surface area. Comparison of commercial grade and PF 51 1 SPL grade carbon is given below:
  • Characteristics of the said highly active carbon grade PF 51 1 SPL are:
  • Formula IVa compound (l OOg: 0.279m) was basified with sodium bicarbonate solution and extracted in dichloromethane. Separate the organic layer, washed with water. Organic layer dried over anhydrous sodium sulphate. Organic layer containing free base compound of formula III was condensed with valeryl chloride (45g:0.373m) in the presence of triethylamine (36g:0.356m) at 0-5°C and stirred the reaction mass at 0-5°C for 1 hr. After completion of the reaction washed with dilute hydrochloric acid, dilute sodium bicarbonate and water. Separated the organic layer and concentrated completely and added O-xylene. O-xylene layer washed with dilute hydrochloric acid, dilute sodium bicarbonate and water. Separate the organic layer, dried over anhydrous sodium sulphate. Organic layer contains compound of Formula Via. (HPLC purity: 98%)

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Abstract

Disclosed herein is an improved process for the preparation of pure N-Pentanoyl-N-[[2'- (1h-Tetrazol-5-Y1)[1,1'-Biphenyl]-4-Yl]Methyl]-L-Valine employing highly active carbon.

Description

An Improved Process For The Preparation of N-Pentanoyl-N-[[2'-(lH-Tetrazol-5- Yl)[l,l'-Biphenyl]-4-Yl]Methyl]-L- Valine
Field of the Invention
The present invention relates to an improved process for the preparation of pure N- pentanoyl-N-[[2'-(lH-tetrazol-5-yl)[l, -biphenyl]-4-yl]methyl]-L-valine employing highly active carbon.
Background of the Invention
Valsartan, N-pentanoyl-N- [ [2 ' -( 1 H-tetrazol-5 -yl) [ 1 , Γ -biphenyl] -4-yl]methyl] -L- valine, is a known anti-hypertensive agent having the following formula I:
Figure imgf000002_0001
Form ula I
Valsartan, its pharmaceutically acceptable salts, pharmaceutical compositions comprising Valsartan and their use in treating high blood pressure and cardiac insufficiency were first disclosed in U.S. Patent No. 5,399,578 along with its preparation.
Valsartan and/or its intermediates are disclosed in various references including U.S. Patent Nos. 5,399,578, 5,965,592, 5,260,325, 6,271,375, WO 02/006253, WO 01/082858, WO 99/67231 , WO 97/30036 and Peter Buhlmayer, et. al., Bioorganic & Medicinal Chemistry Letters, Vol. 4 (1), pp 29-34, 1994.
The preparation of Valsartan as disclosed in U.S. Patent No. 5,399,578 is as depicted in scheme 1.
l Scheme 1:
Figure imgf000003_0001
In the above scheme, carbaldehyde of Formula II is reacted with L-valine methyl ester hydrochloride (Formula III), followed by treatment with valeryl chloride (Formula V) to produce N-[2'-cyanobiphenyl-4-yl-methyl] N-pentanoyl-L-valine methyl ester (Formula VI). Compound of Formula VI is treated with tri-n-butyl tin azide to give N-(l- oxopentyl)-N-[[2'-(lH-tetrazol-5-yl)[l, -biphenyl]4-yl]methyl-L-valine methyl ester which is then hydrolyzed under alkaline condition to give valsartan. According to another embodiment given in U.S. Patent No. 5,399,578, the benzyl ester analogue of compound of Formula IV is converted to its hydrochloride salt and then breaking the hydrochloride salt with sodium bicarbonate. The purified compound is then reacted with n-valeryl chloride and cyclized with tributyltin azide in xylene. Further, hydrogenation using palladised carbon catalyst gives valsartan of formula I.
Another approach for the synthesis of valsartan is disclosed in general description of Bioorganic & Medicinal Chemistry Letters, Vol. 4 (1), 1994 as shown in Scheme 2.
