WO2008090465A2 - Process for synthesizing desvenlafaxine free base and salts or salvates thereof - Google Patents

Process for synthesizing desvenlafaxine free base and salts or salvates thereof Download PDF

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Publication number
WO2008090465A2
WO2008090465A2 PCT/IB2008/000472 IB2008000472W WO2008090465A2 WO 2008090465 A2 WO2008090465 A2 WO 2008090465A2 IB 2008000472 W IB2008000472 W IB 2008000472W WO 2008090465 A2 WO2008090465 A2 WO 2008090465A2
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process
desvenlafaxine
free base
formula
iv
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PCT/IB2008/000472
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French (fr)
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WO2008090465A3 (en
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Jordi Bosch I Llado
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Medichem, S.A.
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Publication of WO2008090465A2 publication Critical patent/WO2008090465A2/en
Publication of WO2008090465A3 publication Critical patent/WO2008090465A3/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/08Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00Systems containing only non-condensed rings
    • C07C2601/12Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14The ring being saturated

Abstract

The invention relates to a process for manufacturing desvenlafaxine free base and salts or solvates thereof, comprising O-demethylating venlafaxine by treatment with 2- (diethylamino) ethanethiol free base or its hydrochloride salt.

Description

IMPROVED PROCESS FOR SYNTHESIZING DESVENLAFAXINE FREE BASE AND SALTS OR SOLVATES THEREOF

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to United States Provisional Application No. 60/881,467 (filed January 22, 2007), which application is expressly incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

Field of the Invention

The invention relates generally to an improved process for manufacturing desvenlafaxine free base and salts or solvates thereof.

Relevant Background

Desvenlafaxine (Formula I, below) is an active pharmaceutical substance with an empirical formula of C16H25NO2 and a molecular weight of 263.38. Desvenlafaxine, which can also be referred to as desmethylvenlafaxine and/or O-desmethylvenlafaxine, is the major active metabolite of venlafaxine, an active pharmaceutical ingredient indicated for the treatment of major depressive disorder.

Figure imgf000002_0001

U.S. Patent No. 4,535, 186 discloses the first process for preparing desvenlafaxine. In U.S. Patent No.4,535,186, desvenlafaxine is synthesized by the process illustrated in Scheme 1:

Figure imgf000002_0002

Scheme 1 Additional alternative processes for preparing desvenlafaxine are described in the literature. These alternative processes generally proceed via the demethylation of venlafaxine, see, for example, U.S. Patent Application Publication No. 2005/197392, U.S. Patent Nos. 7,026,508, and 6,689,912, and International Patent Publication No. WO07/071404. These processes make use of different demethylating agents, such as lithium diphenylphosphide, alkali metal salts of trialkylborohydrides, high molecular weight thiolate anions, and metal sulfides. However, the use of the aforementioned demethylating agents presents several drawbacks, i.e., requires extensive purification procedures aimed to isolate desvenlafaxine from said demethylating agents and/or corresponding by-products, and involve odor workups, which make these processes unsuitable for industrial implementation.

In view of the foregoing, there is a need for an alternative process for preparing desvenlafaxine from venlafaxine including, for instance, an alternative process which avoids the drawbacks of current state of the art processes (e.g., makes use of simpler and shorter purification procedures, allows an essentially odorless workup, and which is well suited for industrial implementation).

Salts of O-desmethylvenlafaxine, including the fumarate, succinate and formate salts, have been described in the literature. For example, U.S. Patent No. 4,535,186 reports the preparation of O-desmethylvenlafaxine fumarate salt. More recently, the preparation of several polymorphic forms of the succinate salt have been reported in U.S. Patent No. 6,673,838 B2. Additionally, U.S. Patent Application Publication No. 2006/0058552 discloses the preparation of the formate salt.

DESCRIPTION OF THE INVENTION

Reference will now be made in detail to the preferred embodiments of the invention. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein.

The invention relates generally to an improved process for manufacturing desvenlafaxine free base and salts or solvates thereof. The invention provides a process for preparing desvenlafaxine from venlafaxine which makes use of a simple purification procedure, which allows an essentially odorless workup, and which is suitable for industrial implementation. In particular, the invention relates to several newly synthetic processes for preparing desvenlafaxine that include using 2-(diethylamino)ethanethiol free base or its HCl salt to demethylate a phenol protected group during the preparation of desvenlafaxine free base and salts or solvates thereof.

