WO2020083825A1

WO2020083825A1 - Process for the manufacturing of pimavanserin

Info

Publication number: WO2020083825A1
Application number: PCT/EP2019/078543
Authority: WO
Inventors: Mariano Stivanello; Nicola ANTOLINI
Original assignee: Lundbeck Pharmaceuticals Italy S.P.A.
Priority date: 2018-10-23
Filing date: 2019-10-21
Publication date: 2020-04-30
Also published as: IT201800009690A1

Abstract

The present invention relates to a new process for manufacturing 1-(4-fluorobenzyl)-3-(4-iso-butoxyphenyl)-1-(1-methylpiperidin-4-yl)urea, with the INN name pimavanserin, and its hemitartrate salt.

Description

PROCESS FOR THE MANUFACTURING OF PIMAVANSERIN

Field of the invention

The present invention relates to a new process for manufacturing 1-(4-fluorobenzyl)-3-(4-iso- butoxyphenyl)-1-(1-methylpiperidin-4-yl)urea, with the INN name pimavanserin, and its hemi- tartrate salt.

Background of the invention

The compound 1-(4-fluorobenzyl)-3-(4-isobutoxyphenyl)-1-(1-methylpiperidin-4-yl)urea having the INN name pimavanserin was disclosed for the first time in WO 2004/064738 and has the molecular structure depicted below.

Pimavanserin is an atypical antipsychotic indicated for the treatment of hallucinations and de- lusions associated with Parkinson’s disease psychosis. Pimavanserin is marketed by Acadia Pharmaceuticals under the brand name Nuplazid, as the hemitartrate salt.

Pimavanserin can be obtained by various synthetic routes, as disclosed by Acadia Pharma- ceuticals in e.g. WO 2004/064738, WO 2006/037043, WO 2007/133802 and WO

2008/144326 and processes disclosed in for example and US 2008/0280886, WO

2016/141003, WO 2017/036432 and WO 2017/054786.

There is a need within the field to improve the method of producing pimavanserin and/or to find alternative processes for producing pimavanserin. In particular, there is a need for a method that is efficient and cost-effective and is readily applicable on industrial scale.

It is furthermore desirable to obtain the intermediates and final pimavanserin in a very high purity, thus avoiding additional laborious purification steps. Summary of the invention

The present invention relates to a new process for producing pimavanserin, 1-(4-fluoroben- zyl)-3-(4-isobutoxyphenyl)-1 -(1 -methylpiperidin-4-yl)urea.

In particular, the invention relates to a process for manufacturing of pimavanserin, said pro- cess comprising contacting 2,2,2-trichloro-N-(4-isobutoxybenzyl)acetamide with N-(4-fluoro- benzyl)-1-methylpiperidin-4-amine in the presence of an amidine compound such as Diazabi- cycloundecene (DBU) or Diazabicyclononene (DBN) to obtain pimavanserin.

The process occurs without isolation of 1-isobutoxy-4-(isocyanatomethyl)benzene, which is formed in situ and continuously converted to Pimavanserin by reaction with N-(4-fluoroben- zyl)-1 -methylpiperidin-4-amine.

In one embodiment, the invention relates to pimavanserin or pimavanserin hemitartrate di- rectly obtained by the process of the invention. In a further embodiment, the invention relates to a pharmaceutical composition comprising pimavanserin or pimavanserin hemitartrate di- rectly obtained by the process of the invention.

Definitions

Pimavanserin:

Throughout the description, the term“pimavanserin” without specification of any particular salt form is intended to include any form of the compound, such as the free base and pharmaceu- tically acceptable salts. The free base and pharmaceutically acceptable salts include anhy- drous forms and solvated forms such as hydrates. The anhydrous forms and the solvates in- clude amorphous and crystalline forms. In a particular embodiment, pimavanserin is in the form of the hemitartrate salt and is then denoted“pimavanserin hemitartrate”.

Purity:

In the present context, the term“purity” indicates the percentage by area of the product deter- mined by a chromatographic method, such as gas chromatography (GC) or high performance liquid chromatography (HPLC).

Therapeutically effective amount:

In the present context, the term "therapeutically effective amount" of a compound means an amount sufficient to alleviate, arrest, partly arrest, remove or delay the clinical manifestations of a given disease and its complications in a therapeutic intervention comprising the admin- istration of said compound. An amount adequate to accomplish this is defined as "therapeuti- cally effective amount". Effective amounts for each purpose will depend e.g. on the severity of the disease or injury as well as the weight and general state of the subject. It will be under- stood that determining an appropriate dosage may be achieved using routine experimenta- tion, by constructing a matrix of values and testing different points in the matrix, which is all within the ordinary skills of a trained physician.

Treatment and treating:

In the present context,“treatment” or“treating” is intended to indicate the management and care of a patient for the purpose of alleviating, arresting, partly arresting, removing or delaying progress of the clinical manifestation of the disease. The patient to be treated is preferably a mammal, in particular a human being.

Detailed description of the invention

The inventors have found a new process for producing pimavanserin, 1-(4-fluorobenzyl)-3-(4- isobutoxyphenyl)-1-(1-methylpiperidin-4-yl)urea. The process has been improved compared to the process very briefly suggested in WO 2004/064738 and more detailed in US

2008/0280886.

