JP2002532470A - Preparation of paroxetine maleate - Google Patents

Abstract

  (57) [Summary] The paroxetine free base is reacted with maleic acid in a temperature range of less than 40 ° C., or an alkanol or ketone is used as a reaction solvent, or an alkanol, hydrocarbon, ketone or ester solvent is used as a recrystallization solvent, or an appropriate solvent is used. By combining temperature and solvent, 2-[(3S, 4R) -trans-4- (4'-fluorophenyl) -3- (3 ", 4" -methylenedioxyphenoxymethyl) piperidin-1-yl] A paroxetine maleate substantially free of butane-1,4-dioic acid is prepared.

Description

DETAILED DESCRIPTION OF THE INVENTION

TECHNICAL FIELD [0001] The present invention relates to a novel method for producing a pharmaceutically active compound. More specifically, the present invention provides a process for preparing the maleate salt of paroxetine free base that is free of structurally similar impurities.

BACKGROUND OF THE INVENTION Antidepressants and medicaments having anti-Parkinsonian properties are disclosed in US Pat. No. 3,912,743.
And U.S. Pat. No. 4,007,196. Of particular interest among the disclosed compounds is paroxetine, ie, 4- (4'-
It is the (-)-trans isomer of fluorophenyl) -3- (3 ', 4'-methylenedioxyphenoxymethyl) piperidine. This compound, as its hydrochloride, is used in therapy, especially in the treatment and prevention of depression, obsessive-compulsive disorder (OCD) and panic disorder. A particularly useful salt of paroxetine is maleate. US Patent No. 400719
Example 2 of No. 6 discloses a process for preparing paroxetine maleate by crystallization from ethanol / diethyl ether. It has been found that paroxetine maleate can now be obtained as a salt having a 1: 1 (molar) ratio of paroxetine to maleic acid, as well as a salt having a 2: 1 (molar) ratio of paroxetine to maleic acid. . The 1: 1 salt was also found to exist in two polymorphs, referred to as Form A and Form B. Preparations and polymorphs of 1: 1 and 2: 1 salts are described in GB9822386.1.

[0003] Now, the known procedure for producing paroxetine maleate involves substantial amounts (3
2-[(3S, 4R) -trans-4- (4'-fluorophenyl)], which is in the form of a salt with an undesired impurity, typically paroxetine itself.
-3- (3 ", 4" -methylenedioxyphenoxymethyl) piperidin-1-yl] butane-1,4-dioic acid. As a result of the chemical similarity to the desired paroxetine salt, the detection of this impurity is not easy; this has not been mentioned in the literature so far and no method has been described to prevent or eliminate it.

DISCLOSURE OF THE INVENTION [0004] The present invention relates to a solvent suitable for reacting paroxetine free base with maleic acid in a temperature range which has heretofore been considered a sub-optimal lower limit, or for reacting or recrystallizing the product. Or by combining an appropriate temperature and a solvent, 2-[(3S, 4R) -trans-4- (4′-fluorophenyl)
) -3- (3 ", 4" -Methylenedioxyphenoxymethyl) piperidin-1-yl]
It is based on the finding that paroxetine maleate substantially free of butane-1,4-dioic acid can be prepared.

BEST MODE FOR CARRYING OUT THE INVENTION Accordingly, in one aspect, the present invention provides 2-[(3S, 4R) -trans-4
Process for producing paroxetine maleate substantially free of-(4'-fluorophenyl) -3- (3 ", 4" -methylenedioxyphenoxymethyl) piperidin-1-yl] butane-1,4-dioic acid Wherein the paroxetine free base is reacted with maleic acid in a solution at a temperature of less than 40 ° C., and the maleate is crystallized from the solution. Heretofore, reaction temperatures above 70 ° C. were considered to be advantageous. The disadvantages of crystallization at low temperatures are overcome by careful control of the crystallization conditions, such as adding the desired salt or polymorphic seed. Using this procedure, 2: 1 and 1: 1 salts thereof can be prepared by contacting a stoichiometric amount of a paroxetine free base with an acid. It is preferred to use seeding to prepare the paroxetine 1: 1 maleate salt of Form B. In another embodiment, the present invention provides a method, comprising providing substantially 2-[(3S, 4R) -trans-4- (4'-fluorophenyl) -3- (3 ", 4" -methylenedioxyphenoxymethyl. ) Piperidine-l-yl] butane-l, 4-dioic acid-free paroxetine maleate, which comprises reacting paroxetine free base with maleic acid in a alkanol or ketone solvent in solution. A method is provided, characterized in that the maleate is crystallized from a solution.

