NZ504069A - Preparing 4-dimethylamino-1-(4-amino-2-hydroxymethylphenyl)-1-(4-fluorophenyl)butan-1-ol or 4-dimethylamino-1-(4-acetylamino-2-hydroxymethylphenyl)-1-(4-fluorophenyl)butan-1-ol using Grignard reagent 4-halogen-fluorophenyl - Google Patents

Abstract

Citalopram is a well-known selective, centrally active serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor, accordingly having antidepressant activities. A more favourable and safer procedure for manufacturing Citalopram using a more convenient starting material is disclosed. A method is outlined for the preparation of citalopram that comprises steps of: a) reacting a compound of Formula IV wherein R1 is H or C1-6 alkylcarbonyl with a Grignard reagent of 4-halogen-fluorophenyl; b) reacting the resulting compound of Formula V wherein R1 is as defined above, with a Grignard reagent of 3-halogen-N,N-dimethylpropyl-amine; c) effecting ring closure of the resulting compound of Formula VI wherein R1 is as defined above, and converting the resulting compound of Formula VII wherein R1 is as defined above, into the corresponding 5-cyano derivative, i.e.,citalopram, which is isolated as a base or a pharmaceutically acceptable salt thereof.

Description

New Zealand Paient Spedficaiion for Paient Number 504069 1 Method for the Preparation of Citalopram * ;The present invention relates to a method for the preparation of the well known antidepressant drug citalopram and intermediates used m the process. ;Background of the Invention. ;Citalopram is a well known antidepressant drug that has now been on the market for some years and has the following structure: ;It is a selective, centrally active serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor, accordingly having antidepressant activities. The antidepressant activity of the compound has been reported in several publications, eg. J. Hyttel, Prog Neuro-Psychopharmacol & Biol Psychiat., 1982, 6, 277-295 and A. Gravem, Acta Psychiatr. Scand., 1987, 75 , 478-486. The compound has further been disclosed to show effects m the treatment of dementia and cerebrovascular disorders, EP-A 474580. ;Citalopram was first disclosed m DE 2,657,013 corresponding to US 4,136,193. This patent publication describes the preparation of citalopram by one method and outlines a further method which may be used for preparing citalopram. ;According to the process described, the corresponding l-(4-fluorophenyl)-l,3-dihydro-5-iso-benzofurancarbonitrile is reacted with 3-(N,N-dimethylamino)propyl-chloride in the presence of methylsulfinylmethide as condensing agent. The starting material was prepared from the corresponding 5-bromo derivative by reaction with cuprous cyanide. ;According to the method, which is only outlined m general terms, citalopram may be obtained by ring closure of the compound: ;intellectual property office of N.Z. ;1 < aug 2001 RECEIVED ;WO 98/19512 ;PCT/DK97/00513 ;2 ;Br ch2oh ch3 ;ch3 ;Formula ii in the presence of a dehydrating agent and subsequent exchange of the 5-bromo group with cuprous cyanide. The starting material of Formula ii is obtained from 5-bromophthalide by two successive Grignard reactions, i.e. with 4-fluorophenyl magnesium chloride and N,N-5 dimethylaminopropyl magnesium chloride, respectively ;A new and surprising method and an intermediate for the preparation of citalopram were described in US Patent No 4,650,884 according to which an intermediate of the formula ;10 is subjected to a nng closure reaction by dehydration with strong sulfunc acid in order to obtain citalopram The intermediate of Formula iii was prepared from 5-cyanophthalide by two successive Grignard reactions, i.e. with 4-fluorophenyl magnesium halogenide and N,N-dimethylaminopropyl magnesium halogenide, respectively. ;15 Finally, methods of preparing the individual enantiomers of citalopram are disclosed in US Patent No 4,943,590 from which it also appears that the ring closure of the intermediate of Formula iii may be carried out via a labile ester with a base. ;It has now, surprisingly, been found that citalopram may be manufactured by a novel 20 favourable and safe procedure using convenient starting matenals. ;nc^^^CH2OH ;F ;Formula iii substitute sheet (rule 26) ;Printed from Mimosa ;WO 98/19512 ;PCT/DK97/00513 ;3 ;Summary of the invention ;Accordingly, the present invention relates to a novel method for the preparation of citalopram comprising the steps of: ;5 a) reacting a compound of Formula IV ;H I ;O Formula IV ;wherein R1 is H or C,.5 alkylcarbonyl, with a Grignard reagent of 4-halogen-fluorophenyl; b) reacting the resulting compound of formula V ;H ;wherein R1 is as defined above, with a Grignard reagent of 3-halogen-N,N-dimethylpropyl-amine; ;c) effecting nng closure of the resulting compound of Formula VI ;10 ;Formula V ;H ;15 ;F ;wherein R1 is as defined above, and d) converting the resulting compound of Formula VII ;Formula VI ;substitute sheet (rule 26) ;Printed from