Method for the preparation of pimavanserin base

Abstract

Disclosed is a process for the synthesis of pimavanserin base with a high yield and purity, which comprises: a) converting tert-butyl-N-[(4-propan-2-yloxyphenyl)methyl]carbamate (Formula (I)) to 1-(isocyanatomethyl)-4-propan-2-yloxybenzene of formula (II) b) adding N-[(4-fluorophenyl)methyl]-1-methylpiperidin-4-amine (Formula (IV)) to the solution obtained in a) to give pimavanserin base, and c) purifying the pimavanserin base obtained in step b). ##STR00001##

Claims

1. Process for the preparation of pimavanserin base comprising the following steps: a) converting tert-butyl-N-[(4-propan-2-yloxyphenyl)methyl]-carbamate (I) ##STR00012## to 1-(isocyanatomethyl)-4-propan-2-yloxybenzene of formula II ##STR00013## in the presence of an organic base and an organic acid or an anhydride of said acid in an organic solvent, to obtain a solution of (II) in said solvent; b) adding N-[4-(fluorophenyl)methyl]-1-methylpiperidin-4-amine (IV) ##STR00014## to the solution obtained in a), to obtain pimavanserin base (V) ##STR00015## and c) purifying the pimavanserin based obtained in step b).

2. The process according to claim 1, wherein the organic base is selected from pyridine and 2-chloropyridine.

3. The process according to claim 1, wherein the organic base is 2-chloropyridine used in a ratio of 3:1 equivalents relative to tert-butyl-N-[(4-propan-2-yloxyphenyl)methyl]-carbamate (I).

4. The process according to claim 1, wherein the organic acid anhydride is selected from trifluoroacetic anhydride and trifluoromethanesulphonic anhydride.

5. The process according to claim 4, wherein the organic acid anhydride is trifluoromethanesulphonic anhydride used in a ratio of 1-1.1:1 equivalents relative to tert-butyl-N-[(4-propan-2-yloxyphenyl)methyl]-carbamate (I).

6. The process according to claim 1, wherein the organic acid is selected from trifluoroacetic acid and trifluoromethanesulphonic acid.

7. The process according to claim 1, wherein compound (IV) is obtained by neutralization of N-[(4-fluorophenyl)methyl]-1-methylpiperidin-4-amine dihydrochloride of formula (III) ##STR00016##

8. The process according to claim 1, wherein compound (IV) is used in a ratio of 1-1.1:1 equivalents relative to tert-butyl-N-[(4-propan-2-yloxyphenyl)methyl]-carbamate (I).

Description

DESCRIPTION OF THE INVENTION

(1) We have surprisingly found that pimavanserin base can be obtained with high purity and high yields by a process that gives rise to the desired product with no need to isolate 1-(isocyanatomethyl)-4-propan-2-yloxybenzene II, an unstable, toxic intermediate, as in the procedure described in U.S. Pat. No. 7,790,899.

(2) Said process also presents numerous advantages, including a single synthesis step, a high overall molar yield, easy purification of the crude end product, and the use of raw materials and reagents which are readily available on the market, inexpensive, and less toxic than those used in the procedures of the prior art cited above.

(3) The process according to the invention (Scheme 3) comprises:

(4) a) converting tert-butyl-N-[(4-propan-2-yloxyphenyl)methyl]carbamate (I)

(5) ##STR00007##

(6) to 1-(isocyanatomethyl)-4-propan-2-yloxybenzene (II)

(7) ##STR00008##

(8) in the presence of an organic base and an organic acid or an anhydride of said acid in an organic solvent, to give a solution of (II) in said solvent;

(9) b) adding N-[(4-fluorophenyl)methyl]-1-methylpiperidin-4-amine (IV)

(10) ##STR00009##

(11) to the solution obtained in a), to give pimavanserin base (V)

(12) ##STR00010##

(13) c) purifying the pimavanserin base obtained in step b).

(14) ##STR00011##

(15) Both the starting substrates described in the synthesis process according to the invention are commercially available.

(16) The formation of 1-(isocyanatomethyl)-4-propan-2-yloxybenzene (II) (stage a) is conducted by reacting tert-butyl-N-[(4-propan-2-yloxiphenyl)-methyl]carbamate (I) in a suitable polar aprotic solvent such as tetrahydrofuran, 1,4-dioxane, dichloromethane, tert-butyl methyl ether, diethyl ether, dimethylsulphoxide, dimethylformamide, dimethylacetamide, ethyl acetate, toluene or acetone, more preferably tetrahydrofuran, 1,4-dioxane, dichloromethane, ethyl acetate or toluene, and even more preferably dichloromethane, in the presence of an organic base such as pyridine or 2-chloropyridine, more preferably 2-chloropyridine, with the addition of trifluoroacetic or trifluoromethanesulphonic anhydride, or alternatively trifluoroacetic acid or trifluoromethanesulphonic acid, at a temperature ranging between 0° C. and the boiling point of the solvent, more preferably between 10° C. and 65° C., and even more preferably between 20° C. and 30° C., for a reaction time ranging between 10 min and 3 hours, more preferably between 50 min and 2 hours. The 2-chloropyridine is preferably used in the ratio of 3:1 equivalents relative to tert-butyl-N-[(4-propan-2-yloxiphenyl)methyl]-carbamate (I).

