CZ2015688A3 - A method of producing 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-methylpiperidin-4-yl) of urea and its deuterated analogs - Google Patents

Abstract

The present invention relates to an improved process for the production of highly pure 1- (4-fluorobenzyl) -3- (4-isobutoxybenzyl) -1- (1-methylpiperidin-4-yl) urea of formula I known under the generic name pimavanserin. The process is based on 4-isobutoxybenzylamine of formula VII, which in the first step is reacted with a reagent of formula X wherein X = CH, N; R @ 1 = H, C1 -C3 alkyl, is converted to the correspondingly substituted N- (4-isobutoxybenzyl) -1-carbamide of formula XI. This is converted to the crude pimavanserin of formula I in the next step by reaction with N- (4-fluorobenzyl) -1-methylpiperidin-4-amine of formula II, which contains a very low amount of disubstituted impurity IX. Pimavanserin is an inverse serotonin 5-HT 2A receptor agonist and is currently tartrate tested for the treatment of psychosis in Parkinson's patients and has the potential to be part of the therapy of other psychotic conditions.

Description

Field of technology

The invention relates to an improved process for the preparation of 1- (4-fluorobenzyl) -3- (4-isobutoxybenzyl) -1- (1-methylpiperidin-4-yl) urea of formula I known under the generic name pimavanserin.

Pimavanserin is an inverse serotonin 5-HT ₂ and receptor agonist and is currently in the form of tartrate in phase III clinical trials for the treatment of psychosis in patients with Parkinson's disease and has the potential to be involved in the treatment of other psychotic conditions.

Prior art

Pimavanserin of formula I is prepared according to published patent applications (WO2004064738, WO2006036874, WO2006037043) from the starting N- (4-fluorobenzyl) -1-methylpiperidin-4-amine of formula II by reaction with 1-isobutoxybenzyl isocyanate of formula III to give crude pimavansin ( .

Said patents also describe the synthesis of N- (4-fluorobenzyl) -1-methylpiperidin-4-amine of formula II by reductive alkylation of 4-fluorobenzylamine of formula IV with 1-methylpiperidin-4-one of formula V. The second component for the synthesis of pimavanserin of formula I, 4- According to said patents, the isobutoxybenzyl isocyanate of formula III can be obtained by reacting 4-isobutoxybenzylamine of formula VII, which can be prepared in two steps from 4-isobutoxybenzaldehyde of formula VI, with phosgene or its equivalents. Another described synthesis of 4-isobutoxybenzyl isocyanate of formula III starts from 2- (4-isobutoxyphenyl) acetic acid of formula VIII, which upon reaction with diphenylphosphoryl azide (DPPA; diphenyl phosphorazidate) gives the isocyanate of formula III (Scheme 2).

NaBH ₃ CN or NaBH (OAc) ₃

Scheme 2

However, the described methods for synthesizing pimavanserin have a number of disadvantages. The main disadvantages include the use of 4-isobutoxybenzyl isocyanate of formula III, which, like all substances of this type, is toxic, odorless and highly reactive. Another disadvantage is that the described methods of its synthesis use either highly toxic phosgene or also highly toxic diphenylphosphoryl azide (DPPA), which, like all azides, is potentially explosive.

Another disadvantage of this process is the fact that the crude pimavanserin of the formula I contains some impurities, the removal of which leads to considerable losses. Namely, N- (4-fluorobenzyl) -1-methylpiperidin-4-amine of the formula II and 1,3-bis (4-isobutoxybenzyl) urea of the formula IX are mentioned as unpleasant impurities in this respect.

O

Also described are partially deuterated pimavanserin analogs which, due to their kinetic isotope effect, show lower sensitivity to metabolic degradation and may therefore have corresponding therapeutic advantages such as lower dosage, higher effect, lower inter-individual deviations and others (WO2008141057). However, their synthesis is similar to the methods already discussed described in published patent applications WO2004064738, WO2006036874 and WO2006037043 using partially deuterated starting materials.

The essence of the invention

The present invention relates to a novel efficient process for the preparation of highly pure 1- (4-fluorobenzyl) -3- (4-isobutoxybenzyl) -1- (1-methylpiperidin-4-yl) urea - pimavanserin, which is based on known intermediates in its synthesis of V- (4- fluorobenzyl) -1-methylpiperidin-4-amine of formula II and 4-isobutoxybenzylamine of formula VII. The process starts from a 4-isobutoxybenzylamine of formula VII, which in the first step is converted into an appropriately substituted N- (4-isobutoxybenzyl) -1-urea by reaction with a reagent of formula X (where X = CH, N; R = H, C 1 -C 3 alkyl) XI. This is converted in the next step by reaction with N- (4-fluorobenzyl) -1-methylpiperidin-4-amine of formula II to the crude pimavanserin of formula I, which contains a very low amount of disubstituted impurity of formula IX (Scheme 3).

