Process for preparation of 1-[2-(dimethyl amino)-1-(4-hydroxyphenyl) ethyl]-cyclohexanol and salts thereof

Abstract

A high yield process of preparation of [1-[2-(Dimethylamino)-1-(4-hydroxyphenyl)ethy]-cyclohexanol] through potassium salt mediated demethylation of [1-[2-(Dimethyl amino-1-(4-methoxyphenyl) ethyl cyclohexanol] in monoethylene glycol under phase transfer conditions, as well as the preparation of salt of [1-[2-(Dimethylamino)-1-(4-hydroxyphenyl)ethyl]-cyclohexanol].

Claims

1. A process for preparation of 1-[2-(dimethylamino)-1-(4-hydroxyphenyl)ethyl]-cyclohexanol of Formula (I), comprising steps of: ##STR00007## i) reacting 1-[2-(dimethyl amino-1-(4-methoxyphenyl) ethyl cyclohexanol of Formula (II) ##STR00008## with at least one potassium salt selected from the group consisting of potassium hydroxide and a potassium alkoxide, in an organic solvent to obtain a mixture; ii) heating the mixture to a temperature in a range of from about 190? C. to about 220? C.; iii) diluting the mixture with water to obtain an aqueous phase; and iv) acidifying the aqueous phase with an acidic reagent, and filtering to obtain the 1-[2-(dimethylamino)-1-(4-hydroxyphenyl)ethyl]-cyclohexanol of Formula (I).

2. The process as claimed in claim 1, wherein the potassium alkoxide is potassium t-butoxide.

3. The process as claimed in claim 1, wherein the organic solvent is at least one selected from the group consisting of monoethylene glycol and an alcohol.

4. The process as claimed in claim 1, wherein acidifying the aqueous phase comprises adjusting the pH between 3 to 5 with the acidic reagent being at least one acid selected from the group consisting of hydrochloric acid, phosphoric acid, and acetic acid.

5. The process as claimed in claim 1, wherein the process provides yield ranging from about 95% to about 99.5%.

6. The process as claimed in claim 1, wherein the 1-[2-(dimethylamino)-1-(4-hydroxyphenyl)ethyl]-cyclohexanol has a purity ranging from about 97.0% to about 99.5% measured by HPLC method.

7. A process for obtaining a salt of 1-[2-(dimethylamino)-1-(4-hydroxyphenyl)ethyl]-cyclohexanol, comprising steps of: a) reacting 1-[2-(dimethyl amino-1-(4-methoxyphenyl) ethyl cyclohexanol of Formula (II) with at least one potassium salt selected from the group consisting of potassium hydroxide and a potassium alkoxide, in an organic solvent to obtain a mixture; ##STR00009## b) heating the mixture to a temperature in a range of from about 190? C. to about 220? C.; c) diluting the mixture with water to obtain an aqueous phase; d) acidifying the aqueous phase with a first acidic reagent and filtering to obtain 1-[2-(dimethylamino)-1-(4-hydroxyphenyl)ethyl]-cyclohexanol of Formula (I); and e) reacting the 1-[2-(dimethylamino)-1-(4-hydroxyphenyl)ethyl]-cyclohexanol of Formula (I) with a second acidic reagent in an aqueous organic solvent to obtain the salt.

8. The process as claimed in claim 7, wherein the second acidic reagent is at least one selected from the group consisting of succinic acid, fumaric acid, and oxalic acid.

9. The process as claimed in claim 7, wherein the salt of 1-[2-(dimethylamino)-1-(4-hydroxyphenyl)ethyl]-cyclohexanol is of purity ranging from about 98.0 to about 99% measured by HPLC method.

10. The process as claimed in claim 3, wherein the organic solvent is monoethylene glycol.

11. The process as claimed in claim 4, wherein acidifying the aqueous phase comprises adjusting the pH to 4.

12. The process as claimed in claim 8, wherein the second acidic reagent is succinic acid.

13. The process as claimed in claim 1, wherein 1-[2-(dimethyl amino-1-(4-methoxyphenyl) ethyl cyclohexanol of Formula (II) is reacted with potassium hydroxide.

