WO2017054786A1 - Procédé de production du 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-méthylpipéridine-4-yl)urée et de ses analogues deutérés - Google Patents

Procédé de production du 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-méthylpipéridine-4-yl)urée et de ses analogues deutérés Download PDF

Info

Publication number
WO2017054786A1
WO2017054786A1 PCT/CZ2016/000104 CZ2016000104W WO2017054786A1 WO 2017054786 A1 WO2017054786 A1 WO 2017054786A1 CZ 2016000104 W CZ2016000104 W CZ 2016000104W WO 2017054786 A1 WO2017054786 A1 WO 2017054786A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
accordance
fluorobenzyl
pimavanserin
Prior art date
Application number
PCT/CZ2016/000104
Other languages
English (en)
Inventor
Stanislav Radl
Jan Stach
Ondrej Klecan
Josef Zezula
Original Assignee
Zentiva, K. S.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Zentiva, K. S. filed Critical Zentiva, K. S.
Publication of WO2017054786A1 publication Critical patent/WO2017054786A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C07D233/60—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with hydrocarbon radicals, substituted by oxygen or sulfur atoms, attached to ring nitrogen atoms

Definitions

  • 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.
  • 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).
  • 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.
  • DPPA diphenyl phosphoryl azide
  • 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).
  • 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)-
  • 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 ⁇ , -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.
  • 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.
  • 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 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.
  • N-(4-isobutoxybenzyl)-l H-imidazole- 1 -carbamide (XIa) 2.0 g; 7.32 mmol
  • THF 25 ml
  • N-(4-fluorobenzyl)-l-methylpiperidine-4-amine (II) 1.8 g; 8.05 mmol
  • 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.
  • 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 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%).
  • 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%).
  • 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%).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Hydrogenated Pyridines (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne un procédé amélioré de production du 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-méthylpipéridine-4-yl)urée (pimavansérine), un agoniste inverse du récepteur 5-HT2A de la sérotonine de formule (I). La pimavansérine brute préparée par ce procédé contient une très faible quantité de l'impureté disubstituée.
PCT/CZ2016/000104 2015-10-02 2016-09-14 Procédé de production du 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-méthylpipéridine-4-yl)urée et de ses analogues deutérés WO2017054786A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CZ2015-688A CZ2015688A3 (cs) 2015-10-02 2015-10-02 Způsob výroby 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-methylpiperidin-4-yl)močoviny a jeho deuterovaných analogů
CZPV2015-688 2015-10-02

Publications (1)

Publication Number Publication Date
WO2017054786A1 true WO2017054786A1 (fr) 2017-04-06

Family

ID=57120970

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CZ2016/000104 WO2017054786A1 (fr) 2015-10-02 2016-09-14 Procédé de production du 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-méthylpipéridine-4-yl)urée et de ses analogues deutérés

Country Status (2)

Country Link
CZ (1) CZ2015688A3 (fr)
WO (1) WO2017054786A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107216271A (zh) * 2017-06-02 2017-09-29 沈阳药科大学 酒石酸匹莫范色林杂质及其制备方法
WO2018007842A1 (fr) * 2016-07-08 2018-01-11 Egis Gyógyszergyár Zrt. Sels de pimavansérine utiles pour l'élaboration d'une préparation pharmaceutique.
WO2019008595A1 (fr) * 2017-07-03 2019-01-10 Jubilant Generics Limited (Formerly A Division Of Jubilant Life Sciences Limited) Procédé pour la préparation de la 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-méthylpipéridin-4-yl)urée et de ses sels
CN110054583A (zh) * 2018-01-19 2019-07-26 广东东阳光药业有限公司 一种制备哌马色林或其盐的方法
WO2019179920A1 (fr) 2018-03-19 2019-09-26 Lundbeck Pharmaceuticals Italy S.P.A. Procédé de fabrication de pimavansérine
IT201800009690A1 (it) 2018-10-23 2020-04-23 Lundbeck Pharmaceuticals Italy Spa Processo per la produzione di pimavanserina

