FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule 13)
TITLE OF THE INVENTION
“IMPROVED PROCESSES FOR THE PREPARATION OF 2-CYANO-4'METHYLBIPHENYL DERIVATIVES (OTBN)”
We, CADILA HEALTHCARE LIMITED, a company incorporated under the Companies Act, 1956, of Zydus Tower, Satellite Cross Roads, Ahmedabad-380015, Gujarat, India.
The following specification describes the invention:
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Field of invention:
The present invention describes improved process(es) for the preparation of 2-cyano 4'-methylbiphenyl derivatives more specifically to the preparation of Ortho-tolylbenzo nitrile (OTBN).
Background to the invention:
The present invention generally relates to a new process for the preparation of a biphenyl derivative. More precisely, the subject of the invention is a new process for the preparation of OTBN. OTBN stands for 2-cyano 4'-methylbiphenyl (structure I.), although there are other names which are more precise: 2-(4-methylphenyl)benzonitrile, 2-cyano 4'-methylbiphenyl.

2-Cyano 4'-methylbiphenyl.can be widely used as an intermediate, especially for the final synthesis of commercially beneficial biphenylmethyl derivatives which includes antihypertensive, angiotensin II antagonist class of drugs with the suffix 'Sartan'. Some of them are Losartan, Valsartan, Irbesartan, Candesartan, Telmisartan, Tasosartan etc. Most of these Saltans have a biphenyl skeleton and hence, development of a cheap, rugged and industrially applicable process for preparing this key intermediate is of importance to the process chemists. These sartan derivatives have proved to be useful due to their pharmacological properties, especially their angiotensin II antagonist properties. These properties make the compounds in question particularly advantageous in the treatment of syndromes of the cardiovascular system such as hypertension or heart failure and in the treatment of diseases of the central nervous system and in the treatment of glaucoma and of diabetic retinopathy.
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Various methods have been reported in the chemical literature making possible the preparation of 2-cyano 4'-methylbiphenyl.
Some of them includes, those described in J. Med. Chem., 34, pp. 2525-2547 (1991), EP 953564, EP 470,794, US 4942221, US 6194599, Huaxue Yu Shengwu Gongcheng (2004), 21(3), 39-41, Jingxi Huagong Zhongjianti (2003), 33(6), 40-48; Zhongguo Yiyao Gongye Zazhi (2001), 32(9), 385-387; Huaxue Yu Nianhe (2001), (4), 151-152; EP 854135 etc.
There are generally two schemes of synthesis described in the literature:
i) one general process uses either Palladium catalyst or a compound containing
Palladium, involving boronic acid/ boranets as raw materials,
ii) the other general process uses other metal catalysts such as Mn, Mg, Ni, Co, Zn or
their oxides or salts.
Schematically, the two general processes may be shown as

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The Palladium based processes have the problems of high cost of boronic acids/ boranets as well as the catalyst, difficulty in optimizing and scaling up in an industrial scale and risk of contamination of the catalyst, a heavy metal.
The processes which uses other metal catalysts like Ni, Zn or Mn suffer from the problems of either low yield, use of expensive bromide or iodide intermediates (typical in processes describing the use of Ni catalyst), or, when Manganese halides are used, since Manganese halides are hygroscopic, there arises handling problems or when metal Manganese is used, since it is necessary to add an equimolar amount of a metal manganese to the 2-halobenzonitrile, the metal manganese has to be treated after terminating the reaction, thereby industrial wastes are generated (EP 953564). When MnO 2 is used, again the process becomes costly and difficult to scale up in a cost-effective way. Therefore, there is a need to develop a process, which is robust, efficient, and scalable and is cost effective. We herein disclose such an improved process
Summary of the invention
It is an object of the present invention to provide an improved process for the preparation of 2-cyano 4'-methylbiphenyl derivatives (OTBN).
In a further embodiment is provided a process for preparing compound of formula (I), which is scalable, robust and cost effective.
A further embodiment is provided a process wherein the costly THF is replaced with toluene & other cheaper solvent(s).
The above and other embodiments are described in further details below. Detailed Description:
The present invention describes an improved process for preparation of compound of formula (I)