14. The process as claimed in claim 1, wherein 1-[2-(dimethyl amino-1-(4-methoxyphenyl) ethyl cyclohexanol of Formula (II) is reacted with a potassium alkoxide.

15. The process as claimed in claim 7, wherein 1-[2-(dimethyl amino-1-(4-methoxyphenyl) ethyl cyclohexanol of Formula (II) is reacted with potassium hydroxide.

16. The process as claimed in claim 7, wherein 1-[2-(dimethyl amino-1-(4-methoxyphenyl) ethyl cyclohexanol of Formula (II) is reacted with a potassium alkoxide.

Description

BRIEF DESCRIPTION OF FIGURE

(1) FIGURE: HPLC diagram indicating the purity level of the [1-[2-(Dimethylamino)-1-(4-hydroxyphenyl)ethyl]-cyclohexanol]

SUMMARY OF INVENTION

(2) The invention relates to synthesis of Desvenlafaxine, [1-[2-(Dimethylamino)-1-(4-hydroxyphenyl)ethyl]-cyclohexanol] by the process of demethylation of 1-[2-(Dimethyl amino-1-(4-methoxyphenyl) ethyl cyclohexanol which is mediated through potassium salt in monoethylene glycol, under phase transfer conditions. The [1-[2-(Dimethylamino)-1-(4-hydroxyphenyl)ethyl]-cyclohexanol]synthesised by said process has a purity of more than 99% as measured by HPLC. The invention also relates to the preparation of [1-[2-(Dimethylamino)-1-(4-hydroxyphenyl)ethyl]-cyclohexanol]succinate with high yield. The process can be scaled up for mass production of [1-[2-(Dimethylamino)-1-(4-hydroxyphenyl)ethyl]-cyclohexanol] easily.

DETAILED DESCRIPTION OF INVENTION

(3) The foregoing description of the embodiments of the invention has been presented for the purpose of illustration. It is not intended to be exhaustive or to limit the invention to the precise form disclosed as many modifications and variations are possible in light of this disclosure for a person skilled in the art in view of the Figures, description and claims. It may further be noted that as used herein and in the appended claims, the singular a an and the include plural reference unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by person skilled in the art.

(4) The present invention is in relation to a process for preparation of 1-[2-(Dimethylamino)-1-(4-hydroxyphenyl)ethyl]-cyclohexanol (formula (I)), comprising acts of

(5) ##STR00003## i) reacting 1-[2-(Dimethyl amino-1-(4-methoxyphenyl) ethyl cyclohexanol of formula (II)

(6) ##STR00004## with potassium salt, in an organic solvent to obtain a mixture; ii) heating the mixture; iii) diluting the mixture with water to obtain an aqueous phase; and iv) acidifying the aqueous phase with an acidic reagent and filtering to obtain 1-[2-(Dimethylamino)-1-(4-hydroxyphenyl)ethyl]-cyclohexanol of formula (I).

(7) In an embodiment of the present invention, the potassium salt is selected from a group comprising potassium hydroxide and potassium t-butoxide.

(8) In an embodiment of the present invention, the organic solvent is selected from group comprising monoethylene glycol and other primary alcohols, preferably monoethylene glycol.

(9) In another embodiment of the present invention, the mixture is heated to a temperature ranging from about 190? C. to about 220? C.

(10) In still another embodiment of the present invention, acidifying the aqueous phase comprises adjusting the pH between 3 to 5 preferably 4, with a reagent selected from a group comprising an acidic reagent selected from a group comprising hydrochloric acid, phosphoric acid, acetic acid.

(11) In yet another embodiment of the present invention, the process provides yield ranging from about 95% to about 99.5%.