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004064738A2 (fr) 2003-01-16 2004-08-05 Acadia Pharmaceuticals Inc. Agonistes inverses selectifs pour le recepteur de la serotonine 2a/2c utilises comme agents therapeutiques contre les maladies neurodegeneratives
WO2006036874A1 (fr) 2004-09-27 2006-04-06 Acadia Pharmaceuticals Inc. Sels de n-(4-fluorobenzyl)-n-(1-methylpiperidin-4-yl)-n'-(4-(2-methylpropyloxy)phenylmethyl)carbamide et leur preparation
WO2008141057A1 (fr) 2007-05-08 2008-11-20 Auspex Pharmaceuticals, Inc. Urées substituées
WO2014085362A1 (fr) * 2012-11-27 2014-06-05 Acadia Pharmaceuticals Inc. Méthodes pour le traitement de la psychose de la maladie de parkinson à l'aide de pimavansérine
CN104844502A (zh) * 2015-06-05 2015-08-19 济南涛瑞医药科技有限公司 一种匹莫范色林的制备方法
CN105111135A (zh) * 2015-09-09 2015-12-02 安徽省逸欣铭医药科技有限公司 取代的尿素衍生物制备方法
CN105153016A (zh) * 2015-10-12 2015-12-16 北京诺康达医药科技有限公司 一种匹莫范色林的制备方法
CN105820110A (zh) * 2016-05-09 2016-08-03 杭州科巢生物科技有限公司 匹莫范色林新合成方法
WO2016141003A1 (fr) * 2015-03-02 2016-09-09 Teva Pharmaceutical Industries Ltd. Procédés et intermédiaires pour la préparation de pimavansérine

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004064738A2 (fr) 2003-01-16 2004-08-05 Acadia Pharmaceuticals Inc. Agonistes inverses selectifs pour le recepteur de la serotonine 2a/2c utilises comme agents therapeutiques contre les maladies neurodegeneratives
WO2006036874A1 (fr) 2004-09-27 2006-04-06 Acadia Pharmaceuticals Inc. Sels de n-(4-fluorobenzyl)-n-(1-methylpiperidin-4-yl)-n'-(4-(2-methylpropyloxy)phenylmethyl)carbamide et leur preparation
WO2006037043A1 (fr) 2004-09-27 2006-04-06 Acadia Pharmaceuticals Inc. Synthese de n-(4-fluorobenzyl)-n-(1-methylpiperidin-4-yl)-n'-(4-(2-methylpropyloxy)phenylmethyl)carbamide, tartrate de ce compose et ses formes cristallines
WO2008141057A1 (fr) 2007-05-08 2008-11-20 Auspex Pharmaceuticals, Inc. Urées substituées
WO2014085362A1 (fr) * 2012-11-27 2014-06-05 Acadia Pharmaceuticals Inc. Méthodes pour le traitement de la psychose de la maladie de parkinson à l'aide de pimavansérine
WO2016141003A1 (fr) * 2015-03-02 2016-09-09 Teva Pharmaceutical Industries Ltd. Procédés et intermédiaires pour la préparation de pimavansérine
CN104844502A (zh) * 2015-06-05 2015-08-19 济南涛瑞医药科技有限公司 一种匹莫范色林的制备方法
CN105111135A (zh) * 2015-09-09 2015-12-02 安徽省逸欣铭医药科技有限公司 取代的尿素衍生物制备方法
CN105153016A (zh) * 2015-10-12 2015-12-16 北京诺康达医药科技有限公司 一种匹莫范色林的制备方法
CN105820110A (zh) * 2016-05-09 2016-08-03 杭州科巢生物科技有限公司 匹莫范色林新合成方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
PETAR A. DUSPARA ET AL: "Synthesis and Reactivity of N -Alkyl Carbamoylimidazoles: Development of N -Methyl Carbamoylimidazole as a Methyl Isocyanate Equivalent", THE JOURNAL OF ORGANIC CHEMISTRY, vol. 77, no. 22, 16 November 2012 (2012-11-16), US, pages 10362 - 10368, XP055269988, ISSN: 0022-3263, DOI: 10.1021/jo302084a *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018007842A1 (fr) * 2016-07-08 2018-01-11 Egis Gyógyszergyár Zrt. Sels de pimavansérine utiles pour l'élaboration d'une préparation pharmaceutique.
CN107216271A (zh) * 2017-06-02 2017-09-29 沈阳药科大学 酒石酸匹莫范色林杂质及其制备方法
CN107216271B (zh) * 2017-06-02 2018-11-13 沈阳药科大学 酒石酸匹莫范色林杂质及其制备方法
WO2019008595A1 (fr) * 2017-07-03 2019-01-10 Jubilant Generics Limited (Formerly A Division Of Jubilant Life Sciences Limited) Procédé pour la préparation de la 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-méthylpipéridin-4-yl)urée et de ses sels
CN110054583A (zh) * 2018-01-19 2019-07-26 广东东阳光药业有限公司 一种制备哌马色林或其盐的方法
WO2019179920A1 (fr) 2018-03-19 2019-09-26 Lundbeck Pharmaceuticals Italy S.P.A. Procédé de fabrication de pimavansérine
IT201800009690A1 (it) 2018-10-23 2020-04-23 Lundbeck Pharmaceuticals Italy Spa Processo per la produzione di pimavanserina
WO2020083825A1 (fr) 2018-10-23 2020-04-30 Lundbeck Pharmaceuticals Italy S.P.A. Procédé de fabrication de pimavansérine