Mimosa ;F Formula VII ;wherein R1 is as defined above, into the corresponding 5-cyano derivative, i.e. citalopram, which is isolated as the base or a pharmaceutically acceptable salt thereof. ;In another aspect, the present invention provides the novel intermediates of Formula V. ;In a further aspect, the present invention provides the novel intermediates of Formula VI. ;In a further aspect, the present invention provides the novel intermediates of Formula VII. ;In yet another aspect, the present invention relates to an antidepressant pharmaceutical composition comprising citalopram manufactured by the process of the invention. ;Throughout the specification and claims, C[.6 alkyl refers to a branched or unbranched alkyl group having from one to six carbon atoms inclusive, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl, 2,2-dimethyl-l-ethyl and 2-methyl-1 -propyl. ;Grignard reagents of 4-halogen-fluorophenyl that may be used in step a) are the magnesium halogenides, such as the chloride, bromide or iodide. Preferably the magnesium bromide is used. Grignard reagents of 3-halogen-N,N-dimethylpropylamine that may be used are the magnesium halogenides, such as the chloride, bromide or iodide, preferably the magnesium chloride Preferably the two reactions are performed successively without isolation of the intermediate. ;The ring closure of the compound of Formula VI may be effected by an acid or when R1 is C,^ alkylcarbonyl, it may alternatively be carried out via a labile ester with a base. Acidic ring closure is performed by an inorganic acid, such as a sulfuric or phosphoric acid, or an organic acid, such as methylsulfonic, p-toluenesulfonic or trifluoroacetic acid. The basic ring closure is performed via a labile ester, such as the methane sulfonyl, p-toluene sulfonyl, 10-camphorsulfonyl, trifluoroacetyl or trifluoromethanesulfonyl ester with addition of a base, such as tnethyl amine, dimethylaniline or pyridine. The basic reaction is performed in an intellectual property office of n.z. ;1 4 AUG 7001 ;WO 98/19512 ;PCT/DK97/00513 ;5 ;inert solvent, preferably with cooling, m particular about 0 °C and is preferably earned out by a one-pot procedure, i.e. with esterification and simultaneous addition of the base. ;When R1 is H, the conversion of R'-NH- into cyano is preferably performed by diazotation 5 and followed by reaction with CN~. Most preferably NaN02 and CuCN and/or NaCN are used. When R1 is C,.5 alkylcarbonyl, it is initially subjected to hydrolysis thereby obtaining the corresponding compound wherein R1 is H which is the converted as described above. The hydrolysis may be performed either in acidic or basic environment. ;10 The process of the invention may be carried out with or without isolation of the intermediates. ;The process of the invention may also be used to prepare the active (S)-enantiomer of citalopram. In that case, the compound of formula VI is separated into the optically active 15 enantiomers by a procedure analogous to the one described in US Patent No 4,943,590 thereby obtaining the (S)-enantiomer of the compound of formula VI which is used in the ring closure reaction in step c). Accordingly, the individual enantiomers of the intermediates of formulas VI and VII, respectively, are embraced by the formulas. ;20 Other reaction conditions, solvents, etc. are conventional conditions for such reactions and may easily be determined by a person skilled in the art. ;The starting material of formula IV wherein R1 is H is commercially available and may be prepared by known procedures (Tirouflet, J., Bull. Soc. Sci. Bretagne 26, 1959, 35) and com-25 pounds wherein R1 is acyl may be prepared from the amino compound (R1 is H) by conventional acylation. ;In one embodiment of the invention, R1 is C,.6 alkylcarbonyl, in particular methyl-, ethyl-, propyl-, or butylcarbonyl. ;30 ;In another embodiment of the invention R1 is H. ;The compound of general Formula I may be used as the free base or as a pharmacologically acceptable acid addition salt thereof. As acid addition salts, such salts formed with organic or 35 inorganic acids may be used. Exemplary of such organic salts are those with maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis-methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citracomc, aspartic, stearic, palmitic, itaconic, glycolic, p-amino-benzoic, glutamic, ;SUBSTITUTE SHEET (RULE 26) ;Printed from Mimosa ;WO 98/19512 ;PCT/DK97/00513 ;6 ;benzene sulfonic and theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-bromotheophylline. Exemplary of such inorganic salts are those with hydrochloric, hydrobromic, sulfunc, sulfamic, phosphoric and nitric acids. ;5 The acid addition salts of the compounds may be prepared by methods known in the art. The base is reacted with either the calculated amount of acid in a water miscible solvent, such as acetone or ethanol, with subsequent isolation of the salt by concentration and cooling, or