HK1055744A - Method for the preparation of citalopram - Google Patents

Description

Process for the preparation of citalopram

The present invention relates to a process for the preparation of the well-known antidepressant drug citalopram, 1- [3- (dimethylamino) propyl ] -1- (4-fluorophenyl) -1, 3-dihydro-5-isobenzofurancarbonitrile.

Background

Citalopram is a well known antidepressant drug that has been on the market for some years, having the following structure:it is a selective, centrally acting serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor and therefore has antidepressant activity. The antidepressant activity of this compound has been reported in several publications, such as prog.&Biol.psychiat., 1982, 6, 277-. EP-A-474580 also discloses the effect of the compound in the treatment of dementiｃA and cerebrovascular diseases.

Citalopram was originally disclosed in DE 2,657,013, which corresponds to US 4,136,193. This patent publication describes one process for the preparation of citalopram and outlines another process that may be used for the preparation of citalopram.

According to the described process, 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 was prepared from the corresponding 5-bromo derivative by reaction with cuprous cyanide.

International patent application WO 98/019511 discloses a process for the preparation of citalopram in which a (4- (cyano, alkoxycarbonyl or alkylaminocarbonyl) -2-hydroxymethylphenyl- (4-fluorophenyl) methanol compound is ring-closed the resulting 5- (alkoxycarbonyl or alkylaminocarbonyl) -1- (4-fluorophenyl) -1, 3-dihydroisobenzofuran is converted to the corresponding 5-cyano derivative, which is then alkylated with a (3-dimethylamino) propyl halide to obtain citalopram.

We have now surprisingly found that citalopram may be prepared by a novel and convenient process in which 1- (4-fluorophenyl) -1, 3-dihydroisobenzofuran is alkylated with a compound which can be converted to dimethylaminopropyl.

The alkylation process of the present invention is particularly advantageous because the formation of by-products from the polymerization of the alkylating agent is avoided, thereby potentially reducing the amount of alkylating agent used. In addition, the process of the invention provides higher yields.

Summary of The Invention

The present invention relates to a process for the preparation of citalopram comprising reacting a compound of formula (III),wherein Y is cyano OR a group which can be converted into cyano, R is hydrogen, -OR¹、NH₂、NHCH₃or-N (CH)₃)₂Wherein R is¹Selected from hydrogen, alkyl, alkenyl, alkynyl and aryl or aralkyl optionally substituted with alkyl;

the following reactions are carried out in either order:

i) reducing the double bond in the side chain-CH ═ CH-COR; and

ii) converting the group-COR or its reduced form into a dimethylaminomethyl group; and

iii) if Y is not cyano, converting the group Y into cyano;

the citalopram base or a pharmaceutically acceptable acid addition salt thereof is then isolated. The above-mentioned conversions of i), ii) and iii) can be carried out in any order.

In a particular embodiment of the invention, the reduction of the double bond mentioned in i) above is carried out before converting the group-COR or its reduced form into a dimethylaminomethyl group (as described in ii) above).

The conversion of the group Y to a cyano group may be carried out at any suitable time during the reaction. In a particular embodiment, the compound of formula (III) used is a compound wherein Y is cyano.

According to a preferred embodiment of the invention, the compound of formula (III) is prepared by reacting a compound of formula (I) with a compound of formula (II) to form a compound of formula (III):in the formula IY is cyano or a group which can be converted into cyano,in formula II, R is hydrogen, -O-R¹、-NH₂、-NHCH₃、-N(CH₃)₂Wherein R is¹Selected from hydrogen, alkyl, alkenyl, alkynyl and aryl or aralkyl optionally substituted with alkyl.

In another aspect, the present invention provides novel intermediates having the general formula (III).

In a further aspect, the present invention relates to an antidepressant pharmaceutical composition comprising citalopram prepared by the process of the present invention.

The group Y which can be converted into cyano can be chosen from halogen, -O-SO₂-(CF₂)_n-CF₃(wherein n is 0-8), -CHO, -COOR ', -CONR ' R ' or-NHR ', wherein R ' and R ' are selected from hydrogen, alkyl, alkenyl, alkynyl or aryl or aralkyl optionally substituted with alkyl, R ' is hydrogen or alkylcarbonyl, or Y is a group represented by the following formula (IV):wherein U is O or S; r¹²-R¹³Each independently selected from hydrogen and alkyl, or R¹²And R¹³Together form C_2-5An alkylene chain, thereby forming a spiro ring; r¹⁰Selected from hydrogen and alkyl, R¹¹Selected from hydrogen, alkyl, carboxyl or precursor groups thereof, or R¹⁰And R¹¹Together form C_2-5An alkylene chain, thereby forming a spiro ring; y may be any other group that can be converted to a cyano group.

