Patent Application
20050209467
The present invention relates to a novel method for the preparation of 1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile, which is a well known antidepressant, citalopram.
Citalopram is a selective, centrally acting serotonin (5-hydroxytryptamine; 5HT) reuptake inhibitor having antidepressant activity. This activity has been described e.g. in J. Hyttel, Prog. Neuro-Psychopharmacol. & Biol. Psychiat., 1982, 6, 277-295 and A. Gravem, Acta Psychiatr. Scand., 1987, 75, 478-486. In EP-A 474 580 it has been disclosed that citalopram has also effects in the treatment of dementia and cerebrovascular disorders.
Citalopram has the following structure:
Citalopram was first described in DE 2,657,013 corresponding to U.S. Pat. No. 4,136,193. It was prepared by the reaction of 1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile with a 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 a reaction with cuprous cyanide. The other, in general terms outlined reaction comprises the ring closure of 5-bromo dihydroxy compound of formula A
in the presence of a dehydrating agent. After the ring closure the 5-bromo group is replaced by a cyano group using cuprous cyanide. A compound of formula A is obtained from 5-bromophthalide by two successive Grignard reactions.
Other preparation methods are described e.g. in U.S. Pat. No. 4,650,884, U.S. Pat. No. 4,943,590, WO 98/19511, WO 98/19512, WO 98/19513, WO 99/30548, WO 2000/12044, WO 2000/13648 and WO 2000/23431.
In U.S. Pat. No. 4,943,590 preparation methods of individual enantiomers of citalopram are disclosed. In the process described dihydroxy compound of formula B
is first transferred into an ester and ring closure is then achieved in the presence of a base.
In WO 02/060886 there is discribed a process where 5-cyanophthalide is first halogented and thereafter citalopram is obtained via two Grignard reactions.
The present invention is directed to novel processes for the preparation of citalopram comprising halogenation of a phthalide compound of formula II,
wherein R is a suitable group to be changed to CN, to afford an acid halogenide compound of formula III
wherein R is as defined above and X is halogen, and threafter obtaining citalopram through two successive reactions with suitable organometallic halides or organoboranes or by a reaction with organometallic 4-fluorophenylhalide or 4-fluorophenylborane followed by reduction and alkylation, and an exchange of R to cyano to afford citalopram. The order of the reactions can be varied depending e.g. on the starting compound used. The benefit of the first step to the acid chloride is a higher selectivity of the following reaction.
Resulting citalopram can be purified by methods known in the art and it is isolated as the base or a pharmaceutically acceptable salt thereof.
Another aspect of the present invention are novel intermediate compounds of formula IIa and IVa
wherein R′ is as defined in claim 2 and X is a halogen excluding from compounds of formula ma those wherein R′ is CN, R1 is Cl or Br while X is Br, or R′ is I while X is Cl, and from compounds of formula IVa those compounds where R′ is CN.
Still another aspect of the present invention are the preparation methods of novel intermediate compounds of formula IIIa and IVa.
Halogen means chloro, bromo, or iodo.
Alkyl means branched or unbranched alkyl groups having 1 to 6 carbon atoms, inclusive. Examples are methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl, etc.
Aryl means mono or bicyclic carboxylic aromatic group, such as phenyl and naphthyl, in particular phenyl or ring substituted phenyl. Also heteroaryl groups are possible.
Protective group R1 in —CH2OR1 can be e.g. methyl, benzyl, allyl, or any other group which protects 0 from the reaction with halogenation agents used.
Protective groups R2 and R3 in —NR2R3 can be e.g. alkyl or aryl, e.g. benzyl or allyl, or alkylcarbonyl, e.g. acetyl.
The process of the present invention from the selected cyanophthalide compounds to citalopram via acid halogenide is not described in any of the patents mentioned or in any other publication known.
Surprisingly, it has been found that if certain phthalide compounds used as starting materials in the citalopram process are halogenated, the reaction of the resulting compound of formula III or IIIa with an organometallic 4-fluorophenylhalide or with a 4-fluorophenyl borane is very selective and the following reactions give citalopram in good yield and purity. Citalopram can be prepared from compounds of formula III or IIIa via two Grignard reactions, using first organoborane reagents and thereafter Grignard reaction, or it can be prepared by Grignard or organoboron reaction followed by reduction of the ketone and ring closure and alkylation with the dimethylaminopropyl moiety. If 5-substituent is not cyano, the compound is cyanated in a suitable phase by methods known in the art.
