MXPA01005674A - Method for the preparation of 5-cyanophthalide - Google Patents

Abstract

A method for the preparation of 5-cyanophthalide in which 5-carboxyphthalide is converted to the corresponding amide of Formula (IV) in which R is hydrogen or C1-6 alkyl, which is then reacted with a dehydrating agent thereby obtaining 5-cyanophthalide. The conversion of 5-carboxyphthalide to the corresponding amide of Formula (IV) may be carried out via the corresponding C1-6 alkyl or phenyl ester or the acid chloride, which is converted to the amide of Formula (IV) by amidation with ammonia or a C1-6 alkylamine. By the process 5-Cyanophtalide, an important intermediate used in the preparation of the antidepressant drug citalopram, is prepared in high yields by a convenient, cost effective procedure.

Description

METHOD FOR THE PREPARATION OF 5-C IANOFTA IDA DESCRIPTION OF THE INVENTION The present invention relates to a novel process for the preparation of 5-cyanophthalide which is an intermediate used in the manufacture of the well-known antidepressant drug citalopram, 1 - [3 - (dimethylamino) p ropi 1] - 1 - ( 4-fluorophenyl) -1,3-dihydro-5-isobenzofurancarbonitrile.

BACKGROUND OF THE INVENTION Citalopram is a well-known antidepressant drug that has been on the market for some years now and has the following structure: Formula I It is a centrally active, selective serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitor, thus having an anti-inflammatory activities. The activity of the compound has been reported in several publications, for example, J. Hyttel, Prog. Neu ro - Psychopha rma c ol. & Biol. Psychiat. , 1982, 6, 277-295 and A. Gravem, Acta Psychiatr. Scand. , 1987, 75, 478-486. Citalopram is prepared by the process described in U.S. Patent No. 4,650,884, according to which 5 - cia no fa 1 i da is subjected to two successive Grignard reactions, that is, with halogenide of 4 - f 1 u or ro - f in i Ima gnesium and halide of N, N-dime ti 1 ami nopr op i Ima gesio, respectively, and the resulting compound of the formula Formula II is subjected to a ring closure ion by dehydrating a strong sulfuric acid. The enantiomers can be prepared by the method in US Pat. No. 4,943,590, separating the enantiomers from the intermediate; Formula II and carrying out closing of a n i i 1: > enantioselective in order to obtain the desired enantiomer.

Therefore, this year is an important intermediary for the manufacture of citalopram and it is important to produce this material in an adequate quality, through 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, 26, 1951, 35 and in Levy and Stephen, J. Chem. Soc., 1931, P c 7. By this method, 5-aminophthalide is reversed in the corresponding 5-cyanof tali. followed by reaction with C '_. C N The 5-aminofide was obtained from 4-amino-to-1-imido by a two-step reduction procedure. The synthesis of certain alkyl and phenylnitriles of acid chlorides is described in Tetrahedron Letters, 1982, 23, 1505-150 in Tetrahedron, 1998, 54, 9281. While a number of other methods failed, it has been discovered that 5-cyanophtha- ide can be prepared in high yields by an effective method. e regarding costs, convenient from 5-carboxif alida.

Description of the Invention Accordingly, the present invention provides a novel method for the preparation of 5-cyanophthalide from 5-caboxboxy phthalate which comprises converting 5-caboxylate to an amide of 1. to Formula IV Formula IV e n l a c u a l R is hydrogen or alkyl of C 1 - 6 and b) after reacting the amide of the Formula VI dehydrating obtaining from that modc 5-cyanophthalide Formula V The conversion of 5-ca.sub.bo.sub.i to t.sub.1 to the amide of Formula IV can be carried out by means of an ester of Formula VI or an acid chloride of Formula VII or by means of the ester and the acid chloride: Fopnula VII wherein R 1 is C 1-6 alkyl or phenyl. The acid chloride is conveniently obtained by treatment of 5-caboxylate with pure P0C13, PCI5 or SOCI2 or in a suitable solvent, such as toluene or toluene comprising a catalytic amount of N-dimethyldimine. gives . The ester is obtained by 5-ca-round treatment with an alcohol RiOH, where Ri is as defined above, in the presence of an acid, preferably a mineral acid or a Lewis acid, such as HCl, H2SO4, P0C13 , PC15 or S0C12. Alternatively, the ester can be obtained from the acid chloride by reaction with an alcohol. The ester of Formula VI or the acid chloride of Formula VII is then converted to the amide of Formula IV by amidation with ammonia or a C 1-6 alkylamine, preferably t-butylamine.