The alkylation step of reacting a compound of formula (I) with a compound of formula (II) is suitably carried out by treating a compound of formula (I) with a base, such as LDA (lithium diisopropylamine), LiHMDS (lithium hexamethyldisilazane), NaH, NaHMDS (sodium hexamethyldisilazane) or a metal alkoxide, such as NaOMe, KOMe, LiOMe, sodium tert-butoxide, potassium tert-butoxide or lithium tert-butoxide, in an aprotic organic solvent, such as THF (tetrahydrofuran), DMF (dimethylformamide), NMP (N-methylpyrrolidinone), an ether, such as diethyl ether or dioxane (dioxalane), toluene, benzene or an alkane and mixtures thereof. The anion formed is then reacted with a compound of formula (II) whereby a group of formula-CH ═ CH-COR is introduced in position 1 of the isobenzofuranyl ring system.

Where the-COR group is-CON (CH) can suitably be reduced by reduction in toluene using Red-A1 as reducing agent₃Is converted into the corresponding compound wherein this group is dimethylaminomethyl.

when-COR is-CONHCH₃or-CONH₂When present, it may be converted to a dimethylaminomethyl group by, in either order, reductive amine formation and methylation or reductive amination formation of a dimethylaminomethyl group.

The reduction of the amide can be carried out in toluene using Red-Al as reducing agent.

Methylating agents, e.g. MeI or Me, may be used₂SO₄(wherein Me is methyl) methylation of the amine is carried out. The methylation is carried out using the general procedure for carrying out this reaction.

Alternatively, methylation can be by reductive amination to form dimethylaminomethyl groups. According to this method, with NH₂Or NHCH₃Compounds of radicals in reducing agents, e.g. NaBH₄Or NaBH₃With a compound such as formaldehyde, paraformaldehyde or trioxane in the presence of CN. The reductive amination is carried out using the general procedure for carrying out this reaction.

When R is-CHO, it can be converted to a dimethylaminomethyl group by reductive amination with dimethylamine or a salt thereof. Suitably by reaction with a reducing agent, such as NaBH₄Or NaBH₃CN with dimethylamine in the presence of N. Dimethylamine can be added to the reaction as the dimethyl ammonium chloride salt or as the dimethylamine metal salt.

When R is-COOR¹When desired, they may be formed by conversion to the corresponding amide followed by reduction, and optionally methylation or reductive aminationDimethylaminomethyl to effect conversion to dimethylaminomethyl.

Amides may be obtained by reaction of esters with amines, preferably NH (Me)₂Or a salt thereof.

When R is-COOR¹Alternatively, this group can be converted to the dimethylaminomethyl group by first reducing to the corresponding alcohol, then converting the alcohol group to the appropriate leaving group and subsequently carrying out the following reaction:

a) reacting with dimethylamine or a salt thereof,

b) with methylamine, followed by methylation or reductive amination to form dimethylamino groups, or

c) Reacted with a nitride and then reduced to form the corresponding amino compound, followed by methylation or reductive amination to form a dimethylamino group.

From which-COR is-COOR by reduction of the ester using Red-A1 as reducing agent¹The compound of (1) to prepare an alcohol.

The alcohol group may be converted to a suitable leaving group, such as a halogen, or corresponding to the formula-O-SO, by reaction with a reagent such as thionyl chloride, methanesulfonyl chloride, toluenesulfonyl chloride and the like₂-R⁰Sulfonate of (2), wherein R⁰Is alkyl, alkenyl, alkynyl or aryl or aralkyl optionally substituted with alkyl.

