Form 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULE 2003
PROVISIONAL SPECIFICATION
[See section 10 and rule 131
1. TITLE OF THE INVENTION
"A process for preparation of 4'-[(2-n-propyl-4-methyl-6-(l-methyl-benzimidazol-2-yl)-benzimidazol-1 -yl)methyll-biphenyl-2-carboxylic acid"
2. APPLICANT
(a)NAME: USV LIMITED
(b)NATIONALITY: Indian Company incorporated under the
Companies Act 1956 (c)ADDRESS: B.S.D. Marg, Govandi, Mumbai 400 088, Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION
The following specification describes the nature of this invention and
the manner in which it is to be performed.
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A process for preparation of 4'-[(2-n-propyl-4-methyl-6-(1-methyl-benzimidazol-2-yl)-benzimidazol-1-yl)methyl]-biphenyl-2-
carboxylic acid
Field of the invention :
An improved process for the preparation of 4'-[(2-n-propyl-4-methyl-6-(l-methyl-
benzimidazol-2-yl)-benzimidazol-1 -yl)methyl] -biphenyl-2-carboxylic acid
(telmisartan) or a pharmaceutically acceptable salt and intermediates thereof. The present invention is also directed to a method for carrying out the highly regioseAlective aromatic nitration of methyl-4-butyramido-3-methylbenzoate.
Background of the invention :
Telmisartan is chemically known as 4'-[(2-n-propyl-4-methyl-6-(l-methyl-
benzimidazol-2-yl)-benzimidazol-l-yl)methyl]-biphenyl-2-carboxylic acid, and has the following structural formula (I) is an angiotensin-II receptor antagonist, useful in the treatment of hypertensive diseases, heart diseases and is commercially available in tablet form under the brand name MICARDIS.


US 5591762 or EP 0502314 and J. Med. Chem.,1993, 36, (25) disclose a process for preparing telmisartan and its pharmaceutically acceptable salts and a pharmaceutical composition. Also described is a method of alkylation of 2-n-propyl-4-methyl-6-(l'-methylbenzimidazole-2'-yl) benzimidazole (III) with terf-butyl-4'-bromomethyl-biphenyl-2-carboxylate (IVc) by using potassium tert-butoxide in DMSO/DMF solvent with 56% yield, which on subsequent hydrolysis with trifluoro acetic acid provided telmisartan, The crude product obtained was then purified over a silica gel column and finally crystallized from acetone.

