Title of Invention

METHOD FOR THE PREPARATION OF 5-CYANOPHTHALIDE

Abstract The present invention relates to a method for the preparation of 5-cyanophthalide comprising a) conversion of5-carboxyphthalide to an amide of Formula IV
Full Text

METHOD FOR THE PREPARATION OF 5-CYANOPHTHALIDE
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, l-[3-(dimethylamino)propyI]-l-(4-fluorophenyl)-l,3-dihydro-5-
isobenzofurancarbonitrile.
Background of the Invention.
Citalopram is a well known antidepressant drug that has now been on the market for some years and has the following structure:

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, 5,277-295 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-fluoro-phenyl magnesium halogenide and N,N-dimethylaminopropyl magnesium halogenide, respectively, and the resulting compound of the formula


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 intemiediate 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, 26, 1951, 35 and in Levy and Stephen, J. Chem. Soc, 1931, 867. By this method, 5-aminophthalide is converted to the corresponding 5-cyanophthalide by diazotation followed by reaction with CuCN. 5-Aminophthalide 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.
Though a number of other methods failed, it has been found that 5-cyanophthalide may be prepared in high yields by a convenient, cost-effective procedure from 5-carboxyphthalide.
Description of the invention
Accordingly, the present invention provides a novel method for the preparation of 5-cyanophthalide from 5-carboxyphthalide comprising



wherein R, is C1-6 alkyl or phenyl. The acid chloride is conveniently obtained by treatment of 5-carboxyphthalide with POCI3, PCI5 or SOCI2 neat or in a suitable solvent, such as toluene or toluene comprising a catalytic amount of N,N-dimethylfonnamide. The ester is obtained by treatment of 5-carboxyphthalide with an alcohol R,OH, wherein R1 is as defined above, in the presence of an acid, preferably a mineral acid or a Lewis acid, such as HCl, H2SO4 POCI3, PCI5 or SOCl2. Altematively, the ester may 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 an C^g alkylamine, preferably t-butyl amine.
Throughout the specification and Claims, C1-6 alkyl refers to a branched or unbranched alkyl group having from one to six carbon atoms inclusive, such as methyl, ethyl, 1-propyl, 2-pro-pyl, 1-butyl, 2-butyl, 2-methyl-2-propyl, 2,2-dimethyl-l-ethyl and 2-methyl-l-propyl.
The dehydrating agent used in step b) may be any suitable dehydrating agent, and the optimal agent may easily be determined by a person skilled in the art. Examples of suitable dehydrating agents are SOCI2, POCI3 and PCI5, preferably SOCl2.
The reaction in step b) is carried out neat or in a suitable solvent, such as toluene, sulfolan or conveniently acetonitrile. When the reaction is carried out in a solvent, 1.0 - 1.5, preferably 1.0 - 1.2 equivalents of dehydrating agent is used per equivalent of the amide of Formula V. Furthermore, when a solvent is used, a catalytic amount of N,N-dimethylformamide may be needed, in particular when the dehydrating agent is SOCl2. 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.
5-Cyanophthalide 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.
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 via an ester, R, is preferably methyl or ethyl.
In a particularly preferred embodiment of the invention 5-carboxyphthalide of Formula HI is reacted with an alcohol, R,OH, preferably ethanol, in the presence of POCI3, in order to obtain the corresponding ester of Formula VI, which is then reacted with ammonia thereby giving 5-carbamoylphthalide, which in turn is reacted with SOCI2 in toluene comprising a catalytic amount of N,N-dimethylformamide.
Surprisingly, substantially no reaction takes place at the lactone ring. 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 and uses more convenient and cheaper reactants and conditions.
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 SO3 or by electrochemical hydrogenation of trimellithic acid.
Examples
The invention is further illustrated by the following examples.
Example 1
Preparation of 5-Cyanophthalid
S-Chiorocarbonylphthalid
5-Carboxyphthalid (53 g, 0.3 mole) was suspended toluene (200 mL) and thionylchloride (44 g, 0.6 mole). N,N-dimethylformamide (DMF) (1 mL) was added and the mixture was heated at reflux temperature for 3 hours. The mixture was cooled to room temperature and n-heptane was added (200 ml). The crystals formed were collected and washed with