It has been shown that it is possible to demethylate phenol protected compounds using 2-(diethylamino)ethanethiol free base or its HCI salt {see Magano et al., J. Org. Chem., vol. 71: 7103-7105 (2006)). The use of 2-(diethylamino)ethanethiol in the Magano process did not afford any alkylphenol, or result in any compounds which were structurally related to desvenlafaxine. Thus, the invention includes using 2-(diethylamino)ethanethiol free base or its HCl salt in the production of desvenlafaxine free base and salts or solvates thereof from venlafaxine. More precisely, once the reaction has been performed, the excess of 2-(diethylamino)ethanethiol and its by-product 2-(diethylamino)ethyl methyl sulfide are easily extracted into an aqueous phase, which also allows an essentially odorless workup.

Scheme 2 (below) illustrates one synthetic process for preparing desvenlafaxine free base and salts or solvates thereof using 2-(diethylamino)ethanethiol free base or its HCl salt. In particular, this process involves preparing desvenlafaxine directly from venlafaxine (Formula IV) via treatment with 2-(diethylamino)ethanethiol free base or its HCl salt.

Figure imgf000004_0001

Scheme 2

In Scheme 2 (above) the conversion of the compound of Formula IV to desvenlafaxine can be accomplished using 2-(diethylamino)ethanethioI free base or its HCl salt.

The N,N-demethylated intermediate of Formula III can be prepared by O- demethylation of the corresponding intermediate of Formula II using 2-diethylaminoethane thiol free base or its HCI salt as illustrated in Scheme 3 below. The compound of Formula III can then be N,N-dimethylated by conventional means, for example by reductive methylation by treatment with formaldehyde and a reducing agent such as formic acid, sodium triacetoxiborohydride, sodium cyanoborohydride and combinations thereof. EtjNCHjCHjSH HCI

NaOSu. DMF. reflux

Figure imgf000005_0001
Figure imgf000005_0002
Figure imgf000005_0003

Scheme 3

In Schemes 2 and 3, the 2-(diethylamino)ethanethiol can be used as a base or as its HCl salt. Additionally, in both of Schemes 2 and 3, (i) other bases can be used instead of sodium terf-butanoate (NaO/Bu) including sodium methanolate (NaOMe), potassium tert- butanoate (KO/Bu), sodium hydride (NaH), lithium amide (LiNH2), sodium hydroxide (NaOH), and combinations thereof; (ii) other organic solvents can be used instead of DMF (N,N- dimethyl formamide) including NMP (l-methyl-2-pyrrolidinone) and/or DMA (N,N- dimethylacetamide), an ether solvent, a polyether solvent, polyethylene glycol and combinations thereof; and (iii) suitable reducing agents for performing the reductive amination depicted in Scheme 3 include: formic acid, sodium triacetoxiborohydride, sodium cyanoborohydride and combinations thereof. The demethylation reaction illustrated in Schemes 2 and 3 could be performed at temperatures of approximately 150° -195° C.

Prefereably, the base is sodium methanolate (NaOMe).

Preferably, the organic solvent is an ether solvent, more preferably, is a polyether solvent, and more preferably is polyethylene glycol.

The desvenlafaxine free base of formula (I) can be isolated by a process as follows: i. adjusting the reaction mixture obtained to a pH of approximately 9.5 with an acid to obtain desvenlafaxine free base; ii. isolating desvenlafaxine free base, iii. optionally purifying the solid, and iv. optionally drying the solid. Preferably the acid is a hydrogen halide acid and, more preferably the acid is hydrochloric acid.

Compounds represented in Schemes 2 and 3 can be employed as raw materials or as intermediates to produce desvenlafaxine, and can optionally be employed in their free base form or as one of its salts and/or solvates thereof, where appropriate. Similarly, desvenlafaxine obtained according to Schemes 2 and 3 can be isolated in its free base form or as one of its salts or solvates thereof.

The processes of the invention further include converting the desvenlafaxine free base into various salts and solvates thereof. Preferably, the salt or solvate is desvenlafaxine succinate salt and, more preferably, desvenlafaxine succinate monohydrate. The process for converting the desvenlafaxine free base into desvenlafaxine succinate salt includes: i. treating desvenlafaxine with succinic acid in a mixture of acetone and water; ii. heating the mixture to reflux; iii. isolating desvenlafaxine succinate; and iv. drying the solid.

The resulting desvenlafaxine succinate has a purity of at least approximately 99% as measured by HPLC and, more preferably, has a purity of at least approximately 99.9%, as measured by HPLC.

It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention and specific examples provided herein without departing from the spirit or scope of the invention. Thus, it is intended that the present invention covers the modifications and variations of this invention that come within the scope of any claims and their equivalents.

The following examples are for illustrative purposes only and are not intended, nor should they be interpreted, to limit the scope of the invention.

Specific Examples

General Experimental Conditions:

HPLC Method

In the examples described below, the following analytical chromatographic HPLC method was used:

The chromatographic separation was carried out in a Kromasil C8, 5 μm, 25 cm x 4.6 mm. I. D column at room temperature.

