JP2003502422A - Preparation of paroxetine and structurally related compounds - Google Patents

Abstract

(57) [Summary] The (−) trans isomer of 4- (4′-fluorophenyl) -3- (3 ′, 4′-methylenedioxyphenoxymethyl) piperidine is particularly depressed and obsessive-compulsive disease as a hydrochloride. (OCD) and used to treat panic. R ¹ is a method for producing a compound represented by the formula (1), which is a substituted phenyl group, or a pharmaceutically acceptable salt thereof, wherein R ¹ is as described above, and R ² is a C _1-6 alkyl group. , a method comprising hydrolyzing C _{3- 6} cycloalkyl group, an aralkyl group, a carbamate solution represented by the formula (2) is a phenyl group or substituted phenyl group with a base, bases and carbamic A method is described that comprises forming a micronized complex with an acid ester and heating the complex in the form of a suspension in a solvent. Embedded image

Description

Detailed Description of the Invention

[0001] (Technical field)   The present invention relates to a novel method for producing pharmaceutically active compounds and intermediates thereof.

[0002] Medicaments with antidepressant and anti-Parkinsonian properties are described in US Pat. No. 3,912,743.
And U.S. Pat. No. 4,0071,967. A particularly important compound of the disclosure is paroxetine, namely 4- (4'-fluorophenyl) -3- (3 ', 4'-methylenedioxyphenoxymethyl) piperidine (
-) The trans isomer. This compound is used as a hydrochloride salt in therapy, among other things,
Used in the treatment of depression, obsessive-compulsive disorder (OCD) and panic.

[0003]   The previously published process for paroxetine is the carbamate ester:

[Chemical 3] (Wherein R ² is typically an alkyl, aryl or arylalkyl group).

In US Pat. No. 400719, R ² is Ph and the carbamic ester is hydrolyzed by refluxing in benzene for 4 hours with potassium hydroxide containing methyl cellosolve. Clearly, it is better not to use benzene,
It was found that the use of methyl cellosolve formed a transesterified intermediate which retarded hydrolysis and the residue from the hydrolyzed product was difficult to remove and left behind.

European Patent No. 0810225 discloses KO with N-ethoxycarbonyl derivatives.
Disclosed is the production of paroxetine, which is hydrolyzed by heating in ethanol / water containing H for 3 hours at 90 ° C. In European Patent No. 0152273,
Phenylcarbamate ester of paroxetine analog in toluene
Hydrolyze at 0 ° C. for 4 hours with KOH and ethylene glycol monomethyl ether.

In the earlier application EP 0223403 of the present application, N-phenoxycarbonyl derivatives in toluene are treated with KOH in toluene under reflux for 2 hours. We faced significant difficulties in addressing the scale-up of this process. Even with vigorous stirring during reflux, the reaction time is prolonged and the reaction is incomplete. Although such a method is acceptable at the research stage, it is not applicable for use on an industrial scale. Studies have shown that the reaction conditions at temperatures well below the reflux temperature are critical to the success of the reaction, and by the time the reflux temperature is reached, the reaction may fail completely. In particular, potassium hydroxide dissolves at the reflux temperature of toluene, such as 4- (4′-fluorophenyl) -3- (3 ″, 4 ″ -methylenedioxyphenoxymethyl) -1-phenoxycarbonylpiperidine. It was found to form an almost insoluble complex of paroxetine carbamate derivatives. Once this material is formed, complete reaction is not possible within a reasonable time. Moreover, cleaning and preparing the industrial reactor for the next step is difficult and time consuming.

As a result of further research, the reaction conditions were surprisingly modified so that the reaction could be carried out in an efficient, reliable and renewable manner suitable for industrial scale production.

[0008] (Disclosure of the invention)   The invention, in its broadest sense, has the formula (2):

[Chemical 4] [Wherein R ² is a C _1-6 alkyl group, a C _3-6 cycloalkyl group, an aralkyl group, phenyl or a substituted phenyl group, and R ¹ is as defined below]. By hydrolyzing the acid ester, the formula (1):

[Chemical 5] [Wherein, R ¹ is a substituted phenyl group, preferably 3,4-methylenedioxyphenyl], and a method for producing the paroxetine derivative.

