WO2005111010A1

WO2005111010A1 - An improved process for the preparation of 5-cyanophthalide

Info

Publication number: WO2005111010A1
Application number: PCT/IN2004/000132
Authority: WO
Inventors: Arava Arava Veera Reddy; Rajendiran Chinnapillai Rajendiran; Inderasena Indrasena Reddy; Venkat Venakt Jasti
Original assignee: Suven Life Sciences Ltd,
Priority date: 2004-05-13
Filing date: 2004-05-13
Publication date: 2005-11-24

Abstract

The invention disclosed an improved process for the preparation of 5-cyanophthalide which comprises reacting 5-carboxyphthalide with ammonium carbonate in the presence of ethyl polyphospate with or without a solvent and isolating the 5-cyanophthalide formed by conventional methods .

Description

AN IMPROVED PROCESS FOR THE PREPARATION OF 5 -CYANOPTHALIDE

INTRODUCTION

The invention relates to an improved process for the preparation of 5-cyanophthalide. The 5-cyanophthalide prepared by the process of the present invention having the formula 1 given below is a key intermediate for the manufacture of the well-known antidepressant drug Citalopram of the formula 2 .

The 5-cyanophthalιde of the formula (1) has previously been prepared by a variety of synthetic pathways. In several of this synthetic pathway, except in the process reported in Bull.Soc. Sci. Bretagne (1951), 26, 35., and J. Chem. Soc, (1931), 867, Where the process is described using the 5-amιnophthalιde of the formula (4) as starting material as given in the scheme-1 below.

1 DIAZOTIZATION 2 COPPER CYANIDE

Scheme-1 The 5-carboxyphthalide of the formula (3) is an intermediate for all the other processes. The process described in the WO 00/39112 for the preparation of 5- cyanophthalide of the formula (1) using the intermediate of the formula (3) in three steps as given in the scheme-2.

Scheme-2

Yet another method described in US patent no 6441201 for the preparation of 5- cyanophthalide of the formula (1) using the same intermediate of the formula (3) using sulfamide as a reagent and sulfolane as a solvent as shown scheme-3

SLPHONAMIDE/THIONYLCHLORIDE SULFOLANE

Scheme-3

US Pat No 2003/0013895 discloses the method for the preparation of 5- cyanophthalide of the formula (1) starting from the compound of the formula (3) by preparing oxazoline or thiazoline derivatives of the formula (6) followed by dehydration to get the 5-Cyanophthalide as described in the scheme-4

Scheme-4

Another patent EP1321464 discloses the method of converting the derivatives of 5-carboxyphthalide of the formula (7) with an alkylchloroformate so to obtain mixed anhydride 8, the latter being reacted with an alkyldisilazine so to obtain an amide derivative of the formula (9) and latter being dehydrated to get the 5- cyanophthalide of the formula (1) as described in scheme-5.

M = N a , K , N H 4 Scheme-5

All the above described methods uses the corrosive and environmentally hazardous chemical reagents like thionylchloride, phosphorous chloride, trmethylsilylchloride etc., for the reaction and most of the process carried out in two to three steps to get the pure final product of the formula 1. Hence there is continuous urge to develop a safe, economical and environment friendly process for the key and important intermediate 5-cyanophthalιde of the formula (1)

Accordingly the main objective of the present invention is to provide an improved process for the preparation of 5-cyanophthalιde of the formula (1) without employing corrosive and environmentally hazardous chemical reagents like thionylchloride, phosphorous chloride, trmethylsilylchloπde and the like.

Another objective of the present invention is to provide an improved process for the preparation of 5-cyanophthalιde of the formula (1) which is environmentally friendly.

Still another objective of the present invention is to provide an improved process for the preparation of 5-cyanophthalιde of the formula (1) which is economical and can be employed industrially.

Yet another objective of the present invention is to provide an improved process for the preparation of 5-cyanophthalιde of the formula (1) which is simple using one pot reaction.

Still another objective of the present invention is to provide an improved process for the preparation of 5-cyanophthalιde of the formula (1) in high yield of 89- 95% as compared to 56-83% overall yield in the prior art processes.

