[go: up one dir, main page]

WO2016199049A1 - Procédé de préparation de ledipasvir - Google Patents

Procédé de préparation de ledipasvir Download PDF

Info

Publication number
WO2016199049A1
WO2016199049A1 PCT/IB2016/053387 IB2016053387W WO2016199049A1 WO 2016199049 A1 WO2016199049 A1 WO 2016199049A1 IB 2016053387 W IB2016053387 W IB 2016053387W WO 2016199049 A1 WO2016199049 A1 WO 2016199049A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
group
salt
preparation
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/IB2016/053387
Other languages
English (en)
Inventor
Bandi Parthasaradhi Reddy
Kura Rathnakar Reddy
Bandi Vamsi Krishna
Mogili NARASINGAM
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hetero Research Foundation
Original Assignee
Hetero Research Foundation
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 Hetero Research Foundation filed Critical Hetero Research Foundation
Publication of WO2016199049A1 publication Critical patent/WO2016199049A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • 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 the preparation of Ledipasvir and process for the preparation of their intermediates.
  • Ledipasvir (Coded as GS-5885), Methyl [(2S)-l- ⁇ (6S)-6-[5-(9,9-difluoro-7- ⁇ 2- [(lR,3S,4S)-2- ⁇ (2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl ⁇ -2-azabicyclo[2.2.1]hept-3-yl]-lH- benzimidazol-6-yl ⁇ -9H-fluoren-2-yl)-lH-imidazol-2-yl]-5-azaspiro[2.4]hept-5-yl ⁇ -3-methyl- 1 -oxobutan-2-yl] carbamate a compound of formula I is marketed by Gilead. Ledipasvir is most commonly used in combination with Sofosbuvir for treatment of Hepatitis C under the trade name HARVONITM
  • US 8,088,368 B2 discloses Ledipasvir and its physiologically acceptable salts.
  • US'368 discloses the following scheme for the preparation of Ledipasvir.
  • US 2013/0324740 Al discloses the process for preparation of Ledipasvir by using metal catalyst chosen from Pd(0) or Pd(II) compounds or Pd or Ni in combination with ligands and base. Further this patent application discloses use of oxalic acid to form salt of the di- protected Ledipasvir. US '740 discloses the preparation of Lediapasvir, which is as follows.
  • Y and Z are independently selected from Br and— BiORXOR 1 )
  • the objective of the present invention is to provide a process for the preparation of Ledipasvir using Bis(triphenylphosphine)palladium(II) dichloride with high yield and high purity.
  • Another objective of the invention is to provide process for the preparation of intermediates useful in preparation of Ledipasvir.
  • Another objective of the present invention is to provide process for the preparation of Ledipasvir which is economically feasible.
  • the present invention provides a process for the preparation of Ledipasvir of formula I, which comprises:
  • the present invention relates to intermediate compound of formula III. In another embodiment the present invention relates to a process for the preparation of intermediate compound of formula III.
  • Lg represents a leaving group
  • the present invention relates to intermediate compound of formula VI or its salt. In another embodiment the present invention relates to a process for the preparation of intermediate com ound of formula II,
  • X represents a leaving group, which comprises:
  • the present invention relates to intermediate compound of formula IV or its salt.
  • Formula IV wherin X is a leaving group.
  • the present invention relates to a process for the preparation of Ledipasvir of formula I, which com rises the condensation of compound of formula II,
  • Lg is a leaving group in the presence of Bis(triphenylphosphine)palladium(II) dichloride and base, wherein base is selected from group comprising of propionoate salt, acetate and phosphate.
  • the propionate salt is selected from alkali metal propionates such as potassium propionate, sodium propionate; acetates are selected from sodium, potassium or cesium acetate; and phosphates are selected from alkali metal phosphate such as sodium or potassium phosphate.
  • the condensation of compound of formula II and compound of formula III is carried out in the presence of an organic solvent selected from esters such as aliphatic esters or aromatic esters wherein aliphatic esters are selected from ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate or mixtures thereof.
  • an organic solvent selected from esters such as aliphatic esters or aromatic esters wherein aliphatic esters are selected from ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate or mixtures thereof.
  • substituents X and Lg used throughout the present invention are independently selected from halogen such as fluorine, chlorine, bromine, iodine and— B(OR)(OR').
  • the substituents R and R' are independently selected from the group consisting of hydrogen and straight or branched Ci-8-alkyl, or R and R' together represent a straight or branched Ci-8-alkylene, C3-8- cycloalkylene, or C 6 -i2-arylene. Any alkyl, alkylene, cycloalkylene, or arylene as defined herein is optionally substituted with one or more substituents selected from the group consisting of Ci_ 6 -alkyl,— C(0)N(C 1-6 -alkyl) 2 , and— C(0)0(C 1-6 -alkyl).
  • Lg when X is halogen, Lg is— B(OR)(OR') and in another embodiment when X is— B(OR)(OR'), Lg is halogen.
  • the condensation of compound of formula II and formula III is carried out at a temperature in the range of 25°C to 100°C.
  • isolation of compound of formula I is carried out at a temperature in the range of 0°C to 30°C.
  • the present invention relates to a process for the preparation of intermediate compound of formula III which comprises:
  • the present invention relates to a process for the preparation of intermediate compound of formula II which comprises:
  • X is a leaving group
  • Pg is a protecting group is carried out in the presence of acid selected hydrohalic acid, nitric acid, sulfuric acid and a solvent, wherein the solvent is halogenated hydrocarbons selected from group comprising of methylene dichloride, ethylene dichloride, chloroform, carbon tetrachloride or mixtures thereof to obtain a compound of formula IV or its salt Formula IV wherein X is a leaving group
  • Pg is amine protecting group selected from Carbobenzyloxy, tert-Butyloxycarbonyl, p-Methoxybenzyl carbonyl, 9- Fluorenylmethyloxycarbonyl, Acetyl, Benzoyl, Benzyl, Carbamate, p-Methoxybenzyl, 3,4- Dimethoxybenzyl, p-methoxyphenyl, Tosyl and sulfonamides.
  • the salts are selected from acids such as hydrohalic acid, nitric acid or sulfuric acid wherein the salt formation is carried out by taking the acid in dioxane.
  • hydrohalic acids are selected from hydrochloric acid, hydrobromic acid or hydroiodic acid.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un procédé pour la préparation de ledipasvir à l'aide de dichlorure de Bis(triphénylphosphine)palladium(II) ainsi qu'un procédé pour la préparation d'intermédiaires de ledipasvir.
PCT/IB2016/053387 2015-06-09 2016-06-09 Procédé de préparation de ledipasvir Ceased WO2016199049A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN2865/CHE/2015 2015-06-09
IN2865CH2015 2015-06-09

