WO2003080565A1

WO2003080565A1 - Process for the manufacture of substituted phenylacetonitriles

Info

Publication number: WO2003080565A1
Application number: PCT/IN2002/000132
Authority: WO
Inventors: Jagdish Chand Saigal; Rajender Pershad Gupta; Vinayak Shankar Gorule; Vilas Vasant Pandit; Rajesh Dilip Joshi
Original assignee: Global Bulk Drugs & Fine Chemicals Pvt. Ltd.
Priority date: 2002-03-26
Filing date: 2002-06-13
Publication date: 2003-10-02

Abstract

A process of preparation of phenyl methyl compound of general formula (IA) comprising condensation of phenyl acetonitrile or its derivatives of formula (III) and cycloalkanone (IV) in the presence of a phase transfer catalyst (PTC) and a water soluble base: (III), (IV), (IA), where, either of R5 and R6 independently could be in para position and R5, R6 are independently hydrogen, hydroxyl, alkyl, alkoxy, alkanoyloxy, cyano, nitro, alkylmercapto, amino, alkylamino, dialkylamino alkanamido, halo, trifluoromethyl, or taken together methylenedioxy, R7 is hydrogen or alkyl group of 1 to 7 carbon atom. Compounds of formulae II, V and VI are respectively derivatives of compounds IA, III and IV: (II), (V), (VI).

Description

PROCESS FOR THE MANUFACTURE OF SUBSTITUTED PHENYLACETONITRILES.

The invention relates to an improved process for the manufacture of phenyl methyl compound and its derivative of a general formula I. More particularly the invention relates to an improved process for the manufacture of l-[cyano-(p-methoxyphenyl)methyl]cyclohexanol of formula (II).

Formula I Formula II

In formula I either of R5 and R6 independently could be in para position and R5,R6 are independently hydrogen, hydroxyl, alkyl, alkoxy, alkanoyloxy, cyano, nitro, alkylmercapto, amino, alkylamino, dialkylamino alkanamido, halo, trifluoromethyl, or taken together methylenedioxy n is 0,1,2,3 or 4.

In the compound of formula I, when R5 or R6 is in para position and either one of them is -OCH3 and the other is H; R4 and R7 is hydrogen; the dotted line representing optional unsaturation is removed ; and n =2 the compound has the formula II which is known as 1-cyano- (p_methoxyphenyl)methyl]cyclohexanol.

When R5 or R6 in formula I is independently in para position and when R4 is H and there is an optional unsaturation the compound is of formula IA

Formula IA The compounds of general formula I, I A and in particular the compound of formula II are intermediates for the synthesis of corresponding phenyl ethyl amine and their derivatives which are potential antidepressants.

PRIOR ART

US Pat.4,535,186 and its corresponding EP 0112669 A2 teaches the art of preparation of the compound of formula IA which is produced by the reaction of cycloalkanone of formula IN with an appropriately substituted (ortho or para) phenyl acetonitrile of formula III. The reaction disclosed in the said literature is depicted as under:

Formula III Formula IV formula IA

The said reaction is usually carried out in presence of bases e.g. n-butyl lithium under inert atmosphere in the presence of solvent like anhydrous tetrahydrofiιran(THF) in the temperature range of-60 to -75°C.

The compound of formula II is described in said US Patent 4,535,186 and its corresponding EP 0112669 A2, as well as J. Med. Chemistry 1990,.33.2889-2905.

Formula VI Formula II WO 00/32556 and WO 00/59851 also teaches the preparation of the compound of formula II in which the same synthesis as in US 4,535,186 is carried out with lithium di isopropyl amide in presence of anhydrous THF and an inert atmosphere .The temperature of the reaction is usually 70°C.

Yet another method disclosed by Cheng et al [CA 113: 17266] the compound of formula II is obtained by a reaction which is carried out in solvent phase using bases like NaOCH₃, NaOEt, NaNH₂, NaH, n-butyl lithium and Li diisopropyl amide. The bases may be used singly or in combination.

