Title:
PROCESS FOR THE SYNTHESIS OF CITALOPRAM
Document Type and Number:
WIPO Patent Application WO/2001/002383
Kind Code:
A2
Abstract:
A new process is described for the synthesis of citalopram characterized by the conversion of 1-(4'-fluorophenyl)1-3-(dimethylaminopropyl)-5-halophthalane in the corresponding Grignard reagent; this intermediate product may be converted into citalopram via intermediate formation of an aldehyde and in the subsequent transformation of the functional group via oxime or hydrazone; or else be converted into citalopram via reaction with compounds containing a cyano group bound to a leaving group. The process described makes it possible to obtain citalopram in high yields, and does not involve the use of drastic conditions of temperature.
Inventors:
BOLZONELLA EVA (IT)
CASTELLIN ANDREA (IT)
NICOLE ANDREA (IT)
CASTELLIN ANDREA (IT)
NICOLE ANDREA (IT)
Application Number:
PCT/EP2000/006426
Publication Date:
January 11, 2001
Filing Date:
July 06, 2000
Export Citation:
Assignee:
VIS FARMACEUTICI S P A (IT)
BOLZONELLA EVA (IT)
CASTELLIN ANDREA (IT)
NICOLE ANDREA (IT)
BOLZONELLA EVA (IT)
CASTELLIN ANDREA (IT)
NICOLE ANDREA (IT)
International Classes:
C07D307/87; (IPC1-7): C07D307/87
Domestic Patent References:
| WO1998019513A2 | 1998-05-14 | |||
| WO1998019512A2 | 1998-05-14 |
Foreign References:
| EP0171943A1 | 1986-02-19 | |||
| GB1526331A | 1978-09-27 |
Attorney, Agent or Firm:
Gervasi, Gemma (9 Milano, IT)
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Claims:
CLAIMS
| 1. | A process of synthesis of 1 [3 (dimethylamino) propyl]1 (4fluorophenyl)1,3 dihydro5isobenzofurancarbonitrile (citalopram), characterized by the following steps: (i) reaction of 1 (4'fluorophenyl)1 (3dimethylaminopropyl)5halophthalane (I) with activated magnesium, to form the Grignard reagent of formula (I A), where X is a halogen atom, preferably bromine; (ii) reaction of the compound (1 A) with a substituted formamide, to form the 1 (4' fluorophenyl) 13 (dimethylaminopropyl)5phthalanealdehyde (II); (iii) reaction of the compound (II) with a reagent of structure NH2Y, where Y is chosen from amongOH,OCH3,N (CH3) 2,OSO3H, with formation of a compound of formula (III), where Y has the aforesaid meanings; and conversion of (iv) the compound (III) into citalopram (IV). |
| 2. | A process according to Claim 1 in which, in step (i), the compound (I) is dissolved in an organic solvent ("solution b") and added to a mixture of activated magnesium in organic solvent ("solution a"). |
| 3. | A process according to Claim 2, where the compound (I) is used in a weight ratio with respect to magnesium of between 5: 1 and 15: 1, preferably 7.5: 1. |
| 4. | A process according to Claim 2, where the concentration of compound (I) in the solution b is between 0.7M and 1.2M. |
| 5. | A process according to Claim 2, where the volume of solution a is between 40% and 60% with respect to the volume of solution b. |
| 6. | A process according to Claim 2, where the time within which solution b is added is longer than 5 hours. |
| 7. | A process according to Claim 2, where: the compound (I) is used in a molar ratio with respect to magnesium of 1: 2; the concentration of the compound (I) in solution b is 1M; the volume of solution a is 50% with respect to the volume of solution b; the time within which solution b is added is between 6 and 8 hours. |
| 8. | A process according to each of Claims 17, where said substituted formamide is chosen from among dimethylformamide, NformylNmethyl2aminopiridine, trimethylformylethylenediamine, Nformylpiperidina, Nformylmorpholine. |
| 9. | A process according to each of Claims 18, where said substituted formamide is used in molar ratio of approximately 2: 1 with respect to the compound (1). |