The resulting compound with the appropriate leaving group is then reacted with dimethylamine or a salt thereof, e.g. M⁺，^-N(CH₃)₂(wherein M is⁺Is Li⁺Or Na⁺) The reaction is suitably carried out in an aprotic organic solvent, such as THF (tetrahydrofuran), DMF (dimethylformamide), NMP (N-methylpyrrolidone), an ether, such as diethyl ether, or dioxane, toluene, benzene, or an alkane, and mixtures thereof. The leaving group can also be replaced by a dimethylamino group by reaction with dimethylammonium chloride in the presence of a base. Alternatively, with a suitable leaving group [ e.g. -O-SO₂-R⁰(R⁰As defined above) ofSulfonic acid radical]The compound of (a) can be reacted with a nitride, such as sodium nitride, and then reduced using Pd/C as a catalyst to form a free amino group, followed by methylation or reductive amination to form a dimethylamino group.

The leaving group may also be replaced by a dimethylamino group by reaction with methylamine, followed by methylation or reductive amination to form dimethylamine.

Methylating agents may be used, such as MeI and Me₂SO₄(wherein Me is methyl) is methylated. The methylation is carried out using the general procedure for carrying out this reaction.

Alternatively, methylation is carried out by reductive amination as described above.

When Y is halogen or CF₃-(CF₂)_n-SO₂O-where n is 0 to 8, by reaction between a palladium catalyst and a catalytic amount of Cu⁺Or Zn²⁺In the presence of a cyanide source, e.g. KCN, NaCN, CuCN, Zn (CN)₂Or (R)¹⁵)₄NCN reaction, or with Zn (CN) in the presence of a palladium catalyst₂Reaction to effect conversion to a cyano group, wherein (R)¹⁵)₄Denotes four groups which may be the same or different, selected from hydrogen and linear or branched alkyl. Y can be halogen or CF in the presence of a palladium catalyst as described in WO 0013648₃-(CF₂)_n-SO₂-O- (wherein n is 0-8) with a cyanide source.

When Y is Cl or Br, it can also be prepared by reaction with a cyanide source, for example KCN, NaCN, CuCN, Zn (CN), in the presence of a nickel catalyst₂Or (R)¹⁵)₄The NCN reaction effects the conversion to a cyano group, wherein (R)¹⁵)₄Denotes four groups which may be the same or different, selected from hydrogen and linear or branched alkyl. Y can be halogen or CF in the presence of a nickel catalyst as described in WO 0011926₃-(CF₂)_n-SO₂-O- (wherein n is 0-8) with a cyanide source.

When Y is an oxazoline or thiazolinyl group represented by the general formula (IV), the conversion to a cyano group can be effected as described in WO 0023431.

When Y is CHO, it can be prepared by reacting a formyl group with the reagent R¹⁶-V-NH₂Reaction to convert it to an oxime or similar group, followed by dehydration to a cyano group with a common dehydrating agent, such as thionyl chloride, acetic anhydride/pyridine, pyridine/HCl or phosphorus pentachloride, wherein R is¹⁶Is hydrogen, alkyl, aryl or heteroaryl, and V is O, N or S. Preferred reactants R¹⁶-V-NH₂Is hydroxylamine and wherein R¹⁶A compound in which V is N or O and is an alkyl group or an aryl group.

When Y is-COOH, the conversion to cyano can be via the corresponding acid chloride, ester or amide.

The acid chloride may be obtained by reacting with POCl₃、PCl₅Or SOCl₂Conveniently by treating the acid as such or in a suitable solvent, such as toluene or toluene containing a catalytic amount of N, N-dimethylformamide. The esters can be prepared by reacting an acid, preferably a mineral acid or a Lewis acid, such as HCl, H₂SO₄、POCl₃、PCl₅Or SOCl₂In the presence of an alcohol. Alternatively, the ester may be obtained by reacting an acid chloride with an alcohol. The ester or acid chloride may then be converted to an amide by amidation with ammonia or an alkyl amine, preferably tert-butylamine.

The conversion to the amide may also be achieved by reacting the ester with ammonia or an alkyl amine under pressure and with heating.

The amide group is then converted to a cyano group by dehydration. The dehydrating agent may be any suitable dehydrating agent, and the optimal dehydrating agent can be easily determined by one skilled in the art. An example of a suitable dehydrating agent is SOCl₂、POCl₃And PCl₅Preferably SOCl₂。

In a particularly preferred embodiment, the carboxylic acid is reacted with an alcohol, preferably ethanol, in POCl₃In the presence of a catalyst to obtainTo the corresponding ester, which is then reacted with ammonia to give the corresponding amide, which is subsequently reacted with SOCl in toluene with a catalytic amount of N, N-dimethylformamide₂And (4) reacting.