In particular, the invention relates to a process for manufacturing of pimavanserin, said pro- cess comprising the following step,

contacting N-(4-fluorobenzyl)-1-methylpiperidin-4-amine with 2,2,2-trichloro-N-(4-isobu- toxybenzyljacetamide in presence of an amidine compound such as Diazabicycloundecene (DBU) or Diazabicyclononene (DBN) to obtain pimavanserin.

Said process step is a combination of steps 5 and 6 illustrated in scheme 1 below:

Scheme 1:

In the present invention, steps 5 and 6 occur without isolation of 1-isobutoxy-4-(isocy- anatomethyl)benzene.

Steps 1 , 2, 3 and 4 are further embodiments of the invention, exemplifying processes for preparation of intermediates.

In step 1) N-(4-fluorobenzyl)-1-methylpiperidin-4-amine is prepared by reacting 4-fluoroben- zylamine and N-methylpiperidin-4-one under catalytic hydrogenation.

WO 2004/064738 suggests the use of the toxic sodium cyanoborohydride for the reduction. This step has been exemplified in WO 2009/039461 which relates to the synthesis of pima- vanserin metabolite derivatives. In WO 2009/039461 N-(4-fluorobenzyl)-1-methylpiperidin-4- amine is obtained in a yield of 50%.

WO 2006/037043 and US 2008/0280886 disclose the use of triacetoxy borohydride as reduc- tive agent obtaining N-(4-fluorobenzyl)-1-methylpiperidin-4-amine in yields of 92% and >82%. WO 2007/133802 discloses reduction using a palladium catalyst obtaining a yield of 78.1%.

The present inventors have performed the reduction by catalytic hydrogenation using Pd/C as catalyst. Crude N-(4-fluorobenzyl)-1-methylpiperidin-4-amine was purified through formation of the hydrochloride salt followed by base liberation using the methods known to the person skilled in the art. N-(4-fluorobenzyl)-1-methylpiperidin-4-amine was thus obtained in high yields and very high purities without the need of fractional distillation and recovery of product from impure fractions as described in WO 2007/133802.

In step 2), p-hydroxybenzonitrile is reacted with an excess of isobutyl bromide under William- son ether synthesis conditions to obtain methyl-4-isobutoxybenzonitrile.

The reaction takes place in a polar solvent like ethanol, methanol, dimethylformamide (DMF) or dimethylsulfoxide (DMSO), or mixtures thereof; in presence of an organic or inorganic base, such as for example K2CO₃, Na₂C0₃ and LhCChThe reaction time can be slightly re- duced by running the reaction at about 2 bar of pressure.

Step 3), Step 3 involves reduction of the 4-isobutoxybenzonitrile to give the corresponding primary amine which is (4-isobutoxyphenyl)methaneamine.

The reduction can be performed via catalytic hydrogenation using for example Pd/C as cata- lyst.

In step 4), 2,2,2-trichloro-N-(4-isobutoxybenzyl)acetamide is prepared either by reacting (4- isobutoxyphenyl)methaneamine with trichloroacetyl chloride in presence of a base such as triethylamine (TEA) to scavenge the HCI gas formed, or by reacting (4-isobutoxyphenyl)me- thaneamine with hexachloroacetone.

Steps 5-6) The inventors found that steps 5 and 6 can conveniently be combined avoiding isolation of the unstable 1-isobutoxy-4-(isocyanatomethyl)benzene.

Pimavanserin is formed by reacting N-(4-fluorobenzyl)-1-methylpiperidin-4-amine with 2,2,2- trichloro-N-(4-isobutoxybenzyl)acetamide in presence of an amidine compound such as Di- azabicycloundecene (DBU) or Diazabicyclononene (DBN) as catalyst analogous to the pro- cess described in Braverman et al., Tetrahedron Letters 40 (1999) 3236-3238.

N-(4-fluorobenzyl)-1-methylpiperidin-4-amine, amidine compound and 2,2,2-trichloro-N-(4-iso- butoxybenzyl)acetamide are dissolved in an organic solvent such as for example a solvent selected from the group consisting of toluene, xylene, heptane, acetonitrile, isopropylacetate, tetrahydrofuran (THF), 2-methyltetrahydrofuran (MTHF), 1 ,4-dioxane, cyclopentyl methyl ether, dichloromethane, dimethylformamide, dimethylacetamide, N-methylpyrrolidinone, N- ethylpyrrolidinone and dimethylsulfoxide; and the mixture is heated to give directly a crude pi- mavanserin solution.

Alternatively, a solution of one of the three reagents is added into a hot mixture of the other two. For example a solution of 2,2,2-trichloro-N-(4-isobutoxybenzyl)acetamide in acetonitrile is added into the mixture of N-(4-fluorobenzyl)-1-methylpiperidin-4-amine and Diazabicyclo- nonene in acetonitrile at reflux.

Alternatively, a solution of two of the three reagents is added into a hot mixture of the other one. For example a solution of 2,2,2-trichloro-N-(4-isobutoxybenzyl)acetamide and Diazabicy- clononene in acetonitrile is added into the mixture of N-(4-fluorobenzyl)-1-methylpiperidin-4- amine in acetonitrile at reflux.

The amidine compound leads to the transformation of the trichloroacetamide to the corre- sponding isocyanate derivative by elimination of chloroform. The in-situ formed isocyanate then reacts with N-(4-fluorobenzyl)-1-methylpiperidin-4-amine to give pimavanserin.