First aspect of the present invention is a method for the preparation of 1-(3-dimethylaminopropyl)-1-(4-fluoro-phenyl)-1,3-dihydroisobenzofuran-5-carbonitrile of formula I
comprising the steps:
Another aspect of the present invention is a method for the preparation of 1-(3-dimethylaminopropyl)-1-(4-fluoro-phenyl)-1,3-dihydroisobenzofuran-5-carbonitrile comprising the steps:
Still another aspect of the present invention is a method for the preparation of 1-(3-dimethylaminopropyl)-1-(4-fluoro-phenyl)-1,3-dihydroisobenzofuran-5-carbonitrile comprising the steps:
Still another aspect of the present invention is a method for the preparation of a compound of formula VI,
comprising reduction of a compound of formula IVa wherein X is a halogen and R′ is as defined in claim 2 excluding compounds where R′ is CN, and changing R′ to CN.
First step of the process is the halogenation of a compound of formula II or IIa to form the acid halogenide compound of formula III or IIIa where X is halogen, preferably chloro or bromo, most preferably chloro, and R is as defined in claim 1 and R′ as defined in claim 2.
The halogenation can be performed by any suitable method known in the art, eg. by the reaction with thionyl chloride in the presence of a suitable Lewis acid catalyst and a phase transfer catalyst. Catalysis by amines, e.g. pyridine or 4-dimethylaminopyridine or by N,N-dimethylformamide (DMF) is also possible. If DMF is used as a catalyst, no phase transfer catalyst is needed. Suitable Lewis acid catalysts are e.g. MgCl2, MgBr2, SnCl2, SnCl4, ZnCl2, TiCl4, AlCl3, FeCl3, BF3Et2O, BCl3, B(OEt)3, B(OMe)3, B(O-iPr)3, preferably boron based Lewis catalyst is used. Types of phase transfer catalyst used are halides of aromatic or aliphatic ammonium salts, for example tetramethylammonium chloride, tetrabutylammonium chloride or benzyl triethylammonium chloride. The catalyst is used 0.1 to 20 mol %, preferably 0.5 to 10 mol % based on the moles of phthalide derivative. The reaction with catalysts is preferably performed without any solvent, but if a solvent is used, any inert, high boiling solvent such as toluene, xylene, chlorobenzene or dichlorobenzene can be used.
The halogenation reagent used can be any suitable reagent used for halogenation, e.g. thionyl chloride, PCl3, PCl5, CCl4 in triphenyl phosphine, oxalyl chloride or cyanuric chloride in trialkyl amine.
The reagents for preparing the corresponding bromo compound can be e.g. PBr3, PBr5, PPh3Br2, thionyl bromide or oxalyl bromide.
The halogenation reagent is used in the range from 0.5 to 1000 equivalents (based on phthalide derivative), preferably 1 to 10 equivalents, most preferably 1 to 5 equivalents. Reaction temperature can be from 20 to 150° C. or reflux temperature, preferably 80 to 140° C., most preferably 100 to 130° C. The reaction time is from 0.5 to 15 h, preferably less than 3 h.
The reaction will be completed readily and conversion is close to 100%. The product can be isolated and purified by suitable methods known in the art or the following step can be performed without purification of compound of formula m or IIIa.
Starting materials are either commercially available (e.g. if R′ is cyano or halogen) or they can be prepared by methods known in the art. If R′ is —OSO2(CF2)nCF3 the compounds can be prepared from the corresponding hydroxy compounds by a conventional triflation reaction. —CH2OR′ compounds can also be prepared from corresponding hydroxy compounds and —NR2R3 compounds from corresponding amino compounds by adding a suitable protective group by methods known in the art. Compounds with a CH3-group can be prepared e.g. as described by Noguchi et al. in Heterocycles, 23(5), p. 1085-1088. Compounds where R or R′ is —COOR4 or —CONR5R6 are commercialy available or they can be prepared from 5-carboxyphthalide by reaction with thionyl chloride and then with C1-6 alkanol or C1-6 alkylamine. If R or R′ is —C(OR7)2 compounds can be prepared e.g. as described in WO 02/48133. Preparation of oxazolinyl and thiazolinyl compounds is described e.g. in WO 01/51477.
The advantage of making the acid halogenide is that the following reaction with an organometallic 4-fluorophenyl halide or with 4-fluorophenyl borane is very selective unlike the reaction of the lactone directly with 4-fluorophenylmagnesium halide, where the resulting ketone compound is more reactive than lactone and undesirable side products are formed.