(IYa) R=Me (IVb) R=Et (IVc) R = t-Bu

In US2004/0236113 4'-[(2-n-propyl-4-methyl-6-(l-methyl-benzimidazol-2-yl)-
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benzimidazol-l-yl)methyl]-2-cyanobiphenyl has been synthesized by reacting (III) with 4-bromomethyl-2'-cyanobiphenyl and subsequently hydrolysing the nitrile group in ethylene glycol at 185 °C to yield telmisartan.
Chinese patent application CN 1344712 discloses a process to prepare telmisartan wherein 2-n-propyl-4-methyl-6-(l'-methylbenzimidazole-2'-yl) benzimidazole (III)
was reacted with 4'-bromomethyl-biphenyl-2-carboxylic acid methyl (IVa) or ethyl ester (IVb) to form a telmisartan methyl or ethyl ester intermediate, which was then converted to telmisartan by acid or base hydrolysis.
WO 2005/108375 has disclosed "one pot" synthesis of telmisartan by condensing (III) with 4'-bromomethyl-biphenyl-2-carboxylic acid methyl ester (IVa) followed by basic hydrolysis.
WO 2006/044648 disclose the method of preparation of telmisartan by the condensation of (III) with 4'-bromomethyl-biphenyl-2-carboxylic acid methyl ester(IVa) using phase transfer catalyst at temperature 80°C followed by acidic hydrolysis.
Drawbacks of the process as described in US5591762 are viz. very poor yield (56%) in the condensation step, use of potassium tert-butoxide and DMSO and use of column chromatography for purification. Poor yield makes the process uneconomical. Potassium tert-butoxide is expensive and is unstable. Conventional column chromatography is time consuming and uneconomical due to consumption of huge quantity of solvents. The solvent dimethylsulfoxide has a high boiling point of greater than about 140°C, it is very difficult to remove from the reaction using various techniques known to ordinarily skilled in the art. The inefficient and harsher reaction conditions employed for condensation step results in a lower yield of the telmisartan alkylester intermediate product.
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Thus, there is a need to develop a process for preparing telmisartan alkylester and telmisartan that is environmentally friendly, easy to practice, cost effective and high yielding .
The key step in the synthesis of intermediate III is the nitration of methyl-4-(butyrylamino)-3-methyl benzoate(V).
US 5591762 or J. Med. Chem, 1993, 36, (25) disclose a process of nitration of methyl-4-(butyrylamino)-3-methyl benzoate using fuming nitric acid at -15°C temperature or mixture of nitric acid with sulfuric acid at 0°C temperature respectively. The crude purity obtained by these processes is only ~ 90 % mainly due to formation of di and tri-nitrated byproducts. There are no good, safe and reliable methods available in the prior art for regioselective nitration of formula(V) at 5th position.
Fuming nitric acid is corrosive in nature and the lot of effluent is collected during the workup. Handling of nitric acid is dangerous particularly when concentrated nitric acid is used as a nitrating agent. The lower temperature of -15 °C results in accumulation of starting materials in the reaction mixture leading to sudden initiation and possibility of a runway reaction thus assuming dangerous proportions on large scale.
Hence there is a need for a safer and regioselective nitration reaction for nitrating compound of formula V to compound of formula VI
Objects of the invention :
An object of the invention is to provide regioselective nitration of methyl-4-butyramino-3-methylbenzoate (V).
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Another object of the invention is to produce methyl-4-butyrylamino-3-methyl-5-nitrobenzoate on an industrial scale.
Yet another object of the process is to produce highly pure telmisartan form A.
Summary of the invention :
The present invention provides a process for the nitration of methyl-4-butylamino-3-methylbenzoate ester (V), comprising:
Dissolving methyl-4-butyramino-3-methylbenzoate (V) in a mixture of acetic anhydride and acetic acid at ambient temperature and cooling the reaction mixture; adding nitric acid in acetic acid to provide methyl-4-butyrylamino-3-methyl-5-nitrobenzoate (VI) and isolating (VI) from the reaction mixture and further converting compound of formula (VI) to compound of formula (III).

Further 2-n-propyl-4-methyl-6-(l'methylbenzimidazole-2'-yl) benzimidazole of formula (III) is condensed with 4'-halomethyl-biphenyl-2-carboxylic acid alkyl ester of formula (VII) comprising;
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Compound of formula (III) is dissolved in dimethyl formamide and the reaction mixture is cooled and further sodium hydride is added to the reaction mixture. The compound(VII) is then charged at a lower temperature to yield Telmisartan alkylester of formula(II). The alkylester of formula II is then treated with an organic solvent.

Telmisartan alkylester of formula II is further hydrolysed by known methods to
provide telmisartan (I)


