US. 7276629
Sertraline hydrochloride, (1S-cis)-4-(3,4 dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine hydrochloride, having the formula:
is approved, under the trademark Zoloft®, by the U.S. Food and Drug Administration, as a serotonin re-uptake inhibitor for the treatment of depression, obsessive-compulsive disorder, panic disorder and post-traumatic disorder. Only cis sertraline is therapeutically active.
U.S. Pat. No. 4,536,518 describes a synthesis of sertraline hydrochloride from sertralone having the following formula:
The process for synthesizing sertraline from sertralone has 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”:
The imine is then reduced to sertraline. The reduction process of U.S. Pat. No. 4,536,518 involves 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 diastereoisomers (“(±)-cis/trans-sertraline”) in the ratio of approximately 3 to 1. The '518 patent discloses that reduction with NaBH4 gives a cis:trans ratio of about 1:1.
Two publications, WO 01/30742 and WO 98/27050, disclose the stereoselective reduction of sertraline-imine derivatives. The publication, WO 01/30742, discloses replacing the methyl group of sertraline 1-imine with an optionally substituted bulky benzyl group to increase the cis to trans ratio during hydrogenation, followed by additional steps of converting the bulky group to a methyl group. Additionally, the publication, WO 01/30742, discloses: “The reduction may be performed using complex hydrides (e.g. NaBH4) or by hydrogenation. Reduction performed by catalytic hydrogenation tends to give better selectivity that reduction using the complex hydrides. For example, aliquots of N-[4-(3,4 dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]-benzylamine were reduced with NaBH4 and Raney nickel/H2 respectively, and subsequently reductively alkylated with formaldehyde, whereafter the cis/trans ratio was analyzed. The result was a ratio of 53.8/46.2 using NaBH4 compared to 82.9/17.1 for Raney nickel/H2 which clearly demonstrates the selectivity for the catalytic hydrogenation. An even higher selectivity with a cis/trans ratio of 93.5/6.5 has been observed using palladium on carbon.”
The publication, WO 98/27050, discloses obtaining sertraline by reducing an N-oxide derivative of the imine. In Example 1, the N-oxide derivative is hydrogenated with Raney nickel catalyst, while in Example 2 a 10% palladium on carbon is used as a catalyst. A cis product with an 81% yield is obtained in both instances. According to WO 98/27050, the N-oxide group may then be removed by addition of HCl to the N-oxide compound in ethanol.
The publication, WO 01/16089, discloses a process of reductive amination of sertralone to cis and trans sertraline. In Example 1, sertralone is reduced in the presence of Raney nickel and methylamine. The yield provided in Example 1 is 48–51% of the cis isomer.
The publication, WO 99/57093, discloses a process of selective hydrogenation with a palladium catalyst pretreated with an alkyl halide. The publication discloses that the process of the '518 patent may lead to 10% of dechlorinated side products, while the process of the publication has a “total amount of said contaminated by-products . . . below 0.5%.” In regards to the cis/trans ratio, the ratio provided is 85–95% in the description of the invention. Alkyl halides however are problematic for use on an industrial scale since halogenated reagents are often not environmentally friendly.
U.S. Pat. No. 6,593,496 discloses preparing sertraline-I imine by reacting sertralone with monomethylamine and either titanium tetrachloride or molecular sieves. The hydrogenation illustrated in scheme 1 is carried out with a palladium catalyst in THF.
In US 2003/0105364, a process is provided for obtaining optically pure sertralone through chromatography. The examples do not illustrate hydrogenation.
In US 2003/0166970, a process for making (±)-sertraline with a cis/trans ratio of greater than about 3:1 is provided by hydrogenation of sertraline-1-imine at a temperature of at least about 40° C. using a palladium or a platinum catalyst.