Throughout the specification and claims, C? _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-d-ime-ti-1-ethyl-1-yl and 2-methyl-1-propyl. The dehydrating agent used in step b) can be any suitable dehydrating agent, and the optimum agent can be easily determined by a person skilled in the art. Examples of suitable dehydrating agents are S0C12, P0C13 and PCI5, preferably S0C12. The reaction of step b) is carried out in pure form or in a suitable solvent. Such as toluene, sulfolane or conveniently acetonitrile. When the reaction is carried out in a solvent, 1.0-1.5, preferably 1.0-1.2 equivalents of the dehydrating agent is used per equivalent of the amide of Formula V. Additionally, when a solvent is used, a catalytic amount of N, N-dimethylformamide. The reaction of step b) is carried out at an elevated temperature, preferably at the reflux temperature of the solvent.

The reaction time is not important and can be easily determined by one skilled in the art. The liquid phase may be isolated in a conventional manner, for example, by the addition of water, filtration and subsequent washing of the crystals. Additional purification may be performed, if desired, by recrystallization. In a preferred embodiment of the process of the invention, R in Formula IV is H or t-butyl. When the reaction in step a) is carried out by means of an ester, Ri is preferably methyl or useful. In a particularly preferred embodiment of the invention 5-ca rb ox ifi of Formula III is reacted with alcohol, RiOH, preferably ethanol in POC13, to obtain the corresponding / -ter. of Formula VI, which is then reacted with ammonia thereby providing 5-.moylphthalide, which in turn is reacted ~ r '1 _, in toluene comprising a critical amount of N, N- Dimethylformamide Surprisingly, substantially no reaction occurs in the lactone ring, Therefore, by the process of the invention, 5-ia is obtained with high yields and the process is much more convenient than the process known and uses more convenient and more economical reagents and conditions The 5-car box is used as starting material can be obtained by the methods described in the US Patent No. 3,607,884 or the German Patent No. 2630927, ie Endo reaction of a concentrated solution of terephthalic acid with formaldehyde in liquid S03 or by hydrogenation of the thermochemistry of t r imel i tic acid.

The invention is illustrated by the following examples. Example 1 Preparation of 5-Cyanof tal ida - . 5 - . 5-Carboftened tallow 5-carboxycarbonyl ester (53 g, 0.3 g) was suspended in toluene (200 ml) and thionyl chloride (44 g, 0.5 mol) N, N-dimethylformamide (DMF) (1M) was added. mL) and the mixture was heated at reflux temperature for 3 hours.-The mixture was cooled to room temperature and n-heptane (200 ml) was added.The crystals formed were collected and washed with heptanol (100 ml). g, 88% DSC start: 131 ° C. XH NMR (0DC13, 500 MHz): 5.47 (2H, s), 8.06 (1H, d, J = 7.5 Hz), 8.28 (1H, d, J = 7.5 Hz) 28 (1H d J = 7.5 Hz 1H i 3 C NMR (CDC13, 125 MHz): 69.4, 125.1, 126.1, 131.1, 131.6, 137.8, 146.6, 167.4, 169.0. - e. B i lcarba ilf talida Method A): 5 -Ca rbox i f t a li da (36 g, 0.2 mol) was suspended in thionyl chloride (100 mL). DMF (1.5 L) was added and the mixture was refluxed for 1 hour. Toluene (200 ml) was added and the solvents were evaporated i n va c u o. The residue was dissolved in tetrahydrofuran (THF) (200 mL) and added to a solution of t e r. bu t i 1 amine (31 g, 0.42 mol) in THF (200 mL) at 5 ° C. The mixture was allowed to warm to room temperature and was stirred overnight. Then the reaction was poured into ice water (400 mL) and the precipitated crystals were separated by filtration. The crystals were washed with water (100 mL) Yield: 41 g, 87 DSC start: 189.5 ° C.

