WO2017054786A1

WO2017054786A1 - A production method of 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-methylpiperidin- 4-yl)urea and its deuterated analogs

Info

Publication number: WO2017054786A1
Application number: PCT/CZ2016/000104
Authority: WO
Inventors: Stanislav Radl; Jan Stach; Ondrej Klecan; Josef Zezula
Original assignee: Zentiva, K. S.
Priority date: 2015-10-02
Filing date: 2016-09-14
Publication date: 2017-04-06
Also published as: CZ2015688A3

Abstract

The present invention relates to an improved production method of 1-(4-fluorobenzyl)-3-(4--isobutoxybenzyl)-1-(1--methylpiperidin-4-yl)urea (Pimavanserin), an inverse agonist of the serotonin 5-HT_2A receptor of formula (I). Crude pimavanserin prepared by this method contains a very low quantity of the disubstituted impurity.

Description

A production method of l-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-l-(l-methylpiperidin- 4-yl)urea and its deuterated analogs

Field of the invention

The invention relates to an improved production method of l-(4-fluorobenzyl)-3-(4- isobutoxybenzyl)-l-(l— methylpiperidin-4-yl)urea of formula I, known under the generic name of pimavanserin.

Pimavanserin is an inverse agonist of the serotonin 5-HT_2A receptor and is currently in the tartrate form in stage III of clinical trial for the treatment of psychosis in patients suffering from Parkinson's disease and has potential to become part of the therapy of other psychotic conditions.

Background Art

Pimavanserin of formula I is produced, according to the published patent applications (WO2004064738, WO2006036874, WO2006037043), from the input N-(4-fluorobenzyl)-l- methylpiperidine-4~amine of formula II through a reaction with 1-isobutoxybenzyl isocyanate of formula III, providing crude pimavanserin (Diagram 1).

Diagram 1

The above mentioned patents also describe synthesis of N-(4-fluorobenzyl)-l- methylpiperidine-4-amine of formula II by reductive alkylation of 4-fluorobenzylamine of formula IV with l-methylpiperidin-4-one of formula V. According to the above mentioned patents, the other component for synthesis of pimavanserin of formula I, 4-isobutoxybenzyl isocyanate of formula III can be obtained through a reaction of 4-isobutoxybenzylamine of formula VII, which can be prepared in two stages from 4-isobutoxybenzaldehyde of formula VI with phosgene or its equivalents. Another described synthesis of 4-isobutoxybenzyl isocyanate of formula III is based on 2-(4-isobutoxyphenyl)acetic acid of formula VIII, which provides, through a reaction with diphenyl phosphoryl azide (DPPA; diphenyl phosphorazidate), the isocyanate of formula III (Diagram 2).

Diagram 2

However, the above mentioned methods of pimavanserin synthesis feature a number of disadvantages. The main disadvantages comprise the use of 4-isobutoxybenzyl isocyanate of formula III, which is, as all the substances of this type, toxic, unpleasantly malodorous and highly reactive. Another disadvantage is that the described methods of its synthesis either use the highly toxic phosgene, or the also toxic diphenyl phosphoryl azide (DPPA), which is additionally as all azides potentially explosive.

Another disadvantage of the said method is the fact that crude pimavanserin of formula I contains some impurities the removal of which leads to considerable losses. Namely, as unpleasant impurities from this point of view N-(4-fluorobenzyl)-l-methylpiperidine-4-amine of formula II and l,3-bis(4-isobutoxybenzyl)urea of formula IX are mentioned.

Partly deuterated analogs of pimavanserin are also described that exhibit, based on the kinetic isotope effect, lower sensitivity to metabolic degradation and can thus have the corresponding therapeutic advantages as a lower dosage, higher effect, lower inter-individual deviations and more (WO2008141057). However, their synthesis is analogous to the above mentioned methods described in the published patent applications WO2004064738, WO2006036874 and WO2006037043 with the use of partly deuterated input substances. Disclosure of the Invention

The invention relates to a new efficient preparation method of highly pure l-(4-fluorobenzyl)-

3- (4-isobutoxybenzyl)-l-(l-methylpiperidin-4-yl)urea - pimavanserin that is based on the known intermediates of its synthesis, namely N-(4-fluorobenzyl)-l-methylpiperidine-4-amine of formula II and 4-isobutoxybenzylamine of formula VII. The method is based on

4- isobutoxybenzylamine of formula VII, which is, in the first stage through a reaction with the reagent of formula X (where X = CH, N; R = H, alkyl C1-C3), converted to the correspondingly substituted N-(4-isobutoxybenzyl)-l -carbamide of formula XI. In the next stage, it is converted, through a reaction with N-(4-fluorobenzyl)-l-methylpiperidine-4-amine of formula II, to crude pimavanserin of formula I, which contains a very low quantity of the disubstituted impurity of formula IX (Diagram 3).

