WO2001032643A1

WO2001032643A1 - Method for the preparation of 5-carboxyphthalide

Info

Publication number: WO2001032643A1
Application number: PCT/DK2000/000606
Authority: WO
Inventors: Hans Petersen
Original assignee: H. Lundbeck A/S
Priority date: 1999-11-01
Filing date: 2000-11-01
Publication date: 2001-05-10
Also published as: AU1130901A

Abstract

By a method comprising reaction of terephthalic acid (formula (II)) with trioxane or paraformaldehyde in the presence of a Lewis acid or a mineral acid, 5-carboxyphthalide is obtained with very high purity and in high yields at mild reaction conditions.

Description

METHOD FOR THE PREPARATION OF 5-CARBOXYPHTHALIDE

The present invention relates to a novel process for the preparation of 5-carboxyphthalide, a starting material for the manufacture of the well-known anti depressant drug citalopram, l-[3- (dimethylamino)propyl]-l -(4-fluorophenyl)-l ,3-dihydro-5-isobenzofurancarbonitrile.

Background of the Invention.

Citalopram is a selective serotonin reuptake inhibitor which has successfully been marketed as an antidepressant drug for some years. It has the following structure:

Formula I and it may be 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 dicarbinol compound is subjected to a ring closure reaction by dehydration. The 5-cyanophthalide may in its turn be obtained by reaction of 5- carboxyphthalide with a dehydrating agent and a sulfonamide of the formula H₂N-SO,-R wherein R is NH₂, alkyloxy, optionally substituted phenyloxy, or substituted phenyl in order to obtain 5-cyanophthalide, cf. our co-pending Danish patent application No. PA199801718.

5-Carboxyphthalide has been described as a useful intermediate in the polymer and paint industry. However, no reliable commercial source is available at present. A known process comprises catalytic hydrogenation of trimellithic acid (DE-A1 2630927). This process provides a mixture of the 5- and 6-carboxyphthalides and, accordingly, it requires elaborate and costly purification. According to J. Org. Chem. 1970, 35, p. 1695-1696, 5- carboxyphthalide is synthesised by reaction of terephthalic acid with trioxane in liquid SO₃. During this process, trioxane sublimates and precipitates thereby obstructing the equipment.

Though a number of other methods failed, it has now been found that 5-carboxyphthalide may be prepared from terephthalic acid in high yields by a convenient, cost-effective procedure. Description of the invention

Accordingly, the present invention provides a process for the manufacture of 5- carboxyphthalide

comprising reaction of terephthalic acid

with trioxane or paraformaldehyde

in the presence of a Lewis acid or a mineral acid.

The Lewis acid may be any suitable Lewis acid. Examples of suitable Lewis acids are ZnCl₂, PC1₅, SnCL,, TiCl₄, etc. Alternatively, a mineral acid is used. Any suitable mineral acid such as poly-phosphoric acid may be used.

By the process of the invention, 5-cyanophthalide is obtained with very high purity and in high yields. Furthermore, as compared with the prior art process (J. Org. Chem. 1970, 35, p. 1695-1696), the process of the invention takes place at much milder reaction conditions without precipitation of sublimated trioxane which obstructs the equipment e.g. by precipitating in condensers. Thus, the reaction in liquid SO₃ according to J. Org. Chem. 1970, 35, p. 1695-1696 requires very expensive equipment and is very unpleasant to handle.

In the method of the invention, the terephthalic acid is condensed with trioxan or paraformaldehyde liberating water that reacts with the acid present. When the reaction is complete, 5-carboxyphthalide may be isolated as follows: The reaction mixture is hydrolysed with water. The condensed product, 5-carboxyphthalide inclusive possible diphthalide impurities may then be filtered off, and the 5-carboxyphthalide may be dissolved in aqueous medium by adjusting pH to about 6.7 to 7.3, leaving possible diphthalide impurities in the solid phase. The diphthalide present may be filtered off whereupon 5-carboxyphthalide may be precipitated by acidification, washed with water and dried.

Preferably 1.0-1.33 equivalents CH₂O and 1.0-2.5, preferably 1.0-2 equivalents acid are used per equivalent terephthalic acid. Also lower amount of acid such as 0.1 to 1.0 equivalents may possibly be used.

The reaction is carried out in a suitable solvent such as nitrobenzene trifluoromethyl benzene, methylcyclohexane. A person skilled in the art may easily determine suitable solvents.

The reaction of terephthalic acid with trioxane or paraformaldehyde is carried out at elevated temperature, at about 50-155 °C, preferably 135-145°C, most preferably at about 140°C. The reaction time is not critical and may easily be determined by a person skilled in the art.

The adjustment of pH to 6.3 to 7.3 in order to dissolve the 5-carboxyphthalide formed may be effected by NaOH.

Acidification in order to precipitate the 5-carboxyphthalide may be carried out by adding sulphuric acid or a mineral acid until pH = 2.

The terephthalic acid used as a starting material is commercially available.

Examples The invention is further illustrated by the following example.

Example 1 5-CarboxyphthaIid

Terephthalic acid (10 kg) is charged into a reactor. ZnCl₂ (2 equivalents in nitrobenzene) is added and then paraformaldehyde (1.33 equivalents, 0.24 kg/kg terephthalic acid) is added.

The mixture is agitated at 125 °C for 17 hours. Water (13 kg/kg terephthalic acid and filter aid is added, the temperature is adjusted to about 70 °C. The precipitate is filtered of, washed with water and suspended in water. The pH of the suspension is adjusted to about 7 with NaOH, activated carbon, 0.07 kg/kg is added, and then the mixture is filtered, the precipitate is rinsed with water. The temperature of the filtrate is adjusted to about 65°C and the pH is adjusted to about 2 with 50% sulfuric acid. The 5-carboxyphthalide precipitated is separated by filtration washed and dried. Yield 83%.

Claims

1. A method for the preparation of 5-carboxyphthalide

comprising reaction of terephthalic acid

with trioxane or paraformaldehyde

,o.

o o

HO(CH₂)_nH or ^^ in the presence of a Lewis acid or a mineral acid.

2. The method of Claim 1 wherein trioxane is used as reactant.

3. The method of Claim 1 wherein para- formaldehyde is used as reactant.

4. The method of Claims 2 or 3, wherein the acid is a Lewis acid, such as ZnCl₂, PC1₅, SnCl₄ or TiCl₄.

5. The method of Claim 2 or 3 wherein the acid is a mineral acid, such as a poly- phosphoric acid.

6. The method of any of Claim 1 to 5 wherein 1.0-1.33 equivalents CH₂O and 1.0-2.5, preferably 1.0-2 equivalents acid are used per equivalent terephthalic acid.

7. The method of any of Claim 1 to 5 wherein the reaction of terephthalic acid with trioxane or paraformaldehyde is carried out at elevated temperature, e.g. at about 50-145 °C, preferably 115-125°C, most preferably at about 120°C.