The second step comprises the reaction of the acid halogenide compound of formula III or IIIa with an organometallic or organoboron reagent to afford the compound of formula IV or IVa.
The reagent used is a 4-fluorophenylborane or a 4-fluorophenylmetallo halide, wherein the metallic component can be Mg, Li, Cu, or Zn, preferably Mg or Cu. Preferably the reagent is a 4-fluorophenylmagnesium halide or a Grignard reagent of a 1-halide substituted 4-fluorobenzene, wherein the halogen component is preferably Cl or Br. Most preferably 4-fluorophenylmagnesium bromide is used. The amount of the reagent used is from 0.5 to 2.5 equivalents, preferably from 1 to 1.5 equivalents, based on the equivalents of the compound of formula III or IIIa.
The reaction is carried out in an inert organic solvent such as toluene or dimethylformamide or in commonly used ethers such as tetrahydrofuran, diethylether, di-n-butylether, tetrabutylmethyl ether, ethylene glycol dimethyl ether, 1,4-dioxane or mixtures thereof. The preferred solvents are tetrahydrofuran and ethylene glycol dimethyl ether or their mixtures with toluene. Cu, Ni, Pd, Ti, Fe or Zn compounds can be used as catalysts, preferably the reaction is performed without any catalyst. Reaction temperature is −80 to 60° C., preferably −20 to 20° C. The reaction is selective and the resulting compound of formula IV or IVa can be isolated and purified by crystallization or any other suitable method known in the art. The following reaction can also be performed without isolation of the intermediate of formula IV or IVa.
The following step can be the exchange of R or R′ group to cyano group, whereafter citalopram is achieved by the reaction of compound of formula V with an organometallic 3-dimethylaminopropylhalide with a spontaneous ring closure to citalopram. The other possibility is the reduction of the compound of formula V and thereafter alkylation to afford citalopram. Citalopram can be purified by methods known in the art and it can be isolated as a base or as a pharmaceutically suitable salt.
The metallo component of the organometallic 3-dimethylaminopropyl halide reagent used can be Mg, Li, Cu, or Zn, preferably Mg or Cu, most prefereably Mg. Preferably the reagent is a Grignard reagent of a 3-(N,N-dimethylamino)propyl halide, wherein the halide is Cl or Br. Most preferably the reagent is 3-(N,N-dimethylamino)propylmagnesiumchloride. The reaction is carried out in an inert organic solvent such as toluene or dimethylformamide or in commonly used ethers such as tetrahydrofuran, diethylether, di-n-butylether, tetrabutylmethyl ether, ethylene glycol dimethyl ether or 1,4-dioxane or mixtures thereof. The preferred solvents are tetrahydrofuran or ethylene glycol dimethyl ether or their mixtures with toluene. Cu, Ni, Pd, Ti, Fe or Zn compounds can be used as catalysts, preferably the reaction is performed without any catalyst. Reaction temperature is −80 to 60° C., preferably −20 to 20° C. and the reaction time is from 0.5 to 15 h, preferably less than 3 h. The organometallic reagent is used from 0.5 to 2.5 equivalents, preferably from 1 to 1.5 equivalents, based on the equivalents of the compound of formula IV or IVa.
The reduction can be performed by methods well known in the art and the alkylation can be performed e.g. as described in EP 1125907.
The exchange reaction R or R′ to cyano can be performed by methods known in the art. If R′ is halogen or —OSO2(CF2)nCF3, the reaction with different cyanide compounds can be used e.g. as described in WO 00/13648 or in WO 00/11926.
Amide compounds can be converted to cyano compound e.g. as described in WO 01/66536 or in WO 99/30548 and amines as described in WO 98/19512.
—CH3-group is first oxidized to an acid and thereafter reacted with a primary amine to an amide, which is transferred to cyano as above described.
If R or R′ is —C(OR7)2, the conversion can be made first to aldehyde and then to cyano using standard procedures.
When R or R′ is an oxazoline or thiazoline, the conversion to cyano can be performed as described in WO 00/23431.
—OR-compounds are first deprotected to the corresponding alcohols which are sulphonated to a —OSO2(CF2)nCF3— group.
Another route to citalopram comprises the reaction of a compound of formula IVa where R′ is as defined in claim 2 excluding compounds where R′ is CN, with an organometallic 3-dimethylaminopropyl halide to afford a compound of formula VIIIa, which is then subjected to the exchange reaction R′ to CN to afford citalopram.