heptane (100 mL). Yield 52 g, 88%. DSC onset: 131 °C. 'H NMR (CDCI3, 500 MHz): 5.47 (2H, s), 8.06 (1H, d , J =7.5 Hz), 8.28 (1H, d, J=7.5 Hz), 8.3 (1H, s). 13C NMR (CDCI3, 125 MHz): 69.4, 125.1, 126.1, 131.1, 131.6, 137.8, 146.6, 167.4, 169.0.
5-tert.Butylcarbamylphthalid
Method A):
5-Carboxyphthalid (36 g, 0.2 mole) was suspended in thionylchloride (100 mL). DMF (1.5 mL) was added and the mixture was refluxed for 1 hour. Toluene (200 mL) was added and the solvents were evaporated in vacuo. The residue was dissolved in tetrahydofuran (THF) (200 mL) and added to a solution of tert.butylamine (31 g, 0.42 mole) in THF (200 mL) at 5 °C. The mixture was allowed to warm to room temperature and stirred overnight. The reaction was then poured into ice water (400 mL) and the precipitated crystals were filtered off. The crystals were washed with water (100 mL)Yield: 41 g, 87%. DSC onset: 189.5 °C.
Method B):
A solution of 5-chlorocarbonylphthalid (39 g, 0.2 mole) in THF (200 mL) was added to a solution of tert-butylamine (19 g. 0.25 mole) and triethylamine (26 g, 0.25 mole) in THF (200 mL) at room temperature. 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 onset: 192 °C. Purity: 99.5% (hplc, peak area). 'H 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). 'C NMR (DMSO-d^, 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-Ethoxycarbonyiphthalid
Method A):
5-Carboxyphthalid (37 g, 0.2 mole) was suspended in ethanol (400 mL). POCI3 (10 g, 0.07 mole) was added drop-wise and the reaction mixmre was heated to reflux temperamre for 5 hours. Upon cooling to room temperamre, the title compound crystallised. The crystals
were filtered off and washed with ethanol (50 ml). Yield: 35 g, 87%. DSC onset: 151 °C. 'H NMR (DMSO-dg, 250 MHz): 1.36 (3H, t, J=7 Hz), 4.38 (2H, q, J=7 Hz), 5.48 (2H, s), 7.95 (1H, d, J=7.5 Hz), 8.12 (1H, d, J=7.5 Hz), .13C NMR (DMSO-d6, 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-Chlorocarbonylphthalid (39 g, 0.2 mole) was suspended in ethanol (200 mL). The

mixture was heated to reflux for 15 minutes. After cooling, the crystalline material formed was filtered of and washed with ethanol (50 ml). Yield: 36 g, 88%. DSC onset: 151 °C.
5-Carbamylphthalid.
Method A):
5-Ethoxycarbonylphthalid (41 g, 0.2 mole) was suspended in ammonia (lOM solution in
methanol, 200 mL) in a pressure reactor. The reaction temperature was held at 80 °C for 20 hours. After cooling, the reaction mixture was poured onto ice (250 g) and pH was adjusted to pH= 1 using concentrated hydrochloric acid. The mixture was stirred for 2 hours. The crystals formed were filtered off and washed with water (4x100 mL) and dried
in vacuo. Yield: 33 g, 93%. DSC onset: 237 °C. 'H NMR (DMSO-d6, 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)). °C NMR (DMSO-d6, 62.5 MHz): 70.0, 122.2, 124.9, 127.2, 128.2, 139.7, 147.4, 167.1, 170.1.
Method B):
5-Chlorocarbonylphthalid (20 g, 0.1 mole) was dissolved in THF (100 mL) and added to ammonium hydroxide (50 mL) in ice water (300 mL). The mixture was stirred for 30 minutes and the precipitated crystals were filtered off. The crystals were washed with
water (100 mL) and dried in vacuo. Yield: 17.1 g, 97%. DSC onset: 237 °C.
5-Cyanophthalid.
Method A):
Dry 5-carbamylpIithalid (36 g , 0.2 mole) was suspended in toluene (600 mL) and thionyl-
chloride (36 g, 0.3 mole) was added. DMF (2 mL) was added. The reaction mixture was
heated at 75 °C for 6 hours. Toluene (100 mL) was removed by destination and the remaining solution was cooled to room temperature. The crystals formed were filtered off and washed with toluene (150 mL) and water (100 mL). The product was recrystallised
firom tohiene. Yield: 22 g, 80%. DSC onset:203 ^C.
Method B):
Tert.-Butylcabamylphthalid (23.3 g, 0.1 mole) was suspended m thionylchloride (100 mL).
The mixture was heated to reflux for 30 min. Toluene (100 mL) was added and the
solvents were removed in vacuo. The title product was crystallised firom acetic acid or
toluene.
Yield 15.5 g, 93% from toluene. DSC onset: 203 °C. Purity: 98% (hplc, peak area).





