FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION
"NOVEL AND COST EFFECTIVE PROCESS FOR THE PRODUCTION OF
CYANOCYCLOHEXANE"
2. APPLICANT (S)
(a) NAME: WANBURY LIMITED
(b) NATIONALITY: Indian Company incorporated under the Indian
Companies Act, 1956
(c) ADDRESS: B- Wing, 10th Floor, BSEL Tech Park, Sector 30 A,
Plot no.39/5 & 39/5A, Opp. Vashi Railway Station, Navi-Mumbai- 400 703, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION:
The present invention relates to a process for the production of a compound of formula 1 cyanocyclohexane in good yield and purity. More particularly, instant invention provides a process, which employs a novel method for preparation of the intermediate carboxamide in high yields.
BACK GROUND AND PRIOR ART:
Cyanocyclohexane is an important intermediate for synthesis of pharmaceutically relevant molecules. It has been employed as a reagent for the synthesis of Pyridines (Advanced Synthesis & Catalysis, 350(10), 1449-1456; 2008), Imidazoles (Synlert. (I), 63-66; 2009), Pyrazines (Tetrahedron Letters, 50(7), 767-769; 2009), modified strecker synthesis (Tetrahedron Letters, 50(16), 1844-1846; 2009), Benzotriazepinone derivatives (PTHrp receptor Ugands) (PCT Int. Appl., 2007135417, 29 Nov 2007), Quinolines (Angewandte Chemie, International Edition. 47(20), 3805-3810; 2008), Quinazolines (Synthesis, (5), 823-827; 2008), Gabapentin (PCT Int. Appl., 2008004115, 10 Jan 2008) Platinum complexes (U.S. Pat. Appl. Publ., 2007173485, 26 Jul 2007), Spirocycles (Chemistry--A European Journal, 13(13), 3606-3616; 2007), Norstatines (European Journal of Organic Chemistry, (20), 4585-4595; 2006), Carbamines (Journal of the American Chemical Society, 128(27), 8712-8713; 2006), Oxadiazoles (Heterocycles, 60(10), 2287-2292; 2003),Carbopalladation reactions (Journal of Organic Chemistry, 67(26), 9428-9438; 2002) etc.
US 4786638 describes a process for the synthesis of compound of cyano cyclohexane by reacting cyclohexane carboxylic acid with chlorosulfonyl isocyanate in the presence of dimethylformamide.
The conversion of cyclohexanecarboxylic acid, to its acid chloride has been exemplified (Organic syntheses, coll. Vol. 4, p.339 (1963); vol.39, p. 19 (1959). But the process employs toxic solvents such as benzene. A novel process has been found for the preparation of the cyclohexanecarboxylicacid chloride. This process avoids employment

of toxic solvents such as benzene and resorts to distillation of the excess halogenating
agent.
An efficient one-pot synthesis of nitriles from acid chlorides has been described
(Tetrahedron Letters, 23 (14), 1505 - 1508; 1982). It involves reaction of the acid chloride
with the sulfamide. The compound of cyclohexane carboxylic acid has been converted
into carboxamide in the presence of metal oxides is described in Bulletin of the chemical
society of Japan, 62 (4), 1333-1334, 1989.
The conversion of the carboxamide to cyanocyclohexane has been exemplified by several examples. TPPBr2 (Letters in Organic chemistry, 4(5), 319-321; 2007) has been employed to obtain cyanocyclohexane in 63 % yield. Similarly, several other reagents such as Oxalyl chloride and DMF (Swern oxidation) (Tetrahedron letters, 38 (12), 2099-2102, 1997, Triethyl amine and trifluoroacetic acid in the presence of an ionic liquid (Jpn, Kokai Tokkyo Koho, 11092438) Urea derivatives and Ruthenium catalysts (Journal of molecular catalysis, 58 (1), 87-94; 1990), are described. Mostly the above methods involve extractive work up with organic solvents and involve expensive reagents.
The prior art method as discussed above use inherently toxic organic solvents and expensive reagents that coerces an extractive work-up. Further, the yield of cyanocyclohexane in prior art processes is 60-70%.
Therefore, there is still a need in the art to develop effective and efficient method for preparation of cyano cyclohexane, a voluble compound for the preparation of many pharmaceutical molecules.
Thus the object of the invention is to provide an efficient, industrially viable and eco-friendly process for the preparation of cyanocyclohexane in high yield and purity, by employing a eutectic mixture (NaCl + H20) along with Aq. NH3 to obtain the caboxamide intermediate ( Formula 2) in high yields and purity. Further, the current invention has totally avoided the use of toxic solvents such as benzene and expensive reagents by employing a novel work up method.

