Novel process for preparing (+)-cis-sertraline WO 2001068566
The methods of the present invention for making (+)-cis-sertraline allow sertraline-precipitant, or sertraline-mandelate, to be made directly from the sertraline racemate resulting from the hydrogenation, reduction, of the sertraline- 1-imine. This improved, efficient and cost effective purification is possible when the sertraline racemate has a relatively high cis/trans ratio, such as, about 8:1 to about 12:1, as well as when the content of dechlorinated-sertraline side products is low, such as, less than about 1%. The methods of the present invention successfully eliminate the need for several purification steps prior to selectively precipitating (+)-cis-sertraline with an optically active selective precipitant.
Sertraline hydrochloride, (lS-cis)-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-N- methyl-1-naphthalenamine hydrochloride, having the formula
is the active ingredient in Zoloft®, a medication approved by the U.S. Food and Drug Administration, for the treatment of depression, obsessive-compulsive disorder and panic disorder.
Sertralone
U.S. Patent No. 4,536,518 describes a synthesis of sertraline hydrochloride from sertralone. The process for synthesizing sertraline hydrochloride from sertralone comprises two steps. First, sertralone is condensed with methyl amine in the presence of an acid catalyst, to yield the Schiff base of sertralone, sertraline- 1-imine.
Sertraline 1-imine
The imine, or Schiff base, is then reduced to sertraline. The reduction process of U.S. Patent No. 4,536,518 comprises the hydrogenation of sertraline- 1-imine concentrate at room temperature for two hours over 10% Pd/C catalyst in an atmosphere of hydrogen (1 atm pressure). The product is a racemic mixture of the cis and trans diastereomers ("(±)- cis/trans-sertraline") in the ratio of approximately 3 to 1. This hydrogenation step can introduce a number of contaminants, including dechlorinated side-products, if not carefully controlled. One very problematic group of side products are dechlorinated- sertraline derivatives. It is desirable to have a hydrogenation method that reduces the amount of dechlorinated-sertraline side products or eliminates these side products.
The purification of cis-sertraline from (±)-cis/trans-sertraline as described in the '518 patent is relatively complicated and expensive requiring multiple recrystallizations, and the (±)-cis/trans-sertraline so produced has a cis/trans ratios lower than 3:1. It is therefore desirable to have a method of initially making cis/trans-sertraline base from sertraline- 1-imine with cis/trans ratios greater than 3:1. It is also desirable to have a simple and cost effective purification of (+)-cis-sertraline from (±)-cis/trans-sertraline base or from (±)-cis/trans-sertraline hydrochloride.
EXAMPLES
EXAMPLE 1 Step 1: Preparation of sertraline- 1-imine (Schiff base):
Sertralone (100 g) was dissolved in toluene (1400 mL) and the solution so obtained was cooled to 0-5 °C. Methyl amine gas (38.7 g) was bubbled through the solution while maintaining the temperature between 0-5 °C. To the above solution, TiCl4(20 mL) was added dropwise while maintaining the temperature below 10°C. The reaction mixture was allowed to warm to room temperature and then was stirred at room temperature for 3 hours. Upon completion of the reaction, TiO2 was removed by filtration and the filtrate was evaporated to dryness. The solid obtained after evaporation was sertraline- 1-imine (101.17 g; yield 100%).
Step 2: Preparation of (drVcis/trans-sertraline (sertraline racemate) free base:
A slurry of sertraline- 1-imine (Schiff base) (10 g) in t-butyl-methyl-ether (MTBE) (270 mL) was hydrogenated in the presence of Pd/C (10% loading) at 40 °C, at 1 atm H2 pressure. After approximately 5 hours the reaction was complete. Filtration of the reaction mixture through a cellite pad and evaporation of the solvent afforded (±)- cis/trans-sertraline free base (sertraline racemate free base) (10 g) as an oil.
Step 3: Preparation of crude f+)-sertraline mandelate:
Sertraline racemate free base (75.6 g) was dissolved in ethanol (760 mL) and the solution heated to about 50°C. (D)-Mandelic acid (37.6 g) was added and the solution was heated to reflux. The mixture was cooled to room temperature and stirred for 3 hours. Filtration and washing with ethanol followed by drying at about 60 °C afforded the product crude (+)-sertraline mandelate, in 83.7% yield (40.7g), 94.6% SS-sertraline, 3.01% RR-sertraline.
The optical purity of the (+)-sertraline mandelate was established by chiral HPLC.
