AU2006201612B2 - Method for the preparation of 5-cyanophthalide - Google Patents

Description

1 METHOD FOR THE PREPARATION OF S The present invention relates to a novel process for the preparation of cyanophthalide which is an intermediate used for the manufacture of the well known antidepressant drug citalopram, 1-[ 3 -(dimethylamino)propyl]-l-(4-fluorophenyl)-1,3- Background of the Invention.

Citalopram is a well known antidepressant drug that has now been on the market for 0 some years and has the following structure:

NC

SN

NCH,

F

Formula I It is a selective, centrally active serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor, accordingly having antidepressant activities. The antidepressant activity of the compound has been reported in several publications, eg. J. Hyttel, Prog. Neuro- Psychopharmacol. Biol. Psychiat., 1982, 6, 277-295 and A. Gravem, Acta Psychiatr. Scand., 1987, 75 ,478-486.

Citalopram is prepared by the process described in US Patent No 4,650,884, according to which 5-cyanophthalide is subjected to two successive Grignard reactions, i.e. with 4-fluorophenyl magnesium halogenide and N,N-dimethylaminopropyl magnesium halogenide, respectively, and the resulting compound of the formula N C WC OH I 3

N

CH

3

F

Formula II is subjected to a ring closure reaction by dehydration with strong sulfuric acid.

Enantiomers of citalopram may be prepared by the method described in US Patent No 4,943,590, i.e. by separating the enantiomers of the intermediate of Formula II and performing enantioselective ring closure in order to obtain the desired enantiomer.

Thus, 5-cyanophthalide is an important intermediate for the manufacture of citalopram and it is important to produce this material in an adequate quality, by a convenient process and in a cost-effective way.

A method for the preparation of 5-cyanophthalide has previously been described in Bull. Soc. Sci. Bretagne, 1951, 26, 35 and in Levy and Stephen, J. Chem. Soc., 1931, 867. By this method 5-aminophthalide is converted to the corresponding cyanophthalide by diazotation followed by reaction with CuCN. was obtained from 4-aminophthalimide by a two step reduction procedure.

Synthesis of certain alkyl- and phenylnitriles from acid chlorides is described in Tetrahedron Letters, 1982, 23, 14, 1505 1508, and in Tetrahedron, 1998, 54, 9281.

It has been found that 5-cyanophthalide may be prepared in high yields by a convenient, cost-effective procedure from the 2-(l-oxo-l,3-dihydroisobenzofuran-5yl)oxazoline or -thiazoline intermediates of Formula IV.

Description of the invention Accordingly, the present invention provides a novel method for the preparation of cyanophthalide comprising treatment of a compound of Formula IV R4 R3 R2

N

RI

X

Formula IV wherein X is O or S; R' R 2 are each independently selected from hydrogen and C-.

6 alkyl, or R' and R 2 together form a C 2 -5 alkylene chain thereby forming a spiro-ring; R 3 is selected from hydrogen and Ci-6 alkyl, R 4 is selected from hydrogen, C 1 alkyl, a carboxy group or a precursor group therefore, or R 3 and R 4 together form a C2-5 alkylene chain thereby forming a spiro-ring; with a dehydration agent or alternatively where X is S, thermally cleavage of the thiazoline ring or treatment with a radical initiator, such as peroxide or with light, to form 5-cyanophthalide having the formula

NC

Formula

III

The dehydration agent may be phosphoroxytrichloride, thionylchloride, phosphorpentachloride, PPA (polyphosphoric acid), and P 4 0 1 0 The reaction may be carried out in the presence of an organic base, such as pyridine or a catalytic amount of a tertiary amide.

Preferably, the compound of Formula IV is treated with SOC1 2 as a dehydrating agent and the reaction is carried out in toluene comprising a catalytic amount of N,Ndimethylformamide.