PIMAVANSERIN

WO 2004/064738 and WO 2009/039461 disclose preparation of 1-isobutoxy-4-(isocy- anatomethyl)benzene by reacting 2-(4-isobutoxyphenyl)acetic acid with diphenylphosphoryl azide (DPPA) and 8,8-bis-dimethylamino-naphthalene (Proton SpongeTM). After isolation 1- isobutoxy-4-(isocyanatomethyl)benzene was used for further processing to Pimavanserin (WO 2004/064738) or a related metabolite derivative (WO 2009/039461 ).

The pimavanserin process disclosed in WO 2006/037043, US 2008/0280886 and other known references also implies isolation of 1-isobutoxy-4-(isocyanatomethyl)benzene with the consequence that the end product, pimavanserin, is obtained in a modest yield.

By the current process, steps 5) and 6) can be performed without the isolation of the unstable 1-isobutoxy-4-(isocyanatomethyl)benzene.

Step 7) In this step, crude pimavanserin is mixed with ethanol and tartaric acid and precipi- tated as the hemitartrate.

Pimavanserin hemitartrate

Pimavanserin was obtained as a hemitartrate salt in a high purity such as a purity above 95%. Each of the intermediates obtained according to process steps 1 , 2, 3 and 4 can be used for further processing in isolated form or without being isolated, and in all purities.

In a preferred embodiment, one or more of said intermediates have been isolated before fur- ther processing, such that for example N-(4-fluorobenzyl)-1-methylpiperidin-4-amine obtained from step 1 ) has been isolated before it is used for the reaction in steps 5-6).

In a further embodiment, one or more said intermediates have been isolated and purified be- fore further processing, such that for example N-4-fluorobenzyl)-1-methylpiperidin-4-amine obtained from step 1 ) has been isolated and purified before it is used for the reaction in steps 5-6).

In one embodiment, one or more of said intermediates are used for further processing in a purity of at least 90%, such as at least 95%, such as at least 97%, such as at least 98% such as at least 99.0%, such as at least 99.5, 99.6, 99.7, 99.8 or 99.9%. Purity is measured by GC or HPLC as described in the experimental section.

The present invention also relates to a pharmaceutical composition comprising Pimavanserin obtained by the process of the invention. The pharmaceutical composition may further corn- prise at least one pharmaceutically acceptable excipient, carrier and/or diluent, and may be in a solid dosage form, such as a tablet, for oral administration.

Methods for the preparation of solid pharmaceutical preparations are well known in the art. See, e.g., Remington: The Science and Practice of Pharmacy, 21^st ed., Lippincott Williams & Wilkins (2005). Solid preparations, such as tablets, may be prepared by mixing the active in- gredients with an ordinary carrier, such as an adjuvant and/or diluent, and subsequently corn- pressing the mixture in a tableting machine. Non-limiting examples of adjuvants and/or dilu ents include: corn starch, lactose, talcum, magnesium stearate, gelatin, lactose, gums, and the like. Any other appropriate adjuvant or additive such as colorings, aroma, and preserva- tives may also be used provided that they are compatible with the active ingredients. The pharmaceutical compositions of the invention thus typically comprise an effective amount of Pimavanserin and one or more pharmaceutically acceptable carriers.

Pimavanserin obtained according to the present invention may be administered by any suita- ble administration route, e.g. orally or parenterally, and it may be presented in any suitable form for such administration, e.g. in the form of tablets, capsules, powders, syrups or solu- tions or dispersions for injection. In an embodiment, the pharmaceutical composition will corn- prise Pimavanserin in a therapeutically effective amount. Preferably, the amount of Pimavanserin in a pharmaceutical composition in a unit dosage form is from 1 mg to 50 mg, such as from 5 mg to 25 mg, such as for example 5, 6, 7, 8, 9,

10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24 or 25 mg.

Pimavanserin has been approved for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis. It is furthermore being investigated for the treatment of symptoms within Alzheimer’s Disease (AD), Schizophrenia and Major Depressive Disorder. It is envisaged that Pimavanserin obtained by the process of the invention may be used in the treatment of CNS disorders such as Parkinson’s Disease (PD), Alzheimer’s Disease (AD), Schizophrenia and Major Depressive Disorder. In particular, Pimavanserin obtained by the process of the invention may be used in the treatment of hallucinations and delusions associ- ated with Parkinson’s disease psychosis.

All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference in their entirety and to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein (to the maximum extent permitted by law), regardless of any separately provided incorporation of particular documents made elsewhere herein.

The use of the terms“a” and“an” and“the” and similar referents in the context of describing the invention are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

The description herein of any aspect or aspect of the invention using terms such as“compris- ing”,“having,”“including” or“containing” with reference to an element or elements is intended to provide support for a similar aspect or aspect of the invention that“consists of”,“consists essentially of” or“substantially comprises” that particular element or elements, unless other- wise stated or clearly contradicted by context (e.g., a composition described herein as corn- prising a particular element should be understood as also describing a composition consisting of that element, unless otherwise stated or clearly contradicted by context).

It should be understood that the various aspects, embodiments, implementations and fea- tures of the invention mentioned herein may be claimed separately, or in any combination.