[0009] This method involves bringing finely divided, eg sand-like, complexes of potassium hydroxide and carbamate derivatives to temperatures well below the reflux temperature of toluene (110.6 ° C.), eg 70 ° C. and Forming at temperatures between 90 ° C. is included. The complex is easily stirred and reacts completely in a short time to form paroxetine. Once formed, ensure that the well-stirred mixture is heated to reflux temperature to complete the reaction, usually within 1 hour. A sand-like complex of potassium hydroxide and carbamate derivative is obtained by heating a mixture of carbamate and potassium hydroxide to a suitable temperature, preferably in the form of flakes.
Then, it can be prepared by stopping heating and stirring vigorously. 4- (
In the case of 4'-fluorophenyl) -3- (3 ", 4" -methylenedioxyphenoxymethyl) -1-phenoxycarbonylpiperidine, suitable temperatures are 70 ° C and 90 ° C.
However, for other carbamic acid esters, it may be determined by simple experimentation. Preferably 3 to 10 equivalents, more preferably 6 and 8 equivalents of base are used. Preferably the solvent is toluene.

Commercial potassium hydroxide flakes contain 10-20% water and other sources of water are well present during the reaction. The inventors have found that in the absence of excess water, the hydrolysis reaction is faster and the level of side reaction products is lower. Such conditions can be achieved by changing the equipment to a Dean and Stark or similar arrangement so that water is removed during the reaction and carrying out the reaction in a dehydration medium. Preferably, the dehydrating medium is toluene and excess water is removed by azeotropic distillation, preferably the water content is less than 30% of the compound of formula (2), more preferably 20%. It is less than 10%, more preferably less than 10%.

In the reaction using toluene as a solvent, the carbamate concentration is important. At low concentration, it is not desirable due to occupying the container and other reasons,
On the other hand, at a high concentration, the reaction becomes incomplete. A suitable concentration on a weight / weight basis is
Concentrations between 4% and 10%, preferably between 5.5% and 9%, most preferably between 6.5% and 8.0%.

[0012] Potassium phenylate is a by-product of the above method and must be removed. It has been found that the aqueous cleaning described in EP 0223403 is not sufficient on an industrial scale even if a large amount of water is used, and using such a large amount of water naturally leads to efficient factory production. Not desirable. If the optimum reaction conditions are adapted to the reaction with KOH, most of the potassium phenylate can be removed as a crystalline precipitate by filtration. However, instead of the aqueous wash at ambient temperature of the prior art, a hot wash with preheated water, preferably water at a temperature between 60 ° C and 95 ° C, more preferably between 70 ° C and 80 ° C, is performed. It is preferable. The amount of water used is
The amount of toluene used in the reaction is preferably between 1/2 and 1/20, more preferably between 1/3 and 1/5.

Contrary to expectations when considering the large excess of potassium hydroxide used in this reaction, it was found that potassium phenylate was sufficiently removed by this method and this KOH was concentrated at high temperature. The solution is usually very reactive and is believed to cause decomposition of the desired product. After washing, the product of the paroxetine derivative can be isolated from the toluene solution in a sufficiently pure form by evaporation, from which any of the known salts can be formed.

The crystallization of paroxetine hydrochloride from the toluene reaction solution has been disclosed in the prior literature, but it has been found not applicable on an industrial scale. The product initially tends to precipitate as an oil, which solidifies to form a bulk product containing unacceptable amounts of impurities and solution that is difficult to remove from the reaction vessel.

We have added a co-solvent to a solution of the compound in toluene, benzene or xylene, followed by acidification with a pharmaceutically acceptable acid to crystallize and optionally seed the desired salt. A method has been developed in which the compound of formula (1) is isolated as a pharmaceutically acceptable salt, especially hydrochloric acid, by adding crystals. Preferably, the co-solvent is an alcohol, ketone, ester or chlorinated hydrocarbon. More preferably, the co-solvent is an alcohol, most preferably ethanol, typically IMS. Preferably, the co-solvent is added to the reaction solvent after aqueous washing but before cooling to ambient temperature. Preferably, the co-solvent is added at between 50 ° C and 60 ° C, typically 55 ° C. IM
In the case of S, an amount corresponding to 1/20 and 1/60 of the volume of the toluene solution is added, preferably between 1/30 and 1/40.

