FI112223B - Preparation of citalopram by halogenation of 5-cyanophthalide to give an intermediate which is reacted with organometallic 4-fluorophenyl halide or 4-fluorophenylborane to give a benzophenone compound convertible to citalopram - Google Patents

Abstract

Preparation of 1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (citalopram) (I) comprises halogenation of 5-cyanophthalide to give a compound (II), which is reacted with an organometallic 4-fluorophenyl halide or 4-fluorophenylborane to give a benzophenone compound (III). (III) Is reacted with organometallic dimethylaminopropyl halide to give (I). Preparation of 1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (citalopram) (I) comprises halogenation of 5-cyanophthalide to give a compound of formula (II), which is reacted with an organometallic 4-fluorophenyl halide or 4-fluorophenylborane to give a benzophenone compound of formula (III). (III) Is reacted with organometallic dimethylaminopropyl halide to give (I), which is isolated as the base or salt. X = halo. Independent claims are also included for: (1) new intermediates (II) and (III); (2) preparation of (I) comprising reaction of (III) with an organometallic 3-dimethylaminopropyl halide; (3) preparation of (III) by reacting (II) with 4-fluorophenylborane or 4-fluorophenylmetallo halide; and (4) preparation of (II) by halogenating 5-cyanophthalide.

Description

112223

METHOD FOR THE MANUFACTURE OF SITALOPRAM

This invention relates to a process for the preparation of 1- (3-dimethylaminopropyl) -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile, a known antidepressant, si or opram.

BACKGROUND OF THE INVENTION

Citalopram is a selective central nervous system serotonin (5-hydroxytryptamine; 5HT) reuptake inhibitor with anti-depressive effects. This effect is described e.g. in J. Hyttel, Prog. Neuro-Psychopharmacol. & Biol. Psychiat., 1982, 6, 277-295 and A. Gravem, Acta 10 Psychiatr. Scand., 1987, 75, 478-486. EP-A 474 580 discloses that citalopram also has an effect in the treatment of dementia and cerebrovascular disorders.

Citalopram has the following structure:

F

: O

: ' joy

* 1 NC

Citalopram was first described in DE 2,657,013, which corresponds to US 4,136,193. It was prepared by reaction of 1- (4-fluorophenyl) -1,3-dihydro-5 · ·,, isobenzofuranecarbonitrile with 3- (N, N-dimethylamino) propyl halide · ·, in the presence of a condensing agent. The starting material was prepared from the corresponding 5-bromo, ·, derivative by reaction with copper (I) cyanide. The second, outlined * I I> · »'; The reaction of I, 20 comprises a ring of a 5-bromohydroxy compound of formula IV * »» »t» i »i» i »i n i

IV

2 112223 I /) ^ / ~~ NMe2

Vw / ^ 2 OH

Br in the presence of a dehydrating agent. After ring closure, the 5-bromo group is replaced by a cyano group using copper (I) cyanide. The starting material for the compound of formula IV is obtained from 5-bromophthalide by two successive Grignard-5 reactions.

Another manufacturing method involving ring closure is described in US 4,650,884. In that process, F

i) ^ / ~ NMe2 0H V

CH2OH NC

The ring closure of the dihydroxy compound is achieved by dehydration. 10 with concentrated sulfuric acid. The starting material is prepared from 5-cyanophthalide by two successive Grignard reactions.

'. Other processes for the preparation of citalopram are described in WO patent applications

98/19511, WO 98/19512, WO 98/19513, WO 99/30548, WO 2000/12044, WO 2000/13684 and WO 2000/23431. US 4,943,590 describes methods for the preparation of single enantiomers of citalopram, ·,: 15. In the method described, the formula. · · ·. The dihydroxy compound of V is first converted to an ester and subsequently sealed in the presence of a base.

