WO2000068182A1

WO2000068182A1 - Process for crystallizing (r)-fluoxetine hydrochloride

Info

Publication number: WO2000068182A1
Application number: PCT/US2000/009801
Authority: WO
Inventors: John Brennan; William David Diseroad; Lynne Ann Hay; David Mitchell
Original assignee: Eli Lilly And Company
Priority date: 1999-05-10
Filing date: 2000-04-28
Publication date: 2000-11-16
Also published as: AU4798400A; AR023838A1

Abstract

The present invention relates to processes for crystallizing (R)-fluoxetine hydrochloride.

Description

PROCESS FOR CRYSTALLIZING (R) -FLUOXETINE HYDROCHLORIDE

This application claims the benefit of US Provisional Application No. 60/133,264, filed May 10, 1999.

The present application relates to processes for crystallizing (R) -fluoxetine hydrochloride.

(R) -Fluoxetine hydrochloride, (R) -N-methyl-3- (4- trifluoromethylphenoxy) -3-phenylpropylamine hydrochloride, is useful for the treatment of depression and other indications. For example see, US Patent No. 5,708,035. Thus, a convenient and efficient method for crystallizing

(R) -fluoxetine hydrochloride is highly desirable. Also, for commercial applications the use of non-chlorinated solvents is desirable.

The preparation and crystallization of (R) -fluoxetine hydrochloride, as well as the racemate, are known in the art. For example, the art describes the crystallization of (R) -fluoxetine hydrochloride from methylene chloride/ethyl acetate (U.S. Patent No. 4,918,207 and J. Org. Chem. , 53, 2915-2920 (1988)); from acetonitrile (U.S. Patent No. 5,708,035); from diethyl ether (Tet. Lets., 30, 5207-5210 (1989); and J. Org. Chem. , 53, 4081-4084 (1988)).

We have found that the crystallization of (R) - fluoxetine hydrochloride is greatly facilitated by the use of mixed solvents. These mixed solvents include a solubilizing solvent and a miscible non-chlorinated anti- solvent. Accordingly, the present invention provides a convenient and efficient method for crystallizing (R) - fluoxetine hydrochloride from mixed solvents comprising a solubilizing solvent and a miscible non-chlorinated anti- solvent.

The present invention provides processes for crystallizing (R) -fluoxetine hydrochloride from a mixed solvent, comprising a solubilizing solvent selected from the group consisting of toluene, Cι-C₆ alkyl acetate, C₃-Cs alkyl ketone, C₂-C₆ alkanol, and Cι-C alkyl nitrile and a miscible non-chlorinated anti-solvent. As used herein, the term "Ci-C_δ alkyl acetate" refers to the acetate esters of straight chain, branched, and cyclic Ci-Cs alkyl alcohols having from 1 to 6 carbon atoms and includes methyl acetate, ethyl acetate, iso-propyl acetate, propyl acetate, iso-butyl acetate, sec-butyl acetate, butyl acetate, a yl acetate, iso-amyl acetate, and the like.

As used herein, the term "C₃-C₈ alkyl ketone" refers to straight chain, branched, and cyclic alkyl ketones having from 3 to 8 carbon atoms, inclusive of the carbonyl carbon, and includes acetone, butanone, 2-pentanone, 3-pentanone, hexanone, methyl iso-butyl ketone, cyclohexanone, and the like.

As used herein, the term "C₂-C₆ alkanol" refers to straight chain, branched, and cyclic alkyl alcohols having from 2 to 6 carbon atoms and includes ethanol, propanol, iso-propanol, butanol, sec-butanol, iso-butanol, t-butanol, amyl alcohol, iso-amyl alcohol, t-amyl alcohol, hexanol, cyclopentanol , cyclohexanol, and the like.

As used herein, the term "C₁-C₄" alkyl nitrile" refers to alkyl nitriles having from 1 to 4 carbon atoms, exclusive of the nitrile carbon, and includes acetonitrile, propionitrile, butyronitrile, iso-butyronitrile, and the like.

As used herein, the term "anti-solvent" refers to a solvent in which (R) -fluoxetine is significantly less soluble compared to the selected solubilizing solvent.