The prior art processes disclosed in the aforesaid literature suffers from one or more of the following disadvantages:

1. Costly bases are used which is prone to fire hazard as well. 2. Hazardous as well costly solvent like THF has been utilized which needs special precaution to handle.

3. The system needs an inert atmosphere.

4. All the above mentioned processes need specialized and costly equipment for safe and efficient handling of hazardous chemicals used therein.

It is found that the yield of the compound of formula I obtained by the aforesaid processes is in the range of 82% at - 78°C and decreases to almost zero at around -5°C. When the condensation of compound of formula (V) and compound of formula (VI) was carried out using n-butyl lithium in THF at - 78°c as per the reported procedure yield is 80% by wt. A reaction with sodamide as a base at -78 °C in THF gave the required product (II) in 62% yield Keeping Sodamide as a base, the rise in temperature from -78 c to -5°C, decreased the yield to 30%

OBJECTS OF THE INVENTION

The object of the present invention is to provide a process for synthesis of phenyl methyl compound of formula IA and derivatives thereof by the use of phase transfer catalyst.

It is another object of the present invention to provide a process for the manufacture of l-[cyano- (p-methoxyphenyl)methyl]cyclohexanol of formula II by use of a phase transfer catalyst. It is a further object of the present invention to manufacture the said compound in a safer and cost effective manner.

It is yet another object of the present invention on carry out the process of manufacture of the said compound at normal temperature

SUMMARY OF THE INVENTIOIN :

Thus the present invention relates to a process of preparation of phenyl methyl compounds of general formula IA comprising condensation of meta or para methoxy phenyl acetonitrile or its derivatives of formula III and cyclo alkanone of formula IV in the presence of a phase transfer catalyst and a water soluble base.

R

Formula III Formula IV Formula IA where, either of R5 and R6 independently could be in para position and R5,R6 are independently hydrogen, hydroxyl, alkyl, alkoxy, alkanoyloxy, cyano, nitro, alkylmercapto, amino, alkylamino, dialkylamino alkanamido, halo, trifluoromethyl, or taken together methylenedioxy, R7 is hydrogen or alkyl group of 1 to 7 carbon atom.

According to a preferred aspect of the invention there is provided a process for the preparation of l-[cyano-(p-methoxyphenyl)methyl]cyclohexanol of formula II comprising condensation of para methoxy phenyl acetonitrile or its derivatives of formula (V) and cyclohexanone of formula(VI) in the presence of a phase transfer catalyst and a water soluble base,

Formula V Formula VI Formula II

The aforesaid reactions are carried out at a temperature of between 10 to 30 °C. The compound of formula II obtained by the above process is purified to get the compound of formula II in high yield of above 90%

DETAILED DESCRIPTION OF THE INVENTION

According to one embodiment of the present invention the compounds of formula V andVI are solublised in aqueous phase by the use of a phase transfer catalyst so that the reaction can be carried out in that homogeneous phase. The mole ratio of cycloalkanone to phenyl acetonitriles is maintained at 1 to 2 and most preferably at 1.3 to 1.40.

The phase transfer catalyst used in the process is selected from TBAB (tetrabutyl ammonium bromide), TEBAB (tetraethyl benzyl ammonium bromide), or Cetrimide(cetyl trimethyl ammonium bromide). The use of phase transfer catalyst is not however limited to the compounds mentioned above and other phase transfer catalysts may be used. The phase transfer catalyst in the mole equivalent range of 0.005-0.0025 with respect to phenyl acetonitriles is used. In particular the catalyst TBAB is used in the range of 0.001 -0.002 mole equivalent with respect to phenyl acetonitriles. The phase transfer catalyst may be used either singly or in combination.