The process may be described according to the following general scheme:

The process involves reacting a compound of formula (IV) with Mg to obtain compound of formula (V) and subsequently (V) is reacted with a compound of formula (III) in presence of a suitable oxidizing agent(s) such as KMnO4, V2O3 or V2O5, VO(acac)2, Ceric Ammonium Nitrate (CAN), NaBrO3, CrO3-Py, Pyridinium dichromate (PDC), Pyridinium chlorochromate (PCC), TMS-C1 on silica, NaOCl and the like, in the presence of suitable solvent(s) to obtain the compound of formula (I).
Suitable solvents which may be used may be selected from THF, toluene, Xylene, 1,4-dioxane, 1,3 dioxalane, diethyl ether, methyl-t-butyl ether, diisopropyl ether, dilatory ethane, NMP and the like or their suitable combinations.
The coupling of (V) with (III) is further enhanced by additives such as TMS-C1, TMS-O-TMS, ammonium chloride, (nBu)4N(+)Cl(_) and the like. In a further embodiment, the reactivity may be still further enhanced by using suitable Lewis acids such as MgBr2, TiO2, ZrO2, A12O3, ZnO, CuO and the like.
The process as describe herein is further exemplified by the following non-limiting example, which describes one of the various possible preferred embodiments and should not be construed as limiting the scope of the invention in any way.

Example 1
A mixture of 0.464 g Potassium permanganate, 1.26 g Trimethyl silyl chloride in tetrahydrofuran is stirred at 10 to 45 °C for 1 to 4 h. 5 g of 2-Chlorobenzonitrile was added and cooled to -5 °C. To this reaction mixture was added p-methylphenyl magnesium chloride (8.7 g) (in tetrahydrofuran / toluene) at -5 to 0 °C over a period of 1 to 3 h and the mixture kept at 0 to 5 °C for l h and at 25 to 40 °C for 1-2 h. The reaction mixture was quenched with dilute hydrochloric acid and the layers were separated. Organic layer was washed with water, saturated sodium bicarbonate solution and then saturated sodium chloride solution. Solvent distilled off to get 10 g of crude product (I) with purity >60 %. The resulting crude product was distilled out under high vacuum to get pure product. Example 2
A mixture of 0.464 g potassium permanganate, 1.26 g trimethyl silyl chloride in tetrahydrofuran was stirred at 10 to 45 °C for 1 to 4 h. To it was added 1 g of 2-chlrobenzonitrile and cooled to -5 °C. To this reaction mixture was added p-methylphenyl magnesium chloride (8.7 g) (in tetrahydrofuran / toluene) at -5 to 0 °C and 4 g of 2-chlorobenzonitrile solution in toluene simultaneously over a period of 1 to 3 h and the mixture kept at 0 to 5 °C for l h and at 25 to 30 °C for 1 h. The reaction mixture was quenched with dil. hydrochloric acid and layers were separated. The organic layer washed with water, saturated sodium bicarbonate solution and then saturated sodium chloride solution. Solvent distilled off to get 10 g of crude product (I) with purity >70 %. The resulting crude product was distilled out under high vacuum lo get pure product.
Example 3
A mixture of 0.5 g potassium permanganate, in tetrahydrofuran was stirred at 10 to 45 °C for 1 to 3 h. To it was added 5 g of 2-chlrobenzonitrile and cooled to -5 °C. To this reaction mixture was added p-methylphenyl magnesium chloride (8.7 g) (in tetrahydrofuran / toluene) at -5 to 0 °C over a period of 1 to 3 h and the mixture kept at 0 to 5 °C for lh and at
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25 to 30 °C for 1 h. The reaction mixture was quenched with dilute hydrochloric acid and the layers were separated. The organic layer was washed with water, saturated sodium bicarbonate solution and then saturated sodium chloride solution. Solvent distilled off to get 10 g of crude product (I). The resulting crude product was distilled out under high vacuum to get pure product.
Example 4
Example 2 was repeated by simultaneous addition of p-methylphenyl magnesium chloride (in tetrahydrofuran / toluene) and 2-chlorobenzonitrile solution and subsequent processes as described earlier were followed to obtain the pure product (I).




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