It is our surprising findings that in the ethylpolyphosphate medium the only reagent which gives the product namely 5-cyanophthalιde of the formula (1) is ammonium carbonate . we tried ammonium chloride, ammonium suphate , ammonium formate, ammonium oxalate, ammonium dihydrogenphosphate but none of them reacts and produces the product( namely 5-cyanophthalide) . only ammonium carbonate reacts with the compound of the formula 3 to give 5- cyanophthalide of the formula (1)

The reaction of the process of the present invention is shown in the scheme-6

AMMONIUM CARBONATE

ETHYLPOLY PHOSPHATE

Scheme-6

This is the first time that ammonium carbonate has been used for converting the carboxylic acid group to carbonitrile with ethyl polyphosphate as dehydrating agent though there was a journal literature appeared in Synthesis 142,(1983) using ethylpolyphosphate and ammonia to convert the carboxylic acid to carbonitrile for different compounds. It is significant that this is the first time that ammonium carbonate in the presence of ethylpolyphosphate results in the conversion of a carboxylic acid into the corresponding carbonitrile.

Accordingly the present invention provides an improved process for the preparation of 5-cyanophthalide of the formula (1)

which comprises reacting 5-carboxyphthalide of the formula (3)

with ammonium carbonate in the presence of ethyl polyphospate with or without a solvent and isolating the 5-cyanophthalιde formed by conventional methods.

The reaction is carried out as one pot reaction without isolating any intermediates with simple workup procedure by conventional methods. For example the 5- cyanophthahde formed may be isolated by adding water and filtering the product. Further purification could be done if required by crystallisation.

The solvents which can be used for recrystalisation may be selected from Toluene, Methanol, Acetonitπle, Ethylacetate, Dimethylformamide and Dimethylsulphoxide preferably methanol and acetonitile and most preferably in Acetonitπle.

The reaction can be carried out neat or in a suitable solvents such as methylene dichloπde, chloroform, ethylene dichloπde, ether and acetonitπle. Preferably with chloroform and most preferably with acetonitπle.

The reaction temperature could be between 25-150° C and suitably between 25 to 35° and 75-85° C.

For the reaction the ethyl polyphosphate is used 5-15 times of w/w on 5- carboxyphthalide preferably 9-10 times to get the optimum yield. The ammonium carbonate can be used in the mole ratio of 2-5 equivalent and preferably between 2 to 3 equivalent to complete the reaction.

Further the process of the present invention is most advantageous to the fact that it is one- step reaction and the work up procedure is very simple . Besides the usage of cheap raw materials make the process economical . Due to the above facts the productivity could increase to many fold in lesser cycle time thereby decrease the overall cost substantially.

The compound of the formula (3) can be prepared by using methods known in the literature viz. ,J. Chem. Soc. 4731, 26 (1961) and US Pat. No 3,607,884 . The ethyl polyphosphate can also be prepared using the known literature method J.Org.Chem, 2665, 34, (1964).

The details of the invention are given in Examples given below which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention. EXAMPLE-1 In a clean 2L three necked round bottomed flask are placed 5-carboxyphthalιde lOOg (0.56 M), ethyl polyphosphate 500g and acetonitnle 500ml. The reaction mixture thus obtained is cooled to 3-0° C and charged ammonium carbonate 176.2g (1.12 ) over the period of three hours keeping the temperature below 3-0° C. After the addition of ammonium carbonate is over the reaction mixture is stirred for three hours while allowing the temperature to raise to 20-25° C . Then the temperature is raised with simultaneous distillation of acetonitnle till the temperature reaches to 90-95° .Maintain the reaction mass at 90-95° C for 12 hours and diluted with deminarahsed water 1000ml and stir for 30 minutes. Filter the solid and wash thoroughly with water and dried to get 85gm (95.1%) of the product 5-cyanophthalιde with GC purity 99.158%. This is purified using acetonitnle as a solvent to get the product of purity by GC 99.59%.

