HK1068069B - Method for the preparation of intermediate of citalopram - Google Patents

Description

Process for the preparation of intermediates of citalopram

The application is a divisional application of Chinese patent application 01133947.0 filed on 8, 17.2001.

Technical Field

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

Background

Citalopram is a well-known antidepressant drug that has been on the market for several years and has the following structural formula:

formula I

It is a selective, centrally active 5-hydroxytryptamine (5-hydroxytryptamine; 5-HT) reuptake inhibitor and thus has antidepressant activity. Antidepressant activity of this compound has been reported in several publications, such as J.Hyttel prog.neuro-Psychopharmacol. & biol.Psychiat.1982, 6, 277-295 and A.Gravem Acta Psychiatr.Scand.1987, 75, 478-486. Further effects in the treatment of dementiｃA and cerebrovascular diseases are disclosed in EP-A-474580.

Citalopram is disclosed for the first time in DE 2657013 corresponding to US 4136193. This patent publication describes a process for the preparation of citalopram and outlines another process which 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 by reacting the corresponding 5-bromo derivative with cuprous cyanide.

By ring-closure of the compounds of the formula II in the presence of dehydrating agents according to the methods described only briefly

Formula II

And then exchanging the 5-bromo group with cuprous cyanide to obtain citalopram. The starting material of formula II is obtained from 5-bromo-2-benzo [ c ] furanone by two consecutive Grignard reactions, i.e. with 4-fluorophenylmagnesium chloride and N, N-dimethylaminopropylmagnesium chloride, respectively.

A new and surprising process and intermediates for the preparation of citalopram is described in US 4650884, according to which process an intermediate of formula III is prepared

Formula III

Dehydrating with concentrated sulfuric acid to perform ring-closing reaction to obtain citalopram. The intermediate of formula III is obtained from 5-cyano-2-benzo [ c ] furanone by two consecutive Grignard reactions, i.e. using 4-fluorophenyl magnesium halide and N, N-dimethylaminopropyl magnesium halide, respectively.

Other processes are disclosed in international applications WO98019511, WO98019512 and WO 98019513. WO98019512 and WO98019513 relate to processes in which 5-amino, 5-alkoxycarbonyl or 5- (secondary aminocarbonyl) -2-benzo [ c ] furanone is subjected to two successive grignard reactions, a ring closure reaction and the resulting 1, 3-dihydroisobenzofuran derivative is converted to the corresponding 5-cyano compound, i.e. citalopram. International patent application WO98019511 discloses a process for the preparation of citalopram wherein a (4-substituted-2-hydroxymethylphenyl- (4-fluorophenyl) methanol compound is subjected to a ring closure reaction and the resulting 5-substituted 1- (4-fluorophenyl) -1, 3-dihydroisobenzofuran is converted to the corresponding 5-cyano derivative which is alkylated with a (3-dimethylamino) propyl halide to give citalopram.

Finally, a process for the preparation of the individual enantiomers of citalopram is disclosed in US4943590, wherein it is also indicated that the ring closure reaction of the intermediate of formula III may be performed via a labile ester base.

It has now surprisingly been found that citalopram may be prepared in a new, advantageous and safe way using convenient starting materials.

Disclosure of Invention

The present invention therefore relates to a novel process for the preparation of citalopram of formula I,

formula I

The method comprises the following steps:

converting the compound of formula VIII to a compound of formula IV,

of the formula VIII

Wherein Z is a halogen atom or a halogen atom,

formula IV

The compound of formula IV is subsequently converted to citalopram.