Alternatively, the dehydration agent may be a Vilsmeier reagent, i.e. a compound S which is formed by reaction of a chlorinating agent, preferably an acid chloride, e.g.

phosgene, oxalyl chloride, thionyl chloride, phosphoroxychloride, phosphorpentachloride, trichloromethyl chloroformate, also briefly referred to as "diphosgene", or bis(trichloromethyl) carbonate, also briefly referred to as "triphosgene", with a tertiary amide such as N,N-dimethylformamide or a N,N- 1 dialkylalkanamide, e.g N,N-dimethylacetamide. A classic Vilsmeyer reagent is the chloromethylenedimethyliminium chloride. The Vilsmeier reagent is preferably prepared in situ by adding the chlorinating agent to a mixture containing the starting \O 0 oxazoline or thiazoline derivative of formula IV and the tertiary amide.

When X is S and the conversion of the thiazoline group into the cyano group is made by thermal transformation, the thermal decomposition of compound IV is preferably carried out in an anhydrous organic solvent, more preferably an aprotic polar solvent, such as NN-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide or acetonitrile. The temperature at which the thermal decomposition transforms the 2thiazolyl group to a cyano group is between 60 °C and 140 The thermal decomposition may conveniently be carried out by reflux in a suitable solvent, preferably acetonitrile. The thermal cleavage may conveniently be carried out in the presence of oxygen or an oxidation agent. Compounds of Formula IV where X is S and R 4 is a carboxy group or a precursor for a carboxy group can also be converted to citalopram by treatment with a radical initiator such as light or peroxides.

Throughout the specification and the claims, Ci-6 alkyl refers to a branched or unbranched alkyl group having from one to six carbon atoms inclusive, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl, 2,2-dimethyl-lethyl and 2-methyl-1-propyl.

Accordingly, by the process of the invention, 5-cyanophthalide is obtained in high yields and the process is much more convenient than the known process. It is a socalled robust process. The usage of CuCN is eliminated thereby minimising the amount of undesirable by-products and making an environmentally compatible process.

In a further aspect, the invention relates to a method for preparing the intermediate of Formula IV comprising: a) reacting a functional derivative of 5-carboxyphthalide of Formula

V

SFormula V with a 2-hydroxy- or 2 -mercaptoethanamine of Formula

VI

Formula VI 0 in which X, R 1

R

4 are as defined above, submitting the amide of Formula VII thus obtained RI R2 M-Co R4 ~IO Formula

VII

in which X, R 1

R

4 are as defined above, to a ring closure by dehydration; thereby obtaining the 2-(1-oxo-l, 3 -dihydroisobenzofuran- 5 -yl)oxazoline or -thiazoline of Formula IV Formula IV ND Preferably, the functional derivative used in step a) is an ester, such as alkylester, O arylester or alkylarylester derivative of 5-carboxyphthalide, or an acidhalide derivative of Preferably, the dehydrating agent used in step b) is SOC12, POC13 and PC15, most preferably SOC12.

IND The reaction in step b) is carried out neat or in a suitable solvent, such as toluene, sulfolan or acetonitrile. Furthermore, when a solvent is used, a catalytic amount of N,N-dimethylformamide may be needed, in particular when the dehydrating agent is SOC12. Preferably, toluene is used as the solvent, if necessary in the presence of a catalytic amount of N,N-dimethylformamide.

The reaction in step b) is carried out at elevated temperature, preferably at the reflux temperature of the solvent.

The reaction time is not important and may easily be determined by a person skilled in the art.

The 5-carboxyphthalide used as a starting material may be obtained by the methods described in US patent No 3,607,884 or German patent No 2630927, i.e. by reacting a concentrated solution of terephthalic acid with formaldehyde in liquid SO 3 or by electrochemical hydrogenation of trimellithic acid.

In a preferred embodiment of the process of the invention, R 3 is methyl or ethyl.

may be isolated in a conventional way, e.g. by addition of water, filtration and subsequent washing of the crystals. Further purification may, if desired, be performed by recrystallisation.