Scheme 2:
Figure imgf000004_0001
WO 2008/007391 , discloses process for the preparation of valsartan by reacting compound of Formula XII
Figure imgf000005_0001
Formula XII
with a mixture of metal azide and alkyl tin halide in a suitable solvent to give N-[[2'-(lH- tetrazol-5-yl)[l , l '-biphenyl]-4-yl]methyl]-L-Valine of Formula XIII.
Figure imgf000005_0002
Formula XIII
Compound of Formula XIII or its silyl protected derivative is then condensed with 5-phenyl thio valeryl chloride to give N-(5-(phenylthio)-l-oxo-pentyl)-N-[[2'-(lH- tetrazol-5-yl)[l , l '-biphenyl]- -yl]methyl]-L-valine of Formula XIV.
Figure imgf000005_0003
Formula XIV
Desulfurisation of compound of Formula XIV with a mixture of transition metal halide hydrate and reducing agent in presence of a base gives valsartan. The synthetic processes disclosed in the above mentioned prior arts involve, inter- alia the use of tributyltin azide which leads to increased tin content in final product as an impurity of approx. 20 ppm or above. Moreover, when working with large scale preparations, the tin by-products are difficult to remove, thus requiring extensive and tedious workup. It would therefore be highly desirable to provide a process for the preparation of pure valsartan, which would reduce the tin content in the final product i.e. Valsartan.
According to pharmeuropa, limit for heavy metals in valsartan is maximum 20 ppm, whereas according to official monograph of US Pharmacopoeia, limit for heavy metals in valsartan is 0.001% i.e. 10 ppm.
Thus, there remains a need for an environment friendly, industrially feasible process for the preparation of pure valsartan for human consumption, as valsartan with tin content of more than 20 ppm is not acceptable for human use.
Object and Summary of the Invention
It is a principal object of the present invention to improve upon limitations in the - prior art by providing an improved process for the preparation of pure N-pentanoyl-N- [[2'-(lH-tetrazol-5-yl)[l ,l '-biphenyl]-4-yl]methyl]-L-valine (valsartan) for human consumption.
It is another object of the present invention to provide a commercially viable, economical and environment friendly process for preparing pure valsartan with low tin content, acceptable for human consumption.
It is yet another object of the present invention to provide process for the preparation of valsartan using highly active carbon, acceptable for human consumption.
The above and other objects are further attained and supported by the following embodiments described herein. However, the scope of the invention is not restricted to described embodiments herein after.
In accordance with one embodiment of the present invention there is provided a process for producing N-pentanoyl-N-[[2'-(lH-tetrazol-5-yl)[l ,l '-biphenyl]-4-yl]methyl]- L-valine, acceptable for human consumption, wherein the process comprising treating crude N-pentanoyl-N-[[2'-(lH-tetrazoI-5-yl)[l ,l '-biphenyl]-4-yl]methyl]-L-valine with highly active carbon having pore volume of 0.8 to 1.8 cc/gm. In accordance with another embodiment of the present invention, the highly active carbon used is having surface area of 1200 - 1800 m7gm.