2-[(3S, 4R) -trans-4- (4′-fluorophenyl) -3- (3 ″, 4 ”
-Methylenedioxyphenoxymethyl) piperidin-1-yl] butane-1,4-
Preferred solvents for preparing paroxetine maleate substantially free of dionic acid are alcohols such as propan-2-ol, ketones such as methyl isobutyl ketone or acetone. A particularly suitable solvent is propan-2-ol, in particular one of paroxetine.
: 1 is suitable for preparing the maleate Form A. The reaction of paroxetine and maleate in propan-2-ol gives Form A of paroxetine maleate with little or no formation of impurities, even at elevated temperatures.

In a further aspect of the invention, 2-[(3S, 4R) -trans-4- (4′-fluorophenyl) -3- (3 ″, 4 ”-methylenedioxyphenoxymethyl) piperidine-1-. Purify the paroxetine maleate salt containing il] butane-1,4-dioic acid by crystallization from an alkanol or ketone solvent to obtain paroxetine maleate salt with low levels of impurities. Solvents that can be used to prepare substantially pure paroxetine maleate can also be used to purify impure salts by crystallization operations. It was surprising that some unfavorable solvents for the preparation of paroxetine maleate, such as ethyl acetate, could be used successfully for purification. The desired polymorph of the 1: 1 maleate salt of paroxetine can be prepared by inoculating a suitable seed before crystallization and recrystallizing from a different solvent after purification.

2-[(3S, 4R) -trans-4- (4′-fluorophenyl) -3- (3 ″, 4 ″
-Methylenedioxyphenoxymethyl) piperidin-1-yl] butane-1,4-
Products that are "substantially free" of dionic acid impurities typically contain less than 5% impurities. A low level of impurities is suitably below 2%, more preferably below 1% and optimally below 0.2%. Paroxetine maleate may be obtained as a solvate, which becomes isolated with the solvent in which the salt is dissolved during isolation from solution. Any such solvates form a further aspect of the present invention. The solvate may be heated, for example, dried in an oven, or an excluded solvent that does not form a solvate (di
It can be returned to the unsolvated salt by treating with a splacement solvent).

Paroxetine free base is disclosed in US Pat. No. 4,007,196 and EP-B-02.
Can be prepared according to the method outlined in 23403. Maleic acid is commercially available. 2-[(3S, 4R) -trans-4- (4 ′) obtainable by the method of the present invention.
Paroxetine maleate substantially free of -fluorophenyl) -3- (3 ", 4" -methylenedioxyphenoxymethyl) piperidin-1-yl] butane-1,4-dioic acid is another aspect of the present invention. Another embodiment can be formed and used therapeutically as a pharmaceutically acceptable salt of paroxetine.

The 2-[(3S, 4R) -trans-4- (4′-fluorophenyl) -3- (
3 ", 4" -methylenedioxyphenoxymethyl) piperidin-1-yl] butane-
Paroxetine maleate substantially free of 1,4-dionic acid (hereinafter referred to as “compound” of the present invention) is used for the following disorders: alcoholism, anxiety, depression, obsessive-compulsive disorder, panic disorder, chronic pain, It can be used for the treatment and prevention of obesity, senile dementia, migraine, heavy eating, anorexia, blush fear, premenstrual syndrome (PMS), adolescent depression, hair loss, dysthymia and substance abuse. These obstacles are hereinafter referred to as “obstacles”.