VII X XI XII

Diagram 3 Detailed description of the Invention

The invention relates to a new efficient preparation method of highly pure l-(4-fluorobenzyl)- 3-(4-isobutoxybenzyl)-l-(l-methylpiperidin-4-yl)urea - pimavanserin of formula I, which does not contain the amine of formula II, or the doubled impurity of formula IX.

The method is based on the known 4-isobutoxybenzylamine of formula VII, which reacts with the reagent of formula X, preferably with Ι, -carbonyldiimidazole (CDI) of formula Xa, producing the correspondingly substituted N-(4-isobutoxybenzyl)-l -carbamide of formula XI. This reaction can be carried out in a number of solvents at an elevated temperature. Polar aprotic solvents of the ester or ether type are suitable, preferably tetrahydrofuran or 2-methyltetrahydrofuran. The reaction can be carried out at temperatures in the range from 40°C to the boiling point, preferably at 50 - 60°C. During the reaction the heterocycle of formula XII falls off as a side product, which can be, together with the excess reagent of formula X, removed by washing with water, possibly with an addition of an inorganic base, preferably sodium carbonate, or an acid, preferably diluted hydrochloric acid. The obtained crude product can be repurified by crystallization from various solvents, preferably C2 - C4 alcohols with a straight or branched chain, preferably from isopropyl alcohol.

The carbamide of formula XI obtained this way reacts with N-(4-fluorobenzyl)-l- methylpiperidine-4-amine of formula II in the second stage, producing l-(4-fluorobenzyl)-3- (4-isobutoxybenzyl)-l-(l-methylpiperidin-4-yl)urea - pimavanserin of formula I. The reaction can be carried out at temperatures in the range from 40°C to the boiling point, preferably at 50 - 60°C. During the reaction the heterocycle of formula XII falls off as a side product, which can be removed by washing with water, possibly with an addition of an inorganic base, preferably sodium carbonate, or an acid, preferably diluted hydrochloric acid. The product can be obtained as a free base or as a salt with organic acids. The above mentioned reaction stages can be carried out either in two separate steps with isolation of the intermediate product of formula XI, or in a single step without isolation and purification.

The above described method of synthesis of pimavanserin of formula I is also applicable to the preparation of the respective partly deuterated analogs.

Examples

Example 1

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

To solid 4-isobutoxybenzylamine hydrochloride (10.0 g; 46.4 mmol) a solution of sodium carbonate (7.4 g; 69.5 mmol) in water (200 ml) was added, the mixture was then extracted with 2-methyltetrahydrofuran (2 x 100 ml) and the united extracts were dried with magnesium sulfate. After the removal of the drying agent by filtration the solution was heated up to 60°C in an oil bath and subsequently carbonyldiimidazole (11.3 g; 69.5 mmol) was added all at a time. The mixture was further stirred at 60°C for 16 h, then the reaction mixture was washed with a 5% solution of sodium carbonate (2 x 100 ml) and water (1 x 100 ml). The organic phase was then evaporated on a vacuum evaporator, the amount of 9.33 g of the crude evaporation product was obtained. The evaporation product was recrystallized from isopropyl alcohol (50 ml), the amount of 8.5 g (67%) was obtained. 1H NMR (CDC1₃, 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, 1H₅ NH), 6.96 - 6.95 (m, 1H, imidazole CH), 6.86 (d, 2H, J = 8.7 Hz, ArH), 4.50 (d, 2Η, J = 5.6 Hz, CH -NH), 3.70 (d, 2H, J = 6.6 Hz, CH₂-CH-(CH₃)₂), 2.07 (nonet, 1H, J= 6.6 Hz, CH₂-CH-(CH₃)₂), 1.02 (d, 6H, J = 6.7 Hz, CH₂-CH-(CH₃)₂). ¹³C NMR (CDC1₃, 500 MHz, 298 ): 159.07 (Ar-C-0-CH₂), 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 (CH₂-CH-(CH₃)₂), 44.46 (CH₂-NH), 28.20 (CH₂-CH- (CH₃)₂), 19.21 (CH₂-CH-(CH₃)₂) Example 2