In accordance with one preferred embodiment of the present invention, there is provided a process for producing N-pentanoyl-N-[[2'-(lH-tetrazol-5-yl)[l ,l '-biphenyl]-4- yl] methyl] -L-valine of Formula 1,
Figure imgf000007_0001
Formula I
comprising the steps of:
a) reacting 4-halomethyl-2'-cyanobiphenyl compound of Formula Villa
Figure imgf000007_0002
Formula Villa
with L-valine alkyl ester of Formula Illb or acid addition salt of Formula Ilia)
Figure imgf000007_0003
Formula Illb Formula Ilia
in presence of a base and solvent, to obtain N-[2'-cyanobiphenyl-4-yl-methyl] (L)-valine alkyl ester of Formula IVb or its acid addition salt of Formula IVa
Figure imgf000008_0001
Formula IVb Formula IVa
wherein X represents halogen selected from CI or Br, and wherein R\ represents C 1 -C4 alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, 2-methyl propyl, or benzyl;
b) reacting the compound of Formula IVb or acid addition salt of Formula IVa with valeroyl halide of Formula Va
Figure imgf000008_0002
X= CI or Br
Formula Va
in presence of a base and organic solvent to obtain N-[2'-cyanobiphenyl-4-yl- methyl] N-pentanoyl-L- valine alkyl ester of Formula Via
Figure imgf000008_0003
Formula Via
(c) subjecting the resultant compound of Formula Via to cyclo addition reaction with alkali metal azide and tri-n-butyl tin chloride in solvent to obtain compound of Formula Vila and quenching the reaction with base to obtain crude N-pentanoyl-N-[[2'- (lH-tetrazol-5-yl)[l ,l '-biphenyl]-4-yl]methyl]-L-valine and
Figure imgf000009_0001
Formula Vila
(d) treating crude N-pentanoyl-N-[[2'-(lH-tetrazol-5-yl)[l,l '-biphenyl]-4- yl]methyl]-L-valine with highly active carbon having pore volume of 0.8 to 1.8 cc/gm to get pure N-pentanoyl-N-[[2'-(lH-tetrazol-5-yl)[l,l '-biphenyl]-4-yl]methyl]-L-valine of Formula I.
In accordance with another preferred embodiment of the present invention, wherein the N-pentanoyl-N-[[2'-(lH-tetrazol-5-yl)[l,l '-biphenyl]-4-yl]methyl]-L-valine obtained is having tin content equal to or less than 5 ppm, preferably equal to or less than 1 ppm.
Detailed Description of the Invention
While this specification concludes with claims particularly pointing out and distinctly claiming that, which is regarded as the invention, it is anticipated that the invention can be more readily understood through reading the following detailed description of the invention and study of the included examples.
The disclosed embodiment of the present invention deals with a process for producing pure N-pentanoyl-N-[[2'-(lH-tetrazol-5-yl)[l, -biphenyl]-4-yl]methyl]-L- valine (valsartan) employing highly active carbon. The present invention in its aspect is a new, improved, economically and industrially feasible method for preparing pure valsartan acceptable for human consumption.
The present invention provides an improved process for the preparation of N- pentanoyl-N-[[2'-(lH-tetrazol-5-yl)[l , -biphenyl]-4-yl]methyl]-L-valine (valsartan), wherein the process comprising treating crude N-pentanoyl-N-[[2'-(lH-tetrazol-5-yl)[l , l '- biphenyl]-4-yl]methyl]-L-valine with highly active carbon. The highly active carbon used according to the invention is having pore volume in the range of 0.8 to 1.8 cc/gm, preferably 1.0 - 1.3 cc/gm and surface area between 1200 to 1800 m2/gm, preferably 1400 - 1600 m2/gm.
Pure valsartan obtained by the process of the invention is having tin content equal to or less than 5 ppm and preferably less than 1 ppm.
In accordance with the present invention, there is provided an improved process for producing N-pentanoyl-N-[[2'-(lH-tetrazol-5-yl)[l ,l '-biphenyl]-4-yl]methyl]-L-valine of Formula 1 ,
Figure imgf000010_0001
Formula I
comprising the steps of:
a) reacting 4-halomethyl-2'-cyanobiphenyl compound of Formula Villa
Figure imgf000010_0002
Formula Villa
with L- valine alkyl ester of Formula Hlb or acid addition salt of Formula Ilia
Figure imgf000010_0003
Formula Illb Formula Ilia
in presence of a base and solvent, to obtain N-[2'-cyanobiphenyl-4-yl-methyl] (L)- valine alkyl ester of Formula IVb or its acid addition salt of Formula IVa
Figure imgf000011_0001
Formula IVb Formula IVa
wherein X represents halogen selected from CI or Br, and wherein R\ represents C 1 -C4 alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, 2-methyl propyl, or benzyl;
b) reacting the compound of Formula IVb or acid addition salt of Formula IVa with valeroyl halide of Formula Va
Figure imgf000011_0002
X= Cl or Br
Formula Va
in presence of base and organic solvent to obtain N-[2'-cyanobiphenyl-4-yl- methyl] N-pentanoyl-L- valine alkyl ester of Formula Via
Figure imgf000011_0003
Formula Via
(c) subjecting the resultant compound of Formula Via to cyclo addition reaction with alkali metal azide and tri-n-butyl tin chloride in solvent to obtain compound of Formula Vila and quenching the reaction with base to obtain crude N-pentanoyl-N-[[2'- (l H-tetrazol-5-yl)[l , -biphenyl]-4-yl]methyl]-L-valine and
Figure imgf000012_0001
Formula Vila
(d) treating crude N-pentanoyl-N-[[2'-(lH-tetrazol-5-yl)[l ,l '-biphenyl]-4- yl]methyl]-L-valine with highly active carbon having pore volume of 0.8 to 1.8 cc/gm to get pure N-pentanoyl-N-[[2'-(lH-tetrazol-5-yl)[l, -biphenyl]-4-yl]methyl]-L-valine of Formula I.