Embodiments according to the invention

In the following, embodiments of the invention are disclosed. The first embodiment is denoted E1 , the second embodiment is denoted E2 and so forth. E1. A process for manufacturing of pimavanserin, said process comprising the following step:

contacting 2,2,2-trichloro-N-(4-isobutoxybenzyl)acetamide with N-(4-fluorobenzyl)-1-methylpi- peridin-4-amine in the presence of an amidine compound.

E2. The process according to embodiment 1 , wherein said amidine compound is selected from diazabicycloundecene (DBU) and diazabicyclononene (DBN).

E3. The process according to any of embodiments 1-2, wherein said process occurs with- out isolation of 1-isobutoxy-4-(isocyanatomethyl)benzene.

E4. The process according to any of embodiments 1-3, wherein said 2,2,2-trichloro-N-(4- isobutoxybenzyl)acetamide, said N-(4-fluorobenzyl)-1-methylpiperidin-4-amine and said ami- dine compound are dissolved in an organic solvent and the mixture is heated to give pima- vanserin.

E5. The process according to any of embodiments 1-3, wherein one of 2,2,2-trichloro-N- (4-isobutoxybenzyl)acetamide, N-(4-fluorobenzyl)-1-methylpiperidin-4-amine and amidine compound is added into a hot mixture of the other two of 2,2,2-trichloro-N-(4-isobutoxyben- zyl)acetamide, N-(4-fluorobenzyl)-1-methylpiperidin-4-amine and amidine compound, wherein said hot mixture comprises an organic solvent.

E6. The process according to any of embodiments 1 -3, wherein two of 2,2,2-trichloro-N- (4-isobutoxybenzyl)acetamide, N-(4-fluorobenzyl)-1-methylpiperidin-4-amine and amidine compound are added into a hot mixture of the remaining one of 2,2,2-trichloro-N-(4-isobu- toxybenzyl)acetamide, N-(4-fluorobenzyl)-1-methylpiperidin-4-amine and amidine compound, wherein said hot mixture comprises an organic solvent.

E7. The process according to any of embodiments 4-6, wherein said organic solvent is se- lected from the group consisting of toluene, xylene, heptane, acetonitrile, isopropylacetate, tetrahydrofuran (THF), 2-methyltetrahydrofuran (MTHF), 1 ,4-dioxane, cyclopentyl methyl ether, dichloromethane, dimethylformamide, dimethylacetamide, N-methylpyrrolidinone, N- ethylpyrrolidinone and dimethylsulfoxide.

E8. The process according to embodiment 7, wherein said organic solvent is acetonitrile (ACN).

E9. The process according to any of embodiments 1 -9, wherein the process takes place at about reflux temperature.

E10. The process according to any of embodiments 1 -9, wherein said N-(4-fluorobenzyl)-1 - methylpiperidin-4-amine is obtained by:

reacting 4-fluorobenzylamine and N-methylpiperidin-4-one under catalytic hydrogenation to obtain N-(4-fluorobenzyl)-1 -methylpiperidin-4-amine.

E1 1. The process according to embodiment 10 wherein said catalytic hydrogenation is per- formed by the use of a palladium catalyst.

E12. The process according to any of embodiments 1 -1 1 , wherein said 2,2,2-trichloro-N-(4- isobutoxybenzyl)acetamide is obtained by:

reacting p-hydroxybenzonitrile with isobutyl bromide to obtain 4-isobutoxybenzonitrile; fol- lowed by

reducing said 4-isobutoxybenzonitrile to give (4-isobutoxyphenyl)methaneamine; followed by reacting said (4-isobutoxyphenyl)methaneamine with trichloroacetyl chloride in the presence of a base, or by reacting said (4-isobutoxyphenyl)methaneamine with hexachloroacetone; to obtain 2,2,2-trichloro-N-(4-isobutoxybenzyl)acetamide.

E13. The process according to embodiment 12, wherein said 2,2,2-trichloro-N-(4-isobu- toxybenzyl)acetamide is obtained by reacting said (4-isobutoxyphenyl)methaneamine with tri chloroacetyl chloride in the presence of a base. E14. The process according to any of embodiments 12-13, wherein said base is selected from the group consisting of organic bases such as triethylamine (TEA), N-methylmorpholine (NMM) and N,N-diisopropylethylamine (DIPEA); or wherein said base is selected from the group consisting of inorganic bases such as K2CO3, Na2CC>3 and U2CO3.

E15. The process according to embodiment 14, wherein said base is triethylamine (TEA).

E16. The process according to embodiment 15, wherein said 2,2,2-trichloro-N-(4-isobu- toxybenzyl)acetamide is obtained by reacting said (4-isobutoxyphenyl)methaneamine with hexachloroacetone.

E17. The process according to any of embodiments 12-16, wherein the reaction between p- hydroxybenzonitrile and isobutyl bromide takes place in a polar solvent, and in the presence of a base.

E18. The process according to embodiment 17, wherein said base applied in the reaction between p-hydroxybenzonitrile and isobutyl bromide is selected from the group consisting of organic bases such as triethylamine (TEA), N-methylmorpholine (NMM) and N,N-diisopro- pylethylamine (DIPEA); or wherein said base is selected from the group consisting of inor- ganic bases such as K2CO3, Na2CC>3 and U2CO3.

E19. The process according to any of embodiments 17-18, wherein said base applied in the reaction between p-hydroxybenzonitrile and isobutyl bromide is K₂CO₃.

