WO2022222019A1 - Synthèse totale de varénicline - Google Patents

Synthèse totale de varénicline Download PDF

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Publication number
WO2022222019A1
WO2022222019A1 PCT/CN2021/088288 CN2021088288W WO2022222019A1 WO 2022222019 A1 WO2022222019 A1 WO 2022222019A1 CN 2021088288 W CN2021088288 W CN 2021088288W WO 2022222019 A1 WO2022222019 A1 WO 2022222019A1
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WO
WIPO (PCT)
Prior art keywords
formula
acid
compound
chloride
varenicline
Prior art date
Application number
PCT/CN2021/088288
Other languages
English (en)
Inventor
Lihua Zhou
Original Assignee
Suzhou Fude Zhaofeng Biochemical Technology Co., Ltd
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 Suzhou Fude Zhaofeng Biochemical Technology Co., Ltd filed Critical Suzhou Fude Zhaofeng Biochemical Technology Co., Ltd
Priority to PCT/CN2021/088288 priority Critical patent/WO2022222019A1/fr
Publication of WO2022222019A1 publication Critical patent/WO2022222019A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems

Definitions

  • the present invention relates to a process for preparing varenicline or a pharmaceutically acceptable salt thereof.
  • the present invention also relates to intermediate compounds which are useful in such process and to the preparation of such intermediate compounds.
  • Varenicline chemically known as 7, 8, 9, 10-Tetrahydro-6, 10-methano-6H-pyrazino [2, 3-h] [3] benzazepine, is represented by formula (1) .
  • Varenicline and its pharmaceutically salts such as varenicline tartrate is marketed by Pfizer under the trade name of CHANTIX TM as a partial agonist selective for certain subtypes of nicotinic receptors and indicated for smoking cessation.
  • varenicline The synthesis of varenicline and its pharmaceutically salts were described in US6410550B1, US6890927B2, US2008/0275051A1, US8314235B2 and WO2018163190 A1. Most of the reported methods involve the following process:
  • the nitration of formula (2) to form of formula (3) is followed by reduction and cyclization.
  • the nitration reaction is vigorously exothermic, which can cause some safety issues in industrial production. Also it takes several steps for this process to construct the pyrazine ring.
  • varenicline or a pharmaceutically acceptable salt thereof, in higher yield using cheaper and less toxic reagents.
  • room temperature refers to a temperature ranging from about 15 °C to 35 °C, preferably to a temperature ranging from about 20 °C to 30 °C, more preferably to a temperature of 25 °C.
  • salts includes, for example salts with an inorganic acid, e.g. hydrochloric acid, hydroiodic acid, phosphoric acid, phosphonic acid, sulfuric acid, hydrobromic acid or an organic acid, e.g. a carboxylic acid such as formic acid, acetic acid, citric acid, malic acid, maleic acid, tartaric acid, succinic acid, salicylic acid, trifluoroacetic acid, trichloroacetic acid, oxalic acid, benzoic acid or a sulfonic acid such as p-toluene sulfonic acid or methanesulfonic acid.
  • an inorganic acid e.g. hydrochloric acid, hydroiodic acid, phosphoric acid, phosphonic acid, sulfuric acid, hydrobromic acid or an organic acid, e.g. a carboxylic acid such as formic acid, acetic acid, citric acid, malic acid, maleic acid, tartaric acid, succ
  • varenicline of Formula (1) In one aspect, a method for manufacturing varenicline of Formula (1) ,
  • R is selected from the group consisting of H, –CH 3 , -CH 2 CH 3 , -C (CH 3 ) 3 .
  • the above process is preferably carried out by isolating all intermediate compounds, namely intermediate compounds of formula (8) , (9) , (10) and (11) . Also preferably, the process is carried out without isolating intermediate compound of formula (8) , (9) , (10) and (11) . Even more preferably, the above process is carried out as a one-pot reaction, that is, without the need to isolate any of the intermediate compounds of formula (8) , (9) , (10) and (11) , but completing the whole conversion directly to varenicline, or a pharmaceutically acceptable salt thereof.
  • the present application is based on the discovery of a novel, alternative approach to synthesizing varenicline.
  • the synthesis described herein allows for the cost-effective preparation of varenicline by reducing production time and cost.
  • R is selected from the group consisting of H, –CH 3 , -CH 2 CH 3 , -C (CH 3 ) 3 .
  • the first step is a double Mannich reaction which is an effective method for the construction of C-N bond.
  • This reaction can proceed under both acidic and basic conditions, but acidic conditions are more common.
  • the base herein is selected from any organic and inorganic base such as TEA, DBU, DIPEA, KOH, K 2 CO 3 , NaOH, Na 2 CO 3, Cs 2 CO 3 , CsOH, K 3 PO 4 , K 2 HPO 4 , Na 3 PO 4 , and Na 2 HPO 4 .
  • the acid herein is selected from any organic and inorganic acid such as HCl, H 2 SO 4 , H 3 PO 4 , KH 2 PO 4 , NaH 2 PO 4 , HBr, HClO 4 , HBF 4 , AcOH, Tartaric acid, Lactic acid, Citric acid, trifluoromethanesulfonic acid, trifluoroacetic acid and
  • ester groups of formula (8) is hydrolyzed to carboxylic acid groups, which are then removed to form formula (9) .
  • R is H
  • formula (8) is directly converted to formula (9) by decarboxylation.
  • a compound of formula (9) reacts with a Wittig reagent to incorporate a methylene group, leading to the formation of formula (10) .
  • Other possible choice maybe any combination of a methylphosphonium salt and a base.
  • a compound of formula (10) under goes an oxidative [4+2] reaction with pyrazine in the presence of a catalyst and an oxidant to form a compound of formula (11) .
  • the catalyst is selected from the salts containing rare-earth elements, such as the salts of scandium, yttrium, cerium, lanthanum, samarium and europium.
  • the catalyst is selected from Scandium chloride, Scandium nitrate, Scandium triflate, Scandium oxide, Yttrium oxide, Yttrium chloride, Yttrium trifluoromethanesulfonate, Yttrium nitrate, Lanthanum trifluoromethanesulfonate, Lanthanum acetylacetonate, Lanthanum chloride, Lanthanum oxide, Cerium Trifluoromethanesulfonate, Cerium chloride, Ammonium cerium sulfate, Ammonium cerium nitrate, Samarium chloride, Samarium nitrate, Europium chloride, Europium oxide and Europium nitrate.
  • the oxidant is selected from dioxygen, hydrogen peroxide, organic peroxides, inorganic persulfate and inorganic peroxymonosulfate.
  • Formula (11) is treated by hydrogen in the presence of palladium catalyst to form varenicline of Formula (1) .
  • Desired compound of formula (10) was obtained as colorless oil. Yield: 19 g, 84%.
  • the aqueous layers were combined and washed with dichloromethane (200 ml) .
  • the aqueous layer was basified by adding aqueous sodium carbonate solution (20 g in 300 ml water) .
  • the aqueous layer was extracted with dichloromethane (3X 150 mL) .
  • the dichloromethane layers were combined, washed with water (300 mL) then with 0.5%EDTA solution (200 ml) and again with water (300 mL) .
  • the organic layer was dried over sodium sulphate and concentrated to get oil, which solidified on standing. Yield: 9.5 g, 90%.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