The acid addition salt employed herein is hydrochloride or hydrobromide and preferably hydrochloride.
The base used in step (a) is selected from organic or inorganic base. The inorganic base is selected from hydroxides, hydrides, carbonates, bicarbonates or alkoxides salt of alkali or alkaline earth metal, wherein alkali and alkaline earth metal is selected from Li, Na, K, Mg, Ca and the like. The organic base is amine. The preferred base is selected from sodium hydroxide, potassium hydroxide, sodium hydride, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium methoxide, sodium ethoxide, potassium t-butoxide, triethylamine, ethylamine, di-isopropyl ethylamine, tributylamine, dicyclohexyl amine, pyridine and the like. The more preferred base is potassium carbonate or sodium carbonate.
The solvent used in step (a) is selected from amides, sulfoxides, ketones, hydrocarbons, ethers, esters, halogenated hydrocarbons or mixture thereof. The preferred solvent is dimethyl formamide, dimethyl acetamide, dimethyl sulfoxides, acetonitrile, propionitrile, acetone, methyl ethyl ketone, methyl isobutyl ketone, toluene, o-xylene, m- xylene, ^-xylene, cyclohexane, cycloheptane, tetrahydrofuran, diethyl ether, di-isopropyl ether, dioxane, 2-methyl tetrahydrofuran, ethyl acetate, propyl acetate, butyl acetate, methylene dichloride, ethylene dichloride, chloroform or mixture thereof. The more preferred solvent is dimethyl formamide. Reaction of step (a) is carried out at temperature range of 1 G-70°C, preferably at 25-30°C.
The base used in step (b) is selected from organic or inorganic base. The inorganic base is selected from hydroxides, carbonates, bicarbonates or alkoxides salts of alkali or alkaline earth metal, wherein alkali and alkaline earth metal is selected from Li, Na, , Mg, Ca and the like. The organic base is amine. The preferred base is selected from sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium methoxide, sodium ethoxide, potassium t-butoxide, triethylamine, ethylamine, di-isopropyl ethylamine, tributylamine, dicyclohexylamine, pyridine and the like. The more preferred base is triethyl amine.
The solvent used in step (b) is selected from amides, sulfoxides, ketones, hydrocarbons, ethers, esters, halogenated hydrocarbons or mixture thereof. The preferred solvent is dimethyl formamide, dimethyl acetamide, dimethyl sulfoxides, acetonitrile, propionitrile, acetone, methyl ethyl ketone, methyl isobutyl ketone, toluene, o-xylene, m- xylene, ^-xylene, cyclohexane, cycloheptane, tetrahydrofuran, diethyl ether, di-isopropyl ether, dioxane, 2-methyl tetrahydrofuran, ethyl acetate, propyl acetate, butyl acetate, methylene dichloride, ethylene dichloride, chloroform or mixture thereof. The more preferred solvent is methylene dichloride.