(17) The trifluoromethanesulphonic anhydride is preferably used in the ratio of 1-1.1:1 equivalents relative to tert-butyl-N-[(4-propan-2-yloxiphenyl)methyl]-carbamate (I).

(18) The resulting product (II) is not isolated, and can be used directly in solution for the next step.

(19) The free base of compound (III) is converted by reacting N-[(4-fluorophenyl)methyl]-1-methylpiperidin-4-amine dihydrochloride (III) in a suitable basic aqueous solution, such as aqueous sodium hydroxide or aqueous potassium hydroxide, at a temperature ranging between 0° C. and 100° C., more preferably between 15° C. and 65° C., and even more preferably between 20° C. and 30° C., for a reaction time ranging between 5 min and 1 hour, preferably between 10 min and 30 min. Product (IV) is isolated by extraction from the reaction mixture with a polar aprotic solvent such as tetrahydrofuran, 1,4-dioxane, dichloromethane, tert-butyl methyl ether, diethyl ether, dimethylsulphoxide, dimethylformamide, dimethylacetamide, ethyl acetate, acetone or toluene, more preferably tetrahydrofuran, 1,4-dioxane, dichloromethane, ethyl acetate or toluene, and even more preferably dichloromethane. The solvent is evaporated to obtain the product N-[(4-fluorophenyl)methyl]-1-methylpiperidin-4-amine (IV). Compound (IV) is used in a ratio of 1-1.1:1 equivalents relative to tert-butyl-N-[(4-propan-2-yloxiphenyl)methyl]-carbamate (I).

(20) The formation of (V) is conducted (step b)) by reacting the 1-(isocyanatomethyl)-4-propan-2-yloxybenzene (II) with N-[(4-fluorophenyl)methyl]-1-methylpiperidin-4-amine (IV) obtained in step a) in a suitable polar aprotic solvent such as dichloromethane or toluene, at a temperature ranging between 10° C. and 60° C., more preferably between 20° C. and 30° C. The reaction is conducted in the presence of an organic base such as triethylamine, diisopropylethylamine or ethylenediamine, more preferably triethylamine, and reacted for a reaction time ranging between 1 hour and 6 hours, more preferably between 2 hours and 4 hours. The crude product (IV) is isolated by concentrating the solvent at low pressure.

(21) The purification step is preferably performed by crystallisation; the crude reaction product obtained in the preceding step is dissolved in a suitable protic organic solvent such as methanol, and precipitated by adding water. The precipitate is isolated by filtration to obtain pimavanserin base as a white solid with high purity.

(22) The invention will now be further illustrated by the following examples.

Example 1

(23) 10.6 ml of 2-chloropyridine and 7.9 ml of methanesulphonic anhydride are added, at 25° C., to a solution of compound I (10.0 g) in dichloromethane (100 ml). The reaction is maintained under stirring at 25° C. for 50 min. The result is complete conversion of compound I to compound II, which is not isolated but used “as is” for the subsequent synthesis step.

Example 2

(24) Compound III (13.35 g) is solubilised in 65 ml of basic aqueous solution (4 g of NaOH) and left under stirring for 10 min at 25° C. During this time, the solution becomes cloudy. 100 ml of dichloromethane is then added at 25° C., and maintained under stirring for 10 min, again at 25° C. The aqueous phase is separated from the organic phase and eliminated, while the organic phase is evaporated to obtain compound IV (10.0 g).

Example 3

(25) 15.8 ml of triethylamine is added to the solution of example 1, which is maintained under stirring at 25° C., followed by 10.0 g of compound IV suitably dissolved in 100 ml of dichloromethane. The reaction is maintained under stirring for 3 hours at 25° C. Complete conversion of compound II to compound V is observed, stirring is terminated, and the solvent is evaporated. The resulting crude oil is subsequently purified by crystallisation.

Example 4

(26) The crude compound obtained in the preceding step is solubilised at 25° C. in 100 ml of methanol; the solution is then cooled to between 0° C. and 5° C., and 100 ml of water is dripped into it in about 15 min. A solid forms which is left under stirring at between 0° C. and 5° C. for 1 hour, and then filtered through a Büchner funnel. The solid is washed twice with a 1/1 water/methanol mixture (5 ml). The product is dried under vacuum at 50° C. for 18 h to give a white solid, namely 7.2 g of pimavanserin base.