When preparing the hydrochloride salt, after the co-solvent addition, the solution is appropriately cooled to a temperature between 10 ° C. and 30 ° C., preferably between 15 ° C. and 25 ° C., to give the desired paroxetine hydrochloride crystalline form. Seeds, eg hemihydrate, were added (preferably between 0.05% and 1%, more preferably about 0.1% by weight). The solution is acidified with hydrochloric acid, a suitable aqueous concentrated hydrochloric acid, with vigorous stirring. Advantageously, an amount in excess of the theoretically required amount, typically 1.1 and 2 equivalents, preferably 1.3 and 1.8 equivalents,
More preferably between 1.5 and 1.7 equivalents of hydrochloric acid are added. Preferably, the acid is added very quickly with vigorous stirring. As a result, crystallization occurs rapidly, a consistent form is obtained, and formation of lumps and changes in purity can be avoided. Preferably, the mixture may be stirred for at least 30 minutes to fully crystallize, followed by lowering the temperature of the mixture to 1-5 ° C for final crystallization.

Applicants' extensive research has shown that hitherto unrecognized catechol impurities are formed from intermediates of hydrolysis during acidification, which is particularly problematic and can be removed by crystallization. It was found to be difficult and lead to colored products. Such products are typically due to early stages of the manufacturing process or traces of alcohol from protocol wash plants, or impurities in the solvent. Catechol formation can be reduced by first rinsing the reaction vessel with toluene and washing the toluene phase with water. However, more effective methods have also been developed in which the acidification operation is followed by the addition of an aqueous alkaline wash step, which typically uses sodium hydroxide. Preferably, the alkaline wash is conducted above ambient temperature, preferably within the range of 40-60 ° C, more preferably about 50 ° C. In the industry, sodium hydroxide is available as a 50% by weight aqueous solution, so first add hot water, typically between one-third and one-quarter the amount of toluene, then It is convenient to add 50% aqueous sodium hydroxide solution, preferably between 5 and 10 equivalents, more preferably between 6 and 8 equivalents. After washing with alkali, the above treatment with co-solvent, seeding and acid was repeated to isolate the pure paroxetine hemihydrate product.

If desired, the product may be further purified by recrystallisation from propan-2-ol containing between 1% and 10%, preferably between 2% and 4% water. 5 to 10 parts, preferably 7 and 8 parts of propan-2-ol are used, based on the weight of the solid product. It has been found that the product shape improves dramatically when crystallization begins at relatively high temperatures. Therefore, the propan-2-ol solution is preferably cooled from the reflux temperature to between 50 ° C. and 60 ° C., more preferably within the range of 55 ° C. and seeded to the mixture (1-5% by weight of the desired amount). The product of is used as a seed crystal). The mixture is crystallized for 2-4 hours and gradually cooled to 0 ° C. After further stirring (2-4 hours), the product was filtered, washed with aqueous propan-2-ol and dried.

The method of the present invention is described in US Pat. No. 3,912,743 and US Pat. No. 4,007,719.
It can be used for producing the active compound described in No. 6, and preferably for producing paroxetine hemihydrate. As an alternative to the isolation of the hemihydrate, the solvated, amorphous or anhydrous product can be isolated according to previously disclosed methods.

Paroxetine acetate can be converted to the hydrochloride salt and is described in EP 0232340.
Most preferably it is converted to the hemihydrate of the salt as described in No. 3. The present invention includes within its scope the compound paroxetine, in particular paroxetine hydrochloride, especially as the hemihydrate obtained by any of the aspects of the present invention, and any novel intermediates resulting from the process as described Included in the range. Paroxetine is the (-)-trans isomer of 4- (4'-fluorophenyl) -3- (3 ", 4" -methylenedioxyphenoxymethyl) piperidine.
Optical resolution can be performed prior to coupling with phenol according to the method of EP 0152273. Alternatively, the resolution can be carried out at other steps, such as after deprotection of the piperidine nitrogen. Example 2 describes the resolution of N-deprotected compounds.

The paroxetine obtained using the present invention may be used therapeutically as a solid formulation or solution, either oral or parenteral, in dosage forms such as those described in European Patent Application No. 0223403 or WO 96/24595. Can be prescribed. The therapeutic use of paroxetine, especially paroxetine hydrochloride obtained by using the present invention, is described as "disease" below, alcoholism, anxiety, depression, obsessive-compulsive disease, panic disease, chronic pain, obesity, senile dementia, Includes treatments for migraine, pathological starvation, anorexia, phobia, premenstrual syndrome (PMS), adolescent depression, hair loss, dysthymia, and substance abuse.