Publications (1)

Publication Number Publication Date
WO2016199049A1 true WO2016199049A1 (fr) 2016-12-15

Family

ID=57503485

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2016/053387 Ceased WO2016199049A1 (fr) 2015-06-09 2016-06-09 Procédé de préparation de ledipasvir

Country Status (1)

Country Link
WO (1) WO2016199049A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017134548A1 (fr) * 2016-02-01 2017-08-10 Lupin Limited Procédé de préparation de lédipasvir et d'intermédiaires de ce dernier
WO2017195147A1 (fr) * 2016-05-12 2017-11-16 Lupin Limited Procédé de préparation de lédipasvir et d'intermédiaires de ce dernier

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013184702A1 (fr) * 2012-06-05 2013-12-12 Gilead Sciences, Inc. Synthèse de composé antiviral

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013184702A1 (fr) * 2012-06-05 2013-12-12 Gilead Sciences, Inc. Synthèse de composé antiviral

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017134548A1 (fr) * 2016-02-01 2017-08-10 Lupin Limited Procédé de préparation de lédipasvir et d'intermédiaires de ce dernier
WO2017195147A1 (fr) * 2016-05-12 2017-11-16 Lupin Limited Procédé de préparation de lédipasvir et d'intermédiaires de ce dernier

Similar Documents

Publication Publication Date Title
AU2018244916B2 (en) Process for the preparation of 6-(cyclopropaneamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide
CN107721851B (zh) 制备细胞凋亡诱导剂的方法
WO2019082143A1 (fr) Procédé amélioré pour la préparation de ribociclib et de ses sels
WO2013184702A1 (fr) Synthèse de composé antiviral
EA037281B1 (ru) Способы получения противовирусного соединения
JPH03184976A (ja) ベンズイミダゾール誘導体およびその製造法
US9890159B2 (en) Process for making duocarmycin prodrugs
US5543414A (en) Achiral amino acid acyl esters of ganciclovir and its derivatives
WO2009133170A1 (fr) Procédé de préparation de 5-(2-amino- pyrimidin-4-yl)-2-aryl-lh-pyrrole-3-carboxamides
SK11982003A3 (sk) Spôsob výroby 4,6-diaminopyrimido[5,4-d]pyrimidínov a medziprodukty
WO2014049512A2 (fr) Nouveau procédé de préparation d'azilsartan médoxomil
JP3488155B2 (ja) 成長ホルモン分泌促進物質の製造及び中間体
JP2012524119A (ja) Ｃ−ピラジン−メチルアミンの調製
WO2016199049A1 (fr) Procédé de préparation de ledipasvir
US11345683B2 (en) Process for the preparation of lifitegrast
JP2018519290A (ja) Ｄｐｐ−ｉｖ阻害剤の製造のための新規中間体、その製造方法、及びそれを用いたｄｐｐ−ｉｖ阻害剤の製造方法
WO2015019239A1 (fr) Procédé pour la préparation de 1-(3-méthyl-1-phényl-1h-pyrazolo-5-yl)pipérazine
KR20080039510A (ko) 발사르탄 제조 방법
WO2011156355A1 (fr) Procédé de production de sels de phénylguanidine et de leurs intermédiaires
CN115109041B (zh) 一种3cl蛋白抑制剂恩赛特韦的合成方法及其中间体
WO2017072596A1 (fr) Procédé amélioré pour la préparation de lédipasvir
KR20140128998A (ko) 2-페닐-[1,2,4]트라이아졸로[1,5-a]피리딘 유도체의 제조 방법
KR100662110B1 (ko) 테트라졸 유도체의 제조방법
EP3931197B1 (fr) Procédé de préparation de (6s)-3-[(4s)-4-cyano-2-oxo-pyrrolidin-1-yl]-6-méthyl-n-(3,4,5-trifluorophényl)-6,7-dihydro-4 h-pyrazolo [1,5-a] pyrazine-5-carboxamide
Selvakumar et al. Synthesis of non-glutamate-type pyrrolo [2, 3-d] pyrimidines via direct aminocarbonylation of aryl halides using solid Co2 (CO) 8 as a CO source and their antibacterial activity

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: 16806988

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: 16806988

Country of ref document: EP

Kind code of ref document: A1