The present invention further provides pure telmisartan polymorphic form A, wherein crude telmisartan in a mixture of tetrahydrofuran and dimethylformamide at an elevated temperature and charcoaling the resultant solution. The reaction mixture is then cooled to ambient temperature and Telmisartan polymorphic form A is precipitated by adding water.
The invention further provides pharmaceutical compositions comprising telmisatan prepared according to the processes of the present invention and pharmaceutical acceptable excipients.
Detailed description of the invention :
In a preferred embodiment of the present invention methyl-4-butyramino-3 -methyl benzoate (V) is dissolved in a mixture of acetic acid and acetic anhydride and cooled to lower temperatures. To this solution nitric acid in acetic acid. The reaction mixture is quenched in ice-water and filtered and the cake is further washed with chilled water. Methyl-4-butyrylamino-3-methyl-5-nitrobenzoate (VI) thus isolated is dried under vacuum at 50°C.
In a preferred embodiment, the molar ratios of the components are 5-9 mol of fuming nitric acid, 4-8 moles of acetic anhydride and 15-20 moles of acetic acid per mole of benzoate (V).
The present invention discloses a highly regioselective process for nitration of
methyl-4-butyramino-3-methyl benzoate (V) in the 5th position in which the
formation of isomers and possibly di-and/or trinitrated methyl-4-butyramino-3-
methyl benzoate is suppressed.
Substantially isomerically pure methyl-4-butyrylamino-3-methyl-5-nitrobenzoate of formula -VI is obtained as the product. The term isomerically pure denotes, in the
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present context, methyl-4-butyrylamino-3-methyl-5-nitrobenzoate of formula-VI which is free from methyl-4-butyrylamino-3-methyl-2-nitrobenzoate and/or methyl -4-butyrylamino-3-methyl-6-nitrobenzoate. The total content of 2- and 6- nitroisomers
is less than 1%, based on the main product. The nitro compound (VI) is obtained in excellent yield of about 80% to 90% and in good quality (purity according to HPLC > 99 %).
The nitro compound thus obtained is converted to 2-n-propyl-4-methyl-6-(1 '-methylbenzimidazole-2'-yl) benzimidazole (III) by process known in prior art.
Reduction of the obtained nitro compound is carried out in a methanol with hydrogen in presence of 5% Pd/C to provide methyl-4-butyrylamino-3-methyl-5-aminobenzoate (Via) which is then refluxed in acetic acid to obtained (VIb) followed by hydrolysis carried out in presence of aqueous sodium hydroxide and methanol to yield 2-n-propyl-4-metnyl-benzimidazole-6-carboxylic acid (Vic.) The resulting Vic is then condensed with N- methyl o-phenylenediamine in presence of polyphosphorous acid to provide 2-n-propyl-4-methyl-6-(l'methylbenzimidazole-2'-yl) benzimidazole (III) (Scheme-A):
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Scheme - A
Further telmisartan alkylester is prepare by condensing 2-n-propyl-4-methyl-6-(rmethylbenzimidazole-2'-yl) benzimidazole of formula (III)
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with 4'-halomethyl-biphenyl-2-carboxylic acid alkyl ester of formula (VII)