The present invention further provides a method for treating one or more disorders by administering an effective and / or prophylactic amount of a compound of the present invention to a subject in need thereof. The present invention further provides a pharmaceutical composition for use in the treatment and / or prevention of one or more disorders, comprising a mixture of a compound of the present invention and a pharmaceutically acceptable carrier. . The present invention also provides the use of a compound of the present invention for treating and / or preventing one or more disorders.

The present invention also provides the use of a compound of the present invention in the manufacture of a medicament for treating and / or preventing one or more disorders. Optimally, the invention applies to the treatment of depression, OCD and panic disorder. Compositions containing a compound of the present invention may be formulated for administration by any route, for example, oral, sublingual, rectal, topical, parenteral, intravenous or intramuscular administration. The formulation may, if desired, be designed to provide a slow release of the paroxetine salt. The medicament can be, for example, in the form of tablets, capsules, sachets, vials, powders, granules, lozenges, reconstitutable powders or liquid preparations, such as solutions or suspensions, or suppositories.

The composition will usually be calculated on a free base basis, from 1 to 200 mg, more usually from 5 to 100 mg, for example 10, 12.5 mg, for a human patient.
, 15, 20, 25, 30 or 40 mg, such as 10-50 mg, of a unit dose of the composition containing the active ingredient. Most preferably, unit doses contain 20 mg of active ingredient calculated on a free base basis. Such a composition comprises:
Normally, the active ingredient is in the range of 5 to 400 mg calculated on the free base, based on the free base, usually 1 to 6 times a day, for example 2, 3 or 3 times a day. It is administered four times. Most preferably, this unit dose is administered once a day. Preferred unit dosage forms include tablets or capsules.

The compositions of the present invention can be formulated by common mixing operations, such as blending, filling and compacting. Carriers suitable for use in the present invention include diluents, binders, disintegrants, coloring agents, flavorings and / or preservatives. These substances can be used in a conventional manner, for example, in a manner similar to that used for already marketed antidepressants. Specific examples of the pharmaceutical composition include EP-B-02223403 and U.S. Pat.
007196, wherein the products of the present invention can also be used as active ingredients.

EXAMPLES The present invention will be described with reference to the following examples. Example 1 About 30% of 2-[(3S, 4R) -trans-4- (4'-fluorophenyl) -3
Paroxetine maleate (140 g) containing-(3 ", 4" -methylenedioxyphenoxymethyl) piperidin-1-yl] butane-1,4-dioic acid is suspended in ethyl acetate and refluxed for 30 minutes. Heated for minutes. The suspension was cooled at a reflux temperature to a few degrees and filtered. The remaining liquid was slowly cooled to ambient temperature and left to crystallize. The crystallization rate was increased using sonication. The solid product was collected by filtration, dried under vacuum to give paroxetine maleate 1: 1 Form B (52.55
g) was obtained.

Example 2 Paroxetine base (0.72 g) in propan-2-ol was reacted with maleic acid (0.17 g) at 40-50 ° C. and the mixture was stirred vigorously. The crystalline solid was separated from the solution, isolated by filtration and 2-[(3S, 4R) -trans-4.
Paroxetine maleate without 1- (4'-fluorophenyl) -3- (3 ", 4" -methylenedioxyphenoxymethyl) piperidin-1-yl] butane-1,4-dioic acid 1: 1 The salt form A was obtained.

Example 3 Maleic acid (0.52 g) was added to a rapidly stirred solution of paroxetine in toluene (20 ml) at room temperature. Seed crystals of paroxetine maleate Form A were added and the reaction mixture was stirred vigorously. 2-[(3S, 4R) -trans-4- (4'-fluorophenyl) -3- (3 ", 4" -methylenedioxyphenoxymethyl) piperidin-1-yl] butane-1,4-dioic acid Paroxetine maleate free of was isolated by filtration, washed with toluene and dried.