Accordingly, by the process of the invention, 5-cyanophthalide is obtained by the novel use of the 2-(1-oxo-l,3-dihydroisobenzofuran-5-yl)oxazoline or -thiazoline intermediates of Formula IV as reactants. Using these reactants, process conditions IN are much more convenient than the conditions previously described in the known Sprocess for preparing 5-cyanophthalide, especially with the use of SOC12 as a dehydrating agent.

5 Examples The invention is further illustrated by the following examples.

Example 1 SPreparation of 2-[[(1-oxo-l, 3 -dihydroisobenzofuran-5-yl)carbonyl]amino]-2-methyll0 to 1-propanol.

C 5-carboxyphthalide (267g, 1.5mol) is added to thionyl chloride (950 mL) and then N,Ndimethylformamide (12 mL) is added dropwise. The mixture is heated at reflux for 1 hour and the thionyl chloride is destilled off under reduced pressure followed by successive evaporations with toluene (2 x 50 mL) to give a solid residue. The crude acid chloride is then taken up with 1000 mL of tetrahydrofuran. To a solution of 2-amino-2-methyl-lpropanol (400.5g, 4.5 mol) in tetrahydrofuran (500 mL) cooled to +5 0 C, the acid chloride solution is added dropwise whilst maintaining the temperature between +5->+10 0 C. After the addition is completed, the cooling is removed and the mixture is stirred overnight at ambient temperature. Then the mixture is poured into deionized water 0 (2000 mL) and the organic solvent is removed under reduced pressure at 50 OC. After cooling and stirring for 2 hours, the solid product is filtered off and washed with deionized water (2 x 100 mL). The obtained product is dried at 70 °C for 36 hours under reduced pressure. Yield: 285.3g of an off-white product having a purity (HPLC, peak area) 90%. 'H NMR (DMSO d-6, 500 MHz): 1.18 1.32 3.55 5.45 7.88 7.98 8.07 (1H,s).

Example 2 Preparation of 4,4-dimethyl-2-(l-oxo-l, 3 To thionyl chloride (130ml), cooled at -10 oC, 2-[[(l-oxo-1,3-dihydroiso yl)carbonyl]amino]-2-methyl-l-propanol (85g, 0.34mol) is added portionwise with stirring. The temperature is maintained at -10 -5 oC for 1.5 hours whereafter the cooling is removed and the reaction is stirred overnight at ambient temperature. It is then cooled to 0 OC and tetrahydrofuran (860 mL) is added dropwise keeping the temperature 00 O below +8 The obtained suspension is kept under stirring for 2 hours at 5 and then C filtered and the crystals washed with tetrahydrofuran (150 mL). The wet solid is dissolved Sin deionized water (400 mL) and the pH is adjusted to 9.1 by the addition of 25% aqueous O ammonia. The solid is filtered, washed with deionized water and dried for 14 hours at °C under reduced pressure. Yield: 62.8g of a white product having a purity S(HPLC, peak area) 94%. 'H NMR (DMSO d-6, 500 MHz): 1.31 4.18 (2H,s), 5.44 7.9 (1H,d, J=1 1.3Hz), 8.01 (1H,d, J=1 1.3Hz), 8.12 (1H,s).

O Example 3 Preparation of To a suspension of 4,4-dimethyl-2-(1-oxo-1,3-dihydroisobenzofuran-5-yl)oxazoline (23. g, 0.1mol) in thionyl chloride (36 mL) is slowly added N,N-dimethylformamide The solution is heated at reflux for 1 hour and then allowed to cool to room temperature over 3 hours. Then toluene (150 mL) is added and the suspension is filtered and washed with toluene (2 x 50 mL). The wet crystals are taken into deionized water (150 mL) and the pH is adjusted to 8.0 with 25% aqueous ammonia.

