BG64901B1 - Method for the preparation of citalopram - Google Patents

Abstract

A method for the preparation of citalopram is described comprising reaction of a compound of formula wherein R1 is H or C1-6alkylcarbonyl successively with a Grignard reagent of 4-halogen-fluorophenyl and a Grignard reagent of 3-halogen-N,N-dimethylpropylamine, effecting ring closure of the resulting compound of formula and converting the resulting 1,3-dihydroisobenzofuran compound to the corresponding 5-cyano derivative, i.e. citalopram.

Description

The present invention relates to a method for the preparation of the well-known antidepressant citalopram and intermediates used in the method.

BACKGROUND OF THE INVENTION

Citalopram is a well-known antidepressant that has been a commercial product for several years and has the following structure:

Citalopram is a selective central nervous system active serotonin (5-hydroxytryptamine; 5-HT), a reuptake inhibitor, and therefore has antidepressant activity. The antidepressant activity of the compound has been reported in several publications, i. J. Hyttel, Prog. NeuroPsychopharmacol. & Biol. Psychiat., 1982, 6, 277-295 and A. Gravem, Acta Psychiatr. Scand., 1987,75,478-486. The compound also has an effect in the treatment of dementia and cerebrovascular disorders, EP-A 474580.

Citaropram was first disclosed in DE 2,657,271 corresponding to US 4,136,193. The patent describes the preparation of citalopram by a particular method and schematically by another method that could be used to prepare citalopram.

According to the method described, the corresponding 1- (4-fluorophenyl) -1,3-dihydro-5-isobenzofurancarbonitrile is reacted with 3- (N, N-dimethylamino) propyl chloride in the presence of methylsulfinylmethide as a condensing agent. The starting material is obtained from the corresponding 5-bromo derivative by reaction with copper cyanide.

According to the method described only generally, citalopram is prepared by cyclizing the compound:

in the presence of a dehydrating agent and subsequent substitution of the 5-bromo group with copper cyanide. The starting material of formula II is obtained from 5-bromophthalide by two successive Grignard reactions, i.e., with 4-fluorophenyl magnesium chloride and N, N-dimethylaminopropyl magnesium chloride.

A novel and impressive method and intermediate for the preparation of citalopram are described in US 4650884. According to the patent, an intermediate of formula

Formula III undergoes cyclization reaction by dehydration with concentrated sulfuric acid in order to obtain citalopram. The intermediate of formula III is prepared from 5-cyanophthalide by two successive Grignard reactions, respectively with 4-fluorophenyl magnesium halide and N, N-dimethylaminopropyl magnesium halide.

Finally, methods for the preparation of individual enantiomers of citalopram are disclosed in US 4943590, which makes it clear that cyclization of an intermediate of formula III can be carried out using a labile ester and base.

SUMMARY OF THE INVENTION

It has been unexpectedly found that citalopram can be obtained by a novel, appropriate and safe procedure using conventional starting materials.

The present invention relates to a new process for the preparation of citalopram comprising the steps of:

a) reaction of a compound of formula IV,

Formula IV such as R ¹ is H or C _1-6 alkylcarbonyl, with a Grignard reagent 4-halogen-fluorophenyl;

B) reaction of the compound of formula V obtained,

wherein R ¹ is as defined above with the Grignard reagent 3-halogen-1H-dimethylpropylamine;

c) performing a ring contraction in the resulting compound of formula VI,

as R 'is as defined above and

d) conversion of the resulting compound of formula VII

wherein R ¹ is as defined above in the corresponding 5-cyano derivative i.e. citalopram, which is isolated as a base or pharmaceutically acceptable salt.

In another aspect, the present invention provides novel intermediates of formula V.

In another aspect, the present invention provides novel intermediates of formula VI.

In another aspect, the present invention provides novel intermediates of formula VII.

In another aspect, the present invention relates to a pharmaceutical composition, an antidepressant containing citalopram, prepared according to the method of the invention.

In the description and claims C _1-6 alkyl is a branched and unbranched alkyl group having one to six carbon atoms including such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl. 2,2-dimethyl-1-ethyl and 2-methyl-1-propyl.

Grignard reagents 4-halogen-fluorophenyl that can be used in step a) are magnesium halides, such as chlorides, bromides or iodides. Magnesium bromide is preferably used. Grignard reagents 3-halogen-NM-dimethylpropylamine that can be used are magnesium halides, such as chlorides, bromides or iodides, preferably magnesium bromide. Preferably, the two reactions are carried out sequentially without isolating the intermediates.