The mobile phase was prepared by mixing 1,600 g of (NH4)H2P(It buffer solution pH = 4.4 and 313.2 g of acetonitrile HPLC grade. The pH of the mixture should be 4.9, adjust if necessary.

A (NH4)H2PO4 buffer solution (pH = 4.4) was prepared by dissolving 17 g of (NH4)H2PO4 in 1600 mL of water and adjusting the pH = 4.4 with HaPO4 or ammonium hydroxide.

The chromatograph was equipped with a 225 nm detector, and the flow rate was 1.2 mL per minute at room temperature. Test samples (20 μl) were prepared by dissolving the appropriate amount of sample to obtain 1 mg per mL concentration in the mobile phase.

In those conditions the retention time of desvanlafaxine, compound (I), is about 7 minutes, and the retention time of venlafaxine, compound (IV), is about 22 minutes.

EXAMPLE 1: Preparation of Desvenlafaxine (Le., Compound I).

This example illustrates a process for converting Compound IV into desvenlafaxine {i.e., Compound I) according to one aspect of the invention.

In a 100 mL flask 8 g (0.027 mol) of Venlafaxine free base, 13 mL of polyethylene glycol 400 (PEG400) and 6.9 g (0.041 mol) of 2-(diethylamino)ethanothiol were charged. 13.2 g (13.6 mL, 0.073 mol) of 30 % w/w solution of sodium methanolate in methanol were slowly added. The resulting suspension was heated to about 195° C and methanol was distilled off in the meantime. The stirring was continued for four hours at that temperature and then was cooled down to 20-25° C. 30 mL of 1 M hydrochloric acid were added to adjust pH to approx. 9.5. The resulting suspension was filtered at 20-25° C and the solid was dried at 50° C. The solid corresponded to desvenlafaxine (3.4 g; yield: 45 %; purity HPLC: 96.8 %).

EXAMPLE 2: Preparation of Desvenlafaxine Succinate Monohydrate.

This example illustrates a process for converting desvenlafaxine (i.e., Compound I) into desvenlafaxine succinate monohydrate according to one aspect of the invention.

Desvenlafaxine base (18.1 g, 0.069 mol) was charged into a 500 mL round bottomed flask under nitrogen atmosphere with 9.75 g (0.083 mol) of succinic acid, 135 g (170 mL) of acetone and 54 g of deionized water. The suspension was heated to reflux temperature and maintained at this temperature 30 minutes. The resulting solution was cooled to 50-55° C and filtered.

The filtered solution was cooled to 30-35° C in approximately 1 hour. In the interim, seeding was performed at approximately 40-45° C. The suspension was maintained for 3 hours at 30-35° C. Thereafter, the suspension was cooled to 20-25° C in approximately 1 hour, and maintained at this temperature for 2 hours. Then, the suspension was cooled to 10 ± 3° C in approximately 30 minutes and maintained at this temperature for 1 hour. Finally, the suspension was filtered and washed twice with 2 x 7.5 g (2 x 9.4 mL) of acetone. The wet solid was dried under vacuum at 60 ± 5° C to yield 22.96 g of desvenlafaxine succinate (yield: 83.6 %). Analytical data: HPLC Purity: 99.9 %; assay: 99.6 %.

Although the invention has been described and illustrated with a certain degree of particularity, it is understood that the present disclosure has been made only by way of example, and that numerous changes in the conditions and order of steps can be resorted to by those skilled in the art without departing from the spirit and scope of the invention.