• ... · In the process described in WO 2000/12044, the compound 3112223 of the formula VI

F

0 \

NC

ring closure occurs spontaneously after its reaction with 3- (N, N, -dimethylamino) -propylmagnesium halide. Three different ways of preparing Compound VI have been described. One of the methods involves protecting (4-cyano-2-5 hydroxymethylphenyl) -4-fluorophenylmethanol followed by oxidation to produce compounds of formula VI. The starting hydroxymethyl alcohol compound can be obtained from the phthalide compound by a Grignard reaction followed by reduction of the resulting ketone. Another method involves reaction of 5-cyanophthalide with 4-fluoro-magnesium halide, followed by reaction with R-X, wherein R is 10 C 1-6 alkyl, acyl, alkylsulfonyl or arylsulfonyl, and X is a leaving group, resulting in compound VI. In the reaction of 5-cyanophthalide, the resulting ketone can also react with the Grignard reagent used to form unwanted by-products. It is also possible that the product forms a cyclic hemiketal that does not react in the next step. A third process for the preparation of compound VI described in WO 00/12044 can be used to prepare the S-enantiomer of citalopram.

SUMMARY OF THE INVENTION

The present invention relates to a new process for the preparation of citalopram in which. · *. includes halogenation of 5-cyanophthalide to afford the acid halide compound of formula Π, wherein X is halogen, followed by citalopram. Preparation by two consecutive reactions with the appropriate organometallic halides or • '': organoboranes according to Scheme 1. The first step to the acid chloride makes the subsequent reaction selective and allows for spontaneous ring closure after the second reaction with the organometallic halide or organoborane.

4 11222ο

F

ncX> 5 - ^ ncX ^ x x x I A / u

NC

Il III I

Figure 1

The resulting citalopram is isolated as a base or a pharmaceutically acceptable salt thereof.

Another object of the present invention are novel intermediates of Formulas II and III wherein X is halogen, preferably chlorine or bromine, most preferably chlorine.

Yet another object of the invention are processes for the preparation of intermediates of the above formulas I and II.

The invention further relates to antidepressant pharmaceutical preparations containing citalopram prepared according to the process of the invention.

Halogen means chlorine, bromine, iodine or fluorine.

; The process of the present invention from 5-cyanophthalide to citalopram ..., via an acid halide is not described in any of these patents or anywhere. · · ·, In another well-known publication •>

'| '': DETAILED DESCRIPTION OF THE INVENTION

• * ·

Surprisingly, it has been found that if 5-cyanophthalide is halogenated, the resultant formula II

reaction of a compound of formula I

: ''; with fluorophenylborane is very selective and in the following formula III

, ·: ·. Reaction of the compound of the invention with organometallic 3-dimethylaminopropyl halide * · ·, · · · gives citalopram in good yield and purity.

• · · 5 112223

The first step in the process is halogenation of 1-oxo-1,3-dihydroisobenzofuran-5-carbonitrile (5-cyanophthalide) to form a compound of formula II wherein X is halogen, preferably chlorine or bromine, most preferably chlorine.

O

ii ^ l x il

X

The halogenation can be carried out by any suitable method known in the art, e.g. by reaction with thionyl chloride in the presence of a suitable Lewis acid catalyst and a phase transfer catalyst. Catalysis with amines, e.g., pyridine or 4-dimethylaminopyridine or Ν, Ν-dimethylformamide (DMF) is also possible. If DMF is used as a catalyst, no phase transfer catalyst is required.

Suitable Lewis acid catalysts include MgCl, MgBr2, SnCL, SnCL, ZnCl2, TiCl4, Aids, FeCl3, BF3Et20, BC13, B (OEt) 3, B (OMe) 3, B (O-iPr) 3, preferably boron-based Lewis catalyst. The types of phase transfer catalysts used are halides of aromatic or aliphatic ammonium salts, for example tetramethylammonium chloride, tetrabutylammonium chloride or benzyl 15 triethylammonium chloride. The catalyst is used in an amount of 0.1 to 20 mol%, preferably 0.3 to 5 mol%. . _ mole%. The reaction with the catalyst is preferably carried out without a solvent, but if a solvent is used any inert, high boiling solvent such as toluene, xylene, chlorobenzene or dichlorobenzene can be used.

The halogenating reagent used may be any suitable reagent for halogenation, e.g. thionyl chloride, PC13, PCl5, CCL in triphenylphosphine, '· · ·' oxalyl chloride or cyanurea chloride in trialkylamine.