with an excess of the acid in a water immiscible solvent, such as ethylether, ethylacetate or dichloromethane, with the salt separating spontaneously. ;10 ;The pharmaceutical compositions according to the invention may be administered m any suitable way and in any suitable form, for example orally in the form of tablets, capsules, powders or syrups, or parenterally m the form of usual sterile solutions for injection. ;15 The pharmaceutical formulations of the invention may be prepared by conventional methods in the art. For example, tablets may be prepared by mixing the active ingredient with ordinary adjuvants and/or diluents and subsequently compressing the mixture in a conventional tabletting machine. Examples of adjuvants or diluents comprise: Corn starch, potato starch, talcum, magnesium stearate, gelatine, lactose, gums, and the like. Any other adjuvant or 20 additive colourings, aroma, preservatives etc. may be used provided that they are compatible with the active ingredients. ;Solutions for injections may be prepared by solving the active ingredient and possible additives in a part of the solvent for injection, preferably sterile water, adjusting the solution 25 to the desired volume, sterilization of the solution and filling in suitable ampules or vials. Any suitable additive conventionally used in the art may be added, such as tonicity agents, preservatives, antioxidants, etc. ;Examples ;30 ;The process of the invention is further illustrated by the following Examples. ;Example 1 ;4-Dimethylamino-l-(4-amino-2-hydroxymethylphenyl)-l-(4-fluorophenyl)butan-l-ol. 35 A solution of 4-fluorophenylmagnesium bromide prepared from 4-fluorobromobenzene (116 g, 0.66 mole) and magnesium turnings (20 g, 0 8 mole) m dry THF (500 ml), is added dropwise to a suspension of 5-amino-phthalide (30 g, 0.2 mole) m dry THF (500 ml). The ;SUBSTITUTE SHEET (RULE 26) ;Printed from Mimosa ;WO 98/19512 ;PCT/DK97/00513 ;temperature is kept below 5 °C. After the addition is completed, the reaction mixture is stirred for 0 5 hour at room temperature. ;A second Grignard solution prepared from 3-dimethylammopropyl chloride (25 g, 0.2 mole) and magnesium turnings (6 g, 0 25 mole) in dry THF (150 ml) is added to the reaction 5 mixture. The temperature is kept below 5°C during the addition. Stirring is continued for 0.5 hour, then stopped and left overnight at ambient temperature. ;The reaction mixture is broken with ice water (1000 ml) and acetic acid (60 g). THF is evaporated off in vacuo. The aqueous phase is washed with ethyl acetate (2x200 ml). To the aqueous phase is added NH4OH to give a final pH of 9. The aqueous layer is extracted with 10 ethyl acetate (2x200 ml), and the organic phase is filtered and washed with water (100 ml). Evaporation of the solvents in vacuo leaves the title compound (38.8 g, 58 %) as an oil. 'H NMR (CDC13, 500 MHz): 1.45-1.55 (IH, m), 1.65-1 75 (IH, m), 2.2 (6 H, s), 2.27 (IH, m), 2.33 (2H, m), 2.43 (IH, m) 3.6-3.7 (2H, NH2), 3.97 (IH, d J=12.5Hz) 4.25 (IH , J=12.5Hz), 6 58 (IH, d, J=8Hz), 6 62 (IH, s), 6.95 (2H, t, J=8.5 Hz), 7.25 (IH, d, J=8 Hz), 15 7.45 (2H, dt, J=1.2 Hz J=8.5 Hz). ;5-Amino-l-(3-dimethylaminopropyl)-l-(4-fluorophenyl)-1,3-dihydroisobenzofuran. ;Crude 4-dimethylammo-1 -(4-amino-2-hydroxymethylphenyl)-1 -(4-fluorophenyl)butan-1 -ol. is dissolved in H3P04 (60%, 140 g) and heated to 80°C for 2 hours. The reaction mixture is 20 poured on ice water (1000 ml) NH4OH is added to give a final pH of 9. The aqueous layer is extracted with ethyl acetate (2x200 ml). The combined organic phase is filtered, washed with water (100 ml) and dried (MgS04, 10 g) The solvent is evaporated in vacuo. The title compound is obtained as an oil. ;'H NMR (CDC13, 250 MHz): 1.3-1.5 (2H, m), 2.05-2.3 (10 H, s+m), 3 6-3.7 (2H, NH2), 5.0 25 (IH, s), 6.45 (IH, d, J=1.8Hz), 6.55 (IH, dd, J=8 Hz J=1.8 Hz), 6.95 (2H, t, J=8.5 Hz), 7.05 (IH, d, J=8 Hz), 7.45 (2H, dt, J=1.2 Hz J=8.5 Hz). ;J-(3-Dimethylaminopropyl)-l-(4-fluorophenyl)-l,3-dihydroisobenzofuran-5-carbonitrile. 5-Amino-l-(3-dimethylaminopropyl)-l-(4-fluorophenyl)-l,3-dihydroisobenzofuran (18 g, 30 0.06 mole) is dissolved in water (100 ml) and H2S04 (8 ml). NaN02 (4.1 g, 0.06 mole) is dissolved in water (20 ml) and added dropwise below 5°C. The diazotised solution is stirred for 0.5 hour at 0-5°C. pH is brought to 6.5 by adding a saturated solution ofNa^Oj. This solution is added to a mixture of water (100 ml) and toluene (120 ml) containing CuCN(6 g, 0.067 mole) and NaCN (10 g, 0.2 mole) at 50-60 C°. Stirring is continued for 0.5 hour. The 35 phases are separated and the aqueous phase is further extracted with toluene (100 ml). The combined organic phase is washed with NaCN (10% aq., 2x50 ml). The solvent is removed in vacuo and the residue is chromatograhed on silica gel (ethyl acetate: n-heptane: tnethylamine; 85:10:5 ) to give the title compound (6 g, 32%) as an oil. ;SUBSTITUTE SHEET (RULE 26) ;Printed from Mimosa *