The solid is filtered and washed with deionized water (2 x 50 mL) and dried at 60 °C under reduced pressure. Yield: 11.9g of an off-white product having a purity (HPLC, peak area) 92%. An analytical pure sample is obtained by crystallisation from acetic acid or toluene. 'H NMR (DMSO d-6, 500 MHz): 5.48 8.04 8.22 (1H,s) Comprises/comprising and grammatical variations thereof when used in this specification are to be taken to specify the presence of stated features, integers, steps or components or groups thereof, but do not preclude the presence or addition of one or more other features, integers, steps, components or groups thereof.

Claims (13)

1. A method for the preparation of 5-cyanophthalide comprising treatment of a compound of Formula IV Formula IV wherein X is O or S; R' R 2 are each independently selected from hydrogen and CI-6 alkyl, or R' and R 2 together form a C2- 5 alkylene chain thereby forming a spiro-ring; R 3 is selected from hydrogen and C1- 6 alkyl, R 4 is selected from hydrogen, Ci- 6 alkyl, a carboxy group or R 3 and R 4 together form a C2- 5 alkylene chain thereby forming a spiro-ring; with a dehydration agent or alternatively where X is S, thermally cleavage of the thiazoline ring or treatment with a radical initiator to form 5-cyanophthalide having the formula Formula III

2. The method of claim 1 wherein the radical initiator is peroxide or light.

3. The method of claim 1 or claim 2 characterised in that the compound of Formula IV is prepared by a process comprising: a) reacting a functional derivative of 5-carboxyphthalide of Formula V Formula V with a 2-hydroxy- or 2-mercaptoethanamine of Formula VI R1 R2 SHX NH 2 HX R R4 R3 Formula VI in which X, R' R 4 are as defined above, submitting the amide of Formula VII thus obtained Formula VII in which X, R' R 4 are as defined above, to a ring closure by dehydration; thereby obtaining the 2-(1-oxo-1,3-dihydroisobenzofuran-5-yl)oxazoline or -thiazoline of formula IV Formula IV in which X, R' R 4 are as defined above.

4. A method for the preparation of 5-cyanophthalide according to any one of claims 1-3 wherein the compound of formula IV is treated with a dehydrating agent 00 selected from phosphoroxytrichloride, thionylchloride, phosphorpentachloride, PPA (polyphosphoric acid) and P 4 0 1 0 or a Vilsmeier reagent, eventually in combination Swith an organic base, preferably pyridine or a catalytic amount of a tertiary amide.

5. The method of claim 4 wherein the compound of formula IV is treated with SOC12 as a dehydrating agent and the reaction is carried out in toluene comprising a catalytic amount of N,N-dimethylformamide. O CN 6. A method for the preparation of 5-cyanophthalide according to any one of 0 10 claims 1-3 wherein the termally cleavage of the thiazoline ring of a compound of C1 formula IV where X is S is carried out in presence of oxygen or an oxidizing agent.

7. A method for the preparation of 5-cyanophthalide according to any one of claims 1-3 wherein the thiazoline ring of a compound of formula IV where X is S and R 4 is carboxy, is treated with a radical initiator.

8. The method of claim 7 wherein the radical initiator is light or peroxides.

9. The method of any one of claims 1-8 wherein R 3 is methyl or ethyl. The method of any one of claims 2-9 in which the dehydrating agent used in step b) is SOC12, POCI 3 or

11. The method of claim 10 in which the dehydrating used in step b) is SOC1 2

12. The method of any one of claims 2-11 wherein the reaction in step b) is carried out neat or in a suitable solvent.

13. The method of claim 12 wherein the solvent is selected from toluene, sulfolan and acetonitrile.

14. The method of claim 13, wherein the solvent is toluene. 12 The method of any one of claims 10-14 wherein the dehydrating agent used in step b) is SOC12 and the reaction is carried out in toluene comprising a catalytic amount of N,N-dimethylformamide.

16. 5-cyanophthalide prepared by the method of any one of claims 1-15. H LUNDBECK A/S 1o WATERMARK PATENT TRADE MARK ATTORNEYS P21596AU01