: '. : Reagents in bromine substitution may be e.g. PBr3, PBr5, PPh3Br2, thionyl bromide or oxalyl bromide.

t · * ;;; The halogenating reagent is used in an amount of 0.5 to 1000 equivalents to cyanophthalide, preferably 1 to 10 equivalents, most preferably 1 to 5 equivalents. The reaction temperature ... i 'may be from 20 to 1500 ° C or the reflux temperature, preferably from 80 to 1200 ° C, most preferably from 90 to 1000 ° C. The reaction time is from 0.5 to 15 hours, preferably less than 3 hours.

6, 112223

The reaction is easily completed and the conversion is almost 100%. No by-products are formed and the product can be isolated and purified by suitable known procedures or the next step can be carried out without purifying the compound of formula Π. The starting material, 5-cyanophthalide, may be prepared, e.g., as described in Tirouflet, Bull. Soc. Sci.Bretagne, 26,1951, 35-46.

The advantage of making an acid halide is that the following reaction with organometallic 4-fluorophenyl halide or 4-fluorophenylborane is very selective, unlike the reaction of a lactone directly with 4-fluorophenylmagnesium halide, where the resulting ketone compound is more reactive than lactone and undesirable by-products 10 are formed.

The second step involves reacting the acid halide compound of formula Π with an organometallic or organoboron reagent to form a compound of formula ΙΠ.

O

iYY] m AA, -

NC i F

X

The reagent used is 4-fluorophenylborane or 4-fluorophenyl metal halide with. · The metal component may be Mg, Li, Cu or Zn, preferably Mg or Cu. Preferably «* ♦,.; the reagent is 4-fluorophenylmagnesium halide or 4-fluorophenyl substituted with 1-halide. · ·. Grignard reagent for fluorobenzene, wherein the halogen component is preferably Cl or ....: Br. Most preferably, 4-fluorophenylmagnesium bromide is used.

The reaction is carried out in an inert organic solvent such as toluene or dimethylformamide or commonly used ethers such as "" *; / tetrahydrofuran, diethyl ether, di-n-butyl ether, tetrabutyl »';' methyl ether, ethylene glycol dimethyl ether, 1,4 - dioxane or their:. . · In mixtures. Preferred solvents are tetrahydrofuran and ethylene glycol dimethyl ether or mixtures thereof with toluene. The Cu, Ni, Pd, Ti, Fe or Zn; * compounds can be used as catalysts, preferably the reaction is carried out without a ':' 'catalyst. The reaction temperature is -80 to 60 ° C, preferably -20 to 00 ° C. The reaction is selective and the resulting 4- (4-fluorobenzoyl) -2-halomethylbenzonitrile can be isolated and purified by crystallization or any other suitable method known in the art. The following reaction may also be carried out without isolation of the intermediate of formula II.

The final step is the reaction of the compound of formula EH with organometallic 3-dimethylaminopropyl halide followed by spontaneous ring closure to form citalopram. The metal component of the organometallic 3-dimethylaminopropyl halide used may be Mg, Li, Cu, or Zn, preferably Mg or Cu, most preferably Mg. Preferably, the reagent is a Grignard reagent of 3- (N, N-dimethylamino-propylhalide) wherein the halide is Cl or Br.

Most preferably, the reagent is 3- (N, N-dimethylamino) propylmagnesium chloride.

The reaction is carried out in an inert organic solvent such as toluene or dimethylformamide or commonly used ethers such as tetrahydrofuran, diethyl ether, di-n-butyl ether, tetrabutylmethyl ether, ethylene glycol dimethyl ether or 1,4-dioxane. Preferred solvents are tetrahydrofuran or ethylene glycol dimethyl ether or mixtures thereof with toluene. The Cu, Ni, Pd, Ti, Fe or Zn compounds can be used as catalysts, preferably the reaction is carried out without a catalyst. The reaction temperature may be -80 ° C to 600 ° C, preferably -20 ° C to 0 ° C, and the reaction time is 0.5 to 15 hours, preferably less than 3 hours. .