Also Published As

Publication number Publication date
CZ2015688A3 (cs) 2017-04-12

Similar Documents

Publication Publication Date Title
WO2017054786A1 (fr) Procédé de production du 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-méthylpipéridine-4-yl)urée et de ses analogues deutérés
KR101593253B1 (ko) 페닐 및 벤조디옥시닐 치환 인다졸 유도체
JP6013326B2 (ja) キラルトリアゾロンの調製のための方法
JP2022023891A (ja) オメカムチブメカルビルの塩及び塩を調製するプロセス
JP3560986B2 (ja) ５―ｈｔ２ｃ受容体作用薬及びアミノアルキルインダゾール誘導体
CA2861150C (fr) Derive de morphinane
UA128114C2 (uk) Тверді форми 3-((1r,3r)-1-(2,6-дифтор-4-((1-(3-фторпропіл)азетидин-3-іл)аміно)феніл)-3-метил-1,3,4,9-тетрагідро-2h-піридo[3,4-b]індол-2-іл)-2,2-дифторпропан-1-олу і способи одержання конденсованих трициклічних сполук, що містять заміщене фенільне або піридинільне угруповання, в тому числі способи їх застосування
JP2014521726A5 (fr)
TW201725207A (zh) 一種ｂｔｋ激酶抑制劑的結晶形式及其製備方法
HUE023239T4 (en) Modulators of the prostacycline (PGI2) receptor that can be used to treat related diseases
EP2718262A1 (fr) Procédé de préparation d'apixaban
JP2013532164A (ja) トロンビン特異的インヒビターを調製する方法
TW200538116A (en) Process for the preparation of substituted triazole compounds
KR102266680B1 (ko) 벨리노스테트의 다형태 및 이의 제조 방법
US20090264438A1 (en) Polymorphic forms of imatinib mesylate and processes for preparation of novel crystalline forms as well as amorphous and form alpha
SK21596A3 (en) Application of substituted aryloxyalkyl diamines, these substances single, producing method thereof, pharmaceutical compositions on their base and their producing method
JPWO2010107115A1 (ja) グリシントランスポーター阻害物質
BR112020018562A2 (pt) Processo preparativo
AU781837B2 (en) 3-azabicyclo (3.1.0) hexane derivatives having opioid receptor affinity
JP2002521334A (ja) 置換ベンズイミダゾール抗ウィルス剤
JP2019509308A (ja) １−（５−（２，４−ジフルオロフェニル）−１−（（３−フルオロフェニル）スルホニル）−４−メトキシ−１ｈ−ピロール−３−イル）−ｎ−メチルメタンアミン塩の新規な結晶形
CZ216996A3 (en) Indole derivatives, process of their preparation, their use and pharmaceutical compositions containing thereof
EA036954B1 (ru) Ксантинзамещенные алкинилкарбаматы/обращенные карбаматы в качестве антагонистов a2b
RU2536688C2 (ru) Новые бензамидные производные
KR20100046026A (ko) 4-페닐-6-(2,2,2-트리플루오로-1-페닐에톡시)피리미딘-기재화합물의 제조 방법

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16778669

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 16778669

Country of ref document: EP

Kind code of ref document: A1