SUMMARY OF THE INVENTION
In accordance with the above objectives, the present invention provides a novel process for the preparation of Cyanocyclohexane, compound of formula 1, which comprises

reacting cyclohexanecarboxylic acid chloride(formula 3) with aq. ammonia in presence of eutectic mixture (NaCl + H2O) to give cyclohexanecarboxamide (4) and subsequent dehydration followed by quenching with an inorganic base. The inorganic base is selected from source of ammonia or sodium bicarbonate solution.
The process of the present invention provides a unique method for improving the yields of the cyclohexanecarboxamide, compound of formula 3, by employing a eutectic mixture (NaCl + H2O) in the aq. Ammonia solution. The invention further provides a purification process for cyclohexanecarboxamide.

The process also provides for a unique work up method for isolation of cyanocyclohexane, compound of formula 1, by employing an inorganic base.
In a preferred aspect, the process of the preparation of the compound of formula 1, comprises treating compound of formula 2 with a source of halide to yield cyclohexanecarboxylicacid chloride the compound of formula 3. The acid chloride is subjected to ammonolysis followed by dehydration.
Thus, cyclohexanecarboxylic acid chloride is obtained by treating cyclohexane carboxylic acid with a source of halide/halogenating agent. The halogenating agent may be selected from thionyl chloride, phosphorous pentachloride, apple reagent etc.

More particularly the process of the present invention for the preparation of Cyanocyclohexane encompasses
a) reacting cyclohexanecarboxylic acid , compound of the formula 2, with thionyl chloride to obtain a compound of formula 3.
b) treating the compound of formula 3 with aq. NH3 in the presence of a salt to yield compound of formula 4.
c) reacting the cyclohexane carboxamide, compound of formula 4, with a dehydrating agent to yield compound of formula 1.

The present invention also provides substantially pure Cyclohexanecarboxamide, compound of formula 4, and the process of its preparation comprising treating compound of formula 3 with aq. NH3 in the presence of an inorganic salt.
In a further embodiment, cyclohexane carboxamide is dehydrated using thionyl chloride to obtain cyanocyclohexane. The reaction mixture comprising cyanocyclohexane thus obtained is quenched with an inorganic base to avoid solvent extraction work up. The product, cyanocyclohexane is recovered from organic phase by vaccumm distillation to obtain a purity of more than 99%.
The novel process of the present invention has been found to be advantageous in that the reactions involved do not involve extractive work up with organic solvents and the by products obtained in the process are water soluble inorganic salts and thus the desired product, viz. Cyanocyclohexane (formula 1) can be obtained in high yields in a substantially pure form.
As referred to herein 'substantially pure cyanocyclohexane' is cyanocyclohexane of purity greater than 99 %.

Preferably substantially pure cyanocyclohexane (formula 1) has a purity greater than 99.5 % and has no individual impurity that is more than 0.2% by HPLC.
As referred to herein 'substantially pure cyclohexanecarboxamide' is cyclohexanecarboxamide of purity greater than 99.5 % and no individual impurity is greater than 0.2 % by HPLC.
The beauty of the present invention lies in the employment of a novel eutectic combination (NaCl + H2O) for the preparation of the intermediate (formula 4) and further involves a novel work up in isolation of formula 1 by employing an inorganic base to quench the hydrochloric acid that liberated during the dehydration of carboxamide thereby avoiding the solvent extraction work up. The novel process converts the starting material to the intended product in an efficient manner such that toxic solvents are avoided and extractive organic solvent work up is avoided and water soluble inorganic salts are obtained as the byproduct.
DETAILED DESCRIPTION OF THE INVENTION:
The invention will now be described in detail, along with certain preferred and optional embodiments so that various aspects thereof may be more fully understood and appreciated.
Accordingly, the present invention provides an advantageous process whereby, the process of preparation of cyanocyclohexane is performed in aqueous medium thus, eliminating use of toxic solvents. A novel method of preparation was conceived and developed by the current inventors to obtain substantially pure cyanocyclohexane (compound of formula 1).
In a preferred embodiment, the process of the present invention adopts a novel methodology to prepare cyclohexanecarboxamide which comprises reacting Cyclohexane carboxylic acid (compound of formula 2) with halogenating agents such as thionyl chloride etc to obtain the compound of formula 3 followed by its ammonolysis by