Detailed description of the invention

The present invention relates to a novel efficient process for the preparation of highly pure 1- (4-fluorobenzyl) -3- (4-isobutoxybenzyl) -1- (1-methylpiperidin-4-yl) urea - pimavanserin of formula I, containing neither the amine of formula II nor the double impurity of formula IX.

The process starts from the known 4-isobutoxybenzylamine of formula VII, which is reacted with a reagent of formula X, preferably β, β-carbonyldiimidazole (CDI) of formula Xa, to give an appropriately substituted N- (4-isobutoxybenzyl) -1-carbamide of formula XI. This reaction can be performed in a variety of solvents at elevated temperatures. Polar aprotic solvents of the ester or ether type are suitable, preferably tetrahydrofuran or 2-methyltetrahydrofuran. The reaction can be carried out at temperatures ranging from 40 ° C to the boiling point, preferably at 50-60 ° C. The reaction eliminates the heterocycle of the formula XII as a by-product which can be removed, together with the excess reagent of the formula X, by washing with water, optionally with the addition of an inorganic base, preferably sodium carbonate, or an acid, preferably dilute hydrochloric acid. The crude product obtained can be purified by crystallization from various solvents, preferably from straight-chain or branched C2-C4 alcohols, preferably from isopropyl alcohol.

The urea of formula XI thus obtained is reacted in a second step with N- (4-fluorobenzyl) -1-methylpiperidin-4-amine of formula II to give 1- (4-fluorobenzyl) -3- (4-isobutoxybenzyl) -1- (1-methylpiperidin-4- yl) urea-pimavanserin of formula I. The reaction can be carried out at temperatures ranging from 40 ° C to the boiling point, preferably at 50-60 ° C. The reaction eliminates the heterocycle of formula XII as a by-product which can be removed by washing with water, optionally with the addition of an inorganic base, preferably sodium carbonate, or an acid, preferably dilute hydrochloric acid. The product can be obtained as the free base or as a salt with organic acids. The above reaction steps can be performed either in two separate steps with isolation of the intermediate of formula XI, or in a single step without isolation and purification.

The process for the synthesis of pimavanserin of formula I described above is also applicable to the preparation of the corresponding partially deuterated analogs.

Examples of embodiments of the invention

Example 1

N- (4-isobutoxybenzyl) -1H-imidazole-1-urea of formula XIa

To solid 4-isobutoxybenzylamine hydrochloride (10.0 g; 46.4 mmol) was added a solution of sodium carbonate (7.4 g; 69.5 mmol) in water (200 mL), then the mixture was extracted with 2-methyltetrahydrofuran (2 x 100 ml) and the combined extracts were dried over magnesium sulfate. After filtering off the desiccant, the solution was heated to 60 ° C in an oil bath and then carbonyldiimidazole (11.3 g; 69.5 mmol) was added all at once. The mixture was further stirred at 60 ° C for 16 h, then the warm reaction mixture was washed with 5% sodium carbonate solution (2 x 100 mL) and water (1 x 100 mL). The organic phase was then evaporated in vacuo to give 9.33 g of crude residue. The residue was recrystallized from isopropyl alcohol (50 ml) to give 8.5 g (67%). 1 H NMR (CDCl ₃ , 500 MHz, 298 K): 8.08 (s, 1H, imidazole CH), 7.37 (t, 1H, J = 1.5 Hz, s, 1H, imidazole CH), 7.24 (d, 2H, J = 8.7 Hz, ArH), 7.05 - 7.00 (m, 1H, NH), 6.96 - 6.95 (m, 1H, imidazole CH), 6.86 (d, 2H, J = 8.7 Hz, ArH), 4.50 (d, 2H, J =

5.6 Hz, CH ₂ -NH), 3.70 (d, 2H, J = 6.6 Hz, CH ₂ -CH- (CH ₃ ) ₂ ), 2.07 (nonet, 1H, J = 6.6 Hz, CH ₂ -CH- (CH ₃ ) ₂ ), 1.02 (d, 6H, J = 6.7 Hz, CH ₂ -CH- (CH ₃ ) ₂ ). ¹³ C NMR (CDCl ₃ , 500 MHz, 298 K): 159.07 (Ar-CO-CH ₂ ), 148.83 (NH-CO-N), 135.80 (imidazole CH), 130.48 (imidazole CH), 129.36 (ArCH), 128.73 (quart. ArQ, 116.13 (imidazole CH), 114.80 (ArCH), 74.47 (CH ₂ -CH- (CH ₃ ) ₂ ), 44.46 (CH ₂ -NH), 28.20 (CH ₂ -CH- (CH ₃ ) ₂ ), 19.21 (CH ₂ -CH- (CH ₃ ) ₂ )

