WO2010060390A1

WO2010060390A1 - A method of preparation of desvenlafaxine and its salts

Info

Publication number: WO2010060390A1
Application number: PCT/CZ2009/000140
Authority: WO
Inventors: Ludek Ridvan; Stanislav Radl
Original assignee: Zentiva, K.S.
Priority date: 2008-11-27
Filing date: 2009-11-26
Publication date: 2010-06-03
Also published as: CZ2008756A3; CZ301503B6

Abstract

A method of preparation of 4-(2-(dimethylamino)-1-(1-hydroxycyclohexyl)ethyl)phenol of formula (I), known under the generic name desvenlafaxine, and its pharmaceutically acceptable salts, which comprises (a) stirring up O-benzyl desvenlafaxine or its derivative of formula (II), or its salt, where R is selected from H, 4-methyl, 4-methoxy, 3,4-dimethoxy, 2-nitro, 4-nitro, 4-chloro, 4-bromo, 2,6-dichloro and 2,6-difluoro, in an organic solvent or a mixture of organic solvents, followed by dissolution of the starting substance at pH 3 to 8; (b) transformation of O-benzyl desvenlafaxine or its derivative of formula (II) to desvenlafaxine (I) by catalytic hydrogenation; (c) removing the catalyst from the desvenlafaxine solution with the pH value of 3 to 8 by filtration, followed by increasing pH to a value higher than 8 and lower than 11 by addition of an inorganic or organic base; (d) isolation of desvenlafaxine base (I) by filtration; and (e) transformation of desvenlafaxine base (I) to a pharmaceutically acceptable salt.

Description

A METHOD OF PREPARATION OF DESVENLAFAXINE AND ITS SALTS

Technical Field

The invention deals with a new procedure of preparation of 4-(2-(dimethylamino)-l-(l- hydroxycyclohexyl)ethyl)phenol of formula (I)

known under the generic name desvenlafaxine.

Background Art

Desvenlafaxine has been registered for treatment of depression and vasomotoric symptoms related to the menopause (Drugs of the Future 2006, 31(4), 304-309).

Patent no. US 4,535,186 in example 19 describes preparation of desvenlafaxine by debenzylation of the starting "O-benzyl desvenlafaxine", Scheme 1.

(9-benzyl desvenlafaxine

Scheme 1 Here, the reaction is carried out under high dilution (1 g per 100 ml of solvent); the product is obtained by evaporation of the solution after removal of the catalyst by filtration. The solid evaporation product, i.e. desvenlafaxine base, is transformed by the effect of fumaric acid in an acetone - ethanol mixture to the salt characterized by the melting point of 140-142 ⁰C. During a reproduction of the procedure described in the US 4,535,186 patent desvenlafaxine base was obtained that exhibits the characteristics peaks of powder X-ray diffraction: 12.1, 13.2, 15.9 and 20.4, 22.4 and 26.6 ± 0.2 theta. This polymorph was later referred to as form A in patent application WO2007120925.

hi a similar way {Scheme 1) patent application WO 2008/093142 describes preparation of desvenlafaxine base in example 4, where 1.3 g of desvenlafaxine base are prepared from 2 g of O-benzyl desvenlafaxine, dissolved in 50 ml of ethanol, by catalytic hydrogenation. The catalyst is removed from the reaction mixture after debenzylation by filtration and the solvent is evaporated from the filtrate. The evaporation product is dissolved in hexane and the solid product is isolated by filtration.

Other patented procedures (e.g. US 7,026,508, US 6,673,838, WO 03/048104, WO 2007/071404, WO 2007/120923) deal with preparation of desvenlafaxine by demethylation of venlafaxine, Scheme 2. The demethylation agents used include, for example, thiolates.