Sertraline 2 is a widely used antidepressant drug, and patents on various aspects of its synthesis have been covered previously ( Org. Process Res. Dev.2005, 9, 537). The hydrogenation of 1 to 2 is a key step in the synthesis and produces two pairs of enantiomers; one cis and the other trans (Reaction 1). Only one of the cis isomers is active, and hence a stereoselective hydrogenation step is highly desirable. Some processes produce about 25% of the trans pair, and a further process loss arises by removal of one or both of Cl groups during hydrogenation. This patent describes the use of commercial Ni catalyst (e.g., G69 from Süd-Chemie) and also proprietary Co catalysts. The patent states that G69 is preferred although the claims cover both Ni and Co catalysts and the patent gives details of the preparation of the Co catalysts. The reaction is carried out in trickle-bed reactor or in a batch reactor with a variety of solvents being used. A process operated at 65 °C and 5 bar pressure using G69 in MeOH gave a 100% conversion of 1 with a selectivity to cis- 2 of 79.8%. This is understood to be less than other commercial catalysts.
Reaction 1
The option of using the racemic mixture of 1 is also covered in the patent. The resolution of 2was carried out by preparation of the d-(−)-mandelate and crystallisation and isolation of (+)-sertraline mandelate.
The catalyst was prepared using the incipient wetness impregnation of alumina-silica. The support precursor catalyst reduction purchased from Saint-Gobain NorPro (Stow, Ohio) was first calcined at 500° C. for 12 hours before impregnation. Characteristics of the support SA3 135 is given in Table 5. Calcined SA-3 135 (5 grams), granules 1–1.2 mm, was charged into glass flask and evaporated at P=0.02 bar and 25° C. over 1 hour. An aqueous solution of cobalt nitrate (4.0 ml) containing 4.36 g of Co(NO3)2×6H2O (98%), purchased from Aldrich (Milwaukee, Wis.), was added dropwise so that surface of all the granules was saturated by the salt solution. The catalyst was dried at 120° C. for 4 hours and calcined at 500° C. for 4 hours.
The Energy Dispersive X-Ray (“EDX”) analysis indicated the contents of Co, Al, Si, 0: 15.0, 35.8, 13.8 and 35.4% wt., respectively. The XRD patterns of the material were evident for the existence of the phase Co3O4: (peaks at 2θ:18.96, 31.24, 36.68, 38,78, 44.75, 57.55). The average crystal size of CoO estimated in XRD study was 50 nm. The catalyst had surface area 11 m2/g, with an average pore diameter 183 angstroms.
The catalyst (2.3 g) was loaded into a tubular stainless steal reactor (6 mm ID and 150 mm length). In the stream of hydrogen at GHSV (gas hour space velocity) 2500 h−1, the temperature was gradually ramped to 500° C., (5° C./min), and then the temperature was maintained constant at 500° C. for 4 hours. The operating conditions of catalyst reduction were selected over Temperature Programmed Reduction (“TPR”) studies carried out in AMI-100 Catalyst Characterization System from Zeton-Altamira (Pittsburgh, Pa.).
The XRD analysis of the reduced catalysts indicates the existence of the phase Co and CoO (peaks at 2θ: 36.8, 42.47, 61.41, 73.69). After the completion of the catalyst reduction, the temperature in the reactor was decreased to 120° C., and the total pressure of hydrogen was increased to 8 bar. A solution containing N-methyl-4(3,4-dichlorophenyl)-1-(−2H)-naphtalenimine (Imine) in tetrahydrofuran (THF), purchased from BioLab (99.5%), having a concentration of 30 g/L was then fed with hydrogen to the reactor. The rate of the solution feed was 25 g/h and the rate of hydrogen feed was 150 ml/mm.
(The products were analyzed by GC HP6890 (Palo Alto, Calif.): capillary column DB-17, 30 m×0.53 mm×1μ. The initial temperature was 160° C. for 26 minutes, and then the temperature was increased at a rate of 30° C./min to 250° C.).
The results of the GC analysis under conditions mentioned above are shown in table 7, which indicates that the imine was completely hydrogenated to a mixture containing: cis-(1S,4S)-N-Methyl-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphtalenamine(cis-Sertraline) as the major component, trans-(1S,4R)-N-Methyl-4(3,4-dichlorophenyl)-1,2,3,4-.tetrahydro-1-naphtalenamine(trans-Sertraline), (1S,4S)-N-Methyl-4(3-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphtalenamine(DCS-1), (1S,4S)-N-Methyl-4-(4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphtalenamine(DCS-2) and Sertralone.
