KR20010031877A - Method for preparation of citalopram - Google Patents

Abstract

R ¹ is CN, C _1-6 alkyloxycarbonyl or C _1-6 alkylaminocarbonyl. Reduction of the oxo group of the compound of formula 4 and ring closure of the resulting hydroxy compound, whereby corresponding 1- (4-fluorophenyl) -1,3-dihydroisobenzofuran is obtained, and then if R ¹ is cyano, use it directly in the next step and if R ¹ is C _1-6 alkyloxycarbonyl or C _{1- If 6} alkylaminocarbonyl, convert to the corresponding compound wherein R ¹ is cyano; And alkylating the resulting 5-cyano compound with halogenated 3-dimethyl-aminopropyl under basic conditions to obtain citalopram.

(Formula 4)

Description

Method for producing citalopram {METHOD FOR PREPARATION OF CITALOPRAM}

Citalopram is a well known antidepressant that has been on the market for several years and has the following structure:

It is an optional, centrally active serotonin (5-hydroxytrytamine; 5-HT) reuptake inhibitor and therefore has antidepressant activity. Antidepressant activity of the compounds has been described in several papers, such as J. Hyttel, Prog. Neuro-Psychopharmacol. & Biol. Psychiat., 1982, 6,277-295 and A. Gravem, Acta Psychiatr. Scand., 1987, 75, 478-486. This compound is further disclosed in EP-A 474580 to be effective in the treatment of dementia and cerebrovascular disorders.

Citalopram was first disclosed in DE 2,657,271, corresponding to US 4,136,193. This patent describes the preparation of citalopram by one method and outlines another method that may be used to prepare citalopram.

According to the described method, the corresponding 1- (4-fluorophenyl) -1,3-dihydro-5-isobenzofurancarbonitrile is 3- (N, N) chloride in the presence of methylsulfinylmethide as a condensing agent. Reacts with -dimethylamino) propyl. Starting materials are prepared from the corresponding 5-bromo derivatives by reaction with copper cyanide.

According to the method outlined only in general terms, citalopram can be obtained by ring closure of the following compound in the presence of a dehydrating agent and by substitution of copper cyanide with a 5-bromo group:

The starting material of formula (2) is obtained by two successive Grignard reactions, respectively, from 5-bromophthalide with 4-fluorophenyl magnesium chloride and N, N-dimethylaminopropyl magnesium chloride.

Novel and surprising methods and intermediates for the preparation of citalopram have been described in US Pat. No. 4,650,884, whereby the intermediate of the following equation undergoes a ring closing reaction by dehydration with a strong acid to obtain citalopram.

Intermediates of formula 3 are prepared by two successive Grignard reactions, respectively, from 5-cyanophthalide with halogenated 4-fluorophenyl magnesium and halogenated N, N-dimethylaminopropyl magnesium.

Finally, a process for preparing each enantiomer of citalopram is disclosed in US Pat. No. 4,943,590, which also performs a ring closure of the intermediate of Formula 3 via an unstable ester with base.

Surprisingly, citalopram has now been found to be prepared by novel, advantageous and safe methods using convenient starting materials.

The present invention provides a known antidepressant drug citalopram, 1- [3- (dimethylamino) propyl] -1- (4-fluorophenyl) -1,3-dihydro-5-isobenzofurancarbonitrile It is about a method.

Summary of the Invention

The present invention therefore relates to a novel process for the preparation of citalopram comprising the following steps:

a) reducing the compound of formula 4;

(Wherein R ¹ is CN, C _1-6 alkyloxycarbonyl or C _1-6 alkylaminocarbonyl),

b) closing the resulting compound of formula 5 to thereby obtain a compound of formula 6;

(Wherein R ¹ is the same as defined above)

In which R ¹ is as defined above

c) then if R ¹ is cyano noramyeon directly using the compound of formula (6) in the next step and if R ¹ is a compound of C _1-6 alkyloxycarbonyl or C _1-6 alkyl aminocarbonyl if formula (6) R ¹ is Converting to the cyanoin corresponding compound; And

d) alkylating the resulting 5-cyano compound of formula 6 (R ¹ = CN) with halogenated 3-dimethylaminopropyl under basic conditions to obtain citalopram, which is isolated as a base or a pharmaceutically acceptable salt thereof step.

(Formula 1)

In another aspect, the present invention provides a novel intermediate of formula (5).

Yet another aspect of the invention relates to a novel intermediate for the preparation of citalopram of formula (6) when R ¹ is C _1-6 alkyloxycarbonyl or C _1-6 alkylaminocarbonyl.