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

To a solution of N-(4-isobutoxybenzyl)-l H-imidazole- 1 -carbamide (XIa) (2.0 g; 7.32 mmol) in THF (25 ml) N-(4-fluorobenzyl)-l-methylpiperidine-4-amine (II) (1.8 g; 8.05 mmol) was added all at a time and the reaction flask was put in a bath heated up to 60°C. The mixture was further stirred at 60°C for 4 h, then it was left to cool down to the lab. t. The mixture was diluted with MTBE (50 ml) and washed with a 5% solution of sodium hydrogen carbonate (1 x 50 ml) and water (2 x 50 ml). The organic phase was dried with magnesium sulfate and after removal of the drying agent by filtration evaporated until dry. The obtained evaporation product (3.3 g) was recrystallized from isopropyl alcohol (10 ml). The amount of 2.2 g of crystals (70%) was obtained.

Example 3

1 -(4-Fluorobenzyl)-3-(4-isobutoxybenzyl)- 1 -( 1 -methylpiperidin-4-yl)urea of formula I To a suspension of carbonyldiimidazole (Xa) (6.0 g; 36.8 mmol) in 2-methyltetrahydrofuran (60 ml) 4-isobutoxybenzylamine (VII) (6.0 g; 33.5 mmol) was added by dripping under an inert atmosphere at 60°C during 5 minutes, the mixture was further stirred for 1 h at 60°C. Then, N-(4-fluorobenzyl)-l-methylpiperidine-4-amine (II) (8.2 g; 36.8 mmol) was added to the solution by dripping during 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) and subsequently with water (1 x 20 ml). The organic fraction was evaporated until dry, the evaporation product was dissolved in ethyl methyl ketone (50 ml) and a solution of p- toluenesulfonic monohydrate (6.4 g; 33.5 mmol) in ethyl methyl ketone (25 ml) was added to the solution obtained this way in a hot state. The mixture was slowly left to cool to the lab. t, the separated crystalline fraction was removed by filtration and washed with ethyl methyl ketone. The amount of 15.1 g of the crystalline product was obtained (75%).

Example 4

1- (4-Fluorobenzyl)-3-(4-isobutoxybenzyl)-l-(l-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) carbonyldiimidazole (Xa) (4.1 g; 25.5 mmol) was added all at a time under an inert atmosphere at 60°C. Triethylamine (2.6 g; 25.5 mmol) was added by dripping to the suspension obtained this way during 10 minutes and the mixture was further stirred for 40 minutes at 60°C. Then, N-(4-fluorobenzyl)-l-methylpiperidine-4-amine (II) (5.7 g; 25.5 mmol) was added to the solution by dripping during 5 minutes and the mixture was further stirred for 4 h at 60°C and for 16 h at the lab. t. (overnight). The reaction mixture was subsequently washed with 3.5% hydrochloric acid (1 x 50 ml, 1 x 25 ml) and then with saturated salt brine (1 x 50 ml). The organic fraction was transferred to a flask and p- toluenesulfonic acid monohydrate (4.4 g; 23.2 mmol) in 2-methyltetrahydrofuran (25 ml) was added. The obtained turbid solution was evaporated until dry and the evaporation product (16.4 g) was dissolved in ethanol (120 ml). The hot ethanolic solution was filtered and after cooling and seeding the product crystallizes in the form of a salt. The amount of 9.5 g of the crystalline product was obtained (68%).

Example 5

To a suspension o carbonylbis(2-methylimidazole) (1.17 g; 6.14 mmol) in 2- methyltetrahydrofuran (10 ml) 4-isobutoxybenzylamine (VII) (1.0 g; 5.58 mmol) was added by dripping under an inert atmosphere at 60°C during 2 minutes, the mixture was further stirred for 2 h at 60°C. Then, N-(4-fluorobenzyl)-l-methylpiperidine-4-amine (II) (1.36 g; 6.14 mmol) was added to the solution by dripping during 2 minutes and the mixture was further stirred for 4 h at 60°C. The reaction mixture was washed with 3.5% hydrochloric acid (2 x 10 ml) and subsequently with water (1 x 10 ml). The organic fraction was evaporated until dry, the evaporation product was dissolved in isopropyl alcohol (10 ml) and a solution of p-toluenesulfonic hydrate (1.06 g; 5.58 mmol) in isopropyl alcohol (55 ml) was added to the solution obtained this way in a hot state. The mixture was slowly left to crystallize to the lab. , the separated crystalline fraction was removed by filtration and washed with ethyl methyl ketone. The amount of 2.31 g of the crystalline product was obtained (69%).