Alternatively, to form a nitrile, the compound in which Y is-COOH may be reacted with chlorosulfonyl isocyanate, or treated with a dehydrating agent and a sulfonamide as described in WO 0044738.

When Y is-NHR '(wherein R' is hydrogen), it is preferably diazotized and then reacted with CN^-Reacting to convert it to a cyano group, most preferably using NaNO₂And CuCN and/or NaCN. When R '"is alkylcarbonyl, the compound is first hydrolyzed to give the corresponding compound with R'" being H, which is then converted as described above, the hydrolysis being carried out in an acidic or basic environment.

Starting materials of formula (I) wherein Y is halogen may be prepared as described in GB 1526331, wherein Y is-O-SO₂-(CF₂)_n-CF₃The compounds of formula (I) in which Y is an oxazoline or thiazoline group may be prepared in a manner analogous to the compounds described in WO99/00640, the compounds of formula (I) in which Y is an oxazoline or thiazoline group may be prepared in a manner analogous to the compounds described in WO 00/23431, the compounds in which Y is formaldehyde may be prepared in a manner analogous to the compounds described in WO 99/30548, the compounds in which Y is-COOH, and the esters and amides thereof may be prepared in a manner analogous to the compounds described in WO98/19511, and the compounds of formula (I) in which Y is-NHR' may be prepared in a manner analogous to the compounds described in WO 98/19512.

The reaction conditions, solvents, etc. used in the above-mentioned reactions are general conditions for carrying out such reactions, and can be easily determined by those skilled in the art.

The starting material of formula (I) wherein Y is cyano may be prepared as described in U.S. Pat. No. 4,136,193 or WO 98/19511.

The compounds of the formula (II) are commercially available or can be prepared using customary methods from commercially available starting materials.

Citalopram is sold as an antidepressant in the racemic form. However, in the near future the active S-enantiomer of citalopram will also be marketed.

S-citalopram may be prepared by separation of the optical isomers by chromatography.

Throughout the specification and claims, the term "alkyl" refers to a branched or straight chain alkyl group containing from 1 to 6 (inclusive) carbon atoms, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-2-propyl, 2-dimethyl-1-ethyl and 2-methyl-1-propyl.

Similarly, alkenyl and alkynyl respectively denote groups containing 2-6 carbon atoms which respectively contain a double bond and a triple bond, such as ethenyl, propenyl, butenyl, ethynyl, propynyl and butynyl.

The term "aryl" refers to mono-or bicyclic carbocyclic aryl groups such as phenyl and naphthyl, especially phenyl.

The term "aralkyl" refers to arylalkyl groups, wherein aryl and alkyl are as defined above.

"aryl and aralkyl optionally substituted with alkyl" refers to aryl and aralkyl groups that may be optionally substituted with one or more alkyl groups.

Halogen means chlorine, bromine or iodine.

Citalopram may be used as the free base, especially in crystalline form, or as a pharmaceutically acceptable acid addition salt thereof. As the acid addition salt, a salt with an organic acid or an inorganic acid can be used. Examples of such organic salts are those formed with maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, oxalic acid, bismethylsalicylic acid, methanesulfonic acid, ethanedisulfonic acid, acetic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid, malic acid, mandelic acid, cinnamic acid, citraconic acid, aspartic acid, stearic acid, palmitic acid, itaconic acid, glycolic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid and theophylline acetic acid, and 8-halotheophyllines, such as 8-bromotheophylline. Examples of such inorganic salts are those formed with hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid.

The acid addition salts of citalopram may be prepared by methods well known in the art. The base is either reacted with a calculated amount of acid in a water-soluble solvent such as acetone or ethanol followed by concentration and cooling to separate the salt, or reacted with an excess of acid in a water-immiscible solvent such as diethyl ether, ethyl acetate or dichloromethane to separate the salt spontaneously.

The pharmaceutical compositions of the present invention may be administered in any suitable manner and in any suitable form, such as orally in the form of tablets, capsules, powders or syrups, or parenterally in the form of sterile injectable solutions generally.