In particular, the invention relates to a method comprising:

i) reacting a compound of formula IV with a dehydrating agent and a compound of formula H₂N-SO₂-sulfonamide reaction of R, wherein R is:

a) optionally substituted NH₂Or C_1-6An alkoxy group,

b) optionally substituted by halogen, C_1-4Alkyl, cyano, hydroxy, C_1-4Alkoxy, trifluoromethyl, nitro, amino, C_1-4Alkylamino or di-C_1-4An alkylamino-substituted aryloxy or heteroaryloxy group, or

c) Optionally substituted by halogen, C_1-4Alkyl, cyano, hydroxy, C_1-4Alkoxy, trifluoromethyl, nitro, amino, C_1-4Alkylamino or di-C_1-4An alkylamino substituted aryl or heteroaryl group;

or

ii) conversion of the compound of formula IV into the corresponding amide of formula V

Formula V

Wherein R is¹And R²Independently of one another is hydrogen, C_1-6Alkyl, C substituted by one or more substituents selected from the group consisting of_1-6Alkyl groups: aryl and heteroaryl, hydroxy, C_1-6Alkoxy, aryloxy, heteroaryloxy, aryl-C_1-6-alkoxy, or trisubstitutedWherein the substituents in the trisubstituted silyl group are independently C_1-6Alkyl, aryl, heteroaryl or aryl-C_1-6An alkyl group, then reacting the amide of formula V with a dehydrating agent,

thereby obtaining citalopram in base form or a pharmaceutically acceptable salt thereof.

The reaction to convert the 5-carboxy derivative of formula IV to the amide of formula V can be carried out by an activated acid derivative of formula VI:

formula VI

Wherein R is³Is halogen, C_1-6Alkoxy, aryloxy, heteroaryloxy, aryl-C_1-6-alkoxy, heteroaryl-C_1-6-alkoxy, alkyl carbonate, aryl carbonate, alkyl carbamate, aryl carbamate, alkyl thiocarbonate, aryl thiocarbonate, alkyl thiocarbamate, aryl thiocarbamate, alkyl acyloxy, aryl acyloxy, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

In another aspect, the invention relates to a process for preparing an intermediate of formula IV comprising converting a compound of formula VIII wherein Z is halo to a compound of formula IV.

In another aspect, the invention relates to a process for preparing an intermediate of formula VII,

formula VII

Wherein X is selected from halogen, CN, OR⁵Or SR⁶Wherein R is⁵And R⁶Independently selected from C_1-6Alkyl, aryl, heteroaryl or benzyl, these C_1-6Alkyl, aryl, heteroaryl or benzyl are unsubstituted or substituted by: halogen, C_1-4Alkyl, cyano, hydroxy, C_1-4An alkoxy group,trifluoromethyl, nitro, amino, C_1-4Alkylamino or di-C_1-4-alkylamino radical, NR⁷R⁸Wherein R is⁷And R⁸Independently selected from hydrogen, C_1-6Alkyl, aryl, heteroaryl or benzyl, these C_1-6Alkyl, aryl, heteroaryl or benzyl being unsubstituted or substituted by halogen, C_1-6Alkyl, cyano, hydroxy, C_1-4Alkoxy, trifluoromethyl, nitro, amino, C_1-4Alkylamino or di-C_1-4Alkylamino substituted;

y being O, S or NR⁹Wherein R is⁹Selected from hydrogen, C_1-6Alkyl, aryl, heteroaryl or benzyl, these C_1-6Alkyl, aryl, heteroaryl or benzyl being unsubstituted or substituted by halogen, C_1-4Alkyl, cyano, hydroxy, C_1-4Alkoxy, trifluoromethyl, nitro, amino, C_1-4Alkylamino or di-C_1-4Alkylamino substituted;

the method comprises the following steps: converting the compound of formula VIII to a compound of formula VII,

of the formula VIII

Wherein Z is halogen.

In another aspect, the present invention relates to an antidepressant pharmaceutical composition comprising citalopram in base form or any suitable salt thereof prepared by the process of the present invention.