However, in another aspect, the present invention relates to a pharmaceutical composition of an antidepressant drug comprising citalopram prepared by the method of the present invention.

Throughout the specification and claims, C _1-6 alkyl is a branched or unbranched alkyl group having 1 to 6 carbon atoms, for example methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl, 2,2-dimethyl-1-ethyl and 2-methyl-1-propyl.

The halogenated 3-dimethylaminopropyl used may be chloride, bromide or iodide and is preferably chloride.

The reduction of the compound of formula 4 can be carried out with any convenient reducing agent and preferably by basic NaBH ₄ in alcohols such as ethanol or methanol or by zinc in aqueous acetic acid under basic conditions.

The ring closure of the compound of formula (5) can be done via an acid or with an unstable ester with a base. Acid ring closure can be carried out with inorganic acids such as sulfuric acid or phosphoric acid or with organic acids such as methylsulfonic acid, p-toluenesulfonic acid or trifluoro acetic acid. Basic ring closures are unstable esters such as methane sulfonyl, p-toluene sulfonyl, 10-camphorsulfonyl, trifluoroacetyl or trifluoromethanesulfonyl esters with addition of bases such as triethylamine, dimethylaniline, pyridine and the like. It can be carried out via. The reaction is preferably carried out in an inert solvent which is cooled, especially at about 0 ° C. and preferably by a one-bowl method with simultaneous addition of esterification and base.

When R ¹ is an alkylaminocarbonyl group, conversion to cyano groups can be carried out by conventional nitrile synthesis. The amide of formula (5), wherein R ¹ is an alkylaminocarbonyl group, is preferably converted to a cyano compound, ie citalopram, by reaction with a dehydrating agent, most preferably thionyl chloride or phosphorus pentachloride.

When R ¹ is an alkyloxycarbonyl group, conversion to cyano is preferably carried out via a corresponding amino group which is converted to a cyano group in the same manner as the compound of formula 6 when R ¹ is an alkylaminocarbonyl group.

The reaction of alkyloxycarbonyl to amides is carried out by amidation by hydrolysis with acids or bases followed by conversion to acid chlorides and with ammonia or alkylamines, preferably t-butyl amines. Acid hydrolysis can be carried out by the use of any suitable acid such as HBr, HCl, HBr / acetic acid. Basic hydrolysis can be carried out with any suitable base such as K ₂ CO ₃ , NaOH, KOH and the like. Conversion to amides can also be obtained by reaction of an ester (R ¹ is an alkyloxycarbonyl group) with ammonia or alkylamine under pressure and heating. The amide obtained is converted to a cyano group as previously described.

Alternatively esters, ie compounds of formula 6 wherein R ¹ is an alkyloxycarbonyl group, can be hydrolyzed and then reacted with chlorosulfonyl isocyanate to form nitriles.

The alkylation in step d) is carried out in a suitable solvent such as ether, preferably 1,2-dimethoxyethane (DME), THF, diglyme or diethyl ether, preferably lithium diisopropylamine (LDA). Is carried out by addition of halogenated 3-dimethylaminopropyl to the compound of formula 6 (R ¹ = CN) in the presence of

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

Other reaction conditions such as solvents are conventional conditions for such a reaction and are readily determined by those skilled in the art.

Starting materials of the formula (4) can be prepared from the corresponding phthalide compounds by the reaction of Ghalnard reagent of 4-halogen-fluorophenyl as illustrated by magnesium halide in the following scheme:

(Wherein R ¹ is as defined above).

When R ¹ is a cyano group, starting materials of the general formula (7) are Tirouflet, J .; Bull.Soc. It may be prepared as described in Sci. Bretagne 26, 1959, 35.

Other starting materials of formula 4 can be prepared from 5-carboxyphthalide by reaction with thionyl chloride and then C _1-6 alkanol or C _1-6 alkylamine. 5-carboxyphthalide is commercially available and can be prepared by well known methods (Tirouflet, J .; Bull. Soc. Sci. Bretagne 26, 1959, 35).

In a preferred embodiment of the invention R ¹ is cyano.

In another embodiment of the invention, R ¹ is C _1-6 alkyloxycarbonyl and the C _1-6 alkyl group is preferably ethyl, propyl or butyl, preferably ethyl, 2-propyl or t-butyl.

However, in another embodiment of the invention, R ¹ is C _1-6 alkylaminocarbonyl and the C _1-6 alkyl group is preferably ethyl, propyl or butyl, preferably ethyl, 2-propyl or t-butyl, most Preferably t-butyl.