Example 4 A solution of paroxetine base in toluene (2.14 g in 30 ml) was added dropwise over 15 minutes to a solution of maleic acid (0.8 g) in propan-2-ol. The reaction mixture was stirred vigorously. Thereafter, crystallization started and the resulting suspension was stirred for 1 hour. The solid was collected by filtration, washed with propan-2-ol (5 ml),
Dry under vacuum and give 2-[(3S, 4R) -trans-4- (4'-fluorophenyl)
) -3- (3 ", 4" -Methylenedioxyphenoxymethyl) piperidin-1-yl]
Paroxetine maleate substantially free of butane-1,4-dioic acid (2.
05g).

──────────────────────────────────────────────────続 き Continuation of front page (81) Designated country 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, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CR, CU, CZ, DE, DK, DM, 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, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZWF terms (Reference) 4C063 AA01 BB08 CC81 DD10 EE01 4C086 AA01 AA03 BC21 GA02 GA12 MA01 MA04 NA03 NA06 ZA12 ZA15 ZA18

Claims (11)

[Claims] (1) 2-[(3S, 4R) -trans-4- (4'-fluorophenyl)
) -3- (3 ", 4" -Methylenedioxyphenoxymethyl) piperidin-1-yl]
A process for preparing paroxetine maleate substantially free of butane-1,4-dioic acid, comprising reacting paroxetine free base with maleic acid in a solution at a temperature of less than 40 ° C. to convert the maleate from the solution. A process for producing paroxetine maleate, which comprises crystallization. 2. The process according to claim 1, wherein the reaction is carried out in an alkanol, ester, hydrocarbon or ketone. 3. 2-((3S, 4R) -trans-4- (4′-fluorophenyl)
) -3- (3 ", 4" -Methylenedioxyphenoxymethyl) piperidin-1-yl]
A process for preparing paroxetine maleate substantially free of butane-1,4-dioic acid, comprising reacting paroxetine free base with maleic acid in a solution in an alkanol or ketone solvent, and converting the maleate salt from the solution. A method for producing paroxetine maleate, characterized by crystallizing 4. The method according to claim 3, wherein the reaction is carried out at a temperature lower than 40 ° C. 5. The method according to claim 1, wherein the solvent is propan-2-ol, toluene, methyl isobutyl ketone or acetone. 6. A 2-[(3S, 4R) -trans-4- (4′-fluorophenyl)
) -3- (3 ", 4" -Methylenedioxyphenoxymethyl) piperidin-1-yl]
A method for obtaining paroxetine maleate substantially free of butane-1,4-dioic acid, comprising: a) 2-[(3S, 4R) -trans-4- (4′-fluorophenyl).
) -3- (3 ", 4" -Methylenedioxyphenoxymethyl) piperidin-1-yl]
Heating paroxetine maleate salt containing butane-1,4-dionic acid in a solvent, b) filtering the hot solution, and c) cooling the solution to induce crystallization. . 7. The method according to claim 6, wherein the solvent is a hydrocarbon, ketone, alkanol or ester solvent. 8. The method according to claim 7, wherein the solvent is propan-2-ol, toluene, methyl isobutyl ketone, acetone or ethyl acetate. 9. A method for producing 2-[(3S, 4R) -trans-4- (4′-fluorophenyl)
) -3- (3 ", 4" -Methylenedioxyphenoxymethyl) piperidin-1-yl]
Paroxetine maleate substantially free of butane-1,4-dionic acid. 10. A compound comprising the compound according to claim 9 or the product obtained by the method according to any one of claims 1 to 8, and a pharmaceutically acceptable carrier. Or a pharmaceutical composition for use in the treatment or prevention of disorders. 11. A method for treating and / or preventing one or more disorders, comprising an effective amount and / or a prophylactic amount of a compound according to claim 9 or claim 1.
9. A method for treating and / or preventing a disorder, comprising administering a product obtained by the method according to any one of claims to 8 to a subject in need of the treatment and / or prevention.