L'invention concerne un procédé de préparation de varénicline ou d'un sel pharmaceutiquement acceptable de celle-ci. De plus, l'Invention concerne également des composés intermédiaires qui sont utiles dans un tel procédé.
PCT/CN2021/088288 2021-04-20 2021-04-20 Synthèse totale de varénicline WO2022222019A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/CN2021/088288 WO2022222019A1 (fr) 2021-04-20 2021-04-20 Synthèse totale de varénicline

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2021/088288 WO2022222019A1 (fr) 2021-04-20 2021-04-20 Synthèse totale de varénicline

Publications (1)

Publication Number Publication Date
WO2022222019A1 true WO2022222019A1 (fr) 2022-10-27

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/088288 WO2022222019A1 (fr) 2021-04-20 2021-04-20 Synthèse totale de varénicline

Country Status (1)

Country Link
WO (1) WO2022222019A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1285821A (zh) * 1997-12-31 2001-02-28 辉瑞产品公司 芳基稠合氮杂多环化合物
CN101128462A (zh) * 2005-02-24 2008-02-20 辉瑞产品有限公司 高纯度取代喹喔啉的制备
WO2010023561A1 (fr) * 2008-09-01 2010-03-04 Actavis Group Ptc Ehf Procédé de fabrication de varénicline, intermédiaires de la varénicline et leurs sels pharmaceutiquement acceptables

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1285821A (zh) * 1997-12-31 2001-02-28 辉瑞产品公司 芳基稠合氮杂多环化合物
CN101128462A (zh) * 2005-02-24 2008-02-20 辉瑞产品有限公司 高纯度取代喹喔啉的制备
WO2010023561A1 (fr) * 2008-09-01 2010-03-04 Actavis Group Ptc Ehf Procédé de fabrication de varénicline, intermédiaires de la varénicline et leurs sels pharmaceutiquement acceptables

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
AFSAH A. M., OSMAN A. I., SOFAN M.: "Condensation of 4-phenyl-3,5-dicarboethoxycyclopentane-1,2-dione with primary amines", JOURNAL FüR PRAKTISCHE CHEMIE : PRACTICAL APPLICATIONS AND APPLIED CHEMISTRY : COVERING ALL ASPECTS OF APPLIED CHEMISTRY, WILEY, DE, vol. 331, no. 3, 1 January 1989 (1989-01-01), DE , pages 461 - 465, XP055980269, ISSN: 0021-8383, DOI: 10.1002/prac.19893310317 *

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