E20. The process according to any of embodiments 17-19, wherein said polar solvent is se- lected from the group consisting of ethanol, methanol, dimethylformamide or dimethylsulfox- ide or a mixture thereof. E21. The process according to any of embodiments 12-20, wherein said reduction of 4-iso- butoxybenzonitrile to (4-isobutoxyphenyl)methaneamine takes place by catalytic hydrogena- tion.

E22. The process according to embodiment 21 wherein said catalytic hydrogenation is per- formed by the use of a palladium catalyst.

E23. A process for the manufacturing of pimavanserin comprising: i):

step 1 ): reacting 4-fluorobenzylamine and N-methylpiperidin-4-one under catalytic hy- drogenation according to any of embodiments 10-1 1 to obtain N-(4-fluorobenzyl)-1 - methylpiperidin-4-amine, and

ii):

step 2): reacting p-hydroxybenzonitrile with isobutyl bromide to obtain 4-isobutoxyben- zonitrile; followed by

step 3): reducing said 4-isobutoxybenzonitrile to give (4-isobutoxyphenyl)me- thaneamine; followed by

step 4): reacting said (4-isobutoxyphenyl)methaneamine with trichloroacetyl chloride in the presence of a base, or by reacting said (4-isobutoxyphenyl)methaneamine with hexachloroacetone, to obtain 2,2,2-trichloro-N-(4-isobutoxybenzyl)acetamide accord- ing to any of embodiments 12-22, and iii):

steps 5-6): manufacturing pimavanserin from the obtained N-(4-fluorobenzyl)-1- methylpiperidin-4-amine and 2-(4-isobutoxyphenyl)acetic acid, according to any of embodiments 1-9,

wherein i) and ii) can be performed in any order.

E24. The process according to any of embodiments 1-23, wherein the obtained pimavan- serin is precipitated with tartaric acid to be obtained as the hemitartrate. E25. The process according to any of embodiments 1-24, wherein the obtained pimavan- serin is mixed with ethanol and tartaric acid and precipitated as the hemitartrate.

E26. A process for the manufacturing of pimavanserin hemitartrate according to any of em- bodiments 24-25.

E27. The process according to any of embodiments 24-26, wherein said pimavanserin hemitartrate is obtained in a purity of at least 95%, such as at least 97%, such as at least 98.0% or 99.0% (HPLC).

E28. Pimavanserin obtained by the process according to any of embodiments 1-23.

E29. Pimavanserin hemitartrate obtained by the process according to any of embodiments 24-27.

E30. A pharmaceutical composition comprising pimavanserin obtained by the process ac- cording to any of embodiments 1-23 or comprising pimavanserin hemitartrate obtained by the process according to any of embodiments 24-27.

E31. Pimavanserin obtained by the process according to any of embodiments 1-23 or pima- vanserin hemitartrate obtained by the process according to any of embodiments 24-27, for use in the treatment of a CNS disorder such as Parkinson’s Disease (PD), Alzheimer’s Dis- ease (AD), Schizophrenia or Major Depressive Disorder; such as for use in the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis.

E32. A method for the treatment of a CNS disorder such as Parkinson’s Disease (PD), Alz- heimer’s Disease (AD), Schizophrenia or Major Depressive Disorder; such as a method for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis, which method comprises the administration of a therapeutically effective amount of pimavan- serin obtained by the process according to any of embodiments 1-23 or pimavanserin hemi- tartrate obtained by the process according to any of embodiments 24-27. E33. Use of pimavanserin obtained by the process according to any of embodiments 1 -23 or pimavanserin hemitartrate obtained by the process according to any of embodiments 24- 27, in the manufacture of a medicament for the treatment of a CNS disorder such as Parkin- son’s Disease (PD), Alzheimer’s Disease (AD), Schizophrenia or Major Depressive Disorder; such as for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis.

Examples

The invention will be illustrated by the following non-limiting examples.

Gas Chromatography

methods

(analysis of Step 1 )

Column: Rtx-Stabilwax DB; 30 m, 0.25 mm, ft 0.25 mhh

Column temperature: starting temperature 70°C

10°C/min to 240°C

240°C for 10 minutes

Time of analysis: 27 minutes

Inlet temperature: 220°C split mode

Split Ratio: 10:1

Carrier flow: helium (1 .0 ml/min)

Detector: FID 260°C

Gas to detector: Air (400 ml/min)

H2 (40 ml/min)

Make-up: N2 (25 ml/min)

Injection volume: 1 mI

Sample Solution: 10 mg/ml in Acetonitrile

(analysis of Steps 3 and 4)

Column: Rtx-5 Amine; 30 m, 0.53 mm, ft 1 .00 mhh

Column temperature: starting temperature 40°C

40°C for 5 minutes

10°C/min to 300°C

300°C for 9 minutes

Time of analysis: 40 minutes Inlet temperature: 300°C split mode

Split Ratio: 5:1

Carrier flow: helium (6.0 ml/min)

Detector: FID 300°C

Gas to detector: Air (400 ml/min)

H2 (40 ml/min)

Make-up: N2 (25 ml/min)

Injection volume: 1 pi

Sample Solution: 10 mg/ml in Acetonitrile

High Performance Liquid Chromatography (HPLC) method

(analysis of Steps 2, 5-6 and 7)

Column: Phenomenex Phenyl-hexyl, 150 mm x 4.6mm, 3.0 pm

Column temperature: 35°C

Mobile phase A: 0.05% TFA in water : Acetonitrile 95:5 (V/V)

Mobile phase B: 0.05% TFA in water : Acetonitrile 20:80 (V/V)

Gradient:

Flow: 1.0 ml/minute

Detector: UV at 226 nm

Injection volume: 5 pi

Sample Solution: 1.0 mg/ml in Water : Acetonitrile 1 :1 (V/V)

Example 1 : formation of N-(4-fluorobenzyl)-1-methylpiperidin-4-amine from 4-fluorobenzyla- mine and N-methylpiperidin-4-one.