»* ·; · · The ring closes spontaneously after the reaction to form citalopram. Resulting: '': Citalopram can be isolated as a base or pharmaceutically acceptable

t; I

•, ··: salt.

All reactions from 5-cyanophthalide to citalopram can be carried out in the same reactor. . 25 which makes the process convenient and saves costs and manpower when no isolation and purification processes are required.

:: <: The compound of the formula I can be used as the free base or as its pharmaceutically acceptable acid addition salt. The acid addition salts may be. prepared by known methods.

The following examples are merely illustrative of the invention and are not to be construed as limiting it.

112223 o EXAMPLE 1.

2-Chloromethyl-4-cyano-benzoyl chloride: 1-oxo-1,3-dihydro-isobenzofuran-5-carbonitrile (25 g), boron trifluoride dietherate (0.8 ml) and benzyltriethylammonium chloride (0.72 g) were suspended in 5 ml of thionyl chloride ) and refluxed for 17 hours. The excess thionyl chloride was distilled off under a nitrogen atmosphere until a temperature of 95 ° C was reached and reflux was continued for another 24 hours. The product was purified by distillation under reduced pressure. Yield 27.5 g, 92%. Melting point 44-44.5 C. 1 H NMR (CDCl 3, 400MHz): 4.83 (2H, s), 7.74

(1H, dd, J = 1.8 Hz), 7.89 (1H, d, J = 1 Hz), 8.25 (1H, d, J = 8 Hz). 13C NMR

10 (CDCl 3, 100MHz): 42.7, 116.8, 118.0,132.2,133.8,134.0, 135.7, 140.0, 166.9. IR

(KBr): □ 3108, 3077, 2963, 2239, 1755, 1604, 1298, 1195, 1103, 944, 935, 840 cm 'EXAMPLE 2.

3-Chloromethyl-4- (4-fluorobenzoyl) -benzonitrile: A solution of 4-fluorophenylmagnesium bromide (3.76 g) in tetrahydrofuran (15 mL) was added to a cooled solution of 2-chloromethyl-4-cyanobenzoyl chloride (3.95 g) in 10 mL of that the temperature did not rise above 0 0 C. The mixture was slowly warmed to room temperature and stirred overnight. Impregnated ..; : ammonium chloride solution (60 mL) was added and stirring continued for 0.5 h. Phases • 1! 1 20 was separated and the aqueous phase was extracted with diethyl ether (30 mL). The combined organic phases were dried over sodium sulfate, filtered, and dried in vacuo to give a brown solid ci * · 1 '. Flash chromatography (ethyl acetate / n-hexane = 1/10) gave the product as a colorless solid. Yield 2.95 g, 58%. 1 H NMR (CDCl 3, 400MHz): 4.71 (2H, s), 7.16-7.21 (2H, m), 7.46 (1H, d, J = 7.9 Hz), 7.71 (1H, dd, J = 1.5, 7.9 Hz), 7.81-7.86 δ (2H, m), 7.89 (1H, d, J = 1.5 Hz). 13C NMR (CDCl3, 100MHz): 42.3, 115.0, 116.4, 116.6, 117.9, 129.6, 132.95, 132.98, 133.4, 133.5, 134.3, 138.7, 142.4, 165.5, 168.1, t »*; 1,194.5.

* <· <I · S> · f · »» 1 30 · · 9 112223 EXAMPLE 3.

1- (3-Dimethylamino-propyl) -1- (4-fluorophenyl) -1,3-dihydro-isobenzofuran-5-carbonitrile:

A freshly prepared solution of 3-dimethylaminopropylmagnesium chloride (0.6 M in THF, 7.6 5 mL) was added to a cooled solution of 3-chloromethyl-4- (4-fluorobenzoyl) -benzonitrile in ethylene glycol dimethyl ether, so that the temperature did not rise above -4 ° C. minutes at -15 ° C and 100 minutes at room temperature before 0.5 N hydrobromic acid was added to adjust the pH to 10. The phases were separated and the aqueous phase was extracted twice with toluene (25 mL). The combined organic phases were dried over sodium sulfate, filtered and dried in vacuo to give a viscous oil (0.44 g, 75%). Spectral and analytical data were consistent with literature.