Example 2

- (4-Fluorobenzyl) -3- (4-isobutoxybenzyl) -1- (1-methylpiperidin-4-yl) urea of formula I

To a solution of N- (4-isobutoxybenzyl) -1H-imidazole-1-carbamide (XIa) (2.0 g; 7.32 mmol) in THF (25 mL) was added N- (4-fluorobenzyl) -1- methylpiperidin-4-amine (II) (1.8 g; 8.05 mmol) and the reaction flask was placed in a bath heated to 60 ° C. The mixture was further stirred at 60 ° C for 4 h, then allowed to cool to rt. t. The mixture was then diluted with MTBE (50 mL) and washed with 5% sodium bicarbonate solution (1 x 50 mL) and water (2 x 50 mL). The organic phase was dried over magnesium sulphate and, after filtering off the desiccant, evaporated to dryness. The obtained residue (3.3 g) was recrystallized from isopropyl alcohol (10 ml). 2.2 g of crystals (70%) were obtained.

Example 3

- (4-Fluorobenzyl) -3- (4-isobutoxybenzyl) -1- (1-methylpiperidin-4-yl) urea of formula IK A suspension of carbonyldiimidazole (Xa) (6.0 g; 36.8 mmol) in 2-methyltetrahydrofuran ( 60 ml), 4-isobutoxybenzylamine (VII) (6.0 g; dropwise) was added dropwise at 60 ° C under an inert atmosphere.

33.5 mmol) over 5 minutes, the mixture was further stirred for 1 h at 60 ° C. Then, N- (4-fluorobenzyl) -1-methylpiperidin-4-amine (II) (8.2 g; 36.8 mmol) was added dropwise to the solution over 5 minutes, and the mixture was further stirred for 2 h at 60 ° C. . The reaction mixture was washed with 3.5% hydrochloric acid (1 x 70 mL, 1 x 20 mL) followed by water (1 x 20 mL). The organic portion was evaporated to dryness, the residue was dissolved in ethyl methyl ketone (50 ml) and a solution of p-toluenesulfonic acid monohydrate (6.4 g; 33.5 mmol) in ethyl methyl ketone (25 ml) was added hot. The mixture was allowed to cool slowly to rt. m.p., the precipitated crystalline portion was filtered off and washed with ethyl methyl ketone. 15.1 g of crystalline product (75%) were obtained.

Example 4

- (4-Fluorobenzyl) -3- (4-isobutoxybenzyl) -1- (1-methylpiperidin-4-yl) urea of formula I

To a suspension of 4-isobutoxybenzylamine hydrochloride (VII) (5.0 g; 23.2 mmol) in 2-methyltetrahydrofuran (50 mL) at 60 ° C under an inert atmosphere was added carbonyldiimidazole (Xa) (4.1 g; 5 mmol). To the suspension thus obtained, triethylamine (2.6 g; 25.5 mmol) was added dropwise over 10 minutes, and the mixture was further stirred at 60 ° C for 40 minutes. Then, N- (4-fluorobenzyl) -1-methylpiperidin-4-amine (II) (5.7 g; 25.5 mmol) was added dropwise to the solution over 5 minutes, and the mixture was further stirred for 4 h at 60 ° C. and 16 h at lab. t. (overnight). The reaction mixture was then washed with 3.5% hydrochloric acid (1 x 50 mL, 1 x 25 mL) followed by saturated brine (1 x 50 mL). The organic portion was transferred to a flask and p-toluenesulfonic acid monohydrate (4.4 g; 23.2 mmol) in 2-methyltetrahydrofuran (25 mL) was added. The resulting cloudy solution was evaporated to dryness and the residue (16.4 g) was dissolved in ethanol (120 ml). The hot ethanolic solution was filtered and after cooling and seeding the product crystallized as a salt. 9.5 g of crystalline product (68%) were obtained.

Example 5

- (4-Fluorobenzyl) -3- (4-isobutoxybenzyl) -1- (1-methylpiperidin-4-yl) urea of formula I

To a suspension of carbonylbis (2-methylimidazole) (1.17 g; 6.14 mmol) in 2-methyltetrahydrofuran (10 mL) at 60 ° C under an inert atmosphere was added dropwise 4-isobutoxybenzylamine (VII) (1.0 g;

5.58 mmol) over 2 minutes, the mixture was further stirred for 2 h at 60 ° C. Then, N- (4-fluorobenzyl) -1-methylpiperidin-4-amine (II) (1.36 g; 6.14 mmol) was added dropwise to the solution over 2 minutes, and the mixture was further stirred at 60 ° C for 4 hours. . The reaction mixture was washed with 3.5% hydrochloric acid (2 x 10 mL) followed by water (1 x 10 mL). The organic portion was evaporated to dryness, the residue was dissolved in isopropyl alcohol (10 ml) and a solution of p-toluenesulfonic acid hydrate (1.06 g; 5.58 mmol) in isopropyl alcohol (55 ml) was added hot. The mixture was allowed to cool slowly to rt. m.p., the precipitated crystalline portion was filtered off and washed with ethyl methyl ketone. 2.31 g of crystalline product (69%) were obtained.