Example 1a. An autoclave was charged with 4-fluorobenzylamine (70.0 g), N-methyl-piperidone (69.6 g), Pd/C 5% (55% wet, 6.61 g) and methanol (665 ml_). At 25°C hydrogen was charged up to 4 bar of pressure and the mixture was stirred overnight.

The catalyst was removed by filtration and the mixture was concentrated to residue under vacuum obtaining 128 g of crude product (100 % yield = 124.3 g) with a purity of 95.1 % (area, GC). The crude product was dissolved in isopropanol (I PA) (1500 ml.) and HCI 37% (1 12 g) was added obtaining a suspension. The product was isolated by filtration and charged in a re- actor with water and toluene. NaOH 30% was added dropwise (126 ml_). The phases were separated and the organic phase was concentrated to residue under vacuum obtaining 1 11 g (89.3% yield) of an oil with a purity of 99.6% (area, GC).

Example 1b.

An autoclave was charged with 4-fluorobenzylamine (70.0 g), N-methyl-piperidone (69.6 g), Pd/C 5% (55% wet, 6.61 g) and methanol (665 ml_). At 25°C hydrogen was charged up to 4 bar of pressure and the mixture was stirred overnight. The catalyst was removed by filtration and the mixture was concentrated to residue under vacuum.

Another autoclave was charged with 4-fluorobenzylamine (70.0 g), N-methyl-piperidone (69.6 g), Pd/C 5% (55% wet, 6.61 g) and methanol (665 ml_). At 25°C hydrogen was charged up to 4 bar of pressure and the mixture was stirred overnight. The catalyst was removed by filtra- tion and the mixture was concentrated to residue under vacuum.

The two residues were combined (258 g) and dissolved in isopropanol (I PA) (3900 ml.) and HCI 37% (227 g) was added obtaining a suspension. The product was isolated by filtration and charged in a reactor with water and toluene. NaOH 30% was added dropwise (244 ml_). The phases were separated and the organic phase was concentrated to residue under vac- uum obtaining 236 g (94.9% yield) of an oil with a purity of 99.6% (area, GC).

Example 2: formation of methyl 4-isobutoxybenzonitrile from p-hydroxybenzonitrile and iso- butyl bromide.

A medium pressure resistant reactor (ACE Glass Inc.) was charged with methyl p-hydroxy- benzonitrile (80.0 g), isobutyl bromide (185.0 g), potassium carbonate (185.6. g,) and EtOH (400 ml_). The mixture was heated to reflux (95-100 °C at 1.7-1.8 bar) and stirred overnight. Potassium carbonate was separated by filtration and the liquid phase was concentrated to residue. The crude product was dissolved in toluene (3 V) and the organic phase was washed with water and concentrated to residue obtaining 1 15.5 g (98.1 % yield) of product with a pu- rity of 98.8 % (area, HPLC).

Example 3: formation of (4-isobutoxyphenyl)methaneamine from 4-isobutoxybenzonitrile.

An autoclave was charged with 4-isobutoxybenzonitrile (50.3 g), Pd/C 5 % (55 % wet, 6.1 g), methanol (500 ml.) and acetic acid (25 ml_). At 25 °C hydrogen was charged up to 4 bar of pressure and the mixture was stirred overnight. The catalyst was removed by filtration and the mixture was concentrated to residue obtaining the crude product as acetate salt that was sus- pended in a mixture of water and toluene and NaOH 5 % was added dropwise up to pH = 12. The phases were separated and the organic phase was washed with water and concentrated to residue obtaining 47 g (91.3 % yield) of an oil with a purity of 88.9 % (area, GC).

Example 4: formation of 2,2,2-trichloro-N-(4-isobutoxybenzyl)acetamide from (4-isobutoxy- phenvDmethaneamine.

Example 4a.

A reactor was charged with (4-isobutoxyphenyl)methaneamine (10.0 g) and toluene (50 ml_, 5 V) to obtain a solution. Another reactor was charged with trichloroacetyl chloride (15.2 g, 1 .5 eq vs (4-isobutoxyphenyl)methaneamine) and toluene (50 ml.) to obtain a solution and tri- ethylamine (1 1 .3 g, 2 eq) was added dropwise. At room temperature the first solution was added slowly into the latter. The mixture was stirred for 1 h and water (40 ml.) was added.

The aqueous phase was discharged and the organic phase was washed twice with water (2 x 40 ml_). The organic phase was concentrated to residue under vacuum to obtain 24 g of crude product as orange solid that was recrystallized in heptanes (180 ml.) obtaining 13.7 g (76 % yield) of dried product with a purity of 97.1 % (area, GC).