The pharmaceutical formulations of the present invention may be prepared by methods common in the art. For example, tablets may be prepared by mixing the active ingredient with conventional adjuvants and/or diluents and subsequently compressing the mixture in a conventional tabletting machine. Examples of adjuvants or diluents include: corn starch, potato starch, talc, magnesium stearate, gelatin, lactose, gums, and the like. Any other adjuvants or additives, colorants, fragrances, preservatives and the like may be used provided they are compatible with the active ingredient.

The injection can be prepared by the following method: the active ingredient and possible additives are dissolved in a small amount of solvent for injection, preferably sterile water, the solution is adjusted to the desired amount, the solution is sterilized and filled into suitable ampoules or vials (visual). Any suitable additive commonly used in the art may be added, such as muscle building agents, preservatives, antioxidants, and the like.

The invention will now be further illustrated by the following examples.

Example 1

A solution of 1- (4-fluorophenyl) -1, 3-dihydroisobenzofuran-5-carbonitrile (4.8 g, 0.02 mol) in tetrahydrofuran (50 ml) was added dropwise to a solution of LDA (1.6M butyllithium (15 ml), 2.6 g diisopropylamine) at-30 ℃ under a nitrogen atmosphere. After stirring at-30 ℃ for 10 minutes, a solution of the compound of formula (II) (0.02 mol) in tetrahydrofuran (25ml) was added dropwise and allowed to warm to room temperature, followed by stirring for an additional 60 minutes. The reaction was then quenched with ice, extracted with toluene (3 × 50 ml), washed with water (50 ml), and concentrated under reduced pressure. The residue was purified by chromatography on silica gel using a mixture of n-heptane/ethyl acetate as eluent.

Claims (9)

1. A process for the preparation of citalopram comprising reacting a compound of formula (III),wherein Y is cyano OR a group which can be converted into cyano, R is hydrogen, -OR¹、NH₂、NHCH₃or-N (CH)₃)₂Wherein R is¹Selected from hydrogen, alkyl, alkenyl, alkynyl and aryl or aralkyl optionally substituted with alkyl; the following reactions are carried out in either order:

i) reducing the double bond in the side chain-CH ═ CH-COR; and

ii) converting the group-COR or its reduced form into a dimethylaminomethyl group; and

iii) if Y is not cyano, converting the group Y into cyano;

the base of citalopram or a pharmaceutically acceptable acid addition salt thereof is then isolated.

2. A process according to claim 1, wherein the compound of formula (III) is prepared by reacting a compound of formula (I) with a compound of formula (II) to form a compound of formula (III),in formula I, Y is cyano or a group which can be converted into cyano,in formula II, R is hydrogen, -O-R¹、-NH₂、-NHCH₃、-N(CH₃)₂Wherein R is¹Selected from hydrogen, alkyl, alkenyl, alkynyl and aryl or aralkyl optionally substituted with alkyl.

3. The method of claim 1, wherein-COR is-CON (CH)₃And this group is converted to a dimethylaminomethyl group by reduction.

4. The process of claim 1, wherein-COR is-CONHCH₃or-CONH₂And the conversion of these groups is achieved by reduction and methylation or reductive amination in either order to form dimethylaminomethyl groups.

5. The method of claim 1, wherein R is-CHO and the conversion to dimethylaminomethyl group is achieved by reductive amination with dimethylamine or a salt thereof.

6. The method of claim 1 wherein R is-COOR¹And conversion to the dimethylaminomethyl group is effected by conversion to the corresponding amide followed by reduction, and optionally methylation or reductive amination to form the dimethylaminomethyl groupThe transformation of (3).

7. The method of claim 1 wherein R is-COOR¹And this group is converted to the dimethylaminomethyl group by reduction to the corresponding alcohol, followed by conversion of the alcohol group to the appropriate leaving group and subsequent reaction of:

a) reacting with dimethylamine or a salt thereof,

b) with methylamine, followed by methylation or reductive amination to form dimethylamino groups, or

c) Reacted with a nitride and then reduced to form the corresponding amino compound, followed by methylation or reductive amination to form a dimethylamino group.

8. A compound having the following formula (III):wherein Y is cyano OR a group which can be converted into cyano, R is hydrogen, -OR¹、NH₂、NHCH₃or-N (CH)₃)₂Wherein R is¹Selected from hydrogen, alkyl, alkenyl, alkynyl and aryl or aralkyl optionally substituted with alkyl.

9. Citalopram prepared by the process according to claims 1-7.