Throughout the specification and claims, the term "dehydrating agent" refers to any suitable dehydrating agent, and the optimal agent can be readily determined by one skilled in the art. An example of a suitable dehydrating agent is SOCl₂，POCl₃，PCl₅，SOBr₂，POBr₃，PBr₅，SOI₂，POI₃，PI₅，P₄O₁₀Oxalyl chloride, carbonyldiimidazole and Vilsmeier reagent. Preferably, a chlorine-containing reagent is used, most preferably SOCl₂Or POCl₃. The Vilsmerier reagent is formed by mixing N, N-Dimethylformamide (DMF) with a dehydrating agent, such as DMF/SOCl₂And DMF/POCl₃。

Throughout the specification and claims, C_1-6Alkyl means branched or unbranched alkyl having 1 to 6 carbon atoms, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-2-propyl, 2, 2-dimethyl-1-ethyl and 2-methyl-1-propyl. Similarly, C_1-4Alkyl means such a radical having 1 to 4 carbon atoms, C_1-6Alkoxy radical, C_1-4Alkoxy and C_1-4Alkylamino refers to such groups wherein the alkyl moiety is as defined.

Halogen means fluorine, chlorine, bromine or iodine.

In process i) of the invention, a possible but non-limiting reaction mechanism is the reaction of the 5-carboxy compound of formula IV with a dehydrating agent to form the corresponding activated derivative, which is then reacted with a sulfonamide H₂N-SO₂-R reacts, thereby forming citalopram. In the latter reaction, a catalytic amount of acid may be necessary.

Sulfonamide H for use in the process₂N-SO₂R is preferably sulfamide H₂N-SO₂-NH₂。

Optionally substituted NH used in the method₂Tert-butylamine is preferred.

The reaction with the dehydrating agent in the process of the present invention may be carried out without a solvent or in a suitable solvent such as sulfolane or acetonitrile. When a solvent is used in the dehydration reaction of ii), a catalytic amount of N, N-dimethylformamide may be required.

In a preferred embodiment of the present invention, the process for the preparation of citalopram and/or a compound of formula IV or VII comprises:

a) reacting a 5-halo analog of formula VIII

Of the formula VIII

Wherein Z is a halogen atom or a halogen atom,

with Mg or organolithium compounds, e.g. n-butyllithium, or with organometallic complexes consisting of Mg and/or Mn and/or Li and alkyl or aryl groups, followed by reaction with CO₂，CS₂Or a compound of formula IX, or a pharmaceutically acceptable salt thereof,

formula IX

Wherein A and X are independently selected from halogen, CN, OR⁵Or SR⁶Wherein R is⁵And R⁶Independently selected from C_1-6Alkyl, aryl, heteroaryl or benzyl, these C_1-6Alkyl, aryl, heteroaryl or benzyl are unsubstituted or substituted by: halogen, C_1-4Alkyl, cyano, hydroxy, C_1-4Alkoxy, trifluoromethyl, nitro, amino, C_1-4Alkylamino or di-C_1-4Alkylamino radical, NR⁷R⁸Wherein R is⁷And R⁸Independently selected from hydrogen, C_1-6Alkyl, aryl, heteroaryl or benzyl, these C_1-6Alkyl, aryl, heteroaryl or benzyl being unsubstituted or substituted by halogen, C_1-4Alkyl, cyano, hydroxy, C_1-4Alkoxy, trifluoromethyl, nitro, amino, C_1-4Alkylamino or di-C_1-4Alkylamino substituted; y being O, S or NR⁹Wherein R is⁹Selected from hydrogen, C_1-6Alkyl, aryl, heteroaryl or benzyl, these C_1-6Alkyl, aryl, heteroaryl or benzyl being unsubstituted or substituted by halogen, C_1-4Alkyl, cyano, hydroxy, C_1-4Alkoxy, trifluoromethyl, nitro, amino, C_1-4Alkylamino or di-C_1-4Alkylamino substituted;

and in a process for the preparation of citalopram or a compound of formula IV, followed by reaction with water, an aqueous hydroxide such as sodium hydroxide, or an acid;

b) reacting a compound of formula VIII

Of the formula VIII

Wherein Z is Br or I, and the compound is,

coupling with an optionally substituted vinyl or acetylenic group in the presence of a metal catalyst such as a nickel or palladium based catalyst followed by oxidation of the vinyl or acetylenic group to a carboxyl group to provide a compound of formula IV;