Reaction of step (b) is carried out at temperature range of 0-50°C, preferably at 0- 5°C.
The alkali metal azide used in step (c) is sodium azide.
The solvent used in step (c) is selected from amides, sulfoxides, hydrocarbons or mixture thereof. The preferred solvent is dimethyl formamide, dimethyl acetamide, N- methyl pyrrolidone, dimethyl sulfoxides, toluene, o-xylene, w-xylene, /^-xylene, cyclohexane, cycloheptane or mixture thereof. The more preferred solvent is o-xylene.
Reaction of step (c) is carried out at temperature range of 80-180°C, preferably at 145-150°C.
The base used in step (c) is inorganic base, which is selected from hydroxides, carbonates or bicarbonates salts of alkali or alkaline earth metal, wherein alkali and alkaline earth metal is selected from Li, Na, K, Mg, Ca and the like. The preferred base is selected from sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogen carbonate or potassium hydrogen carbonate. The more preferred base is sodium hydroxide.
After using the base in step (c), the reaction mixture is heated to 55-60°C and extracted with water. Then the pH of aqueous layer is adjusted to 9-1 1 and preferably to 10-10.5, with use of acid. The role of pH is important in lowering the metal content, especially tin content. The pH is found to be suitable in the range of 9-1 1.
The resulting valsartan as obtained in step (c) is converted into pure valsartan with or without isolation.
The active carbon used is of grade PF 51 1 SPL, having details as given below. Drastic tin content reduction is observed with highly active carbon and it is due to its macro porosity i.e. large pore volume and high surface area. Comparison of commercial grade and PF 51 1 SPL grade carbon is given below:
Characteristics of the said highly active carbon grade PF 51 1 SPL are:
Figure imgf000014_0002
The process for the preparation of valsartan described in the present invention is demonstrated in the examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.
Example-1
Preparation of N-|Y2'-cyanobiphenyl-4-yl) methyl] -(L)- valine methyl ester hydrochloride
(Formula IV a)
2'-cyano-4-bromomethylbiphenyl (100g:0.367m) was condensed with L-valine methyl ester hydrochloride (80g: 0.477m) in the presence of Potassium carbonate (50g :0.362m) in N,N-Dimethylformamide (6V) at 25-300C for 12hrs. After completion of the reaction, the reaction mass was quenched in water and extracted in toluene. Combined toluene layer washed with water. Hydrochloric acid was added to the organic layer at 20- 25°C. The mass was stirred for 2 hrs at 25-30°C. The solid compound of Formula IVa was collected by filtration and dried. (HPLC purity: 98%, Yield: 1 lOgw/w, 83.46%).
Example-2
Preparation of N-Valeryl-N-|Y2,-cvanobiphenyl-4-yl') methyl] -(L)-valine methyl ester
(Formula Via)
Formula IVa compound (l OOg: 0.279m) was basified with sodium bicarbonate solution and extracted in dichloromethane. Separate the organic layer, washed with water. Organic layer dried over anhydrous sodium sulphate. Organic layer containing free base compound of formula III was condensed with valeryl chloride (45g:0.373m) in the presence of triethylamine (36g:0.356m) at 0-5°C and stirred the reaction mass at 0-5°C for 1 hr. After completion of the reaction washed with dilute hydrochloric acid, dilute sodium bicarbonate and water. Separated the organic layer and concentrated completely and added O-xylene. O-xylene layer washed with dilute hydrochloric acid, dilute sodium bicarbonate and water. Separate the organic layer, dried over anhydrous sodium sulphate. Organic layer contains compound of Formula Via. (HPLC purity: 98%)
Example-3
Preparation of (S) N-(Oxopentyl)-N-[(2,-(lH-tetrazol-5-yl)-Tl,l '-biphenyl -yllmethvI]- L-valine (Formula I) - {No carbon treatment}
Taken organic layer from example 2 containing N-Valeryl-N-[(2'-cyanobiphenyl- 4-yl) methyl]-(L)-valine methyl ester, add tri-n-butyl tin chloride (170g: 0.523m) and sod'ium azide (34g:0.523m). Heated to 135-138°C stirred for 24hrs, cooled to 10-15°C, added a solution of aqueous sodium hydroxide solution (54g in 900ml DM water), heated to 55-60°C for 2-2.5hrs. After completion of the reaction, mass was cooled to 25-30°C and separated out aqueous and organic layers. Wash the aqueous layer (pH 13) twice with 100 ml o-xylene. Cooled the aqueous layer to 15-20°C and adjusted pH to 2.5-3.0 by dilute hydrochloric acid and extract the compound with dichloromethane. Organic layer washed with water and brine solution. Organic layer was concentrated and to get 98g crude Valsartan (Tin content - 806 ppm; HPLC purity - 98%; R-isomer=6.1 %) and valsartan crystallized in ethyl acetate (750 ml) followed by washing of wet cake with chilled dichloromethane (200 ml) and dried in FBD at 40-65°C.