EXAMPLE 4.

1- (3-Dimethylaminopropyl) -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-15 carbonitrile in one vessel 1-oxo-1,3-dihydroisobenzofuran-5-carbonitrile (5 g), Boron trifluoride etherate (0, 2 ml) and benzyltriethylammonium chloride (0.36 g) were suspended in thionyl chloride (18 µl) and warmed to reflux for 6 hours. Excess thionyl chloride was distilled off under a nitrogen atmosphere and reflux was continued for a further 17 hours. Toluene (50 mL) was added 5 "x 20 and volatiles (45 mL) were distilled off. Dry tetrahydrofuran (25 mL) was added and: 6.26 g) in dry tetrahydrofuran (25 ml) was slowly added at -15 ° C. The reaction mixture was stirred at room temperature for 3 'hours and 3-dimethylaminopropyl magnesium chloride (4.36 g) in dry tetrahydrofuran (20 ml) was slowly added at -15 ° C: The reaction mixture was stirred at room temperature overnight and heated to reflux for 1 hour. The reaction was quenched with saturated ammonium chloride solution (300 mL) and the phases were separated. The aqueous phase was extracted 3 times with tertiary butyl methyl ether (100 mL). the combined organic phases II · '...' were washed with brine (100 mL) and dried over sodium sulfate a. Filtration and evaporation of the volatiles yielded: a brown oil, which was dissolved in 1 N hydrochloric acid (250 ml) and toluene (150 ml). The phases were separated and the organic phase was washed with 1N hydrochloric acid (100 mL). The combined aqueous phases 10112223 were treated with concentrated sodium hydroxide solution to give a pH of 14. The mixture was extracted 3 times with toluene (100 mL) and the combined organic phases were washed with brine (100 mL) and dried over sodium sulfate. Filtration and evaporation of the volatiles gave a brown oil. Yield: 1 g, 10%. Spectral and 5 analytical data were in agreement with the scam.

* t »I ·» »• I» »X · t · i> ·: · 1 I · t»! <«» I t · • »» i »<» I t · • · -; »T t ·«: 1 1 t i 1 · i l I »t ·

Claims (14)

A process for the preparation of 1- (3-dimethylaminopropyl) -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile of formula I, 10L10, comprising the steps of: a) Halogenating 5-cyanophthalide to give a compound of the formula II, wherein X is halogen; b) reaction of a compound of formula II with an organometallic 4-fluorophenyl halide or I (i '' -, 10 4-fluorophenylborane) to give a compound of formula III »O 1; 111 NC / X" "| FX:" and c) reaction of a compound of formula III with organometallic; ] / dimethylaminopropyl halide to give 1- (3-dimethylaminopropyl) -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5 ': carbonitrile (citalopram). 112223 The method of claim 1, wherein the organometallic 4-fluorophenyl halide of step b) is a Grignard reagent. The method of claim 1 or 2, wherein the Grignard reagent of step b) is 4-fluorophenylmagnesium bromide. A process according to any one of claims 1 to 3, wherein the organometallic dimethylaminopropyl halide of step c) is a Grignard reagent. A process according to any one of claims 1 to 4, wherein the Grignard reagent of step c) is 3-dimethylaminopropylmagnesium chloride. A process according to any one of claims 1 to 5 wherein X is Cl or 10 Br. A process according to any one of claims 1 to 6 wherein X is Cl. 8. A compound of formula III, O m X • '(wherein X is halogen. The compound of claim 8, wherein X is I, Cl or Br. • »': 10. A compound according to claim 8 or 9 wherein X is Cl. • · A compound of formula Π, t JO? · X • * • · "* '· wherein X is halogen. • · • · · 11 112223 The compound of claim 11, wherein X is Cl or Br. 112223 The compound of claim 11 or 12, wherein X is Cl. The process according to any one of claims 1 to 7, carried out in a single vessel without separation of intermediates. • »• 1 1 · · 112223