Therefore, the present invention further comprises: A pharmaceutical composition for treating or preventing a disease, comprising paroxetine or paroxetine hydrochloride obtained by using the method of the present invention, and a pharmaceutically acceptable carrier; Use of paroxetine or paroxetine hydrochloride obtained by using the method of the present invention for producing a prophylactic drug; and an effective or prophylactic amount of paroxetine or paroxetine hydrochloride obtained by the method of the present invention. A method of treating a disease is provided that comprises administering to a human suffering from one or more diseases.

The invention is illustrated by the examples below. Example 1 4- (4'-Fluorophenyl) -3- (3 ", 4" -methylenedioxyphenoxymethyl) piperidine Potassium hydroxide flakes (83 kg) and 4- (4'-fluoro in 1470 liters of toluene. Carefully add phenyl) -3- (3 ", 4" -methylenedioxyphenoxymethyl) -1-phenoxycarbonylpiperidine (90 kg) to 7
The mixture was heated to about 0 ° C. and stirred vigorously. Once a fine, sandy suspension formed, heating reaction control was performed and the mixture was brought to reflux temperature. Dean and water
It was removed using a Stark apparatus and the mixture was refluxed for 2 hours. The reaction mixture was then cooled to 70 ° C., washed twice with hot water at about 70 ° C. (2 × 400 liters) and separated.

The contents of the reactor were cooled to 55 ° C. and industrial methyl alcohol (IMS) (40
Liter), further cooled to 20 ° C., and paroxetine hydrochloride hemihydrate (
60 g) was sprinkled. Concentrated hydrochloric acid (28 liters) was added with vigorous stirring, and stirring was continued for another 30 minutes. Water (420 liters) and 50% aqueous sodium hydroxide solution (112 kg) were added and the mixture heated to 50 ° C. The contents of the vessel were thoroughly stirred, allowed to settle, and the aqueous layer drained. Then, the toluene layer was washed with water (400 liters) and cooled to 20 ° C.

Paroxetine hydrochloride hemihydrate (60 g) was seeded and the mixture was vigorously stirred while adding concentrated hydrochloric acid (28 liters). Stirring is continued for 2 hours at a temperature of 20 ° C,
Then, the contents of the container were cooled to about 0 ° C. and stirred at the same temperature for 2 hours. The crystalline product obtained from toluene / IMS was filtered, then propane-2 at 65 ° C.
-Dissolved in all (570 liters). Water was added (15 liters) followed by seeds of paroxetine hydrochloride hemihydrate (60 g). Then, the solution was cooled to 55 ° C., stirred at the same temperature for 3 hours, cooled to 0-5 ° C., and further stirred for 2 hours. The slurry was filtered, the solid washed with aqueous isopropyl alcohol and dried under vacuum at 35 ° C. to give catechol-impurity free paroxetine hydrochloride hemihydrate.

Example 2 (±) trans Preparation of paroxetine hydrochloride by resolution of 4- (4′-fluorophenyl) -3- (3 ″, 4 ″ -methylenedioxyphenoxymethyl) piperidine i) (±) trans 4- (4′-fluorophenyl) -3- (3 ″, 4 ″ -methylenedioxyphenoxymethyl) piperidine (1.0 g) was added to methanol (10 g).
ml) and added to a solution of L (−)-di-p-toluoyl tartaric acid (1.25 g) in methanol (10 ml). Seed crystals were added to the mixture and allowed to stand at room temperature,
The crystalline product was tested by chiral HPLC using the following system. By chiral HPLC analysis, substantially pure (-) trans (L) -di-p-
It was confirmed that the toluoyl tartrate salt was isolated. The salt was further purified by recrystallisation from methanol.

Ii) (±) trans 4- (4′-fluorophenyl) -3- (3 ″, 4 ″)
-Methylenedioxyphenoxymethyl) piperidine (0.50g) was dissolved in acetonitrile (10ml) and L-(-)-dibenzoyltartaric acid (0.65g) was added.
Was added to a solution of acetonitrile in acetonitrile (10 ml). Seed crystals were added to the mixture and stirred at room temperature. The crystalline product proved to be significantly enriched in (−) transdibenzoyltartrate by chiral HPLC.