Pure valsartan (Tin content: 80 ppm; HPLC purity: 99.9%; S-isomer: 99.2; R-isomer: 0.8%; Yield: 48g, 40%)
Example-4
Preparation of (S) N-(Oxopentyl)-N-[(2 lH-tetrazol-5-ylH l '-biphenylH-yllmethyll- L-valine (Formula I) - '{Use of commercial grade Carbon} Same as like example-3 except that the product aqueous layer is treated thrice with 10%) commercial BL grade activated carbon at 25-30°C.
Crude valsartan (Tin content: 455 ppm)
Pure valsartan (Tin content: 35 ppm; HPLC purity: 99.90%; S-isomer: 99.3%; R-isomer: 0.7%, Yield: 48g, 40%)
ExampIe-5
Figure imgf000016_0001
L-valine (Formula I) - (Use of commercial grade Carbon} Same as like example-4 except that the product aqueous layer is treated thrice with 10%) commercial BL grade activated carbon at 45-50°C.
Crude valsartan (Tin content: 210.5 ppm)
Pure valsartan (Tin content -18 ppm; HPLC purity: 99.90%; S-isomer: 99.5%; R- isomer: 0.5%, Yield: 48g, 40%).
Example-6
Preparation of (S N-(Oxopentyl -N- |Y2 ' -( 1 H-tetrazol-5 -vD- Γ L -biphenyll -4- yllmethyll - L-valine (Formula VI) - {Use of commercial grade Carbon} Same as like example-5 except that before carbon (commercial BL grade carbon) treatment of the product aqueous layer, pH is adjusted to 10-10,5 with 4.0-4.2 N dilute HC1 solution.
Crude valsartan (Tin content: 150.8 ppm)
Pure valsartan (Tin content -15 ppm; HPLC purity: 99.90%; S-isomer: 99.5%; R- isomer: 0.5%, Yield: 48g, 40%)
ExampIe-7
Preparation of (S) N-COxopentvD-N-r^'-dH-tetrazol-S-vD-rLr-biphenyll^-yllmethyl]-
L-valine (Formula I)
Same as like example-6 except that the product aqueous layer is treated twice with 10% highly activated carbon (PF 51 1 SPL grade) at 45-50°C.
Crude valsartan (Tin content: 60.2 ppm).
Pure valsartan (Tin content - 0.9 ppm; HPLC purity: 99.90%; S-isomer: 99.6%; R- isomer: 0.4%, Yield: 47g, 38.8%)
ExampIe-8
Preparation of (S) N-(OxopentylVN-f(2'-(lH-tetrazol-5-ylVri ,r-biphenyll-4-yllmethyll-
L-valine (Formula I)
Same as like example-7 except that the product aqueous layer is treated thrice with 10% highly activated carbon (PF 51 1 SPL grade) at 45-50°C.
Crude valsartan (Tin content: 25.4 ppm).
Pure valsartan of (Tin content - 0.1 ppm; HPLC purity: 99.90%; S-isomer: 99.72%; R- isomer: 0.28%, Yield: 48g, 40%).