As used herein, the term "ee" or "enantiomeric excess" refers to the percent by which one enantiomer, Ei, is in excess of a second isomer, E₂, in a mixture of both enantiomers (Ei + E₂) , and is calculated by the equation

{ (Ei - E₂) ÷ (E_x + E₂) } x 100% = ee. Herein, the Cahn- Prelog-Ingold designations of (R) - and (S)- are used herein to refer to specific isomers where designated.

As will be appreciated by the skilled artisan, the present invention is most useful as a preparation of a substantially pure (R) -fluoxetine hydrochloride. As used herein the term "substantially pure" refers to enantiomeric purity of (R) -fluoxetine hydrochloride. Accordingly to the present invention substantially pure (R) -fluoxetine hydrochloride can be prepared which is greater than 95%, preferably greater than 98%, more preferably greater than 99%, most preferably greater that 99.3% enantiomerically pure .

In a preferred embodiment present invention provides processes for crystallizing (R) -fluoxetine hydrochloride, of substantial purity, from a mixed solvent, comprising a solubilizing solvent selected from the group consisting of toluene, Ci-Cβ alkyl acetate, C₃-Cs alkyl ketone, C₂-C6 alkanol, and Cχ-C alkyl nitrile and a miscible non- chlorinated anti-solvent. We have found that (R) -fluoxetine hydrochloride has significantly different solubility properties from the racemate. For example, we have found that \ R) -fluoxetine hydrochloride is generally more soluble than is the racemate in common crystallization solvents. For example, in ethyl acetate at 25°C the single enantiomer has solubility of about 130 mg/mL compared to about 2.4 mg/mL for the racemate and in isopropanol at 25°C the single enantiomer has solubility of about 309 mg/mL compared to about 36.5 mg/mL for the racemate. This difference in solubility requires that crystallization of (R) -fluoxetine hydrochloride be controlled to disfavor the preferential precipitation of the racemate which leads to a significant decrease in the purity, in particular the enantiomeric purity of the crystallized product. The present crystallization of (R) -fluoxetine occurs under controlled conditions to efficiently give a high recovery of (R) -fluoxetine hydrochloride having high purity.

Factors which influence the crystallization of (R) - fluoxetine from mixed solvents include the solubility of (R) -fluoxetine hydrochloride in the solubilizing solvent and the anti-solvent, the ratio of total solvent volume to the amount of (R) -fluoxetine, the ratio of solubilizing solvent to anti-solvent, and the initial and final temperatures of the crystallization.

The solubility of (R) -fluoxetine in various solvents can be determined at a given temperature by adding small amounts of (R) -fluoxetine hydrochloride to a fixed volume of solvent in small increments until the last added increment no longer dissolves. Accordingly, using 1.0 mL of solvent, the solubility of (R) -fluoxetine was determined in various solvents at room temperature and are given below in Table A.

The conditions under which (R) -fluoxetine crystallizes from mixed solvent may be determined empirically using the factors mentioned above. Typically, a solution of (R) - fluoxetine hydrochloride is dissolved in the solubilizing solvent and then the anti-solvent is added. Alternately, (R) -fluoxetine hydrochloride in the solubilizing solvent can be added to the anti-solvent. The solvents can also be mixed by vapor diffusion techniques as are well known in the art .