Claims (25)

WO 98/19512 PCT/DK97/00513 8 'H NMR (CDClj , 250 MHz): 1.35 (IH, m), 1.45 (1 H, m), 2.1 (6H, s), 2.15-2.25 (4H, m), 5.12 (IH, d, J=12.5 Hz), 5.18 (IH, d, J=12.5 Hz), 7.00 (2H, t, J=8.5 Hz), 7.4 (2H, t, J=8.5 Hz), 7.45 (IH, d, J=7.5 Hz), 7 5 (IH, s), 7.58 (IH, d, J=7.5 Hz) 5 Example 2 4-Dimethylamino-l-(4-acetylamino-2-hydroxymethylphenyl)-l-(4-jluorophenyl)butan-l-ol. A solution of 4-fluorophenylmagnesium bromide prepared from 4-fluorobromobenzene (11.6 g, 0.067 mole) and magnesium turnings (2 g, 0.08 mole) in dry THF (50 ml), is added dropwise to a suspension of 5-acetylamino-phthalide (5 g, 0.03 mole) in dry THF (50 ml). 10 The temperature is kept below 5 °C. After the addition is completed, the reaction mixture is stirred for 0.5 hour at room temperature. A second Grignard solution prepared from 3-dimethylaminopropyl chloride (3.7 g, 0.03 mole) and magnesium turnings (0.87 g, 0.036 mole) in dry THF (15 ml) is added to the , reaction mixture. The temperature is kept below 5°C during the addition. Stirring is 15 continued for 0.5 hour, then stopped and left overnight at ambient temperature. The reaction mixture is broken with ice water (100 ml) and acetic acid (6 g). THF is evaporated off in vacuo. The aqueous phase is washed with ethyl acetate (2x50 ml). To the aqueous phase is added NH4OH to give a final pH of 9. The aqueous layer is extracted with ethyl acetate (2x50 ml), and the organic phase is filtered and washed with water (50 ml). 20 Evaporation of the solvents in vacuo leaves the title compound (6.6 g, 63 %) as an oil. 'H NMR (DMSO-d6, 500 MHz): 1.15-1.22 (IH, m), 1.40-1.50 (IH, m), 2.02 (9 H, s+s), 2.05 (IH, m), 2.13 (2H, m), 2.20 (IH, m), 3 95 (IH, d J=12.5Hz) 4.48 (IH, d J=12.5Hz), 7.05 (2H, t, J=8.5Hz), 7.14 (2H, dd J=8 5Hz J= 1.2Hz), 7.47 (IH, d J=8 Hz), 7.58 (IH, s), 7.64 (IH, d J=8.5 Hz). SUBSTITUTE SHEET (RULE 26) Printed from Mimosa WO 98/19512 PCT/DK97/00513 9 CLAIMS