Demethylation agent

Solvent

Venlafaxine (D

Scheme 2

The above mentioned methods of preparation of desvenlafaxine by catalytic hydrogenation of O-benzyl desvenlafaxine have a disadvantage of the necessity of high dilution during debenzylation (only 1% to 4% solution), resulting from the low solubility of the starting substance and, especially, of the product in the solvents that are commonly used for catalytic hydrogenation. The described processing is not suitable for the industrial scale either, as evaporation of organic solvents until the evaporation product is obtained is difficult to achieve in a large scale and poses high energy demands.

The present invention offers a convenient solution of preparation of highly pure desvenlafaxine and its pharmaceutically acceptable salts.

Disclosure of Invention

The invention relates to a new method of preparation of 4-(2-(dimethylarnino)-l-(l- hydroxycyclohexyl)ethyl)phenol of formula (I)

known under the generic name desvenlafaxine, and of its pharmaceutically acceptable salts, which method comprises:

(1) stirring up of O-benzyl desvenlafaxine or its derivative of formula (II),

or possibly its salt, where R is selected from H, 4-methyl, 4-methoxy, 3,4-dimethoxy, 2-nitro, 4-nitro, 4-chloro, 4-bromo, 2,6-dichloro and 2,6-difluoro, in an organic solvent or mixture of solvents and subsequent dissolution of the starting substance at pH 3 to 8; (2) transformation of O-benzyl desvenlafaxine or its derivative of formula (I!) to desvenlafaxine (I) by means of catalytic hydro genation;

(3) removal of the catalyst from the desvenlafaxine solution with the pH value of 3 to 8 by filtration and subsequent increase of pH to a value higher than 8 and lower than 11 by addition of an inorganic or organic base;

(4) isolation of the desvenlafaxine base by filtration; and

(5) transformation of the desvenlafaxine base to a pharmaceutically acceptable salt.

Detailed Description of the Invention

The molecule of desvenlafaxine (I) contains both acidic and basic functional groups, and therefore it can form salts at a higher or lower pH value than the so-called isoelectric point, i.e. at the pH of the solution at which the molecule does not carry any charge and is usually the least soluble in protic solvents (e.g. alcohols or mixtures of organic solvents and water), hi the case of desvenlafaxine (I) this pH value is about 9.5 {Scheme 3).

pH (solution) > 9.5

pH (solution) < 9.5

Increased Minimum Increased solubility solubility solubility

Scheme 3

Adding an acid or base to a suspension of desvenlafaxine (I) in a protic solvent causes a change of pH of the solution, i.e. gradual protonation of the amine function when pH of the solution is reduced or gradual deprotonation of the aromatic hydroxyl when pH of the solution is increased, which results in a gradual increase of solubility related to an increasing proportion of ionized desvenlafaxine in the mixture. In the opposite way, when pH of protonated or deprotonated desvenlafaxine is adjusted to 8 to 11, preferably to 9 to 10, its solubility is reduced to the minimum.

We have found out that use of this property of desvenlafaxine (I) can be beneficially made in its preparation from O-benzyl desvenlafaxine or its derivative of formula (II). O-benzyl desvenlafaxine (or its derivatives) of formula (I!) is better soluble in protic solvents than desvenlafaxine (I) and its solubility increases with lowering pH due to the presence of the amine function in the molecule. With regard to a lower stability of desvenlafaxine (I) in strongly acidic solutions it is suitable to set pH of the solution for debenzylation in the range of 3 to 8, best to the value of 5 to 6. For adjusting pH any inorganic or organic acid can be used. It is convenient to use an acid with the ρK_a value in the range of 1 to 5, such as formic, acetic, or phosphoric acids. The starting O-benzyl desvenlafaxine (or its derivatives) of formula (II) in the form of salts with an inorganic or organic acid can also be used, hi this case it is not sometimes necessary to adjust pH by adding more acid because pH of such a solution achieves similar values as pH of a solution obtained when the substance in the base form is dissolved by addition of an acid. The pH values are thus in the range of 3 to 8. By lowering pH of the reaction mixture the solubility of (9-benzyl desvenlafaxine or its derivative of formula (II), and especially that of the resulting desvenlafaxine (I), can be increased to more than 20 g per 100 ml of solvent depending on the used solvent, acid, temperature of the reaction mixture and pH value, hi this manner the volume of the used organic solvent can be easily reduced, thus reducing raw material costs.