Still one possibility is the reduction of the compound of formula IVa to afford a compound of formula VIIa, which is then subjected to the exchange reaction R1 to cyano, if needed, and alkylated to citalopram, or first alkylated and thereafter R1 is changed to cyano to afford citalopram. The alkylation can be performed e.g. as described in U.S. Pat. No. 4,136,193 or in EP 1 125 907.
All the reactions from phthalide to citalopram can be performed in one pot which makes the process convenient and saves costs and labour when no isolation or purification processes of intermediates are needed.
The compound of formula I may be used as a free base or as a pharmaceutically acceptable acid addition salt thereof. The acid addition salts can be prepared by methods known in the art.
The following examples merely illustrate the invention and they are not to be construed as limiting.
A solution of 4-fluoro phenylmagnesium bromide 1M in tetrahydrofuran (25 ml) was added to a cooled solution of 2-chloromethyl-4-chloro-benzoyl chloride 2 (5.0 g) in toluene (35 ml) so that the temperature did not raise above 0° C. The mixture was stirred for two hours in 0° C. After 2 hours reaction time freshly prepared 3-dimethylaminopropylmagnesium chloride (0,79 mol/kg 21,5 ml) was added slowly to cooled reaction mixture at 0° C. The reaction was quenched after 2 hours by addition of water (50 ml) and the pH of the mixture was adjusted to 4-4,5 by addition of concentrated acetic acid. After phase separation the pH of the water layer was adjusted to 8-8,5 by addition of ammonia (25%). Extraction with toluene and evaporation yielded crude product (3,8 g) as brown oil. 1H NMR (CDCl3, 400 MHz): 1.39 (1H, m), 1.52 (1H, m), 2.16-2.31 (4H, m), 2,19 (6H, s), 5,16 (dd, J=1, 8 Hz), 7,02-7,50 (7H, m).
Triphenylphosphine (3.1 g, 0.012 mol) and nickel dichloride (0,38 g, 0.003 mol) in acetonitrile (120 ml) were refluxed for one hour. Zinc powder (0.2 g, 0.003 mol) and a solution of 1-(4-fluorophenyl)-1-(3-dimethylaminopropyl)-5-chlorophthalane (5 g) in warm acetonitrile (100 ml) were added with a time delay of 10 minutes. The mixture was cooled to room temperature and sodium cyanide (1.5 g, 0.03 mol) was added. After refluxing for 15 hours the mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure followed by refluxing of the residue in water (200 ml) for 20 minutes. Filtration and drying in vacuo gave the crude product as an oil.
To a suspension of 3-chloromethyl-4-(4-fluoro benzoyl)benzonitrile (1,0 g) in ethanol (10 ml) was added solid NaBH4 (0,07 g). The mixture was allowed to stir in room temperature overnight. The reaction was quenched by addition on water (5 ml) and the mixture was stirred for two hours. The white precipitate (0,18 g) was filttered and analysed by NMR and GC-MS. The yield was 21%. 1H NMR (CDCl3, 400 MHz): 5,12 (1H, d, J=12, 5 Hz), 5,26 (1H, d, J=12,5 Hz),6,08 (1H, s), 6,95-7,60 (7H).
Diisopropylamine (1 g, 0.01 mol) was added to tetrahydrofuran (5 ml) and cooled to +20° C. Butyl lithium (5.7 ml, 0.009 mol) was added dropwise and the mixture was stirred for 1 hour while the mixture warmed up to room temperature. After re-cooling to −20° C. a solution of 1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (2 g, 0.008 mol) in tetrahydrofuran (15 ml) was added dropwise, the mixture was stirred for 30 minutes and a solution of 3-(dimethylamino) propyl chloride (1.22 g, 0.01 mol) in tetrahydrofuran (5 ml) was added slowly. The reaction mixture was warmed up over night and water (30 ml) was added. Extraction of the aqueous phase with toluene, drying over magnesium sulfate, filtration and evaporation to dryness gave crude citalopram.
Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that, within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein.
| Number | Date | Country | Kind |
|---|---|---|---|
| FI 20021421 | Jul 2002 | FI | national |
The present application is a continuation application of International Patent Application No. PCT/FI2003/000557, filed on Jul. 10, 2003, and claims priority to Finnish Patent Application No. FI 20021421, filed on Jul. 30, 2002, and U.S. Provisional Application No. 60/419,150, filed on Oct. 18, 2002, all of which are incorporated herein by reference in their entireties.
| Number | Date | Country | |
|---|---|---|---|
| 60419150 | Oct 2002 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | PCT/FI03/00557 | Jul 2003 | US |
| Child | 11045087 | Jan 2005 | US |