The use of water-soluble base is limited to metal hydroxide and aqueous ammonia. In particular monovalent metal hydroxides are preferred. . More preferred metal hydroxides are sodium or potassium hydroxide, most preferred hydroxide is however sodium hydroxide. The water-soluble base is used in the range of 10- 15 wt% of the aqueous phase. Preferably, water soluble base is used in an amount of about 10 % by wt. The said metal hydroxide is used in the range of 0.4 to 1.4 molar equivalent with respect to the phenyl aceto nitriles.The most favoured molar equivalent is between 0.46- 1.0. The most preferred reaction temperature is between 15-20 °C. The condensation of p-methoxy phenyl acetonitrile with cyclohexanone using phase transfer catalyst has been found to increase the yield % of the product. Three different catalyst e.g, Tetra ethyl benzyl ammonium bromide (TEBAB), Cetyl trimethyl ammonium bromide (Cetrimide) and Tetrabutyl ammonium bromide (TBAB) used in the system. In a system containing 50% aqueous sodium hydroxude and the two substrate p-methoxy phenyl acetonitrile and cyclohexanone very little yield of l-[cyano-(-p-methoxy phenyl)methyl]cyclohexanol was obtained with the use of phase transfer catalyst. The catalyst system of TBAB along with 10 % sodium hydroxide (0.46- 1.0 equivalent with respect to p-methoxy phenyl acetonitrile )gives high yield of the product.

The advantage of the process of the invention is that the condensing agent utilised is cheaper and is water-soluble. This is safer and easier to handle and does not need any specialised equipment. The above process of invention is described by the following non limiting example

EXAMPLE

Synthesis of l-[cyano-(- p-methoxy phenyl)methyl]cycIohexanol

In a reactor the following in the following order, reactants were charged

a) 300g. of 4-methoxy phenyl aceto nitrile and cooled to 15 °C

b) 815 ml. of 10% Sodium hydroxide solution in water was added

c) 1.3g of TBAB catalyst was added with vigorous stirring and using baffles as an obstruction .In the laboratory thermometer pocket can be used as an baffle.

d) The mixture was stirred vigorously for 30 minutes at 15 to 18 °C. This ensures formation of carbanion

e) Slowly 270 g. of cyclohexanone were added over a period of 30 minutes at 15 to 18 °C

f) The reaction mixture was stirred vigorously at 15 to 18 °C for 3 hrs. g) The solid separated was filtered out washed free of alkali suck dry and dried

h) The crude product was purified from a mixture of petroleum ether and ethyl acetate.(95:5).

Weight of the purified product obtained: 460g HPLC Purity was >95% Yield 92.5% Melting range 122- 124 °C Mass Spectra analysis Molecular weight 245[M+l]+ by CIMS NMR Analysis

δ 7.32, 6.95 (4H, quartet, p-substituted aromatic); 3.8 (3H, singlet, O-CH₃); 3.76 (1H, singlet, CH-CN); 1.56 (10H, multiplet, aliphatic cyclohexyl) ppm.

In table I there is shown the results of condensation reaction of cyano carbinol.

It is evident from the expt. Nos. 9-13 that the right stoichiometry of cyclohexanone to p-methoxy phenyl acetonitrile should be 1.35 expressed as mole. Base concentration of 10% by wt. and 1 molar equivalent with respect to p-methoxy aceto nitrile is preferred. 2 mole % of TBAB (with respect to p-methoxy aceto nitrile) are sufficient for highest conversion of the reaction. Beyond the stoichiometric ratio of 1.40 of the reactants p-methoxy phenyl acetonitrile and cyclohexanone the yield falls. .It is also evident from expt.no.15 that mole ratio of cyclohexanone to p-methoxy phenyl acetonitrile can be reduced to as low as 1.10 and TBAB at a level of .001 mole equivalent with respect to p-methoxy phenyl acetonitrile can be utilised so as to achieve a yield of l-[cyano- (-p-methoxy phenyl)methyl]cyclohexanol at 92% level at 27 °C. Expt No.14 shows that ratio of cyclohexanone to p-methoxy aceto nitrile can be as high as 1.40 at 27 ° C and 1 eq of 10 % sodium hydroxide used to achieve a 92 % yield .This may however lead to inefficient use of the reactant. Expt 18 shows that at 15°C a 92% conversion is achieved in 3 hours using a 1.35 mole ratio of cyclohexanone to p-methoxy aceto nitrile. Expt 12 carried on at 27 °C takes 8 hrs for 90 % conversion . But time of reaction decreases drastically as the reaction is carried at a low temperature of 15 °C. It is evident from expt no 6-8 that the yield of the product l-[cyano-(-p- methoxy phenyl)methyl]cyclohexanol is very poor using high concentration of alkali using all the three phase transfer catalyst.