As is appreciated by those skilled in the art, the mixed solvent crystallization of (R) -fluoxetine hydrochloride according to the present invention can be carried out during the formation of the hydrochloride salt. Generally, the present mixed solvent crystallization can be carried out by combining (R) -fluoxetine and about 1.0 molar equivalent of hydrogen chloride. The hydrogen chloride can be added as a gas or preferably as a solution in either a solubilizing solvent or an anti-solvent. In practice some solubilizing solvents are preferred. Preferred solubilizing solvents are Ci-Cβ alkyl acetates, C₃- Cs alkyl ketones, C₂-C₆ alkanols, and Cι-C alkyl nitriles. Specifically preferred solubilizing solvents are ethyl acetate, iso-propyl acetate, iso-amyl acetate, acetone, butanone, methyl iso-butyl ketone, ethanol, toluene, and acetonitrile. More preferred solubilizing solvents are ethyl acetate, iso-propyl acetate, iso-amyl acetate, acetone, and butanone. Even more preferred solubilizing solvents are ethyl acetate, iso-propyl acetate, and acetone. Suitable anti-solvents include the simple alkanes, such as pentanes, hexanes, heptanes, octanes, cyclohexanes, petroleum distillates, such as petroleum ether and naphtha, and the like; aromatic solvents, such as benzene, toluene, xylene, and the like; and alkyl ethers, such as diethyl ether, methyl t-butyl ether, and the like. Because they are readily removed from the crystallized product the alkanes and alkyl ethers are generally preferred. Generally, the crystallization is carried out at initial temperatures of about 40°C to about 80°C. Typical final temperatures are from ambient temperature to about 0°C . The total solvent volume typically used is about 3 to about 20 mL per gram of (R) -fluoxetine hydrochloride, with about 8 to about 13 mL per gram being generally preferred. Typically the ratio of solubilizing solvent to anti-solvent in the mixed solvent is from about 5:1 to about 1:15, more preferably from about 3:1 to about 1:10. The product is isolated using techniques that are well known in the art, including filtration, decanting, centrifuging, drying, and the like.

In practice a number preferred embodiments have been found. The use of ethyl acetate and methyl t-butyl ether, acetone and methyl t-butyl ether, ethyl acetate and heptane, acetonitrile and methyl t-butyl ether, acetonitrile and toluene, ethanol and toluene are preferred.

The use of ethyl acetate and methyl t-butyl ether is particularly preferred. When ethyl acetate is the solubilizing solvent and methyl t-butyl ether is the anti- solvent the preferred ratio of solubilizing solvent to anti- solvent is from about 2:1 to about 1:10 and the preferred total volume of mixed solvent is about 8 mL to about 15 mL per gram of (R) -fluoxetine . When ethyl acetate is the solubilizing solvent and methyl t-butyl ether is the anti- solvent a more preferred ratio of solubilizing solvent to anti-solvent is from about 2:1 to about 1:4, with 2:1 to 1:3 being most preferred.

The use of acetone and methyl t-butyl ether is also particularly preferred. When acetone is the solubilizing solvent and methyl t-butyl ether is the anti-solvent the preferred ratio of solubilizing solvent to anti-solvent is from about 1:1 to 1:6, with 1:3 to 1:5 being more preferred, and the preferred total volume of mixed solvent is about 8 mL to about 16 mL per gram of (R) -fluoxetine .

The use of ethyl acetate and heptane is also particularly preferred. When ethyl acetate is the solubilizing solvent and heptane is the anti-solvent the preferred ratio of solubilizing solvent to anti-solvent is from about 1.5:1 to about 1:1.5 and the preferred total volume of mixed solvent is about 8 mL to about 12 mL of per gram of (R) -fluoxetine. The present invention is further illustrated by the following examples. These examples are illustrative only and are not intended to limit the invention in any way.

The terms used in the examples have their normal meanings unless otherwise designated. For example "°C" refers to degrees Celsius; "N" refers to normal or normality; "M" refers to molar or molarity; "mol" refers to mole or moles; "mmol" refers to millimole or millimoles; "kg refers to kilogram or kilograms; "g" refers to gram or grams; "mg" refers to milligram or milligrams; "mL" refers milliliter or milliliters; "L" refers to liter or liters; "mp" refers to melting point; "h" refers to hour or hours; "min" refers to minute or minutes; "EA" refers to ethyl acetate; "MTBE" refers to methyl t-butyl ether (sold by Aldrich Chemical Co. as t-butyl methyl ether); "ACN" refers to acetonitrile, etc.

EXAMPLE 1 General procedure for crystallization (R) -fluoxetine hydrochloride .

Combine (R) -fluoxetine hydrochloride (1.0 g, 1.2 mmol) and a solubilizing solvent (about 2 mL to about 6 mL) and heat to dissolve. Remove heating and add a miscible non- chlorinated anti-solvent (about 0.3 to about 12 mL) . Cool, collect the solid, and dry in vacuo at 35°C to 40°C to give (R) -fluoxetine hydrochloride. Results for several mixed solvents are given in Table 1. Table 1

EXAMPLE 2 (R) -Fluoxetine hydrochloride A mixture of (R) -fluoxetine hydrochloride (1.04 g) in ethyl acetate (3.48 mL) was heated to 45°C to 50°C to give a solution. The heat was removed and methyl t-butyl ether (6.96 mL) was added while the solution was still warm. The resulting suspension was cooled to ambient temperature and then to 0°C before the solid was collected by filtration and dried in vacuo at 35°C to 40°C to provide the title compound (0.88 g, 84% recovery, 99.6% ee, 0.33% total related substances) .