employing aq. NH3 in combination with an inorganic salt such as NaCI etc to obtain formula 4.
The present invention further discloses a method for the purification of the cyclohexane carboxamide (formula 4) thus obtained by employing a protic solvent to yield substantially pure product.
As referred to here in substantially pure Cyclohexanecarboxamide , compound of formula 3, is cyclohexanecarboxamide with purity greater than 99 %.
Accordingly, cyanocyclohexane is prepared by a process comprising the following steps:
a) reacting cyclohexanecarboxylic acid (formula 2) with chlorinating agent to obtain
cyclohexanecarboxylic acid chloride (formula 3);
b) treating cyclohexanecarboxylic acid chloride with aq. NH3 at 0-5°C in the
presence of an inorganic salt to yield cyclohexane carboxamide (formula 4), and;
c) dehydrating cyclohexane carboxamide (formula 4) followed by quenching the
reaction mass with an inorganic base to yield substantially pure cyanocyclohexane
(formula 1).

The stepwise preparation of cyanocyclohexane according to the current invention is described herein below:
Preparation of cyclohexanecarboxylicacid chloride:
The acid chloride was prepared according to a process known in the literature (Organic syntheses, coll. Vol. 4, p.339 (1963); vol.39, p.19 (1959) with several modifications. According to the process of the present invention, the acid chloride is prepared by refluxing a solution of the acid in the chlorinating agent. The chlorinating agent can be

selected from thiony1 choride, PC15, apple reagent etc (triphenyl phophine in carbon tetrachloride). The chlorination reaction is conducted at a temperature range of 80-120° C, preferably 80-100° C.
The reaction mixture is subjected to distillation either at atmospheric pressure or at lower pressures to remove the excess chlorinating agent.
Preparation of cyclohexanecarboxamide
The acid chloride is subjected to ammonolysis by employing Aq. NH3 solution in the
presence of an inorganic salt to yield carboxamide. The salt for the reaction is selected
from a group of sodium, ammoinium compounds. The salts may be selected from
chlorides, sulphates etc.
The inorganic salt may be either a chloride or sulphate which is highly soluble. Preferably
the inorganic salt could be sodium chloride, Ammonium chloride etc.
The amide thus obtained may be purified by a protic solvent. The solvent can be selected
from C1-C6 alcohols like methanol, JPA, Ethanol and their combinations with water.
Preparation of cyclohexanecarbonitrile:
The Cyclohexanecarboxamide was dehydrated by employing a dehydrating agent. Dehydrating agent can be selected from phosphorous pentaoxide, vanadium pentoxide, thiony 1 chloride etc. The dehydrating agent preferably used is thiony 1 chloride wherein the stoichiometry of thionyl chloride varies from 1.5-2,2. The dehydration is carried out at a temperature range of 65-95° C.
Each mole of amide leads to generation of two moles of HC1 as such the reaction mixture is rendered acidic during the dehydration process. The acidic reaction mixture was quenched by employing an inorganic base selected from source of ammonia or sodium bicarbonate solution leading to the formation of the water soluble ammonium or sodium salt and the product was isolated in pure form directly by vacuum distillation of the organic phase. The source of ammonia is selected from liquor ammonia, liquid ammonia and ammonia gas.
Further details of the process of the present invention will be apparent from the examples presented below. The examples presented are purely illustrative and are not limited to the