Method B): A solution of 5 - c 1 or r oca rboni 1 f t a 1 ida (39 g, 0.2 mol) in THF (200 mL) was added to a solution of ter -bu ti 1 amine (19 g, 0.25 mol) and triethylamine (26 g, 0.25 mol) in THF (200 mL) at room temperature. ambient. The mixture was stirred for 1 hour. The reaction mixture was then poured into ice water (500 mL). The crystalline material formed was collected and washed with water (100 ml). Yield 42.5 g, 91%, DSC start: 192 ° C. Purity: 99.5% (hplc, peak area). XH NMR (DMSO-d6.500 MHz): 1.4 (9H, s), 5.46 (2H, s), 7.88 (1H, d, J = 7.5 Hz), 7.95 (1H, d, J = 7.5 Hz), 8.04 (1H, s). 13 C NMR (DMSO-d 6, 125 MHz): 28.5, 51.2, 70.0, 122.0, 124.6, 126.6, 128.2, 141.3, 147.2, 165.5, 170.1. - . 5-toxicarbon lf alida Method A): 5-Ca rbox i f t a 1 i da (37 g, 0.2 mol) was suspended in ethanol (400 ml). P0C13 added (10 g, 0.07 mol) per drop and the reaction mixture was heated at reflux temperature for 5 hours. After cooling to room temperature, the title compound crystallized. The crystals were separated by filtration and washed with ethanol (50 ml). Yield: 35 g, 87%. Start DSC: 151 ° C. * H NMR (DMSO-d6, 250 MHz): 1.36 (3H, t, J = 7 Hz), 4.38 (2H, q, J = 7 Hz), 5.48 (2 H, s), 7.95 (1H, d, J = 7.5 Hz), 8.12 (1H, d, J = 7.5 Hz). 13 C NMR (DMSO-d 6, 62.5 MHz): 14.5, 61.5, 70.1, 124.0, 125.2, 128.8, 129.6, 134.8, 147.6, 164.9, 169.8.

Method B) 5 - c 1 or carboni 1 f t a 1 i da (39 g) was suspended 0. 2 mol) in ethanol (200 mL) The mixture was heated to reflux for 15 minutes, after cooling the crystalline material formed was separated by filtration and washed with ethanol (50 mL) Yield: 36 g, Start DSC: 151 ° C.

-Carbamylf talida. Method A): 5 - e t oxi ca rbon i 1 f t a 1 i da (41 g, 0.2 mol) in ammonia (10 M solution in methanol, 200 ml) in a pressure reactor. The reaction temperature was maintained at 80 ° C for 20 hours. After cooling, the reaction mixture was poured onto ice (250 g) and the pH adjusted to pH = 1 using concentrated hydrochloric acid. The mixture was stirred for 2 hours. The crystals formed were separated by filtration and washed with water (4 x 100 ml) and dried in vacuo. Yield: 33 g, 93%. Start DSC: 237 ° C. X H NMR (DMSO-d 6, 250 MHz): 5.47 (2H, s), 7.65 (1H, s (NH)), 7.92 (1H, d, J = 7.5 Hz), 8.06 (1H, d, J = 7.5 Hz ), 8.14 (1H, s), 8.22 (1H, s (NH)). 13 C NMR (DMS0-d ?, 62.5 MHz): 70.0, 122.2, 124.9, 127.2, 128.2, 139.7, 147.4, 167.1, 170.1.