Compounds of general formula (1) can be used as free base or as pharmaceutically acceptable acid addition salts thereof. As acid addition salts, salts formed with organic or inorganic acids may be used. Examples of such organic salts are maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, oxalic acid, bismethylenesalicylic acid, methanesulfonic acid, ethanedisulfonic acid, acetic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid, malic acid, mannic acid Delic acid, cinnamic acid, citraconic acid, aspartic acid, stearic acid, palmitic acid, itaconic acid, glycolic acid, p-aminobenzoic acid, glutamic acid, benzene sulfonic acid and 8-halodeophylline, for example 8-bromodeophylline As well as salts with deophylline acetic acid. Examples of such inorganic salts are salts with hydrochloric acid, bromic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid.

Acid addition salts of compounds can be prepared by methods known in the art. React the base with a calculated amount of acid in a solvent that can be mixed with water, such as acetone or ethanol, and subsequently isolate the salt by concentration and cooling, or a solvent that cannot be mixed with water, such as ethylether, ethyl acetate or dichloromethane The reaction is carried out with an excess of acid and the salt is isolated at the same time.

The pharmaceutical compositions of the present invention may be administered in any suitable method and in any suitable form and may be administered orally or in parenteral form, for example, in the form of tablets, capsules, powders or syrups, or in the form of conventional sterile solutions for injection. .

The pharmaceutical preparations of the present invention can be prepared by conventional methods in the art. For example, tablets may be prepared by mixing the active ingredient with conventional adjuvants and / or diluents and then compressing the mixture in a conventional tablet machine. Examples of adjuvants and diluents include: corn starch, potato starch, talc, magnesium stearate, gelatin, lactose, gums and the like. Other auxiliaries and additives, flavors, preservatives and the like can also be used if they are compatible with the active ingredient.

Injection solutions are prepared by dissolving the active ingredient and possible additives in a portion of the solvent for injection, preferably sterile water, adjusting the solution to the desired volume, sterilizing the solution and filling it with an appropriate ampoule or vial. Any suitable additive conventionally used in the art may be added such as tonics, preservatives, antioxidants and the like.

The invention is further elucidated by the following examples.

Example 1

(4-cyano-2-hydroxymethylphenyl) (4-fluorophenyl) methanol.

Brominated 4-fluorophenylmagnesium solution prepared from 4-fluorobromobenzene (605 g, 3.45 mole) and magnesium turning (107 g, 4.4 mole) in dry THF (1200 mL) was diluted with 5- in dry THF (3000 mL). Dropwise was added to a suspension of cyanophthalide (500 g, 3.14 mole). The temperature was kept below 5 ° C. After the addition was complete the reaction mixture was stirred at room temperature overnight.

Ethanol (4500 mL) was added to the reaction mixture and NaBH ₄ (238 g, 6.30 mole) was added to the mixture in a ratio of 50 g and stirred at room temperature overnight. About 2/3 of the solvent was removed in vacuo and water (4000 mL) was added to the reaction mixture. The resulting solution was extracted with EtOAc (2 × 500 mL). Evaporation of the solvent left the crude title product (780 g) as oil, which was considered pure enough for the next reaction.

Pure samples are obtained after column chromatography on silica gel using EtOAc / n-Heptane (1/1) as eluent. The title compound is obtained as crystals after evaporation of the eluent. DSC start: 116.5 ° C.

Analytical calculations for C ₁₅ H ₁₂ N ₁ F ₁ O ₂ ; C, 70.02; H, 4.71; N, 5.45. Found C, 70.01; H, 4.71; N, 5.51.

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

Crude (4-cyano-2-hydroxymethylphenyl) (4-fluorophenyl) methanol (700 g) was dissolved in H ₃ PO ₄ (60%, 3000 mL) and the solution was heated to 80 ° C. for 3 h. Toluene (1000 mL) was added and the layers were separated. The aqueous layer was further extracted with toluene (1000 mL). The toluene layers were combined and the solvent removed in vacuo. The remaining crystals were recrystallized from EtOH (99%). Yield 219 g (29%). DSC start: 97 ° C.

Analytical calculations for C ₁₅ H ₁₀ N ₁ F ₁ O ₁ ; C, 75.30; H, 4. 22; N, 5.86. Found C, 75.01; H, 4. 22; N, 5.83.