particular embodiments illustrated herein but include the permutations, which are obvious as set forth in the description.
EXAMPLES
Example 1:
Preparation of cyclohexanecarboxylic acid chloride
DMF (4.0 ml) was charged into the solution of cyclohexanecarboxylic acid (200.0 grams) in thionyl chloride (278.90 grams). The reaction mixture was stirred for 15.0 minutes and allowed to reflux at a temperature of 120 - 125 °C for 2 hours. The excess thionyl chloride was distilled off and the reaction mixture was allowed to cool to room temperature. The product was obtained in quantitative yields. Yield: 99 %
Example 2
Preparation of cyclohexanecarboxamide
100.0 grams of sodium chloride was charged into 400 ml aq. NH3 solution (22 % solution). The ammonia gas (138.0 grams) was purged into the above solution at a temperature of 0 - 5 °C. 225.0 grams of the acid chloride (example.1) was added into the solution at a temperature of 0 - 5 °C. The reaction mixture was allowed to warm to room temperature followed by addition of 200.0 ml water. The solid obtained was filtered and washed with 600.0 ml of water. The product was finally dried in the oven at 80 - 85 °C for 10 - 12 hours to yield cyclohexanecarboxamide, 185.0 grams (> 95 % purity).
Example 3
Purification of cyclohexanecarboxamide:
The crude amide (180.0 grams) was dissolved into 720.0 ml of IPA and stirred for 20.0 minutes. The reaction mixture was refluxed at 80 - 85 °C for 2 hours. Then it was allowed to cool to room temperature. The reaction mixture was further cooled to 0-5 °C and maintained at that temperature for 1 hour. The solid obtained was filtered and washed with 100 ml chilled IPA. The product was finally dried in the oven at 80 - 85 °C for 5 hours to yield cyclohexanecarboxamide (148.5 grams).

Purity: 99.8 %
Example 4
Preparation of cyanocyclohexane
The solution of the amide (146.0 grams) (example 3) in thionyl chloride (178.82 ml) was stirred for 15.0 minutes. The reaction mixture was then refluxed at a temperature of 95 -100 °C for 2 hours. The reaction mixture was then coo'ed to room temperature followed by slow addition of 240.0 ml aq. NH3 (22 % solution) and maintained at 0 - 5 °C. The organic layer was then separated and subjected to vacuum distillation (90 mm, bp = 117 — 119 °C) to yield cyanocyclohexane (101 grams)(purity > 99 %)

We claim,
1. A novel process for the production of Cyanocyclohexane (formula 1) comprising

a) reacting cyclohexanecarboxylicacid chloride (formula 3) with aq. NH3 in the presence of an eutectic mixture (NaCl + H2O) to obtain the cyclohexanecarboxamide (Formula 4);
b) treating cyclohexanecarboxamide with a dehydrating agent to obtain cyanocyclcohexane (formula 1); and
c) isolating pure cyanocyclohexane by quenching the reaction mass obtained in step (b) with inorganic base.

2. The process as claimed in claim ], wherein the reaction is carried out in the presence of an inorganic salt.
3. The process as claimed in claim 2, wherein the inorganic salt is selected from chloride or sulphates of sodium or ammonia, more preferably sodium chloride.
4. The process as claimed in claim 1, wherein the molar equivalence of the acid chloride: sodium chloride is in the ratio of 1: 0.5.
5. The process as claimed in claim 1, wherein said process further comprising a step of purifying the cyclohexanecarboxamide (formula 3) by employing a protic solvent.
6. The process as claimed in claim 5, wherein the protic solvent employed is selected from C1-C6 alcohols like methanol, IPA, ethanol and their combinations with water, preferably, Isopropyl alcohol.

7. The process as claimed in claim 1, wherein cyclohexanecarboxamide (formula 4) is obtained in substantially pure form and has a purity greater than 99 % with no individual impurity greater than 0.2 % by HPLC.
8. The process as claimed in claim 1, wherein the inorganic base is selected from sodium bicarbonate or a source of ammonia.
9. The process as claimed in claim 1, wherein the source of ammonia is selected from liquor ammonia, liquid ammonia and ammonia gas.
10. A process as claimed in claim 1 comprises:
a. reacting cyclohexanecarboxylic acid (formula 2) with thionyl chloride to
obtain a compound of formula 3;
b. treating a compound of formula 3 with aq. NH3 in the presence of a salt to
yield compound of formula 4, and;
c. reacting cyclohexane carboxamide (formula 4) with a dehydrating agent to
yield compound of formula 1.