(12) In yet another embodiment of the present invention, the 1-[2-(Dimethylamino)-1-(4-hydroxyphenyl)ethyl]-cyclohexanol has a purity ranging from about 97.0% to about 99.5% measured by HPLC method.

(13) The present invention is also in relation to a process for obtaining salt of 1-[2-(Dimethylamino)-1-(4-hydroxyphenypethyl]-cyclohexanol comprising acts of a) reacting 1-[2-(Dimethyl amino-1-(4-methoxyphenyl) ethyl cyclohexanol of formula (II) with potassium salt in an organic solvent to obtain a mixture;

(14) ##STR00005## b) heating the mixture; c) diluting the mixture with water to obtain an aqueous phase; d) acidifying the aqueous phase with an acidic reagent and filtering to obtain 1-[2-(Dimethylamino)-1-(4-hydroxyphenyl)ethyl]-cyclohexanol of formula (I). e) reacting the 1-[2-(Dimethylamino)-1-(4-hydroxyphenyl)ethyl]-cyclohexanol of formula (I) with a reagent in an aqueous organic solvent to obtain salt.

(15) In an embodiment of the present invention, the reagent is selected from a group comprising succinic acid, fumaric acid, oxalic acid; preferably succinic acid to obtain succinic acid salt of 1-[2-(Dimethyl amino-1-(4-methoxyphenyl) ethyl cyclohexanol.

(16) In yet another embodiment of the present invention, salt of 1-[2-(Dimethylamino)-1-(4-hydroxyphenyl)ethyl]-cyclohexanol is of purity ranging from about 98.0 to about 99% measured by HPLC method.

(17) The schematic diagram (I) shows the process of the synthesis of [1-[2-(Dimethylamino)-1-(4-hydroxyphenyl)ethyl]-cyclohexanol] and its succinate salt from 1-[2-(Dimethyl amino-1-(4-methoxyphenyl) ethyl cyclohexanol:

(18) ##STR00006##

(19) Demethylation of 1-[2-(Dimethyl amino-1-(4-methoxyphenyl) ethyl cyclohexanol to obtain [1-[2-(Dimethylamino)-1-(4-hydroxyphenyl)ethyl]-cyclohexanol] is performed under strong alkaline conditions in the presence of potassium hydroxide and an alcoholic solvent to obtain optimum yield of [1-[2-(Dimethylamino)-1-(4-hydroxyphenyl)ethyl]-cyclohexanol]. The target compound obtained by the high yield process described in the present invention has a purity of more than 99% as measured by HPLC. The process can be scaled up for mass production of [1-[2-(Dimethylamino)-1-(4-hydroxyphenyl)ethyl]-cyclohexanol], as commercially available eco friendly reagents are used in the reaction.

EXPERIMENTAL

(20) The examples described below illustrates the process of synthesis of Desvenlafaxine, [1-[2-(Dimethylamino)-1-(4-hydroxyphenyl)ethyl]-cyclohexanol] however they do not limit the scope of the invention.

Example 1

(21) To a clean flask, 250 g of 1-[2-(Dimethyl amino-1-(4-methoxyphenyl) ethyl cyclohexanol, 1 lt of ethylene glycol, 100 g of polyethylene glycol-400 and 350 g of Potassium hydroxide are added, under nitrogen atmosphere. Reaction mixture is then heated under nitrogen, by raising the temperature to about 195-200? C. over a period of about 3-4 h. The same temperature is then, continuously maintained for a period of 24 h. The temperature of the reaction mixture is lowered to a temperature of about 50? C. and diluted with water and extracted with 1 lt of toluene. Toluene is concentrated in order to obtain unreacted 1-[2-(Dimethyl amino-1-(4-methoxyphenyl) ethyl cyclohexanol of about 95 g to about 100 g. Water layer is then acidified to pH 4 to get 1-[2-(Dimethylamino)-1-(4-hydroxyphenypethyl]-cyclohexanol. On drying the mixture at a temperature ranging from about 75? C. to about 80? C. for 8 hours, 1-[2-(Dimethylamino)-1-(4-hydroxyphenypethyl]-cyclohexanol, is obtained (125-130 g) with a purity of 99.25% measured by HPLC). Yield percentage based on recovery of unreacted 1-[2-(Dimethyl amino-1-(4-methoxyphenyl) ethyl cyclohexanol is 98%.