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

n-BuLi (1.6 N in hexane, 320 mL) was added to diisopropylamine (55 g, 0.5 mole) dissolved in DME (150 mL) at −50 ° C. in a nitrogen atmosphere. 1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile (62 g, 0.26 mole) was dissolved in DME (500 mL) and added dropwise while maintaining the temperature below -40 ° C. . After addition (45 min) the deep red solution was stirred for 20 min. 3-dimethylpropyl chloride (100 g, 0.82 mole) was added in one portion at -50 ° C and cooling was removed. After 60 minutes, the solution was heated to 50 ° C. for 120 minutes. The reaction mixture was poured into iced water (1 L) and extracted with toluene (2 x 500 mL). The organic layer was extracted with HCl (4N, 500 mL). The acid solution was made alkaline (pH = 10) with NaOH (10N) and extracted with toluene (500 mL) washed with water (3 × 200 mL). The toluene layer was dried over anhydrous Na ₂ SO ₄ (50 g), treated with activated carbon and the solvent removed in vacuo. The title compound (64-71 g, 76-84%) was obtained as an oil.

Oxalic acid salt was crystallized from acetone. DSC start: 156 ° C. Analytical calculations for C ₂₂ H ₂₃ N ₂ F ₁ O ₅ ; C, 63.75; H, 5. 60; N, 6.76. Found C, 61.60; H, 5. 62; N, 6.63.

Example 2

(4-ethoxycarbonyl-2-hydroxymethylphenyl) (4-fluorophenyl) methanol.

Brominated 4-fluorophenylmagnesium solution prepared from 4-fluorobromobenzene (21 g, 0.12 mole) and magnesium turning (3.4 g, 0.14 mole) in dry THF (150 mL) was diluted with 5-ethoxy in dry THF (150 mL). To the suspension of carbonylphthalide (20.6 g, 0.1 mole) was added dropwise. The temperature was kept below 5 ° C. After the addition was complete, the reaction mixture was stirred at room temperature overnight.

Ethanol (300 mL) was added to the reaction mixture, NaBH ₄ (7.6 g, 0.2 mole) was added to the mixture in a ratio of about 1 g, and stirred at room temperature for 4 hours. The solvent was removed in vacuo and ammonium chloride (saturated aqueous 300 mL) was added to the remaining oil. The pH of the resulting solution was adjusted to 7.2 with aqueous 4N HCl and extracted with EtOAc (2 × 100 mL). Evaporation of the solvent left the crude title product (30 g) as oil, which was considered sufficiently pure for the next reaction.

Ethyl 1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carboxylate.

Crude (4-ethoxycarbonyl-2-hydroxymethylphenyl) (4-fluorophenyl) methanol (30 g) was dissolved in H ₃ PO ₄ (60%, 250 mL) and the solution was heated to 80 ° C. for 1.5 h. . Water (300 mL) and EtOAc (100 mL) were added and the phases were separated. The aqueous layer was further extracted with EtOAc (100 mL). The organic layers were combined and the solvent removed in vacuo. The remaining slightly impure oil yield was 30 g.

1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carboxylic acid.

Crude ethyl 1- (4-fluorophenyl) -1, 3-dihydroisobenzofuran-5-carboxylate

(30 g) was dissolved in EtOH (96%, 150 ml) and aqueous 2N NaOH (150 ml). The solution was refluxed for 1 hour. One half of the volume was removed in vacuo. The aqueous layer was extracted with EtOAc (2 × 100 ml). The aqueous layer was made acidic (pH = 1, conc. HCl) and cooled to 5 ° C. and the white crystals were filtered off. Yield 16 g. Overall yield was 66% starting from 5-ethoxycarbonylphthalide. Melting point 187-190 ° C.

The obtained compound was then converted to the corresponding cyano compound which was again alkylated as described in Example 1.

Claims (24)