Example 6

- (4-Fluorobenzyl) -3- (4-isobutoxybenzyl) -1- (1-methylpiperidin-4-yl) urea of formula I Suspension of 1,1'-carbonyldi (1,2,4-triazole) (1.17 g 6.14 mmol) in 2-methyltetrahydrofuran (10 ml) was added dropwise 4-isobutoxybenzylamine (VII) (1.0 g at 60 ° C under an inert atmosphere);

5.58 mmol) over 2 minutes, the mixture was further stirred for 2 h at 60 ° C. Then, N- (4-fluorobenzyl) -1-methylpiperidin-4-amine (II) (1.36 g; 6.14 mmol) was added dropwise to the solution over 2 minutes, and the mixture was further stirred at 60 ° C for 5 hours. . The reaction mixture was washed with 3.5% hydrochloric acid (2 x 10 mL) followed by water (1 x 10 mL). The organic portion was evaporated to dryness, the residue was dissolved in isopropyl alcohol (10 ml) and a solution of p-toluenesulfonic acid hydrate (1.06 g; 5.58 mmol) in isopropyl alcohol (55 ml) was added hot. The mixture was allowed to cool slowly to rt. m.p., the precipitated crystalline portion was filtered off and washed with ethyl methyl ketone. 2.17 g of crystalline product (65%) were obtained.

Claims (12)

PATENT CLAIMS A process for the preparation of pimavanserin of formula I, characterized in that it comprises the steps of: a) reacting 4-isobutoxybenzylamine of formula VII or a salt thereof (VII) with a compound of formula X, (X) wherein X may be independently CH or N, and wherein R may be hydrogen or C 1 -C 3 alkyl, to form a carbamide of formula XI, N KN H ', ^N (XI) wherein X may be independently CH or N and wherein R may be hydrogen or C 1 -C 3 alkyl b) reacting N- (4-fluorobenzyl) -1-methylpiperidin-4-amine of formula II or a salt thereof, (II) with the urea of formula XI obtained from step a), to give the pimavanserin of formula I. Process according to Claim 1, characterized in that the reaction in step a) takes place in polar aprotic solvents, preferably in tetrahydrofuran or 2-methyltetrahydrofuran. Process according to claims 1 and 2, characterized in that the starting material of formula VII from step a) is added dropwise to the compound of formula X, which is present in a 5 to 20% excess, preferably in a 10% excess to give compounds of formula XI. Process according to Claim 3, characterized in that the mixture obtained in step b) is further reacted with N- (4-fluorobenzyl) -1-methylpiperidin-4-amine of the formula II, which is in a 5 to 20% excess, preferably in a 10% excess and without prior isolation of the compound of formula XI. Process according to Claim 1, characterized in that the compound of the formula X is β, β-carbonyldiimidazole (CDI) of the formula Xa. O (Xa) Process according to Claim 5, characterized in that in step a), in the reaction 4-isobutoxybenzylamine of formula VII or a salt thereof with 1,1'-carbonyldiimidazole (CDI) of formula Xa, to give a compound of formula XIa. (Xla) 7. A compound of formula XI, (XI) wherein X may be independently CH or N and wherein R may be hydrogen or C 1 -C 3 alkyl. The compound of claim 7 is a compound of formula XIa. O (Xla) A process according to claim 1, characterized in that in step b) the compound of formula XI is reacted with N- (4-fluorobenzyl) -1-methylpiperidin-4-amine of formula II, which is in a 5 to 20% excess , preferably in a 10% excess. Deuterated pimavanserin analogues of formula I, prepared by the process according to claims 1 to 6. Compounds of formula I obtained by the process according to claims 1 to 10 containing at least 95% of substance I and not containing a dimeric impurity of formula IX. O (IX) A process for the purification of pimavanserin of formula I, characterized in that pimavanserin is converted into a salt with organic acids, preferably pivalic, oxalic, succinic, maleic, fumaric, tartaric, citric, p-toluenesulfonic, benzenesulfonic acid, more preferably with 4-toluenesulfonic acid, and the resulting salt is subsequently crystallized from suitable solvents including alcohols, aliphatic acid esters, amides, ethers, or mixtures of these solvents, preferably from methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, -methoxyethanol, methyl acetate, ethyl acetate, isopropyl acetate, N, N-dimethylformamide, ΛζΎ-dimethylacetamide, 1-methylpyrrolidone, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, 1-methoxy-2- (2-methoxyethoxy) ethane.