EXAMPLE 3 (R) -Fluoxetine hydrochloride

A mixture of (R) -fluoxetine hydrochloride (956 g, 2.76 ol) in ethyl acetate (2.9 L) was heated to 50° C to give a solution. Methyl t-butyl ether (6.7 L) was added over approximately 90 minutes at about 40°C to 50°C. The resulting suspension was cooled to 25°C over approximately 90 minutes, and stirred at that temperature for 60 minutes. The slurry was then cooled to 6°C over 40 minutes, filtered, and the filter cake rinsed with a solution of ethyl acetate (1.1 L) and methyl t-butyl ether (2.3 L) . The solid was dried at 30°C to provide the title compound (875 g, 91.5% recovery) .

EXAMPLE 4 (R) -Fluoxetine hydrochloride

Combine (R) -fluoxetine (3.1 g, 10 mmol) and dry methyl t-butyl ether (18.6 mL) to give a solution. Slowly add a solution of anhydrous hydrogen chloride (1 equivalent) in ethyl acetate (6.2 mL) to give a solid. Cool the resulting suspension to about 10° C, filter, rinse with methyl t-butyl ether, and dry in vacuo at about 40°C to provide the title compound.

Claims

WE CLAIM :

1. A process for crystallizing (R) -fluoxetine hydrochloride from a mixed solvent comprising, a solubilizing solvent selected from the group consisting of toluene, Cι-C₆ alkyl acetate, C₃-Cs alkyl ketone, C -C₆ alkanol, and Cι-C alkyl nitrile and a miscible non-chlorinated anti-solvent.

2. A process according to Claim 1 wherein the solubilizing solvent is Ci-Cβ alkyl acetate.

3. A process according to Claim 2 wherein the Ci-Cε alkyl acetate is ethyl acetate.

4. A process according to Claim 2 wherein the Ci-Cε alkyl acetate is iso-amyl acetate.

5. A process according to Claim 3 wherein the miscible non- chlorinated anti-solvent is heptane.

6. A process according to Claim 3 wherein the miscible non- chlorinated anti-solvent is methyl t-butyl ether.

7. A process according to Claim 1 wherein the solubilizing solvent is C₃-Ca alkyl ketone.

8. A process according to Claim 7 wherein the C₃-Cs alkyl ketone is acetone.

9. A process according to Claim 7 wherein the C₃-C₈ alkyl ketone is butanone.

10. A process according to Claim 8 wherein the miscible non- chlorinated anti-solvent is methyl t-butyl ether.

11. A process according to Claim 1 wherein the solubilizing solvent is a C₂-C₆ alkanol.

12. A process according to Claim 11 wherein the C₂-C_δ alkanol is ethanol .

13. A process according to Claim 1 wherein the solubilizing solvent is a Cι-C₄ alkyl nitrile.

14. A process according to Claim 13 wherein the Cι-C alkyl nitrile is acetonitrile.

15. A process according to Claim 6 wherein the ethyl acetate and methyl t-butyl ether are in a ratio of 5:1 to 1:15.

16. A process according to Claim 6 wherein the ethyl acetate and methyl t-butyl ether are in a ratio of 2:1 to 1:10.

17. A process according to Claim 6 wherein the ethyl acetate and methyl t-butyl ether are in a ratio of 2:1 to 1:4.

18. A process according to Claim 6 wherein IHe ethyl acetate and methyl t-butyl ether are in a ratio of 2:1 to 1:3.

19. A process according to Claim 6 wherein the ethyl acetate and methyl t-butyl ether are in a ratio of 2:1 to 1:2.

20. A process according to Claim 5 wherein the ethyl acetate and heptane are in a ratio of 1.5:1 to 1:1.5.