| 10. | A process according to each of Claims 19, carried out continuously in the same reactor, without isolation and/or purification of intermediate products. |
| 11. | A process according to each of Claims 110, where in step (iii) the molar ratios between the compound (II) and the compound NH2Y are between 1: 1 and 3: 1. |
| 12. | A process according to each of Claims 111, where the compound (III) is an oxime and step (iv) is carried out by dehydration with concentrated acetic acid or with acetic anhydride. |
| 13. | A process according to each of Claims 111, where the compound (III) is a hydrazone and step (iv) is carried out by oxidation with methylrhenium trioxide and hydrogen peroxide. |
| 14. | An intermediate product of synthesis of citalopram of formula (I A), where X is a halogen atom, preferably bromine. |
| 15. | A process of synthesis of 1 [3 (dimethylamino) propyl]1 (4fluorophenyl)1,3 dihydro5isobenzofurancarbonitrile (citalopram), characterized by the following steps: (i) reaction of 1 (4'fluorophenyl)1 (3dimethylaminopropyl)5halophthalane (I) with activated magnesium, to form the Grignard reagent of formula (I A); and (ii') reaction of the compound (I A) with a compound containing aCN group bound to a leaving group, to form citalopram (IV). |
| 16. | A process according to Claim 15, where said compound containing aCN group bound to a leaving group is chosen from among the compounds having formulas 1)6). |
Description:
INTERNATIONAL SEARCH REPORT g Inten nal Application No PCT/EP 00/06426 C. (Continuation) DOCUMENTS CONSIDERED TO BE RELEVANT Category ° Citation of document, with indication. where appropriate, of the relevant passages Relevant to claim No. A GB 1 526 331 A (KEFALAS AS) 1,14 27 September 1978 (1978-09-27) cited in the application the whole document 1 INTERNATIONAL SEARCH REPORT Inten nal Application No information on patent family members Patent document Publication Patent family Publication cited in search report date member (s) date l WO 9819513 A 14-05-1998 AU 6609898 A 29-05-1998 CN 1268129 T 27-09-2000 DE 1015416 T 05-10-2000 EP 1015416 A 05-07-2000 ES 2148120 T 16-10-2000 NO 20000008 A 03-01-2000 PL 338015 A 25-09-2000 SK 32000 A 11-07-2000 ZA 9805981 A 28-01-1999 WO 9819512 A 14-05-1998 AU 5116898 A 29-05-1998 EP 1042310 A 11-10-2000 ES 2149734 T 16-11-2000 NO 20002077 A 10-05-2000 ZA 9810058 A 05-05-1999 EP 0171943 A 19-02-1986 AT 38661 T 15-12-1988 AU 574819 B 14-07-1988 AU 4577685 A 13-02-1986 CA 1237147 A 24-05-1988 DE 3566251 D 22-12-1988 DK 89595 A 10-08-1995 DK 356285 A 07-02-1986 ES 545885 D 01-04-1986 ES 8606257 A 01-10-1986 FI 852902 A, B, 07-02-1986 GR 851894 A 03-12-1985 IE 57817 B 21-04-1993 IL 75690 A 31-10-1988 JP 1902596 C 08-02-1995 JP 6025099 B 06-04-1994 JP 61087654 A 06-05-1986 NO 853091 A, B, 07-02-1986 NZ 212541 A 30-05-1988 PT 80913 A, B 01-09-1985 US 4650884 A 17-03-1987 ZA 8505026 A 25-06-1986 ZA 8505026 A 25-06-1986 GB 1526331 A 27-09-1978 AT 360001 B 10-12-1980 AT 571979 A 15-05-1980 AT 360002 B 10-12-1980 AT 572079 A 15-05-1980 AT 359488 B 10-11-1980 AT 947276 A 15-04-1980 AU 509445 B 15-05-1980 AU 2107377 A 13-07-1978 BE 850401 A 14-07-1977 CA 1094087 A 20-01-1981 CH 626886 A 15-12-1981 CH 632258 A 30-09-1982 CH 632259 A 30-09-1982 DE 2657013 A 28-07-1977 DK 13177 A, B, 15-07-1977 ES 454980 A 01-04-1978 FI 770073 A, B, 15-07-1977 FR 2338271 A 12-08-1977 IE 44055 B 29-07-1981 JP 1368581 C 11-03-1987 INTERNATIONAL SEARCH REPORT Interr. ial Application No information on patent family members PC T/EP 00/06426 Patent document Publication Patent family Publication cited in search report date member (s) date GB 1526331 A JP 52105162 A 03-09-1977 JP 61035986 B 15-08-1986 NL 7700244 A, B, 18-07-1977 NO 770109 A, B, 15-07-1977 NZ 183001 A 02-06-1978 SE 429551 B 12-09-1983 SE 7614201 A 15-07-1977 US 4136193 A 23-01-1979 ZA 7700057 A 30-11-1977