Step 4: Preparation of (+)-sertraline mandelate crystals
Crude (+)-sertraline mandelate (40 g) was crystallized from ethanol (920 mL). The hot solution was treated with active carbon, filtrated and cooled to room temperature. The obtained solid was isolated by filtration and washed with ethanol. After drying, the (+)-sertraline-mandelate crystals are obtained in 82.8 % yield (31.95 g) 99.0% SS- sertraline by area, no i-R-sertraline was detected.
Step 5: Preparation of (+ -sertraline hydrochloride Form N:
The crude (+)-sertraline mandelate crystals in toluene were partitioned between a 10% aqueous solution of ΝaOH and toluene. The organic solution was washed with water and the solvent was evaporated to dryness to give (+)-sertraline base (6.9 g). The solution of (+)-sertraline base (3.7 g) in ethanol (18.5 mL) was acidified with hydrogen chloride gas while keeping the temperature at about 10°C. Then the mixture was cooled to room temperature and stirred for 2 hours. After filtration, washing of the solid with ethanol and drying, (+)-sertraline hydrogen chloride ((+)-sertraline HCl) Form N was obtained (3.16 g, yield 82.7%>), 99.6% SS-sertraline by area, no i-i?-sertraline was detected.
The procedure of steps 3-5 was performed 5 times as described above. Table 2 includes the specific conditions and results of these 5 experiments.
Table 2.
Optical purity of (+)-sertraline-mandelate was established by chiral HPLC methods. Table 3 provides additional data and reaction conditions concerning the optical resolution of sertraline. In Table 3, the % Enantiomer RR is the percent area of the RR- enantiomer as determined by chiral HPLC; Chiracel OD-H, 250 x 4.6 nm, 5μ, column temperature 5°C. In Table 3, the Yield %> is the yield of optical resolution, based on the % SS-enantiomer of sertraline hydrochloride practically obtained against the theoretical SS-sertraline hydrochloride enantiomer that could be obtained. The yield was calculated based on the optical purity of (±)-sertraline hydrochloride obtained. In Table 3, the Assay % is the percent of SS-sertraline hydrochloride as determined by chiral HPLC method using SS-sertraline hydrochloride as the standard.
Although certain presently preferred embodiments of the invention have been described herein, it will be apparent to those skilled in the art to which the invention pertains that variations and modifications of the described embodiments may be made without departing from the spirit and scope of the invention. Accordingly, it is intended that the invention be limited only to the extent required by the appended claims and the applicable rules of law.
PATENT CITATIONS
| Cited Patent | Filing date | Publication date | Applicant | Title |
|---|---|---|---|---|
| US4536518 * | Nov 1, 1979 | Aug 20, 1985 | Pfizer Inc. | Antidepressant derivatives of cis-4-phenyl-1,2,3,4-tetrahydro-1-naphthalenamine |
| US5463126 * | Jul 3, 1992 | Oct 31, 1995 | Pfizer Inc. | Process for preparing sertraline |
| Citing Patent | Filing date | Publication date | Applicant | Title |
|---|---|---|---|---|
| WO2002102761A1 * | Jun 14, 2002 | Dec 27, 2002 | Ilpo Laitinen | A novel process for the preparation of (is-cis) -4-(3, 4-dichlorophenyl) -1, 2, 3, 4 - tetrahydro-n-methyl-1-naphthalenamine |
| WO2004092110A2 * | Apr 14, 2004 | Oct 28, 2004 | Mordechay Hershowitz | Hydrogenation of imine intermediates of sertraline with catalysts |
| WO2005023752A2 * | Sep 7, 2004 | Mar 17, 2005 | Ben-Zion Dolitzky | A recycling process for preparing sertraline |
| WO2005121074A2 * | Jun 9, 2005 | Dec 22, 2005 | Keshav Deo | Processes for the preparation of sertraline hydrochloride |
| WO2007119247A2 * | Sep 12, 2006 | Oct 25, 2007 | Dayalji Chauhan Ajay | Improved manufacturing procedure for the preparation of polymorphic form ii of cis-(1s)-n-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthleneamine hydrochloride (sertraline hydrochloride) |
| US6723878 | Jun 14, 2002 | Apr 20, 2004 | Orion Corporation Fermion | Method for preparing sertraline |
| US7262327 * | Sep 7, 2004 | Aug 28, 2007 | Teva Pharmaceutical Industries Ltd. | Recycling process for preparing sertraline |
| US7276629 | Apr 14, 2004 | Oct 2, 2007 | Teva Pharmaceutical Industries Ltd. | Hydrogenation of imine intermediates of sertraline with catalysts |