The content of cis-sertraline in the product of imine hydrogenation was 91%.
| TABLE 5 | |||
| The characteristics of the support SA 3135 | |||
| Parameter | Value | ||
| Aluminum oxide, % wt | 79–81 | ||
| Silicon oxide, % wt | 17–19 | ||
| Sodium oxide, % wt | 0.2–0.4 | ||
| Ferric oxide, % wt | 0.3–0.5 | ||
| Titanium dioxide, % wt | 0.4–0.5 | ||
| Magnesium oxide, % wt | 0.1–0.3 | ||
| Potassium oxide, % wt | 0.1–0.3 | ||
| Surface area, m2/g | 12.5 | ||
| Particle density, g/cc | 1.1 | ||
A catalyst containing 11% cobalt by weight was prepared and reduced as in Example 1, but 3.2 g instead of 4.36 g of Co(NO3)2×6H2O was used for the preparation of the aqueous solution. The hydrogenation was carried out under conditions as provided in Example 1. The content of cis-sertraline in the product of imine hydrogenation was 91%.
The catalyst containing 25% of cobalt by weight was prepared by carrying out the incipient wetness impregnation process twice. The first impregnation was followed by drying at 120° C. for 4 hours, and then calcination at 500° C. for 4 hours was carried out as in Example 1. S Scanning Electronic Microscopy (“SEM”) analysis indicated that the catalyst had 15% of Cobalt (5 g) impregnated for the second time by 4 ml of aqueous solution contained 2.2 g of Co(NO3)2×6H2O. The catalyst was dried and calcinated as mentioned above. The cobalt content after twofold impregnation was 25.1% (Scanning Electronic Microscopy (“SEM”) analysis). The catalyst (2.3 g) was charged in a tubular stainless steal reactor and reduced by hydrogen as in Example 1. The hydrogenation of imine was carried out under operating conditions mentioned as in Example 1. The content of cis-Sertraline in the product was 87% (Table 6).
Example 3 was repeated with the temperature of hydrogenation being increased to 150° C. and the feed rate of solution being increased to 40 g/hr. The content of cis-sertraline was 88.8% (Table 6).
| TABLE 6 | |||||||
| The experimental results of Imine hydrogenation in a trickel bed reactor | |||||||
| GC analysis, % area | |||||||
| T | Cis- | ||||||
| Examples | Catalyst | (° C.) | SRT | Trans-SRT | DCS-1 + DCS-2 | Imine | SRT-one |
| 1 | 15% Co | 120 | 91.0 | 7.0 | 0.1 | Not detected | 0.3 |
| SA- | |||||||
| 3135 | |||||||
| 2 | 11% Co | 120 | 90.4 | 7.1 | 0.1 | Not detected | 0.2 |
| SA- | |||||||
| 3135 | |||||||
| 3 | 25% Co | 120 | 87.0 | 9.4 | 0.1 | Not detected | 0.7 |
| SA- | |||||||
| 3135 | |||||||
| 4* | 25% Co | 150 | 88.8 | 7.0 | 0.1 | Not detected | 0.3 |
| SA- | |||||||
| 3135 | |||||||
| The content of imine in THF was 30 g/L, the feed of the solution was 25 g/h and the feed of hydrogen was 150 ml/min (* the feed the Imine solution was 40 g/h). | |||||||
(±)-Sertraline hydrochloride (5 g) was dissolved in ethanol (20 mL) and KOH powder (85%) was added to the solution. The slurry was stirred at room temperature for 2.5 hrs. After stirring the solids were removed by filtration and the solution was treated with D-(−)-mandelic acid (2.66 g). Precipitation occurred and the stirring was continued for 24 hours. (+)-Sertraline-mandelate was isolated by filtration and washed with ethanol and then dried to yield 2.70 g of (+)-sertraline-mandelate.