1. A method for the preparation of citalopram comprising the steps of a) reacting a compound of Formula IV H I O 5 O Formula IV wherein R1 is H or C,.6 alkylcarbonyl with a Grignard reagent of 4-halogen-fluorophenyl; b) reacting the resulting compound of formula V H F Formula V wherein R1 is as defined above, with a Gngnard reagent of 3-halogen-N,N-dimethylpropyl-10 amine; c) effecting nng closure of the resulting compound of Formula VI H F wherein Rl is as defined above, and d) converting the resulting compound of Formula VII Formula VI SUBSTITUTE SHEET (RULE 26) Printed from Mimosa 10 h A$9 N O ch3 ch3 f Formula VII wherein R is as defined above, into the corresponding 5-cyano derivative, i.e. citalopram, which is isolated as the base or a pharmaceutically acceptable salt thereof.

2. The method of Claim 1 wherein R1 is H.

3. The method of Claim 1 wherein R1 is Ci_6 alkylcarbonyl

4. The method of Claim 3 wherein Ci-6 alkyl is methyl, ethyl, propyl, or butyl.

5. The method of any one of Claims 1-4 wherein the Grignard reagent used is a magnesium halogenide

6. The method of Claim 5 wherein the Grignard reagent used is a magnesium chloride, magnesium bromide or magnesium iodide.

7. The method of Claim 6 wherein the Gngnard reagent used in step a) is the magnesium bromide.

8. The method of Claim 6 wherein the Grignard reagent used in step b) is the magnesium chloride.

9. The method of any one of Claims 1-8 wherein the nng closure of the compound of Formula VI is effected by acidic nng closure performed by an inorganic acid or an organic acid intellectual property office of n.z. 1 k AUG 2001 RECEIVED (ni n. (ft fit (3) 11 ^v: '

10. The method of Claim 9 wherein the inorganic acid is sulfunc or phosphonc acid,

11. The method of Claim 9 wherein the organic acid is methylsulfonic, p-toluenesulfonic or trifluoroacetic acid.

12. The method of Claim 3 wherein the nng closure of the compound of Formula VI is performed by a basic nng closure via a labile ester.

13. The method of Claim 12 wherein the nng closure of the compound of Formula VI is performed by simultaneous estenfication and addition of base.

14. The method of Claim 12 of 13 wherein the labile ester is the methane sulfonyl, p-toluene sulfonyl, 10-camphorsulfonyl, tnfluoroacetyl or trifluoromethanesulfonyl ester and the base is tnethyl amine, dimethylamline or pyridine.

15. The method of Claim 2 wherein the conversion of the group R'-NH- into cyano is performed by diazotation followed by reaction with CIST.

16. The method of Claim 3 wherein the conversion of the group R'-NH- to cyano is performed by hydrolysis of the Ci-6 alkylcarbonyl ammo group, R'-NH-, to the corresponding ammo group wherein R1 is H, followed by diazotation and reaction with CTST.

17. A method of any one of Claims 1-16 characterised in that before it is used m the nng closure reaction in step c), the compound of formula VI is separated into the optically active enantiomers thereby obtaining the (S)-enantiomer.

18. A compound of Formula V INTELLECTUAL PROPERTY OFFICE OF N.Z. 14 AUG 2001 RECEIVED 12 s»^ V/ V4a»- * 7 h r 1-N\^WCH20H F Formula V wherein R1 is H or Ci-6 alkylcarbonyl.

19. A compound of Formula VI h I Formula VI wherein R1 is H or Ci^ alkylcarbonyl.

20. A compound of Formula vii h I .-N r r intellectual property office of n.z. 1 4 AUG 2001 RECEIVED Formula VII wherein R is H or Ci-6 alkylcarbonyl.

21. An antidepressant pharmaceutical composition comprising citalopram manufactured by the method of any one of Claims 1-17.

22. A pharmaceutical composition according to Claim 21, substantially as herein described.

23. A compound according to Claim 18, 19 or 20, substantially as herein described.

24. A method for the preparation of citalopram, substantially as herein described with reference to the Examples.

25. Citalopram, whenever prepared by a method according to any one of Claims 1-17 and 24.