Thus it is evident that low temperature of 15°C, a mole ratio of 1.35 of cyclohexanone to p- methoxy aceto nitrile and a catalyst concentration of .002 equivalent with respect to compound p- methoxy aceto nitrile is required to achieve a highest yield of the cyano compound

It is further evident from the result that solublising the two reactants namely p -methoxy phenyl aceto nitrile and cyclohexanone in aqueous phase provides a cheaper and safer process and does not need any specialised equipment to carry on the reaction.

Table 1 : Results of Condensation Reaction for cyano carbinol

Claims

CLAIM:

1. A process of preparation of phenyl methyl compound of general formula (IA)

comprising condensation of phenyl acetonitrile or its derivatives of formula (III) and cycloalkanone (IV) in the presence of a phase transfer catalyst(PTC) and a water soluble base

Formula III Formula IV Formula IA

where, either of R5 and R6 independently could be in para position and R5,R6 are independently hydrogen, hydroxyl, alkyl, alkoxy, alkanoyloxy, cyano, nitro, alkylmercapto, amino, alkylamino, dialkylamino alkanamido, halo, trifluoromethyl, or taken together methylenedioxy, R7 is hydrogen or alkyl group of 1 to 7 carbon atom.

2. A process according to claim 1, wherein in formula I A when either of R5 and R6 is in para position and either one of them is OCH3 and the other is H ; R4 and R7 is hydrogen ; n is2; and the optional unsaturation is removed the compound is l-[cyano-(p- methoxyphenyl)methyl]cyclohexanol of formula II.

Formula II

3. A process as claimed in claim 1, wherein in formula III when either R5 or R6 is in para position and either one of them is -OCH3 and the other is H ; and R7 is hydrogen the compound is a compound of formula V which is p-methoxy aceto nitrile.

Formula V

4. A process as claimed in claiml, wherein in the compound of Formula IV when n = 2 the compound is a compound of formula VI which is cyclohexanone.

Formula VI

5. A process according to any one of claims 1 to 4, wherein l-[cyano-(-p-methoxy phenyl)methyl]cyclohexanol of formula (II) is produced by condensation of p-methoxy phenyl acetonitrile of formula V with cyclohexanone of formula VI in the presence of a phase transfer catalyst and water soluble base.

Formula V Formula VI Formula II

6. A process according to any one of claims 1 to 5, wherein the reaction is carried out at a temperature of between 10 to 30°C.

7. A process according to claim 6, wherein the reaction is carried out at a temperature of between 15-20°C.

8. A process according to any one of the preceding claims, wherein the phase transfer catalyst is selected from TBAB, TEBAB or Cetrimide.

9. A process according to claim 8, wherein the phase transfers catalyst is TBAB.

10. A process according to any preceding claim wherein 0.0005-0.0025 equivalent of the phase transfer catalyst with respect to compound of formula III is used.

11. A process according to claim 10 wherein 0.001-0.002 equivalent of the phase transfer catalyst with respect to compound of formula III is used.

12. A process according to any preceding claim wherein the water-soluble base is selected from monovalent metal hydroxides or ammonia.

13. A process according to claim 12, wherein the water-soluble base is sodium hydroxide or potassium hydroxide.

14. A process according to claim 12 or 13 wherein sodium hydroxide is added in an amount of 10 - 15 % by wt. of aqueous phase.

15. A process according to claim 14, wherein sodium hydroxide base is added in an amount of 0.4 -1.4 mole equivalent with respect to p-methoxy aceto nitrile.

16. A process according to claim 15, wherein the sodium hydroxide base is added in an amount of 0.46 -1.0 equivalent with respect to p-methoxy aceto nitrile.

17. A process according to any of claim 5 to 16, wherein the cylohexanone and p-methoxy aceto nitrile are reacted in the molar ratio of between 1-2.

18. The process according to claim 17, wherein the cylohexanone and p-methoxy aceto nitrile are reacted in the molar ratio of between 1.35 -1.40