A method for preparing citalopram comprising the following steps. a) reducing the compound of formula 4; (Formula 4) (Wherein R ¹ is CN, C _1-6 alkyloxycarbonyl or C _1-6 alkylaminocarbonyl) b) closing the resulting compound of formula 5 to thereby obtain a compound of formula 6; (Formula 5) (Wherein R ¹ is the same as defined above) (Formula 6) (Wherein R ¹ is the same as defined above) c) then if R ¹ is cyano noramyeon directly using the compound of formula (6) in the next step and if R ¹ is a compound of C _1-6 alkyloxycarbonyl or C _1-6 alkyl aminocarbonyl if formula (6) R ¹ is Converting to the cyanoin corresponding compound; And d) alkylating the resulting 5-cyano compound of formula 6 (R ¹ = CN) with halogenated 3-dimethylaminopropyl under basic conditions to obtain citalopram, which is isolated as a base or a pharmaceutically acceptable salt thereof step. (Formula 1) The method of claim 1 wherein R ¹ is CN. The method of claim 1 wherein R ¹ is C _1-6 alkyloxycarbonyl. The method of claim 1 wherein R ¹ is C _1-6 alkylaminocarbonyl. The process according to claim 3 or 4, characterized in that the C _1-6 alkyl is ethyl-, propyl-, or butyl, preferably ethyl, 2-propyl or t-butyl, most preferably t-butyl. Way. 6. The process according to claim 1, wherein the reduction of the compound of formula 4 is carried out by the use of NaBH ₄ in alcohol such as ethanol or methanol under basic conditions. 7. 7. The acidic reaction according to any one of claims 1 to 6, wherein the ring closure of the compound of formula 5 is carried out by an inorganic acid such as sulfuric acid or phosphoric acid, or by an organic acid such as methylsulfonic acid, p-toluenesulfonic acid or trifluoroacetic acid. Characterized in that by closing the ring. 7. The ring closure of claim 1, wherein the ring closure of the compound of formula 5 is preferably carried out by basic ring closure via an unstable ester with simultaneous esterification and addition of a base. Way. 9. The method of claim 8 wherein the labile ester is methane sulfonyl, p-toluene sulfonyl, 10-camphorsulfonyl, trifluoroacetyl or trifluoromethanesulfonyl ester and the base is triethylamine, dimethylaniline or pyridine How to feature. 4. A process according to claim 3, wherein the conversion of C _1-6 alkyloxycarbonyl to cyano is carried out via the corresponding amide group. The reaction according to claim 10, wherein the reaction of C _1-6 alkyloxycarbonyl to amides is hydrolyzed with an acid or a base followed by conversion to an acid chloride and with ammonia or an alkylamine, preferably t-butyl amine Characterized in that it is carried out by amidation with. The process according to claim 11, wherein the hydrolysis is carried out by the use of a suitable acid such as HBr, HCl, HBr / acetic acid. The process according to claim 11, wherein the hydrolysis is carried out by the use of a suitable base, preferably K ₂ CO ₃ , NaOH or KOH. 9. A process according to claim 8, wherein the reaction of C _1-6 alkyloxycarbonyl to amides is carried out by reacting the ester with ammonia or alkylamine under pressure and heating. The process according to claim 4, wherein the amide is converted to a cyano group by reaction with a dehydrating agent, preferably thionyl chloride or phosphorus pentachloride. The process according to claim 1, wherein the halogenated 3-dimethylaminopropyl used as alkylating agent in step d) is chloride, bromide or iodide, preferably chloride. The process according to claim 1, wherein the alkylation in step d) is carried out in ether, preferably 1,2-dimethoxyethane, THF, diglyme or diethyl ether. 18. The process according to claim 1, wherein the alkylation in step d) is carried out in the presence of a base, preferably lithiumdiisopropylamine. 19. The reaction according to any one of claims 1 to 18, wherein the starting material of formula 4 is reacted with Grignard reagent of 4-halogen-fluorophenyl, preferably halogenated 4-fluorophenylmagnesium, most preferably magnesium bromide. Prepared from the corresponding phthalide compounds. The process of claim 1 wherein R ¹ is cyano and the starting material of formula 4 is prepared from the corresponding phthalide compound by reaction with halogenated 4-fluorophenylmagnesium and the reduction in a) is carried out to NaBH ₄ in alcohol. Wherein the ring closure in b) is carried out with an inorganic acid and the alkylation in d) is carried out by the use of dimethylaminopropyl chloride in ether in the presence of lithium diisopropylamine. Compound of formula (5). (Formula 5) (Wherein R ¹ is CN, C _1-6 alkyloxycarbonyl or C _1-6 alkylaminocarbonyl) Compound of formula 6. (Formula 6) (Wherein R ¹ is C _1-6 alkyloxycarbonyl or C _1-6 alkylaminocarbonyl) An antidepressant pharmaceutical composition comprising citalopram prepared by the method of any one of claims 1 to 20. The compound of formula 6 is subjected to halogenated 3-dimethyl-aminopropyl under basic conditions, carried out in ether, preferably 1,2-dimethoxyethane, THF, diglyme or diethyl ether in the presence of lithium diisopropylamine. A method for producing citalopram comprising alkylation. (Formula 6) (Wherein R ¹ is CN)