While this invention has been described in detail with reference to certain preferred embodiments, it should be appreciated that the present invention is not limited to those precise embodiments. Rather, in view of the present disclosure, which describes the current best mode for practicing the invention, many modifications and variations would present themselves to those skilled in the art without departing from the scope and spirit of this invention.

Claims

We Claim:
1. A process for producing N-pentanoyl-N-[[2'-(lH-tetrazol-5-yl)[l ,l '- biphenyl]-4-yl]methyl]-L-valine, wherein the process comprising treating crude N- pentanoyI-N-[[2'-(lH-tetrazoI-5-yl)[l,l '-biphenyl]-4-yl]methyl]-L-valine with highly active carbon having pore volume of 0.8 to 1.8 cc/gm.
2. The process according to claim 1, wherein the highly active carbon used is having pore volume in a range of 1.0 - 1.3 cc/gm.
3. The process according to claim 1, wherein the highly active carbon used is of grade PF 51 1 SPL.
4. The process according to claim 1 , wherein the highly active carbon used is having surface area of 1200 - 1800 m2/gm.
5. The process according to claim 1 , wherein the highly active carbon used is having surface area of 1400 - 1600 m2/gm.
6. The process according to claim 1, wherein the N-pentanoyl-N-[[2'-(lH- tetrazol-5-yl)[l, -biphenyl]-4-yl]methyl]-L-valine obtained is having tin content equal to or less than 5 ppm.
7. The process according to claim 1 , wherein the N-pentanoyl-N-[[2'-(lH- tetrazol-5-yl)[l, -biphenyl]-4-yl]methyl]-L-valine obtained is having tin content equal to or less than 1 ppm.
8. A process for producing N-pentanoyl-N-[[2'-(lH-tetrazol-5-yl)[l,l '- biphenyl]-4-yI]methyl]-L- valine of .Formula 1 ,
Figure imgf000018_0001
Formula I
comprising the steps of:
a) reacting 4-halomethyl-2'-cyanobiphenyl compound of Formula Villa
Figure imgf000019_0001
Formula Villa
with L-valine alkyl ester of Formula Illb or acid addition salt of Formula Ilia
Figure imgf000019_0002
Formula Illb Formula Ilia
in presence of a base and solvent, to obtain N-[2'-cyanobiphenyl-4-yl-methyl] (L) alkyl ester of Formula IVb or its acid addition salt of Formula IVa
Figure imgf000019_0003
Formula IVb Formula IVa
wherein X represents halogen selected from CI or Br, and wherein R\ represents C1-C4 alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, 2-methyl propyl, or benzyl;
b) reacting the compound of Formula IVb or acid addition salt of Formula IVa with valeroyl halide of Formula Va
Figure imgf000019_0004
X= CI or Br
Formula Va
in presence of a base and organic solvent to obtain N-[2'-cyanobiphenyl-4-yl- methyl] N-pentanoyl-L- valine alkyl ester of Formula Via
Figure imgf000020_0001
Formula Via
(c) subjecting the resultant compound of Formula Via to cyclo addition reaction with alkali metal azide and tri-n-butyl tin chloride in solvent to obtain compound of Formula Vila and quenching the reaction with base to obtain crude N-pentanoyl-N-[[2'- (lH-tetrazol-5-yl)[l,l '-biphenyl -4-yl]methyl]-L-valine and
Figure imgf000020_0002
Formula Vila
(d) treating crude N-pentanoyl-N-[[2'-(lH-tetrazol-5-yl)[l ,l '-biphenyI]-4- yl]methyl]-L- valine with highly active carbon having,pore volume of 0.8 to 1.8 cc/gm to get pure N-pentanoyl-N-[[2'-(lH-tetrazol-5-yl)[l, -bipheny]]-4-yl]methyl]-L-valine of Formula I.