Commonly used precious metals on a suitable carrier, e.g. palladium on carbon, can be used as the catalyst for debenzylation of O-benzyl desvenlafaxine or its derivative of formula (II). Hydrogen may be introduced in the reaction mixture from an external source, or it may be generated in-situ, i.e. directly in the reaction mixture (catalytic transfer hydrogenation). Such sources of hydrogen can be unsaturated hydrocarbons (e.g. cyclohexene, cyclohexadienes), formic acid or its salts. The pressure of hydrogen during catalytic hydrogenation may be 0.1 MPa to 10 MPa, preferably 0.1 MPa to 1 MPa.

The use of formic acid is especially convenient for debenzylation of O-benzyl desvenlafaxine or its derivative of formula (II). Formic acid makes it possible to reduce pH of the reaction mixture to a suitable value and at the same time it may act as the internal source of hydrogen as in contact with the catalyst it gets decomposed to carbon dioxide and hydrogen. Another convenient modification is using formic acid in a mixture with ammonium formate. In this version the conversion is nearly 100% and the generation of secondary products is kept as low as possible. Also, processing of the reaction mixture is very simple and does not require using other organic solvents or their laborious and costly evaporation.

After debenzylation the reaction mixture contains desvenlafaxine (I) and the suspended catalyst, which is removed by filtration. After adjustment of pH of the filtrate with a suitable base (e.g. an aqueous solution of ammonia) to 8 to 11, preferably to 9 to 10, the separated desvenlafaxine base is removed by filtration, washed with water, or a suitable organic solvent, and dried.

The above mentioned procedure only requires the use of minimal amounts of organic solvents and is simple to execute and in addition, during the final processing chemical purity of crude desvenlafaxine increases. Therefore, this purifying effect can be used to prepare highly pure desvenlafaxine base, wherein the desvenlafaxine base is dissolved in a slightly acidic solution and pH is adjusted to 8 to 11, advantageously to 9 to 10, by the action of a suitable base. In this way, non-ionized, i.e. very little soluble desvenlafaxine (I) is obtained in a high yield and purity. Water or a mixture of water with a water-miscible organic solvent selected from the group: methanol, ethanol, 2-propanol, n-butanol, tetrahydrofuran, dioxan, dimethyl sulfoxide, dimethyl formamide, or their mixtures can be used as suitable solvents.

The purified desvenlafaxine base is then transformed by addition of an acid to a pharmaceutically acceptable salt. The used acid is selected from the group: hydrochloric, formic, fumaric, succinic, oxalic acid; fumaric and succinic acid appear to be the most convenient.

The invention is described in a more detailed way in the following examples. These examples, which illustrate the improvement of the procedure in accordance with the invention, exclusively have an illustrative character and do not limit the scope of the invention in any respect. Examples

Example 1: Preparation of desvenlafaxine base (I)

O-Benzyl desvenlafaxine (H, R = H) base (35 g) is stirred up in methanol (300 ml). Ammonium formate (25 g) and 3% Pd/C (3.5 g) are added to the solution. This mixture is stirred at 60 ⁰C for 2 hours. pH of the reaction mixture is adjusted to 5 by addition of formic acid. The mixture is filtered through kieselguhr. The pH value of the filtrate is adjusted to 9.5 by dropwise addition of 25% aqueous solution of ammonia. Then, the suspension is stirred at the laboratory temperature for 1 hour and then filtered. The filter cake is washed with water and dried. Yield 25 g (95%), HPLC purity 99.4%.