Claims

What is claimed is:
1. A process for preparing desvenlafaxine free base of formula (I) and salts or solvates thereof,
Figure imgf000009_0001
(D said process comprising O-demethylating venlafaxine of formula (IV)
Figure imgf000009_0002
(IV) by treatment with 2-(diethylamino)ethanethiol free base or its hydrochloride salt, to obtain desvenlafaxine free base.
2. The process of claim 1, further comprising converting said desvenlafaxine free base into a salt or solvate thereof.
3. The process of claim 1, wherein said step of O-demethylating venlafaxine of formula (IV) comprises: i. reacting a mixture of venlafaxine, 2-(diethylamino)ethanethiol free base or its hydrochloride salt, and at least one organic solvent, in the presence of at least one base, and ii. isolating desvenlafaxine free base of formula (I) from said mixture.
4. The process of claim 3, wherein said at least one organic solvent is at least one of DMF, NMP, DMA, an ether solvent, a polyether solvent, polyethylene glycol and combinations thereof.
5. The process of claim 4, wherein said at least one solvent is an ether solvent.
6. The process of claim 4, wherein said at least one solvent is a polyether solvent.
7. The process of claim 4, wherein said at least one solvent is polyethylene glycol.
8. The process of claim 3, wherein said at least one organic solvent is at least one of sodium methanolate, sodium tert-butanoate, potassium /ert-butanoate, sodium hydride, lithium amide, sodium hydroxide, and combinations thereof.
9. The process of claim 8, wherein said at least one base is sodium methanolate.
10. The process of claim 3, wherein said step of O-demethylating venlafaxine of formula (IV) is at least partially performed at a temperature of approximately 150° C.
1 1. The process of claim 3, wherein said step of O-demethylating venlafaxine of formula (IV) is at least partially performed at a temperature of approximately 195° C.
12. The process of claim 3, wherein said step of isolating said desvenlafaxine free base of formula (I) from said mixture comprises: i. adjusting the reaction mixture obtained to a pH of approximately 9.5 with an acid to obtain desvenlafaxine free base; ii. isolating desvenlafaxine free base, iii. optionally purifying the solid, and iv. optionally drying the solid.
13. The process of claim 13, wherein said acid is a hydrogen halide acid.
14. The process of claim 13, wherein said acid is hydrochloric acid.
15. The process of claim 2, wherein the desvenlafaxine free base is converted into desvenlafaxine succinate salt.
16. The process of point 15, wherein the desvenlafaxine succinate salt is desvenlafaxine succinate monohydrate.
17. The process of claim 15, wherein said converting of said desvenlafaxine free base into desvenlafaxine succinate salt comprises: i. treating desvenlafaxine with succinic acid in a mixture of acetone and water; ii. heating the mixture to reflux; iii. isolating desvenlafaxine succinate; and iv. drying the solid.
18. The process of claim 17, wherein the desvenlafaxine succinate has a purity of at least approximately 99% as measured by HPLC.
19. The process of claim 17, wherein the desvenlafaxine succinate has a purity of at least approximately 99.9%, as measured by HPLC.
20. Desvenlafaxine free base and salts or solvates thereof prepared according to the processes of any of claims 1 to 19.
21. A pharmaceutical composition comprising said desvenlafaxine free base and salts or solvates thereof of claim 20.
PCT/IB2008/000472 2007-01-22 2008-01-22 Process for synthesizing desvenlafaxine free base and salts or salvates thereof WO2008090465A2 (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009053731A1 (en) * 2007-10-26 2009-04-30 Generics [Uk] Limited Process for preparing o-desmethylvenlafaxine
CZ301820B6 (en) * 2009-02-06 2010-06-30 Zentiva, K.S. Novel salts of desvenlafaxine and process of their preparation
EP2394976A1 (en) 2010-06-11 2011-12-14 LEK Pharmaceuticals d.d. Process for demethylating aromatic methyl ethers using 3-mercaptopropionic acid

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US668912A (en) * 1900-12-08 1901-02-26 Peter Fitz Randolph Seed-planter and fertilizer-distributer.
EP0112669A2 (en) * 1982-12-13 1984-07-04 American Home Products Corporation Phenethylamine derivatives and intermediates therefor
US6673838B2 (en) * 2001-02-12 2004-01-06 Wyeth Succinate salt of O-desmethyl-venlafaxine
US20050197392A1 (en) * 1999-04-06 2005-09-08 Sepracor Inc. O-desmethylvenlafaxine and methods of preparing and using the same

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US668912A (en) * 1900-12-08 1901-02-26 Peter Fitz Randolph Seed-planter and fertilizer-distributer.
EP0112669A2 (en) * 1982-12-13 1984-07-04 American Home Products Corporation Phenethylamine derivatives and intermediates therefor
US20050197392A1 (en) * 1999-04-06 2005-09-08 Sepracor Inc. O-desmethylvenlafaxine and methods of preparing and using the same
US6673838B2 (en) * 2001-02-12 2004-01-06 Wyeth Succinate salt of O-desmethyl-venlafaxine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MAGANO ET AL: "2-(Diethyamino)ethanethiol, a New Reagent for the Odorless Deprotection of Aromatic Methyl Ethers" J. ORG. CHEM., vol. 71, 2006, pages 7103-7105, XP002487903 cited in the application *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009053731A1 (en) * 2007-10-26 2009-04-30 Generics [Uk] Limited Process for preparing o-desmethylvenlafaxine
JP2011500777A (en) * 2007-10-26 2011-01-06 ジェネリクス・(ユーケー)・リミテッド O- desmethylvenlafaxine method of manufacture
CZ301820B6 (en) * 2009-02-06 2010-06-30 Zentiva, K.S. Novel salts of desvenlafaxine and process of their preparation
EP2394976A1 (en) 2010-06-11 2011-12-14 LEK Pharmaceuticals d.d. Process for demethylating aromatic methyl ethers using 3-mercaptopropionic acid
WO2011154152A1 (en) 2010-06-11 2011-12-15 Lek Pharmaceuticals D.D. Process for demethylating aromatic methyl ethers using 3 -mercaptopropionic acid

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