The catalyst G-69 (2.9 g) was loaded into a tubular stainless steal reactor (6 mm ID and 150 mm length). In the stream of hydrogen at GHSV (gas hour space velocity) 2500h−1, the temperature was gradually ramped to 150° C., (5° C./min), and then the temperature was maintained constant at 150° C. for 2 hours. After catalyst pre-treatment, the temperature in the reactor was decreased to 90° C., and the total pressure of hydrogen was increased to 8 atmospheres. A solution containing N-methyl-4(3,4-dichlorophenyl)-1-(−2H)-naphtalenimine (Imine) in tetrahydrofuran (THF), purchased from BioLab (99.5%), having a concentration of 30 g/L was then fed with hydrogen to the reactor. The rate of the solution feed was 250 g/h and the rate of hydrogen feed was 150 ml/mm. The content of cis -sertraline in the product of imine hydrogenation was 86%.
| US2486361 * | Oct 20, 1944 | Oct 25, 1949 | Union Oil Co | Catalytic conversion of hydrocarbons |
| US3860532 * | Jun 5, 1972 | Jan 14, 1975 | Nippon Oil Co Ltd | Method for preparing silica-alumina catalysts for the conversion of hydrocarbon |
| US4536518 | Nov 1, 1979 | Aug 20, 1985 | Pfizer Inc. | Antidepressant derivatives of cis-4-phenyl-1,2,3,4-tetrahydro-1-naphthalenamine |
| US6034274 * | Dec 15, 1997 | Mar 7, 2000 | Richter Gedeon | Process for preparing a naphtalenamine derivative |
| US6232501 * | Mar 16, 1999 | May 15, 2001 | Ciba Specialty Chemicals Corporation | Process for the cis-selective catalytic hydrogenation of cyclohexylidenamines |
| US6593496 | May 30, 2000 | Jul 15, 2003 | Pfizer Inc | Process for preparing sertraline from chiral tetralone |
| US20030105364 | Sep 18, 2002 | Jun 5, 2003 | Laurent Berger | Process for the preparation of optically pure or enriched racemic tetralone |
| US20030166970 | Feb 12, 2003 | Sep 4, 2003 | Marioara Mendelovici | Novel process for preparing (+)-cis-sertraline |
| EP1059287A1 | Jun 5, 2000 | Dec 13, 2000 | Pfizer Products Inc. | Process for preparing sertraline from chiral tetralone |
| WO1998027050A1 | Dec 15, 1997 | Jun 25, 1998 | Iren Fellegvari | Process for preparing a naphtalenamine derivative |
| WO1999047486A1 | Mar 16, 1999 | Sep 23, 1999 | Markus Benz | Process for the cis-selective catalytic hydrogenation of cyclohexylidenamines |
| WO1999057093A1 | May 5, 1999 | Nov 11, 1999 | Laszlo Balazs | Process for the preparation of sertraline and its 1,r-stereoisomer |
| WO2001009080A1 | Jul 20, 2000 | Feb 8, 2001 | Markus Benz | Process for the cis-selective catalytic hydrogenation of cyclohexylidenamines |
| WO2001016089A1 | Aug 28, 2000 | Mar 8, 2001 | Sharad Kumar Vyas | A process for the preparation of cis-(1s,4s)-n-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthaleneamine hydrochloride |
| WO2001030742A1 | Oct 20, 2000 | May 3, 2001 | Gea Farmaceutisk Fabrik As | Improved synthesis of racemic sertraline |
| WO2001049638A2 | Jan 1, 2001 | Jul 12, 2001 | Trinadha Rao Chitturi | A process for converting stereoisomers of sertraline into sertraline |
| WO2001068566A1 | Mar 14, 2001 | Sep 20, 2001 | Neomi Gershon | Novel process for preparing (+)-cis-sertraline |
| 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 |
NON-PATENT CITATIONS
| Reference | ||
|---|---|---|
| 1 | * | Rathousky et al., Applied Catalysis A: General, 79 (1991), pp. 167-180. |
| 2 | * | The Merck Index, 12th edition (1996), Budavari ed., Merck & Co. Inc., Whitehouse Station, NJ, entry No. 8612. |
| Citing Patent | Filing date | Publication date | Applicant | Title |
|---|---|---|---|---|
| WO2010076763A2 * | Dec 29, 2009 | Jul 8, 2010 | Piramal Healthcare Limited | An improved process for the manufacture of sertraline |