Iii) Paroxetine free base was converted to (−) trans 4- (4′-fluorophenyl) -3- (3 ″, 4 ″ -methylenedioxyphenoxymethyl) piperidinedi-
It is liberated from p-toluoyl or dibenzoyl tartrate by stirring in a mixture of toluene and dilute aqueous sodium hydroxide solution. The phases are separated and the toluene phase is washed with water. Concentrated aqueous hydrochloric acid is added and the crystalline precipitate is collected by filtration and dried.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 25/06 A61P 25/06 25/18 25/18 25/24 25/24 25/28 25/28 25 / 30 25/30 25/32 25/32 C07D 211/22 C07D 211/22 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH , GM, KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, B A, BB, BG, BR, BY, BZ, CA, CH, CN, CR, CU, CZ, DE, DK, DM, DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR , HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU , ZA, ZW F terms (reference) 4C054 AA02 BB01 CC01 DD01 EE04 EE12 FF05 FF11 4C063 AA01 BB01 CC81 DD10 EE01 4C086 AA01 AA02 AA03 AA04 BC21 GA02 GA07 MA01 MA04 ZA08 ZA12 ZA16 ZA81 ZA18 ZA16 ZA18 ZA18 ZA18

Claims (46)

[Claims] 1. Formula (1): [Wherein R ¹ is a substituted phenyl group] or a pharmaceutically acceptable salt thereof, which is represented by the formula (2): [In the formula, R ¹ is as described above, and R ² is a C _1-6 alkyl group, a C _3-6 cycloalkyl group, an aralkyl group, a phenyl group or a substituted phenyl group]
A method comprising the step of hydrolyzing a carbamate ester solution represented by: with a base to form a finely divided complex of a base and a carbamate ester, and heating the complex in the form of a suspension in a solvent. A method including: 2. The method according to claim 1, wherein the base is potassium hydroxide. 3. A process according to claim 1 and claim 2 wherein the base is used in an amount of between 3 and 10 equivalents, more preferably between 6 and 8 equivalents. 4. The method according to claim 1, wherein the solvent is toluene, benzene or xylene, preferably toluene. 5. The method according to claim 1, wherein R ¹ is 3,4-methylenedioxyphenyl. 6. The method according to claim 1, wherein R ² is phenyl. 7. Potassium hydroxide and its carbamic acid by heating a mixture of the carbamate of formula (2) and potassium hydroxide to a suitable temperature, then stopping the heating and stirring vigorously in the solvent. A method for preparing a finely divided complex derived from an ester. 8. The method according to claim 7, wherein the reaction is carried out under anhydrous or dehydrated conditions. 9. The method of claim 8 wherein the dehydration conditions include removal of water by azeotropic distillation. 10. The carbamic acid ester is 4- (4′-fluorophenyl).
10. A method according to any one of claims 7 to 9 which is -3- (3 ", 4" -methylenedioxyphenoxymethyl) -1-phenoxycarbonylpiperidine at a temperature between 70 ° C and 90 ° C. . 11. The method according to claim 7, wherein the solvent is toluene. 12. The method according to claim 7, wherein the base is KOH, and the complex derived from a carbamate is prepared in-situ by the method according to any one of claims 7 to 11. The method described in one. 13. The process according to claim 12, wherein the water content is dehydrated by azeotropic distillation at reflux temperature until the water content is less than 30%, preferably less than 20%, more preferably less than 10%. 14. The concentration of carbamate on a weight / weight basis is between 4% and 10%, preferably between 5.5% and 9%, most preferably 6.5.
A method according to any one of the preceding claims which is between% and 8.0%. 15. Further, the temperature is between 60 ° C. and 95 ° C., preferably 70 ° C.
A method as claimed in any one of the preceding claims comprising the next step of hot aqueous washing with water between 80 and 80 ° C. 16. The process according to claim 15, wherein an amount of between ½ and ⅕ of the solvent, preferably between ⅓ and ⅕, of water is used in the aqueous wash. 17. The method according to claim 15, wherein the step of aqueous washing is performed by a filtration step. 18. A method of crystallization of a compound of formula (1) as a pharmaceutically acceptable salt, wherein a coexisting solvent is added to a solution of the compound in toluene, benzene or xylene prior to crystallization, A method of acidifying a solution. 19. The method according to claim 18, wherein the coexisting solvent is an alcohol, a ketone, an ester or a chlorinated hydrocarbon. 20. The method according to claim 19, wherein the coexisting solvent is alcohol, preferably ethanol. 21. A coexisting solvent is added between 1/20 and 1/60 of a toluene solution,