The product is confirmed by reported spectral data and also it is idenditical in all respect with that of 5-cyanophthalιde obtained from the reported route. MR 203-204°C

IR (KBr) : 3495 cm^-1 (lactonic ring), 3113 (cm^"1), 3094 (cm^"1), (aromatic), 2232 (cm^"1), (nitrile), 1759 (cm^"1), ( carbonyl).

*HNMR (DMSO-d6, 400 MHz,): 5.46(s,2H), 8.02 (s, 2H), 8.21(s,lH), ¹³CNMR(DMSOd6-100MHz): 70.38(t), 116.56(s), 118.44(s), 126.41(d), 127.93(d), 129.37(s), 133.22(d), 148.14(s), 169.70 (s).

EXAMPLE-2

In a clean 2L three necked round bottomed flask are placed 5-carboxyphthalιde lOg (0.561 M), ethyl polyphosphate 50g and acetonitnle 100ml. The reaction mixture thus obtained is cooled to 3-0° C and charged ammonium carbonate

15.6g (0.112M) over the period of three hours keeping the temperature below 3-

0° C. After the addition of ammonium carbonate is over the reaction mixture is stirred for three hours while allowing the temperature to raise to 20-25° C. Then the temperature is raised with simultaneous distillation of acetonitnle till the temperature reaches to 90-95° ^c .Maintain the reaction mass at 90-95° C for 12 hours and diluted with deminarahsed water 1000ml and stir for 30 minutes. Filter the solid and wash thoroughly with water and dried to get 8gm (89.5%) of the product 5-cyanophthalιde with GC 98.2% purity .This is purified using acetonitnle as a solvent to get the product of purity by GC 99.2%. EXAMPLE-3

In a clean 2L three necked round bottomed flask are placed 5-carboxyphthalιde lOg (0.561 M), ethyl polyphosphate lOOg and acetonitnle 100ml. The reaction mixture thus obtained is cooled to 3-0°C and charged ammonium carbonatel7.6g (0.0805M) over the period of three hours keeping the temperature below 3-0° C. After the addition of ammonium carbonate is over the reaction mixture is stirred for three hours while allowing the temperature to raise to 20-25° C. Then the temperature is raised with simultaneous distillation of acetonitnle till the temperature reaches to 90-95° C .The reaction mass was maintained at 90-95° C for 12 hours and diluted with deminaralised water 1000ml and stir for 30 minutes. Filter the solid and wash thoroughly with water and dried to get 8.3gm (92.9%) of the product 5-cyanophthalιde with GC purity 98.9%. This is purified using acetonitnle as a solvent to get the product of purity by GC 99.3%.

• Advantages of the present invention l .The process is one- step reaction and the work up procedure is very simple . making the process economical 2.The usage of cheap raw materials such as ammonium carbonate and ethylpolyphosphate make the process economical . 3. The productivity of 5-cyanophthalide is enhanced considerably.

Claims

Claims l .An improved process for the preparation of 5-cyanophthalide of the formula (1)

which comprises reacting 5-carboxyphthalιde of the formula (3)

with ammonium carbonate in the presence of ethyl polyphospate with or without a solvent and isolating the 5-cyanophthalide formed by conventional methods .

2. An improved process as claimed in claim 1 where in the ammonium carbonate is used in an amount in the range of 2 to 3 equivalent with respect to the 5- carboxyphthalide used .

3. An improved process as claimed in claim 2 wherein the amount of dehydrating agent used is in the range of 5-15 times (w/w) to the 5- carboxyphthalide used .

4. An improved process as claimed in claim 1 wherein the solvent if used is selected from methylene dichloride, chloroform, ethylene dichlonde, ether and acetonitrile, preferably chloroform and most preferably acetonitnle.

5. An improved process as claimed in claim 4 wherein the reaction temperature used ranges between 25-150 degree C , preferably between 25° to 35° C and more preferably 75-85° C.

6. An improved process as claimed in claim 5 wherein the 5-cyanophthalιde formed is isolated by adding water and filtering the product and if desired further purified by recrystallisation.

7. An improved process as claimed in claim 6 wherein the 5-cyanophthalιde formed is recrystallised using solvents such as ethylacetate, methanol, hexane, toluene and acetonitnle and mixture thereof.