The ring-locking of the compound of formula VI can be carried out with an acid or, when R ¹ is C 1-6 alkylcarbonyl, it may alternatively be carried out via a labile ester or base. The acid cyclization is carried out with an inorganic acid such as sulfuric or phosphoric acid, or an organic acid such as methylsulfonic, p-toluenesulfonic or trifluoroacetic acid. The alkaline cyclization is carried out with a labile ester such as methanesulfonyl, p-toluenesulfonyl, 10-camphorsulfonyl, trifluoroacetyl or trifluoromethanesulfonyl ester and addition of a base such as triethylamine, dimethylaniline or pyridine. The alkaline reaction is carried out in an inert solvent, preferably under cooling, in particular at about 0 ° C and preferably carried out according to a procedure in which the esterification and addition of the base are carried out simultaneously in the same reactor.

When R ¹ is H, the conversion of R'NH- to a cyano group is preferably carried out by diazotization followed by reaction with CN '. The most preferred use is NaNO3 and CuCN and / or NaCN. When R ¹ is C 16 alkylcarbonyl, the compound is initially hydrolyzed and the resulting compound, wherein R 1 = H, is further transformed as described above. The hydrolysis can be carried out either in acidic or alkaline medium.

The method of the invention can be carried out with or without isolation of the intermediates.

The method of the invention can also be used to prepare the active (S) -enatiomer of citalopram. In this case, the compound of formula VI is separated into optically active enantiomers by a procedure analogous to that described in US 4,943,590 to give the (3) -enantiomer of the compound of formula VI used in the cyclization reaction in step c). Accordingly, the individual enantiomers of the intermediates of formulas VI and VII are included in these formulas.

Other reaction conditions, solvents, etc. conditions are conventional for such reactions and can easily be established by one of ordinary skill in the art.

The starting materials of formula IV, wherein R ¹ is H are commercially available and can be prepared by well known procedures (Tiroflet, J .; Bull. Soc. Sci. Bretagne 26, 1959, 35) and compounds wherein R ' is acyl can be obtained from an amino compound (R ¹ is H) by simple acylation.

In one embodiment of the invention, R ¹ is C _1-6 alkylcarbonyl, in particular methyl, ethyl, propyl or butylcarbonyl.

In another embodiment of the invention, R ¹ is HH.

The compound of general formula I can be used as the free base or as a pharmacologically acceptable acid addition salt. As acid addition salts, salts obtained with organic or inorganic acids may be used. Examples of such organic salts are those with maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis-methylsalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, milky, apple, apple, apple aspartic, stearic, palmitic, itaconic, glycol. p-Aminobenzoic, glutamic, benzenesulfonic and theophylline acetic acid, as well as 8 halothoophilins, for example 8-bromoteophilin. Examples of such inorganic salts are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids.

Acid addition salts of the compounds can be prepared by known methods. The base is reacted either with a calculated amount of acid in solvents miscible with water such as acetone or ethanol, followed by isolation of the salts by concentration and cooling, or with excess acid in a solvent that does not mix with water such as ethyl ether, ethyl acetate or dichloromethane , whereby the salt is released spontaneously.

The pharmaceutical compositions of the invention may be administered by any suitable route and in any suitable form, for example orally in the form of tablets, capsules, powders or syrups, or parenterally in the form of conventional sterile injectable solutions.

The pharmaceutical compositions of the invention may be prepared by methods known in the art. For example, the tablets may be prepared by mixing the active ingredient with ordinary excipients and / or diluents and subsequently compressing the mixture into a conventional tabletting machine. Examples of excipients and / or diluents include: wheat starch, potato starch, talc, magnesium stearate, gelatin, lactose, resins and the like. Any other excipients or additives such as coloring agents, flavors, preservatives, etc., that are compatible with the active ingredients may be used.

Injectable solutions may be obtained by dissolving the active ingredient and the corresponding additives in part of the injection solvent, preferably sterile water, bringing the solution to the desired volume, sterilizing the solution and transferring it to suitable ampoules or vials. Any suitable additives commonly used for this purpose as tonics, preservatives, antioxidants and the like can be added.

Examples of carrying out the invention

The method of the invention is illustrated by the following examples.

Example 1.

4-dimethylamino-1- (4-amino-2-hydroxymethylphenyl) -1- (4-fluorophenyl) butan-1-ol

A solution of 4-fluorophenylmagnesium bromide obtained from 4-fluorobromobenzene (116 g, 0.66 mol) and magnesium chips (20 g, 0.8 mol) in dry tetrahydrofuran (500 ml) was added dropwise to a suspension of 5-aminophthalide (30 g , 0.2 mol) in dry tetrahydrofuran (500 ml). A temperature below 5 ° C is maintained. After completion of the addition, the reaction mixture was stirred for 0.5 h at room temperature.