21. A method according to any one of claims 18 to 20, preferably in a volume corresponding to between 1/30 and 1/40. 22. After the addition of the coexisting solvent, the solution may be cooled between 10 ° C. and 30 ° C., preferably between 15 ° C. and 25 ° C., and seed crystals may be added. The method described in one. 23. The method according to claim 22, wherein the seed crystals are added in an amount of between 0.05% and 1% by weight, preferably about 0.1% by weight. 24. A method for preparing the hydrochloride salt of a compound of formula (1) when seed crystals are added and hydrochloric acid, preferably aqueous concentrated hydrochloride salt, is added in excess of the theoretical amount after addition of the co-solvent. Item 24. The method according to any one of Items 18 to 23. 25. Between 1.1 and 2 equivalents, preferably 1.3 and 1.8.
25. The method of claim 24, wherein hydrochloric acid is added during equivalents, more preferably about 1.7 equivalents. 26. The method according to claim 24 or 25, wherein the acid is added rapidly with vigorous stirring. 27. The method according to claim 24, further comprising an aqueous alkaline washing step after the acidification step. 28. The method of claim 27, wherein the alkaline wash is conducted at an elevated temperature, preferably between 40 ° C. and 60 ° C., more preferably at about 50 ° C. 29. The method according to claim 27, wherein the alkali is sodium hydroxide.
The method described in. 30. The alkali washing step comprises adding hot water to the toluene solution in an amount between one third and one fourth of the volume of toluene, after which the amount of alkali added is between 5 and 10 equivalents. 30. The method according to claim 29, comprising adding to it a concentrated sodium hydroxide solution, preferably between 6 and 8 equivalents. 31. The step of adding a coexisting solvent, adding arbitrary seed crystals, and acidifying is repeated as described in any one of claims 18 to 26 after the alkali washing. The method according to any one of 30. 32. The method according to claim 1, wherein the hydrolysis step is carried out without alcohol.
The method described in any one of. 33. The method of claim 32, wherein the trace amount of alcohol is reduced by first rinsing the reaction vessel with toluene and washing the toluene phase with water. 34. After the solid compound of formula (1) is isolated, it comprises a further step of recrystallisation from propan-2-ol containing between 1% and 10%, preferably between 2 and 4% water, Method according to any one of the preceding claims. 35. 5 to 10 parts by weight, preferably 7 parts by weight, of the solid product.
35. The method of claim 34 wherein between 8 and 8 parts by weight propan-2-ol is used. 36. The solid product is dissolved in propan-2-ol under reflux and then the solution is cooled to between 50 ° C. and 60 ° C., preferably about 55 ° C., the expected product as seed crystals. Seed crystals at about 1-5% by weight of the
The method according to claim 34 or claim 35, wherein the crystallization is performed by gradually cooling to 0 ° C. 37. A method of removing catechol from a solution of a compound of formula (1) comprising the step of aqueous alkaline washing. 38. The method according to claim 37, wherein the alkaline wash is carried out at an elevated temperature, preferably between 40 ° C. and 60 ° C., more preferably at about 50 ° C. 39. The method according to claim 37 or 38, wherein the alkali is sodium hydroxide.
The method described in. 40. The alkaline washing step comprises adding hot water to the solution in an amount between one third and one quarter of the solution volume, after which the amount of alkali added is between 5 and 10 equivalents. 40. A method according to claim 39 comprising adding to it a concentrated sodium hydroxide solution, preferably between 6 and 8 equivalents. 41. Of (-) trans-4- (4'-fluorophenyl) -3- (3 ", 4" -methylenedioxyphenoxymethyl) piperidine comprising the method of any one of claims 1-40. Preparation method. 42. (-) Trans-4- (4'-fluorophenyl)-, which can be prepared at any time by the process comprising any one of claims 1-40.
3- (3 ", 4" -methylenedioxy-phenoxymethyl) -piperidine. 43. The (-) trans-4- (according to claim 42 in the form of the hydrochloride salt.
4'-Fluorophenyl) -3- (3 ", 4" -methylenedioxy-phenoxymethyl) -piperidine. 44. A pharmaceutical composition for treating or preventing a disease, which comprises the compound according to claim 42 or 43 and a pharmaceutically acceptable carrier. 45. Use of a compound according to claim 42 or 43 in the manufacture of a medicament for the treatment or prevention of disease. 46. A method according to claim 4 in a human suffering from one or more diseases.
A method for treating a disease, which comprises administering an effective amount or a prophylactic amount of the compound according to 2 or 43.