in process a), an example of an organometallic complex is that of the formula (R)⁴)₃Trialkyl magnesium compound (magnesium) of MgLi, formula (R)⁴)₃A trialkyl manganese compound of MnLi (magnesium) and a compound of formula (R)⁴)₃Mixed magnesium and manganese complexes of MnMgBr, where R⁴Denotes C which may be the same or different_1-6Alkyl or aryl. From Grignard reagents R⁴MgX (X is a halogen) and organolithiums such as n-butyllithium can produce trialkyl magnesiums in situ. From MnCl₂And organolithiums such as n-butyllithium may form trialkyl manganates in situ. From Grignard reagents R⁴MgX and MnCl₂Can prepare (R)⁴)₃MnMgBr. The starting 5-bromo compound of formula VIII can be obtained as described in US 4136193.

Examples of starting materials of the formula IX in process a) are ethyl chloroformate, phenyl chloroformate, benzyl chloroformate, vinyl chloroformate, isobutyl chloroformate, ethyl thiocarbonate, methyl cyanoformate, carbonyldiimidazole and diethyl carbonate. The starting material of formula IX can be purchased commercially or prepared by methods known in the literature.

In process b), the nickel-based catalyst may be any suitable catalytically active Ni (0) or Ni (II) containing complex, such as Ni (PPh)₃)₃And (sigma-aryl) -Ni (PPh)₃)₂Cl and the palladium-based catalyst can be any suitable Pd (0) or Pd (II) containing catalyst) Catalysts such as Pd (PPh)₃)₄，Pd(dba)₃And Pd (PPh)₂Cl₂. The oxidizing agent may be any suitable agent, such as a peroxide in the presence of a ruthenium catalyst. The starting compounds in which B is a triflate group can be obtained as described in WO 0013648. Examples of vinyl or acetylenic groups coupled with compounds of formula VIII include methyl acrylate, 1-bromobut-1-ene, propyne, trimethyl (prop-1-enyl) stannane, E-1-hexenylboronic acid and prop-1-enyl trifluoromethanesulfonate.

The compounds of formula I may be used in the form of the free base or as a pharmaceutically acceptable acid addition salt thereof. As the acid addition salt, a salt with an organic or inorganic acid can be used. Examples of such organic salts are salts with maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, oxalic acid, dimethylene salicylic 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 thereof such as 8-bromotheophylline. Examples of such inorganic salts are salts with hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid.

Acid addition salts of the compounds may be prepared by methods known in the art. The base is reacted with a calculated amount of acid in a water-miscible solvent such as acetone or ethanol, and the salt is then isolated by concentration and cooling; or the base is reacted with an excess of the acid in a water immiscible solvent such as diethyl ether, ethyl acetate or dichloromethane, with automatic separation of the salt.

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

The pharmaceutical formulations of the present invention may be prepared by methods conventional 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 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 such as colorants, fragrances, preservatives and the like may be used provided they are compatible with the active ingredient.

The injection solution can be prepared by dissolving the active ingredient and possible additives in a portion of a solvent for injection, preferably sterile water, adjusting the solution to a desired volume, sterilizing and filling into suitable ampoules or vials. Any suitable additive commonly used in the art may be added, such as tonicity agents, preservatives, antioxidants, and the like.

Detailed Description

The present invention is further illustrated in detail by the following examples, which should not be construed as limiting the scope of the invention.

Example 1

5-carboxy-1- (4-fluorophenyl) -1- (3-dimethylaminopropyl) -1, 3-dihydro-isobenzofuran

Methods a) -Mg

A solution of 1- (4-fluorophenyl) -1- (3-dimethylaminopropyl) -1, 3-dihydro-isobenzofuran-5-yl magnesium bromide in anhydrous THF (90ml), prepared conventionally from 5-bromo-1- (4-fluorophenyl) -1- (3-dimethylaminopropyl) -1, 3-dihydro-isobenzofuran (9g, 0.024mol) and magnesium (0.73g, 0.03mol), was added to dry solid CO₂(50g) In (1). After the addition was complete, the mixture was left at room temperature for 16 hours.