Example 2

(22) To a clean flask, 250 g of 1-[2-(Dimethyl amino-1-(4-methoxyphenyl) ethyl cyclohexanol, 1.5 lt of ethylene glycol, 100 g of polyethylene glycol-400 and 400 g of potassium hydroxide are added, all at once, under nitrogen atmosphere. Reaction mixture is then heated under nitrogen.

(23) Initially, the temperature is raised to about 195-200? C. over a period of 3-4 hours. The same temperature is then, continuously maintained for a period of 48 hours. The temperature of the reaction mixture is lowered to a temperature of about 50? C. and diluted with water and extracted with 1 liter of toluene. Toluene is concentrated in order to obtain unreacted 1-[2-(Dimethyl amino-1-(4-methoxyphenyl) ethyl cyclohexanol of about 45 g. Water layer is then acidified to pH 4 to get 1-[2-(Dimethylamino)-1-(4-hydroxyphenypethyl]-cyclohexanol. On drying the mixture at a temperature ranging from about 75? C. to about 80? C. for 8h, 1-[2-(Dimethylamino)-1-(4-hydroxyphenypethyl]-cyclohexanol the quantity ranging from about 180 g to about 195 g is obtained with a purity of more than 99% measured by HPLC. Yield percentage based on recovery of unreacted 1-[2-(Dimethyl amino-1-(4-methoxyphenyl) ethyl cyclohexanol is 97%.

Example 3

(24) To a clean flask, 250 g of 1-[2-(Dimethyl amino-1-(4-methoxyphenyl) ethyl cyclohexanol 1.25 Lt liter of ethylene glycol, 100 g of polyethylene glycol-400 and 350 g of potassium hydroxide are added, all at once, under nitrogen atmosphere. Reaction mixture is then heated under nitrogen, and the temperature is raised to about 195-200? C., for a period of 3-4 hours. The same temperature is then, continuously maintained for a period of 36 hours. The temperature of the reaction mixture is lowered to a temperature of about 50? C. and diluted with water and extracted with 1 liter of toluene. Toluene is concentrated in order to obtain unreacted 1-[2-(Dimethyl amino-1-(4-methoxyphenyl) ethyl cyclohexanol of about 55 g. Water layer is then acidified to pH 4 to obtain 1-[2-(Dimethylamino)-1-(4-hydroxyphenyl)ethyl]-cyclohexanol. On drying the mixture at a temperature ranging from about 75? C. to about 80? C. degree for 8 h. 1-[2-(Dimethylamino)-1-(4-hydroxyphenypethyl]-cyclohexanol the quantity ranging from about 175 g to about 200 g is obtained with a purity of more than 99% by HPLC. Yield percentage is based on recovery of unreacted 1-[2-(Dimethyl amino-1-(4-methoxyphenyl) ethyl cyclohexanol is 97%.

Example 4

(25) To a clean flask, 250 g of 1-[2-(Dimethyl amino-1-(4-methoxyphenyl) ethyl cyclohexanol, 1 lt of ethylene glycol, 100 g of polyethylene glycol-400 and 605 g of Potassium tert-butoxide are added over a period of 1 h, under nitrogen atmosphere. Reaction mixture is then heated under nitrogen, by raising the temperature to about 195-200? C. over a period of about 3-4 h. The same temperature is then, continuously maintained for a period of 24 h. The temperature of the reaction mixture is lowered to a temperature of about 50? C. and diluted with water and extracted with 1 lt of Toluene. Toluene is concentrated in order to obtain unreacted 1-[2-(Dimethyl amino-1-(4-methoxyphenyl) ethyl cyclohexanol of about 85 g to about 95 g. Water layer is then acidified to pH 4 to get 1-[2-(Dimethylamino)-1-(4-hydroxyphenypethyl]-cyclohexanol. On drying the mixture at a temperature ranging from about 75? C. to about 80? C. for 8 hours, 1-[2-(Dimethylamino)-1-(4-hydroxyphenyl)ethyl]-cyclohexanol, is obtained (115-120 g) with a purity of >99.00% measured by HPLC). Yield percentage based on recovery of unreacted 1-[2-(Dimethyl amino-1-(4-methoxyphenyl) ethyl cyclohexanol is 96%.