A second Grignard solution prepared from 3-dimethylaminopropyl chloride (25 g, 0.2 mol) and magnesium chips (6 g, 0.25 mol) in dry THF (150 ml) was added to the reaction mixture. The temperature was maintained below 5 ° C during the addition. Stirring was continued for 0.5 h and, after stopping, the reaction mixture was left overnight at room temperature.

Ice water (1000 ml) and acetic acid (60 g) were added to the reaction mixture. The tetrahydrofuran is evaporated in vacuo. The aqueous phase was washed with ethyl acetate (2x200 ml). NH ₄ OH was added to the aqueous phase until pH 9. The aqueous layer was extracted with ethyl acetate (2x200 ml) and the organic phase was filtered and washed with water (100 ml). The solvents were evaporated in vacuo to give the title compound (38.8 g, 58%) as an oil.

Ή NMR (CDCl ₃ , 500 MHz): 1.45-1.55 (1H, m), 1.65-1.75 (1H, m), 2.2 (6H, s), 2.27 (1H, m), 2.33 (2H, m), 2.43 (1H, m), 3.6-3.7 (2H, NH ₂ ), 3.97 (1H, d, J = 12.5 Hz), 4.25 (1H, J = 12.5 Hz), 6.58 (1H, d, J = 8 Hz). 6.62 (1H, s), 6.95 (2H, t, J = 8.5 Hz), 7.25 (1H, d, J = 8 Hz),

7.45 (2H, dt, J = 1.2 Hz, J = 8.5 Hz).

5-amino-1- (3-dimethylaminopropyl) -1 (4-fluorophenyl) -1,3-dihydroisobenzofuran

Crude 4-dimethylamino-1- (4-amino-2-hydroxymethylphenyl) -1- (4-fluorophenyl) butan-1-ol was dissolved in H ₃ PO ₄ (60%, 140 g) and heated to 80 ° C for 2 h. The reaction mixture was poured onto ice water (1000 ml). NH ₄ OH was added to pH 9. The aqueous layer was extracted with ethyl acetate (2x200 ml). The combined organic phases were filtered, washed with water (100 ml) and dried (MgSO ₄ , 10 g). The solvent was evaporated in vacuo. The title compound was obtained as an oil.

Ή NMR (CDCl ₃ , 250 MHz): 1.3-1.5 (2H, m), 2.05-2.3 (10H, s + m), 3.6-3.7 (2H, NH ₂ ), 5.0 (1H, s), 6.45 (1H) , d, J = 1.8 Hz), 6.55 (1H, dd, J = 8 Hz, J = 1.8 Hz), 6.95 (2H, t, J = 8.5 Hz), 7.05 (1H, d, J = 8 Hz). 7.45 (2H, dt, J = 12 Hz, J = 8.5 Hz).

1- (3-dimethylaminopropyl) -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile

5-Amino-1- (3-dimethylaminopropyl) -1 (4-fluorophenyl) -1,3-dihydroisobenzofuran (18 g, 0.06 mol) was dissolved in water (100 ml) and H ₂ SO ₄ (8 ml). NaNO ₂ (4.1 g, 0.06 mol) was dissolved in water (20 ml) and added dropwise below 5 ° C. The diazotized solution was stirred for 0.5 h at 0-5 ° C. The pH was adjusted to 6.5 by the addition of a saturated solution of Na ₂ CO ₃ . This solution was added to a mixture of water (100 ml) and toluene (120 ml) containing CuCN (6 g, 0.067 mol) and NaCN (10 g, 0.2 mol) at 50-60 ° C. Stirring was continued for 0.5 h. The phases were separated and the aqueous phase was extracted with toluene (100 ml). The combined organic phases were washed with NaCN (10% aq., 2x50 ml). The solvent was removed in vacuo and the residue was removed

Claims (17)