Volatiles were removed under vacuum and the residue was dissolved with water (100 g). The pH was adjusted to 5.5 by addition of hydrochloric acid (aq, 4N). The aqueous phase was extracted with toluene (100 ml).

Toluene was removed in vacuo to give the title compound as an oil. The yield was 6 g.

Process a) -n-butyllithium

To a solution of 5-bromo-1- (4-fluorophenyl) -1- (3-dimethylaminopropyl) -1, 3-dihydro-isobenzofuran (9g, 0.024mol) in tert-butyl methyl ether (150ml) was added n-butyllithium (1.6M in hexane, 40ml) at-78 ℃ to-65 ℃. The temperature of the solution was raised to-30 ℃ over 2 hours. Adding the reaction mixture to dry solid CO₂(50g) In (1). After the addition was complete, the mixture was left at room temperature for 16 hours. Volatiles were removed under vacuum and the residue was dissolved with water (100 g). The pH was adjusted to 5.5 by addition of hydrochloric acid (aq, 4N). The aqueous phase was extracted with toluene (100 ml). Toluene was removed in vacuo to give the title compound as an oil. Yield 7.5 g.

Process a) -Trialkylmagnesium Compound

To a solution of isopropyl magnesium chloride (8.0ml, 2M in ether) in THF (25ml) was added n-butyllithium (20ml, 1.6M in hexane) at 0 ℃. The resulting mixture was stirred at 0 ℃ for 1 h, then cooled to-78 ℃ and a solution of 5-bromo-1- (4-fluorophenyl) -1- (3-dimethylaminopropyl) -1, 3-dihydro-isobenzofuran (5.0g, 13mmol) in THF (25ml) was added. The mixture was warmed to-10 ℃ over 1 hour, then cooled to-78 ℃ and CO was added₂(5.7g, 130 mmol). The mixture was warmed to room temperature and then evaporated. The residue was chromatographed by ion exchange chromatography (Dowex)^50, acid form), with 1M NH₃Elution afforded the product as a viscous oil.

Example 2

5-cyano-1- (4-fluorophenyl) -1- (3-dimethylaminopropyl) -1, 3-dihydro-isobenzofuran (citalopram, free base)

5-carboxy-1- (4-fluorophenyl) -1- (3-dimethylaminopropyl) -1, 3-dihydro-isobenzofuran (5g, 0.015mol) and sulfamide (1.65g, 0.017mol) were dissolved in sulfolane (15 ml). Thionyl chloride (2.25g, 0.019mol) was added at room temperature and the temperature of the reaction mixture was raised to 130 ℃ for 2 hours. The reaction mixture was cooled to 75 ℃ and water (25ml) was added. The temperature was maintained at 75 ℃ for 15 minutes, and then the reaction mixture was cooled to room temperature. The pH was adjusted to 9 with aqueous ammonia, then n-heptane (75ml) was added. The temperature was raised to 70 ℃ and the hot n-heptane layer was separated and cooled to give the crystalline title compound. Yield 3.77 g. Purity (HPLC peak area) > 97%.

Claims (2)

1. A process for the preparation of a compound of formula IV,

formula IV

Comprising converting a compound of formula VIII to a compound of formula IV,

of the formula VIII

Wherein Z is a halogen atom or a halogen atom,

the steps are as follows:

i) reacting a compound of formula VIII

Of the formula VIII

Wherein Z is a halogen atom or a halogen atom,

with Mg or organolithium compounds or with LiMg (i-Pr) (n-Bu)₂Reacting to obtain a first intermediate;

ii) subsequently reacting said first intermediate with CO₂Reacting to generate a second intermediate;

iii) then reacting said second intermediate with an aqueous acid solution.

2. The process according to claim 1, wherein the organolithium compound is n-BuLi.