Example 2: Preparation of desvenlafaxine base (I)

O-Benzyl desvenlafaxine (II, R = H) base (70 g) is stirred up in methanol (400 ml) and formic acid (12 ml) is added dropwise. Ammonium formate (25 g) and 10% Pd/C (2 g) are added to the solution. The mixture is stirred at 50 ⁰C for 4 hours. pH of the solution is adjusted to 5 by addition of formic acid. The mixture is filtered through kieselguhr. The pH value of the filtrate is adjusted to 9.5 by dropwise addition of 25% aqueous solution of ammonia. Then, the suspension is stirred at the laboratory temperature for 1 hour and then filtered. The filter cake is washed with water and dried. Yield 49 g (93%), HPLC purity 99.5%.

Example 3: Preparation of desvenlafaxine base (I)

O-Benzyl desvenlafaxine (II, R = H) base (70 g) is stirred up in methanol (400 ml) and formic acid (12 ml) is added dropwise. 10% Pd/C (2 g) is added to the solution. Gaseous hydrogen is bubbled through the mixture at the atmospheric pressure (0.1 MPa) at 30 °C for 6 hours. pH of the solution is adjusted to 5 by addition of formic acid. The mixture is filtered through kieselguhr. The pH value of the filtrate is adjusted to 9.5 by dropwise addition of 25% aqueous solution of ammonia. Then, the suspension is stirred at the laboratory temperature for 1 hour and then filtered. The filter cake is washed with water and dried. Yield 50 g (95%), HPLC purity 99.6%. Example 4: Preparation of desvenlafaxine base (I)

By the procedure described in example 1, using 0-(4-methoxybenzyl)-venlafaxine (II, R = MeO) as the starting substance and a mixture of methanol and tetrahydrofuran as the solvent, 87% desvenlafaxine (I) were obtained with the HPLC purity of 99.6%.

Example 5 : Re-purification of desvenlafaxine base (I)

Desvenlafaxine base (52 g, HPLC purity 99.2%) is stirred up in methanol (200 ml) and 2M hydrochloric acid is added dropwise up to the pH of the solution having the value of 4. ^"The solution is stirred up with activated charcoal and filtered through kieselguhr. The pH value of the filtrate is adjusted to 9.6 by addition of 2M solution of sodium hydroxide. The suspension is then stirred at 0⁰C for 1 hour and then filtered. The filter cake is washed with water and cooled 2-propanol. Yield 49 g (94%), HPLC purity 99.9%.

Example 6: Preparation of desvenlafaxine hydrogen fumarate hydrate Desvenlafaxine base (10.5 g) is stirred in a mixture of methanol (66 ml) and water (33 ml) for 30 minutes. Fumaric acid (5.1 g) is added to the suspension. The suspension is heated up to 60°C and stirred for 1 hour. The almost clear solution is filtered through kieselguhr. The mixture is slowly cooled down to 30 °C and stirred for 1 hour; then it is cooled to 5 °C and stirred for 1 hour. Crystals are aspirated and washed with a methanol/water mixture (1:1). Yield 14.8 g (97%).

Example 7: Preparation of desvenlafaxine hydrogen succinate hydrate

Desvenlafaxine base (25 g) is stirred in a mixture of acetone (210 ml) and water (70 ml) for 30 minutes. Succinic acid (12.5 g) is added to the suspension. The mixture is then stirred at 60 ⁰C for 1 hour. The almost clear solution is filtered through kieselguhr. The mixture is slowly cooled down to 30 °C and stirred for 1 hour; then it is cooled to 5 °C and stirred for 1 hour. Crystals are aspirated and washed with acetone. Yield 33 g (91%).