Claims 1. A method for the preparation of citalopram, characterized in that it comprises the steps of: a) reaction of a compound of formula IV, chromatographed on silica gel (ethyl acetate: nheptane: triethylamine 85: 10: 5) to give the title compound (6 g, 32%) as an oil. Ή NMR (CDCl ₃ , 250 MHz): 1.35 (1H, m), ⁵ 1.45 (1H, m), 2.1 (6H, s), 2.15-2.25 (4H, m), 5.12 (1H, d, J = 12.5 Hz), 5.18 (1H, d, J = 12.5 Hz), 7.00 (2H , t, J = 8.5 Hz), 7.4 (2H, t, J = 8.5 Hz), 7.45 (1H, d, J = 7.5 Hz), 7.5 (1H, s), 7.58 (1H, d, J = 7.5 Hz). ¹⁰ Example 2. 4-dimethylamino-1- (4-acetylamino-2hydroxymethylphenyl) -1- (4-fluorophenyl) butan-1-ol 15 A solution of 4-fluorophenylmagnesium bromide obtained from 4-fluorobromobenzene (11.6 g, 0.067 mol) and magnesium chips (2 g, 0.08 mol) in dry tetrahydrofuran (950 ml) was added dropwise to a suspension of 5-acetyl-20 naphthalide ( 5 g, 0.03 mol) in dry tetrahydrofuran (50 ml). The temperature was maintained below 5 ° C. After completion of the addition, the reaction mixture was stirred for 0.5 h at room temperature. 25 A second Grignard solution, obtained from 3-dimethylaminopropyl chloride (3.7 g, 0.03 mol) and magnesium chips (0.87 g, 0.036 mol) in dry THF (15 ml) was added to the reaction mixture. The temperature was maintained below 5 ° C during the addition. Stirring was continued for 0.5 h, then stopped and the reaction was allowed to stand at room temperature overnight. The reaction mixture was poured onto ice water (100 ml) and acetic acid (6 g). The tetrahydrofuran is evaporated in vacuo. The aqueous phase was washed with ethyl acetate (2x50 ml). ΝΗ ₄ ΟΗ was added to the aqueous phase to pH 9. The aqueous layer was extracted with ethyl acetate (2x50 ml) and the organic phase was filtered and washed with water (50 ml). Evaporation of the solvents in vacuo gave the title compound (6.6 g, 63%) as an oil. 45 Ή NMR (DMSO-d ₆ , 500 MHz): 1.15-1.22 (1H, m), 1.40-1.50 (1H, m), 2.02 (9H, s + s), 2.05 (1H, m), 2.13 (2H. m), 2.20 (1H, m), 3.95 (1H, d, J = 12.5 Hz), 4.48 (1H, d, J = 12.5 Hz), 7.05 (2H, t, J = 8.5 Hz), 7.14 (2H. dd, J = 8.5 Hz, J = 1.2 Hz), 50 7.47 (1H, d, J = 8 Hz), 7.58 (1H, s), 7.64 (1H, d, J = 8.5 Hz). Formula IV wherein R ¹ is H or C _1-6 alkylcarbonyl and Grignard reagent 4-halogen-fluorophenyl; B) reaction of the compound of formula V obtained, Formula V wherein R ¹ is as defined above, and Grignard reagent 3-halogen-1H-dimethylpropylamine; c) ringing in the resulting compound of formula VI Formula VI wherein R ¹ is as defined above and d) converting the resulting compound of formula VII wherein R ¹ is as defined above in the corresponding 5-cyano derivative, i. citalopram, which is isolated as a base or pharmaceutically acceptable salt. A method according to claim 1, wherein R 'is H. A process according to claim 1, wherein R ¹ is C _1-6 alkylcarbonyl. The process according to claim 3, wherein the C _1-6 alkyl is methyl, ethyl, propyl or butyl. The process according to claims 1 to 4, characterized in that the used Grignard reagents are magnesium halides, preferably chlorides, bromides or iodides. 6. The method of claim 5, wherein the Grignard reagent used in step a) is magnesium bromide. A method according to claim 5, characterized in that the Grignard reagent used in step b) is magnesium chloride. A method according to claims 1 to 7, characterized in that the ring locking of the compound of formula VI is carried out by acid cyclization which is carried out with an inorganic acid such as sulfuric or phosphoric or organic acid such as methylsulfonic, p-toluenesulfonic or trifluoroacetic acid. A method according to claim 3, characterized in that the ring assembly in the compound of formula VI is carried out by alkaline cyclization using a labile ester, preferably with simultaneous esterification and addition of the base. 10. The process of claim 9, wherein the labile ester is methanesulfonyl, p-toluenesulfonyl, 10-camphorsulfonyl, trifluoroacetyl or trifluoromethanesulfonyl ester and the base is triethylamine, dimethylaniline or pyridine. A method according to claim 2, characterized in that the conversion of the R'-NH- group into a cyano group is carried out by diazotization followed by reaction with CN A method according to claim 3, characterized in that the conversion of the R'-NH- group into a cyano group is carried out by hydrolysis of the C _1-6 alkylcarbonylamino group, R'-NH-, to the corresponding amino group, wherein R ¹ is H, followed by diazotization and reaction with CN '. A method according to claims 1 to 12, characterized in that, before being used in the ring-coupling reaction in step c), the compound of formula VI is separated into optically active enantiomers to give the (8) -enantiomer . A compound of formula V wherein R ¹ is H or C _1-6 alkylcarbonyl. A compound of formula VI wherein R ¹ is H or C _1-6 alkylcarbonyl. A compound of formula VII wherein R ¹ is H or C _1-6 alkylcarbonyl. A pharmaceutical composition, an antidepressant, characterized in that it contains citalopram prepared by the method of any one of claims 1 to 13.