WE CLAIMS
1. A method for the preparation of 5-cyanophthalide comprising a) conversion of 5-carboxyphthalide to an amide of Formula IV

wherein R1 is C1-6 alkyl or phenyl, by treatment of 5-carboxyphthalide with an alcohol R,OH in the presence of an acid and subsequent amidation of the ester of formula VI with ammonia or an C1-6 alkylamine.
3, The method of Claim 1 wherein the conversion of 5-carboxyphthalide to the amide of Formula IV is carried out via an acid chloride of Formula VII:


wherein R^ is Cj.^ alkyl or phenyl, by treatment of 5-carboxyphthalide with PQCI3, PCI5 or SOCI2, reacting the acid chloride of Formula VII thus formed with an alcohol R,OH and performing amidation of the ester of Formula VI with ammonia or an C1-6 alkylamine.
5. The method of Claim 2 wherein the acid used is .a mineral acid or a Lewis acid,
preferably HCl, H2SO4POCI3, PCI5, SOCl2.
6. The method of Claim 2, 4 or 5 wherein R, is methyl or ethyl.
7. The method of any of Claims 1 - 6 in which the dehydrating agent used in step b) is SOCI2, POCI3 or PCI5, preferably SOCl2.
8. The method of any of Claims 1-7 wherein the reaction in step b) is carried out neat or in a suitable solvent, such as toluene, sulfolan or acetonitrile, preferably in toluene,
9. The method of any of Claim 8 wherein the dehydrating agent used in step b) is SOCI2
and the reaction is carried out in toluene comprising a catalytic amount of N,N-dimethylfor-
mamide.
10. The method of any of Claims 1-9 wherein R is H or tert-butyl

11. The method of Claim 2, wherein the 5-carboxyphthalide of Formula III is reacted with an alcohol R1OH, preferably ethanol or methanol, in the presence of POCI3, in order to obtain an ester of Formula VI, which is then reacted with ammonia, thereby giving 5-carbamoyl-phthalide, which in turn is reacted with SOCl2 to 5-cyanophthalide.
12. The method of Claim 11, wherein the 5-carboxyphthalide of Formula III is reacted with ethanol in the presence of POCI3, in order to obtain the ethyl ester of Fomiula VI, which is then reacted with ammonia in methanol, thereby giving 5-carbamoylphthalide, which in turn is reacted with SOCl3 to 5-cyanophthalide.

Documents:

854.pdf

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in-pct-2001-854-che-abstract.pdf

in-pct-2001-854-che-claims filed.pdf

in-pct-2001-854-che-claims granted.pdf

in-pct-2001-854-che-correspondnece-others.pdf

in-pct-2001-854-che-correspondnece-po.pdf

in-pct-2001-854-che-description(complete)filed.pdf

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in-pct-2001-854-che-form 1.pdf

in-pct-2001-854-che-form 26.pdf

in-pct-2001-854-che-form 3.pdf

in-pct-2001-854-che-other document.pdf

in-pct-2001-854-che-pct.pdf


Patent Number 212343
Indian Patent Application Number IN/PCT/2001/854/CHE
PG Journal Number 07/2008
Publication Date 15-Feb-2008
Grant Date 03-Dec-2007
Date of Filing 20-Jun-2001
Name of Patentee H. LUNDBECK A/S
Applicant Address 9 Ottiliavej, DK-2500 Valby- Copenhagen,
Inventors:
# Inventor's Name Inventor's Address
1 PETERSEN, Hans Guldagervej 11, DK-2720 Vanlose,
2 DAHLBERG NIELSEN, Poul Prejlerupvej 26, DK-4560 Vig,
PCT International Classification Number C07D 307/87
PCT International Application Number PCT/DK99/00728
PCT International Filing date 1999-12-22
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 PA 199801718 1998-12-23 Denmark
2 19993096 1999-12-22 Denmark
3 99A002696 1999-12-23 Denmark
4 60113426 1998-12-23 Denmark
5 P990106726 1999-12-23 Denmark