Example 4b.

A reactor was charged with (4-isobutoxyphenyl)methaneamine (20.2 g) and heptanes (40 ml.) to obtain a solution. Another reactor was charged with hexachloroacetone (29.8 g, 1 eq vs (4- isobutoxyphenyl)methaneamine) and heptanes (160 ml.) to obtain a solution. At room temper- ature the first solution was added slowly into the latter. After about 10 % of the first solution was added a suspension was formed. The mixture was stirred for 1 h after the end of the addition and the solid product was isolated by filtration and dried under vacuum, obtaining 32.6 g (89.3 % yield) of product with a purity of 98.7 % (area, HPLC).

Example 4c. A reactor was charged with (4-isobutoxyphenyl)methaneamine (5 g) and heptanes (10 mL) to obtain a solution. Another reactor was charged with hexachloroacetone (7.4 g, 1 eq vs (4-iso- butoxyphenyl)methaneamine) and heptanes (25 mL) to obtain a solution. At room temperature the first solution was added slowly into the latter. After about 10 % of the first solution was added a suspension was formed. The mixture was stirred for 1 h after the end of the addition and the solid product was isolated by filtration and dried under vacuum, obtaining 7.7 g (85.6 % yield) of product with a purity of 97.6 % (area, GC).

Example 4d.

A reactor was charged with (4-isobutoxyphenyl)methaneamine (3.5 g) and heptanes (7 mL) to obtain a solution. Another reactor was charged with hexachloroacetone (5.2 g, 1 eq vs (4-iso- butoxyphenyl)methaneamine) and heptanes (28 mL) to obtain a solution. At room tempera- ture the first solution was added slowly into the latter. After about 10 % of the first solution was added a suspension was formed. The mixture was stirred for 1 h after the end of the ad- dition and the solid product was isolated by filtration and dried under vacuum, obtaining 5.4 g (85.7 % yield) of product with a purity of 95.5 % (area, GC)._

Example 5: formation of pimavanserin from N-(4-fluorobenzyl)-1-methylpiperidin-4-amine and 2,2,2-trichloro-N-(4-isobutoxybenzyl)acetamide.

Example 5a

A reactor was charged with N-(4-fluorobenzyl)-1-methylpiperidin-4-amine (21.9 g), 2,2,2-tri- chloro-N-(4-isobutoxybenzyl)acetamide (32 g), DBU (Diazabicycloundecene) (30 g) and ACN (320 mL). The solution was heated to reflux and maintained under stirring for 1 h. The solvent was removed by distillation under reduced pressure and toluene (320 mL) and water (320 mL) were added. The mixture was stirred vigorously for 20 mins and the phases were sepa- rated. The organic phase was washed twice with water and then concentrated to residue to obtain 46.4 g (100 % yield = 42.1 g) of crude product with a purity of 61.9 % (area, HPLC).

Example 5b

A reactor was charged with 2,2,2-trichloro-N-(4-isobutoxybenzyl)acetamide (5.1 g), N-(4- fluorobenzyl)-1-methylpiperidin-4-amine (3.5 g), DBN (Diazabicyclononene) (3.9 g) and ACN (51 mL). The solution was heated to reflux and maintained under stirring for 4 h. The solvent was removed by distillation under reduced pressure and toluene (50 mL) and water (50 mL) were added. The mixture was stirred vigorously for 20 mins and the phases were separated. The organic phase was washed twice with water and then concentrated to residue to obtain 5.7 g (85 % yield) of crude product with a purity of 65 % (area, HPLC).

Example 5c

A reactor was charged with N-(4-fluorobenzyl)-1-methylpiperidin-4-amine (1.3 g) and ACN (10ml_). The solution was heated to reflux and a solution of 2,2,2-trichloro-N-(4-isobutoxyben- zyl)acetamide (2.0 g) and DBN (1.5 g) in ACN (10 mL) was added. The mixture was main- tained under stirring for 5 h. The solvent was removed by distillation under reduced pressure and toluene (20 mL) and water (20 mL) were added. The mixture was stirred vigorously for 20 mins and the phases were separated. The organic phase was washed twice with water and then concentrated to residue to obtain 2.2 g (84 % yield) of crude product with a purity of 71 % (area, HPLC).

Example 5d

A reactor was charged with N-(4-fluorobenzyl)-1-methylpiperidin-4-amine (1.3 g), DBN (1.5 g) and ACN (10mL). The solution was heated to reflux and a solution of 2,2,2-trichloro-N-(4-iso- butoxybenzyl)acetamide (2.0 g) in ACN (10 mL) was added. The mixture was maintained un- der stirring for 1 h. The solvent was removed by distillation under reduced pressure and tolu ene (20 mL) and water (20 mL) were added. The mixture was stirred vigorously for 20 mins and the phases were separated. The organic phase was washed twice with water and then concentrated to residue to obtain 2.3 g (88 % yield) of crude product with a purity of 68 % (area, HPLC).

Example 6: Precipitation and purification of pimavanserin hemitartrate.

Example 6a (precipitation)

A reactor was charged with crude Pimavanserin (46.0 g) obtained from Example 5a, and ab- solute EtOH (322 mL). The mixture was heated to 50°C obtaining a slightly brown solution. Tartaric acid (8.0 g) was dissolved in absolute EtOH (138 mL) and the solution was added dropwise into the reactor. The mixture was cooled from 50°C to 20°C over a 2 h period obtaining a suspension. The solid was isolated by filtration and dried under vacuum obtaining 21.9 g (41 % yield) of the compound as crystalline powder with a purity of 96.1 % (area, HPLC).