Method B): 5-Chloro nilf talid (20 g, 0.1 mol) was dissolved in THF (100 ml) and reacted with ammonium hydroxide (50 ml) in water.; 00 ml). The mixture was stirred for 30 ml: and the precipitated crystals were separated by filtration. The crystals were washed with slOO ml) and dried in vacuo. Rend imi en t o 17.1 g Start DSC: 237 C 5 -Cianof on the way. Method A): 5 - ca rbami 1 f t a 1 i da dry (36 g, 0. 2 mol) in toluene (600 ml) and thionyl chloride (36 g, 0.3 mol) was added. DMF (2 ml) was added. The reaction mixture was heated at 75 ° C for 6 hours. HE . eliminated toluene (100 ml) by distillation and the remaining solution was cooled to room temperature. The crystals formed were separated by filtration and washed with toluene (150 ml) and water (100 ml). The product. it was recrystallized from toluene. Yield: 22 g, 80%. Start DSC: 203 ° C. Method B): T e r was suspended. - bu i 1 c a r bami 1 phthalyide (23.3 g, 0.1 mol) in thionyl chloride (100 ml). The mixture was heated to reflux for 30 minutes. Toluene (100 ni) was added and the solvents were removed in vacuo. The title product was crystallized from acetic acid or toluene. Yield: 15.5 g, Q 3% toluene. Start DSC: 203 ° C. Purity: 98"(hplc, peak area)

Claims (12)

1. A method for the preparation of 5 c i ano f na 1 i da comprising a) the conversion of 5-ca rboxi f ida to an amide of Formula IV Formula III Formula IV wherein R is hydrogen or alkyl C? -6, and b) then reacting the amide of the Formula IV with a dehydrating agent thereby obtaining the 5-c i a or f t a 1 i da Formula V

2. The method according to claim 1, wherein the conversion of 5-ca rboxi f t a 1 i to the amide of Formula IV is carried out by means of an ester of Formula VI: Formula V'i wherein Ri is C 1-6 alkyl or phenyl, by treatment of 5-carboxymethyl ester with an alcohol R? OH in the presence of an aggregate and subsequent amidation of the ester of Formula VI with ammonia or an alkylamine of C_ .-6.

3. The method according to claim 1, wherein the conversion of 5-c to r or x i f t a 1 i to the amide of Formula IV is carried out by means of an acid chloride of Formula VII: Formula Vü by treatment of 5 - ca r b ox i f t a 1 i with POCI3, PCI5, or S0C12 and subsequent amidation of the acid chloride of Formula VII with ammonia or an alkylamine of C? -6.

4. The method according to the rei indication 1, in which the conversion of 5-ca rboxi f to the amide of Formula IV is carried out by means of an acid chloride of Formula VII and an ester of Formula VI: Formula VII wherein R_ is C? _ alkyl. or phenyl, by treating 5-carboxy f t a 1 i with P0C13, PCI5 or S0C12 by reacting the acid chloride of Formula VII thus formed with an alcohol RiOH and carrying out the amidation of the ester of Formula VI with ammonia or an alkylamine of Cl- 6 - -

5. The method according to the rei indication 2, wherein the acid used is a mineral acid or a Lewis acid, preferably HCl, H2SO4, P0C13, PC15, S0C12.

6. The method according to claim 2, 4 or 5, wherein Rx is methyl or ethyl.

7. The method according to any of Claims 1-6, wherein the dehydrating agent used in step b) is S0C12, P0C13 or PCI5, preferably S0C12.

8. The method according to any of Claims 1-7, wherein the reaction of step b) is carried out in pure form or in a suitable solvent, such as toluene, sulfolane or acetonitrile, preferably in toluene.

9. The method according to any of Claims 1-8, n-1 which the dehydrating agent used in p-j.-or b) is S0C12, and the reaction is carried out in. It also comprises a catalytic amount of N, N-i: m ethyl formamide.

10. The method according to any of Claims 1-9, in which R is H or t erbu tyl.

11. The method according to claim 2, wherein the 5-caboxy ester of Formula III is reacted with an alcohol RiOH, preferably ethanol or methanol, in the presence of P0C13, in order to obtain an ester of Formula VI , which is then reacted with ammonia thereby providing 5-camobamo 1 phthale, which in turn is reacted with SCO 12 to 5-phthalamide.

12. The method according to claim 11, wherein the hydrocarbon of Formula III is replenished with ethanol in the presence of POCI3, to obtain the ethyl ester of Formula VI, which then it is reacted with ammonia in methanol, thereby providing 5-carbamoyl-talid, which in turn is reacted with SOCl2 to 5-cyanide.