Example 6

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

To a suspension of l, -carbonyldi(l,2,4-triazole) (1.17 g; 6.14 mmol) in 2- methyltetrahydrofuran (10 ml) 4-isobutoxybenzylamine (VII) (1.0 g; 5.58 mmol) was added by dripping under an inert atmosphere at 60°C during 2 minutes, the mixture was further stirred for 2 h at 60°C. Then, N-(4-fluorobenzyl)-l-methylpiperidine-4-amine (II) (1.36 g; 6.14 mmol) was added to the solution by dripping during 2 minutes and the mixture was further stirred for 5 h at 60°C. The reaction mixture was washed with 3.5% hydrochloric acid (2 x 10 ml) and subsequently with water (1 x 10 ml). The organic fraction was evaporated until dry, the evaporation product was dissolved in isopropyl alcohol (10 ml) and a solution of p-toluenesulfonic hydrate (1.06 g; 5.58 mmol) in isopropyl alcohol (55 ml) was added to the solution obtained this way in a hot state. The mixture was slowly left to crystallize to the lab. t, the separated crystalline fraction was removed by filtration and washed with ethyl methyl ketone. The amount of 2.17 g of the crystalline product was obtained (65%).

Claims

C L A I M S

1. A method for preparing pimavanserin of formula I,

characterized in that it comprises the steps:

a) a reaction of 4-isobutoxybenzylamine of formula VII or its salt

with the compound of formula X,

wherein X is independently CH or N, and where R is hydrogen or a C1-C3 alkyl, producing the carbamide of formula XI,

where X is independently CH or N, and where R is hydrogen or a C1-C3 alkyl;

b) a reaction of iV-(4-fluorobenzyl)-l-methylpiperidine-4-amine of formula II or its salts

with the carbamide of formula XI obtained from step a), producing pimavanserin of formula I.

2. The method of preparing in accordance with claim 1, characterized in that the reaction in step a) is carried out in polar aprotic solvents, preferably in tetrahydrofuran or 2-methyltetrahydrofuran.

3. The method of preparing in accordance with claims 1 and 2, characterized in that the input substance VII from step a) is added dropwise to the compound of formula X, which is present in a 5 to 20% excess, preferably in 10% excess, producing the compound of formula XI.

4. The method of preparing in accordance with claim 3, characterized in that the mixture obtained in step b) is further reacted with N-(4-fluorobenzyl)-l-methylpiperidine-4- amine of formula II, which is in 5 to 20% excess, preferably in 10% excess and without preceding isolation of the substance of formula XI.

5. The method of preparing in accordance with claim 1, characterized in that the compound of formula X is 1,1 '-carbonyldiimidazole (CDI) of formula Xa.

6. The method of preparing in accordance with claim 5, characterized in that in step a) 4-isobutoxybenzylamine of formula VII or its salts are reacted with Ι, -carbonyldiimidazole (CDI) of formula Xa, producing the compound of formula XIa.

7. The compound of formula XI,

wherein X is independently CH or N, and where R is hydrogen or a C1-C3 alkyl.

8. The compound in accordance with claim 7 is the compound of formula Xla.

9. The method of preparing in accordance with claim 1, characterized in that in step b) the compound of formula XI is reacted with N-(4-fluorobenzyl)-l-methylpiperidine-4- amine of formula II, which is in 5 to 20% excess, preferably in 10% excess.

10. Deuterated analogs of pimavanserin of formula I prepared with the method in accordance with claims 1 to 6.

11. The compounds of formula I, obtained with the method in accordance with claims 1 to 10, containing at least 95% of the compound I and not containing the dimeric impurity of formula IX.

12. A method for purification pimavanserin of formula I, characterized in that pimavanserin is converted to a salt with organic acids, preferably with pivalic, oxalic, succinic, maleic, fumaric, tartaric, citric, ?-toluenesulfonic, benzenesulfonic acid, more preferably with £>-toluenesulfonic acid, and the resulting salt is subsequently crystallized from suitable solvents comprising alcohols, esters of aliphatic acids, amides, ethers, or mixtures of these solvents, preferably from methanol, ethanol, 1- propanol, 2-propanol, 1-butanol, 2-methoxyethanol, methyl acetate, ethyl acetate, isopropyl acetate, N,N-dimethyl formamide, N,N-dimethyl acetamide, 1- methylpyrrolidone, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, l-methoxy-2-(2- methoxyethoxy)ethane.