Claims

1. A method of preparation of 4-(2-(dimethylamino)-l-(l-hydroxycyclohexyl)ethyl)- phenol, desvenlafaxine, of formula (I)

and its pharmaceutically acceptable salts, characterized in that the method comprises (a) stirring up O-benzyl desvenlafaxine or its derivative of formula (II),

or of its salt, where R is selected from H, 4-methyl, 4-methoxy, 3,4-dimethoxy, 2-nitro,

4-nitro, 4-chloro, 4-bromo, 2,6-dichloro and 2,6-difluoro, in an organic solvent or a mixture of organic solvents, followed by dissolution of the starting substance at pH 3 to 8;

(b) transformation of C-benzyl desvenlafaxine or its derivative of formula (II) to desvenlafaxine (I) by catalytic hydrogenation;

(c) removing the catalyst from the desvenlafaxine solution with the pH value of 3 to 8 by filtration, followed by increasing pH to a value higher than 8 and lower than 11 by addition of an inorganic or organic base;

(d) isolation of desvenlafaxine base (I) by filtration; and (e) transformation of desvenlafaxine base (I) to a pharmaceutically acceptable salt.

2. The method according to claim 1, characterized in that the solvent used is an organic solvent miscible with water or a mixture of several organic water-miscible solvents.

3. The method according to claims 1 to 2, characterized in that the catalyst used is palladium on a suitable carrier, preferably on carbon.

4. The method according to claims 1 to 3, characterized in that the catalyst used is palladium on carbon with the palladium content of 1 -20%, preferably in the range of 3-

10 %.

5. The method according to any one of the preceding claims, characterized in that the organic solvent used is selected from the group comprising methanol, ethanol, 2- propanol, n-butanol, tetrahydrofuran, dioxan, dimethyl sulfoxide, dimethyl formamide and their mixtures.

6. The method according to any one of the preceding claims, characterized in that the starting substance (II) is dissolved by means of pH adjustment to a value from 3 to 8 by addition of an acid.

7. The method according to any one of the preceding claims, characterized in that the starting substance (II) is dissolved by means of pH adjustment to a value from 5 to 6 by addition of an acid.

8. The method according to any one of the preceding claims, characterized in that the acid used is formic, acetic or phosphoric acid.

9. The method according to any one of the preceding claims, characterized in that the acid used is formic acid.

10. The method according to any one of the preceding claims, characterized in that the starting substance (II) is used in the form of a salt with an inorganic or organic acid.

11. The method according to any one of the preceding claims, characterized in that the starting substance is used in the hydrochloride form.

12. The method according to any one of the preceding claims, characterized in that formic acid, ammonium formate or their mixture is used as the source of hydrogen for catalytic hydrogenation.

13. The method according to any one of the preceding claims, characterized in that an external source of hydrogen is used for catalytic hydrogenation.

14. The method according to any one of the preceding claims, characterized in that catalytic hydrogenation is performed at the hydrogen pressure in the range of 0.1 MPa to 10 MPa.

15. The method according to any one of the preceding claims, characterized in that the reaction is carried out at a temperature in the range of from 20 ⁰C to the boiling temperature of the reaction mixture, preferably in the range of from 40 °C to 70 ⁰C.

16. The method according to any one of the preceding claims, characterized in that after the removal of the catalyst by filtration adjustment of pH to a value between 8 and 11 by means of an inorganic or organic base is carried out.

17. The method according to any one of the preceding claims, characterized in that after the removal of the catalyst by filtration adjustment of pH to a value between 9 and 10 by means of an inorganic or organic base is carried out.

18. The method according to any one of the preceding claims, characterized in that an aqueous solution of ammonia is used for pH adjustment.

19. The method according to claim 1, characterized in that in step e) desvenlafaxine (I) is dissolved by means of pH adjustment to a value from 3 to 8 by addition of an acid.

20. The method according to claim 1, characterized in that in step e) desvenlafaxine (I) is dissolved by means of pH adjustment to a value from 5 to 6 by addition of an acid.

21. The method according to claims 19 to 20, characterized in that the acid used is hydrochloric, formic, oxalic, fumaric or succinic acid.