9. The process according to claim 8, wherein the acid addition salt is selected from hydrochloride or hydrobromide salt.
10. The process according to claim 8, wherein the base used in step (a) is selected from organic base or inorganic base.
1 1. The process according to claim 10, wherein the organic base is an amine.
12. The process according to claim 1 1 , wherein the amine is selected from a group comprising of triethylamine, ethylamine, di-isopropyl ethylamine, tributylamine, dicyclohexylamine and pyridine.
13. The process according to claim 10, wherein the inorganic base is selected from the group comprising of hydroxide, hydride, carbonate, bicarbonate or alkoxide salt of alkali or alkaline earth metal.
14. The process according to claim 8, wherein the solvent used in step (a) is selected from a group comprising of amides, sulfoxides, nitriles, ketones, hydrocarbons, ethers, esters, halogenated hydrocarbons or mixture thereof.
15. The process according to claim 8, wherein the reaction temperature used in step (a) is 10-70°C.
16. The process according to claim 8, wherein the base used in step (b) is selected from organic base or inorganic base.
17. The process according to claim 16, wherein the organic base is an amine.
18. The process according to claim 17, wherein the amine is selected from the group comprising of triethylamine, ethylamine, di-isopropyl ethylamine, tributylamine, dicyclohexylamine and pyridine.
19. The process according to claim 16, wherein the inorganic base is selected from the group comprising of hydroxide, carbonate or bicarbonate salt of alkali or alkaline earth metal, or ammonia.
20. The process according to claim 8, wherein the organic solvent used in step (b) is selected from the group comprising of amides, sulfoxides, nitriles, ketones, hydrocarbons, ethers, esters, halogenated hydrocarbons or mixture thereof.
21. The process according to claim 8, wherein the reaction temperature used in step (b) is 0-50°C.
22. The process according to claim 8, wherein the alkali metal azide used in step (c) is sodium azide.
23. The process according to claim 8, wherein the base used in step (c) is selected from the group comprising of hydroxide, carbonate or bicarbonate salt of alkali or alkaline earth metal.
24. The process according to claim 8, wherein the solvent used in step (c) is selected from the group comprising of amides, sulfoxides, hydrocarbons or mixture thereof.
25. The process according to claim 8, wherein reaction temperature in step (c) is 80-180°C.
26. The process according to claim 8, wherein the obtained N-pentanoyl-N- [[2'-(lH-tetrazol-5-yl)[l , -biphenyl]-4-yl]methyI]-L-valine of Formula 1 is having tin content equal to or less than 5 ppm.
27. The process according to claim 8, wherein the obtained N-pentanoyl-N- [[2'-(lH-tetrazol-5-yl)[l, -biphenyl]-4-yl]methyl]-L-valine of Formula 1 is having tin content less than 1 ppm.
28. The process according to claim 8, wherein the highly active carbon used is having pore volume in a range of 1.0 - 1.3 cc/gm.
29. The process according to claim 8, wherein the highly active carbon used is of grade PF 51 1 SPL.
30. The process according to claim 8, wherein the highly active carbon used is having surface area of 1200 - 1800 m2/gm.
31. The process according to claim 8, wherein the highly active carbon used is having surface area of 1400 - 1600 m7gm.
PCT/IB2011/002538 2010-10-29 2011-10-25 An improved process for the preparation of n-pentanoyl-n-[[2'-(1h-tetrazol-5-yi)[1,1'-biphenyl]-4-yi]methyl]-l-valine WO2012056294A1 (en)

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CN110078640A (en) * 2019-03-29 2019-08-02 浙江美诺华药物化学有限公司 A kind of synthetic method of Valsartan intermediate

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CN102875485A (en) * 2012-09-29 2013-01-16 华润赛科药业有限责任公司 Method for controlling impurity VLSI-M in valsartan
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CN108047152A (en) * 2017-12-12 2018-05-18 湖南千金协力药业有限公司 A kind of process for purification of Valsartan
CN110078640A (en) * 2019-03-29 2019-08-02 浙江美诺华药物化学有限公司 A kind of synthetic method of Valsartan intermediate
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