wherein
R is a straight or branched chain C1-C4 alkyl.
Preferably, straight or branched chain C1-C4 alkyl is tert-butyl
and Z is halogen.
In a preferred embodiment of the present invention 2-n-propyl-4-methyl-6-(l'methylbenzimidazole-2'-yl) benzimidazole is dissolved in a polar aprotic solvent, preferably DMF and cooled to lower temperature. An alkali metal hydride, preferably sodium hydride is added, followed by addition of tert-butyl-4'-bromomethyl-biphenyl-2-carboxylate (IVc).
The molar ratio of the 4'-halomethyl-biphenyl-2-carboxylic acid alkyl ester of formula (VII) is 1-1.2 mole and of sodium hydride is 2-3 mole per mole of n-propyl-
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4-methyl-6-(rmethylbenzimidazole-2'-yl) benzimidazole of formula (III).
The reaction mass is quenched in ice water and extracted with halogentaed hydrocarbon, preferably methylene dichloride. The collected organic layer is washed with water and the solvent is distilled off completely under vacuum. The compound of formula(II) obtained as residue is further treated with a solvent or a mixture of solvents, preferably chloroform, methylene chloride, ethylene chloride, ethyl acetate, acetonitrile, n-hexane, n-heptane, or ethereal solvents such as diethyl ether, diisopropyl ether, methyl tert-butyl ether tetrahydrofuran, dioxane or mixtures thereof. Further a non polar solvent selected from n-pentane, heptane, octane and hexane is added. Telmisartan ester is precipitated after cooling to 5 °C to 10 °C, filtered and washed with a mixture of diisopropyl ether and n-hexane. The product is dried at elevated temperature of about 65°C to 85 °C. Yield of Telmisartan alkylester intermediate of formula (II) thus obtained is about 80% to 90% and shows a purity according to HPLC > 98 %.
Telmisartan alkylester intermediate of formula II is then converted to Telmisartan of formula I, preferably according to the hydrolysis process under acidic conditions as disclosed in prior art. Telmisartan alkylester intermediate of formula II is subjected to acidic hydrolysis in presence of trifluoroacetic acid and methylene dichloride at temperature 25-30 °C to provide crude telmisartan.
Telmisartan thus obtained may be purified using organic solvents. The organic solvent comprises a polar aprotic solvent or a non polar solvent or mixtures thereof. The non polar solvent is selected from aromatic hydrocarbons and aliphatic hydrocarbons.
Polar aprotic solvent may be selected from diethyl ether, diisopropyl ether, methyl t-butyl ether, tertahydrofuran, dioxane, dimethylsulfoxide, dimethylformamide,
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dimethylacetaminde and the like or a mixture thereof.
An aromatic hydrocarbon may be selected from toluene, xylene and chlorobenzene.
An aliphatic hydrocarbon may be selected from pentane, hexane, heptane and the like or mixtures thereof.
An alkali metal hydride may be selected from sodium hydride, potassium hydride, lithium hydride and calcium hydride.
Recovery may be achieved by quenching the reaction mass in an ice cold water, extracting with chlorinated hydrocarbon, separating and evaporating the organic layer.
Chlorinated hydrocarbon may be selected from chloroform, methylene dichloride and ethylene dichloride.
Isolation of form A may be carried out by using a single or mixture of organic solvents.
In a preferred embodiment of the present invention the crude telmisartan is dissolved in a mixture of THF and DMF, at an elevated temperature, preferably at 60-65 °C. The hot solution is treated with activated charcoal and cooled to ambient temperature. An anti-solvent preferably water is then added to filtrate, in order to precipitate the telmisartan-polymorphic A. It is further cooled to a temperature of about 25-30°C. The precipitate is filtered, washed with chilled THF and dried.
Telmisartan of formula (I) is obtained ia an excellent yield between 80% to 90% and in good quality (purity according to HPLC > 99.5 %).
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Examples :
Example —I
Charge 200 gm (0.85 mole) of 3-methyl-4-butryly amino benzoic acid methyl ester in a mixture of acetic anhydride 648 gm (6.347 mole) and acetic acid 896gm (13.76 mole). Stirred the reaction mass for 30 min at 25-30 °C to obtained clear solution. Cool to 0 to -5 °C. Prepared the solution of 392 gm (6.22 mole) fuming nitric acid and acetic acid 224 gm (3.44 mole) at 0 to -5 °C. added this fuming HN03 solution to reaction mass drop wise at 0 to -5 °C. Maintained the same temperature for 2 hr after completed the addition. Quenched the reaction mass in ice-water. Filter the yellow solid followed by water washed up to neutral PH, dry the solid product at 50 °C under vacuum yield; 197 gm (82.7%)
Example-II
100 gm (0.328 mole) of TL-dibenzimidazole (III) was dissolved in 700 ml DMF cool it to 0 to 5 °C. Added 18 gm (0.75 mole) sodium hydride (60%) lotwise and stirred for 30 min at 0 to 5 °C. Charged 123.5gm (0.35 moles) tert-butyl-4'-bromomethyl-biphenyl-2-carboxylate (IVc) in 1 hr at 0 to 5 °C and stirred for 1 hr. Then add 50 ml methanol and quenched the reaction mass in ice-water. Extracted the reaction mass by 250 ml x 3 times MDC. Collected the organic layer and dried over anhydrous sodium sulfate. Evaporated the MDC and residue was crystallizing in diisopropyl ether and hexane. Yield 150 gm (88.2 %).
Example-III
A solution of 150 gm (0.26 mole) and 460 gm(4.04 mole) of trifluoro acetic acid in 66 ml MDC is stirred at temperature 25-30 °C for 20 hr. Added the water and separated out organic layer, then evaporated to dryness. Dissolved the obtained
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residue to 150 ml aqueous ammonia solution to get clear solution, which was neutralized with acetic acid, the precipitate formed is suction filtered , washed with water and dried at 75-80 °C. Yield 120 gm (88.8 %)
Example-IV
20 gm of crude Telmisartan dissolved to 200 ml THF and 100 ml DMF at 60 to 65 °C. Added 4 gm activated charcoal and stirred for 30 min. filter the hot solution . collect clear filtrate and cool up to 25 to 30 °C. Add distilled water as anti solvent to precipitate the white solid is suction filtered, washed with chilled THF and dried at 65-70 °C. Yield 16 gm
Dated this the 27th day of December, 2006

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Abstract:
The present invention relates a process for preparation of telmisartan alkylester intermediate and further converting it to telmisartan. The present invention is also directed to a method for carrying out the highly regioselective aromatic nitration of methyl-4-butyramido-3-methylbenzoate.
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