Example 6b (purification) A reactor was charged with crude Pimavanserin tartrate (10.0 g) obtained from Example 6a and n-PrOH (90 ml_, 9 V). The mixture was heated to 70 °C obtaining a slightly brown solution. The solution was cooled from 70°C to 20°C over a 1 h period obtaining a thick suspension that was diluted with 20 ml. (2 V) of n-PrOH and heated again to 70 °C. The solution was cooled to 45°C, maintained for 1 h and then cooled to from 45°C to 20°C over a 30 minutes’ period obtaining a white suspension. The solid was isolated by filtration, washed with 20 ml. (2 V) of n-PrOH and dried under vacuum obtaining 8.0 g (80 % yield) of product as white crystalline powder with a purity of 99.7 % (area, HPLC).

Claims

1. A process for manufacturing of pimavanserin, said process comprising the following step:

2. The process according to claim 1 , wherein said amidine compound is selected from diazabicycloundecene (DBU) and diazabicyclononene (DBN).

3. The process according to any of claims 1-2, wherein said process occurs without iso- lation of 1-isobutoxy-4-(isocyanatomethyl)benzene.

4. The process according to any of claims 1-3, wherein said 2,2,2-trichloro-N-(4-isobu- toxybenzyl)acetamide, said N-(4-fluorobenzyl)-1-methylpiperidin-4-amine and said amidine compound are dissolved in an organic solvent and the mixture is heated to give pimavan- serin.

5. The process according to any of claims 1-3, wherein one of 2,2,2-trichloro-N-(4-isobu- toxybenzyl)acetamide, N-(4-fluorobenzyl)-1-methylpiperidin-4-amine and amidine compound is added into a hot mixture of the other two of 2,2,2-trichloro-N-(4-isobutoxybenzyl)acetamide, N-(4-fluorobenzyl)-1-methylpiperidin-4-amine and amidine compound, wherein said hot mix- ture comprises an organic solvent.

6. The process according to any of claims 1-3, wherein two of 2,2,2-trichloro-N-(4-isobu- toxybenzyl)acetamide, N-(4-fluorobenzyl)-1-methylpiperidin-4-amine and amidine compound are added into a hot mixture of the remaining one of 2,2,2-trichloro-N-(4-isobutoxybenzyl)ac- etamide, N-(4-fluorobenzyl)-1-methylpiperidin-4-amine and amidine compound, wherein said hot mixture comprises an organic solvent.

7. The process according to any of claims 4-6, wherein said organic solvent is selected from the group consisting of toluene, xylene, heptane, acetonitrile, isopropylacetate, tetrahy- drofuran (THF), 2-methyltetrahydrofuran (MTHF), 1 ,4-dioxane, cyclopentyl methyl ether, di- chloromethane, dimethylformamide, dimethylacetamide, N-methylpyrrolidinone, N-ethylpyrrol- idinone and dimethylsulfoxide.

8. The process according to any of claims 1-7, wherein said N-(4-fluorobenzyl)-1- methylpiperidin-4-amine is obtained by:

9. The process according to any of claims 1-8, wherein said 2,2,2-trichloro-N-(4-isobu- toxybenzyl)acetamide is obtained by:

10. The process according to claim 9, wherein said 2,2,2-trichloro-N-(4-isobutoxyben- zyl)acetamide is obtained by reacting said (4-isobutoxyphenyl)methaneamine with trichloroa- cetyl chloride in the presence of a base.

1 1. The process according to claim 9, wherein said 2,2,2-trichloro-N-(4-isobutoxyben- zyl)acetamide is obtained by reacting said (4-isobutoxyphenyl)methaneamine with hexachlo- roacetone.

12. The process according to any of claims 9-11 , wherein the reaction between p-hy- droxybenzonitrile and isobutyl bromide takes place in a polar solvent, and in the presence of a base.

13. A process for the manufacturing of pimavanserin comprising: i):

step 1 ): reacting 4-fluorobenzylamine and N-methylpiperidin-4-one under catalytic hy- drogenation according to claim 8 to obtain N-(4-fluorobenzyl)-1-methylpiperidin-4- amine, and

ii):

step 4): reacting said (4-isobutoxyphenyl)methaneamine with trichloroacetyl chloride in the presence of a base, or by reacting said (4-isobutoxyphenyl)methaneamine with hexachloroacetone, to obtain 2,2,2-trichloro-N-(4-isobutoxybenzyl)acetamide accord- ing to any of claims 9-12, and iii):

steps 5-6): manufacturing pimavanserin from the obtained N-(4-fluorobenzyl)-1- methylpiperidin-4-amine and 2-(4-isobutoxyphenyl)acetic acid, according to any of claims 1-7,

wherein i) and ii) can be performed in any order.

14. The process according to any of claims 1-13, wherein the obtained pimavanserin is precipitated with tartaric acid to be obtained as the hemitartrate.

15. The process according to claim 14, wherein said pimavanserin hemitartrate is ob- tained in a purity of at least 95%, such as at least 97%, such as at least 98.0% or 99.0% (HPLC).