(26) The 1-[2-(Dimethylamino)-1-(4-hydroxyphenyl)ethyl]-cyclohexanol thus obtained can be converted to its salt form. The salt is selected from a group comprising succinate, fumarate, oxalate and the like, preferably succinate salt.

(27) The process of synthesis of succinate salt of 1-[2-(Dimethylamino)-1-(4-hydroxyphenyl)ethyl]-cyclohexanol is as follows:

Example 5

(28) To a clean flask, 250 g of 1-[2-(Dimethyl amino-1-(4-methoxyphenyl) ethyl cyclohexanol, 1 lt of ethylene glycol, 100 g of polyethylene glycol-400 and 350 g of potassium hydroxide are added, all at once, under nitrogen atmosphere, Reaction mixture is then heated under nitrogen. Initially the temperature is raised to about 195-200? C. for a period of 3-4 hours. The same temperature is then, continuously maintained for a period of 24 h. The temperature of the reaction mixture is lowered to a temperature of about 50? C. and diluted with water and extracted with 1 lt of toluene. Toluene is concentrated in order to obtain unreacted 1-[2-(Dimethyl amino-1-(4-methoxyphenyl) ethyl cyclohexanol of about 95 g to about 100 g. Water layer is then acidified to pH 4 to get 1-[2-(Dimethylamino)-1-(4-hydroxyphenyl)ethyl]-cyclohexanol. On drying the mixture at a temperature ranging from about 75? C. to about 80? C. degree for 8 hours, 1-[2-(Dimethylamino)-1-(4-hydroxyphenypethyl]-cyclohexanol, the quantity ranging from about 125 g to about 130 g is obtained. The 1-[2-(Dimethylamino)-1-(4-hydroxyphenyl)ethyl]-cyclohexanol is reacted with 56 g of Succinic acid at a temperature 10-50? C. in aqueous acetone (1:3) to obtain succinate salt of 1-[2-(Dimethylamino)-1-(4-hydroxyphenyl)ethyl]-cyclohexanol (130 g) with individual impurity of less than 0.10% of pharmaceutically acceptable salt.

(29) The present invention thus describes an eco-friendly, economical process for synthesis of 1-[2-(Di methylamino)-1-(4-hydroxyphenyl)ethyl]-cyclohexanol also known as Desvenlafaxine from 1-[2-(Dimethyl amino-1-(4-methoxyphenyl) ethyl cyclohexanol also known as Venlafaxine. The process makes use of commercially available reagents with yield ranging from about 97% to about 98%. Thus synthesised 1-[2-(Dimethylamino)-1-(4-hydroxyphenyl)ethyl]-cyclohexanol has a purity of 99% measured by HPLC. The invention also relates to the synthesis of salts of 1-[2-(Dimethylamino)-1-(4-hydroxyphenyl)ethyl]-cyclohexanol. The high yield process is simple and can be easily scaled up for industrial production.

(30) The aforesaid description is enabled to capture the nature of the invention. It is to be noted however that the aforesaid description and the appended figures illustrate only a typical embodiment of the invention and therefore not to be considered limiting of its scope for the invention may admit other equally effective embodiments.

(31) It is an object of the appended claims to cover all such variations and modifications as can come within the true spirit and scope of the invention.