WO2016207915A1 - Procédé de préparation de ledipasvir - Google Patents

Procédé de préparation de ledipasvir Download PDF

Info

Publication number
WO2016207915A1
WO2016207915A1 PCT/IN2016/050198 IN2016050198W WO2016207915A1 WO 2016207915 A1 WO2016207915 A1 WO 2016207915A1 IN 2016050198 W IN2016050198 W IN 2016050198W WO 2016207915 A1 WO2016207915 A1 WO 2016207915A1
Authority
WO
WIPO (PCT)
Prior art keywords
process according
compound
formula
acetate
mixtures
Prior art date
Application number
PCT/IN2016/050198
Other languages
English (en)
Inventor
Arabinda Sahu
Sreenivasarao PATHURI
Nagadurgarao BANDI
Satyanarayana Raavi
Ramesh Kumar SABBAM
Bhavanisankar TIRUMALARAJU
Sivaram Prasad VELLANKI
Original Assignee
Mylan Laboratories Limited
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 Mylan Laboratories Limited filed Critical Mylan Laboratories Limited
Publication of WO2016207915A1 publication Critical patent/WO2016207915A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals

Definitions

  • the present invention relates to a process for the preparation of ledipasvir or its pharmaceutically acceptable salts.
  • Ledipasvir is a hepatitis C virus NS5A inhibitor being developed for the treatment of hepatitis C virus (HCV).
  • Ledipasvir is chemically named 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-l-oxobutan-2-yl]carbamate and is represented by the following chemical structure:
  • Ledipasvir is approved in combination with sofosbuvir for the treatment of chronic hepatitis C virus infection under the brand name of HARVONI ® , marketed by Gilead Sciences. SUMMARY OF THE INVENTION
  • the present invention provides a process for the preparation of ledipasvir or its pharmaceutically acceptable salts, which may include the following steps:
  • Ri and R 2 are independently selected from halogen, wherein
  • Formula 1 may be further converted to a pharmaceutically acceptable salt by salification steps well known in the art.
  • the present invention provides novel synthetic schemes for the synthesis of ledipasvir.
  • novel intermediates are generated as part of the novel synthetic schemes. Together, these schemes and intermediates provide an improved, efficient method for the synthesis of ledipasvir or pharmaceutically acceptable salts thereof.
  • One aspect of the present invention provides a process for the preparation of ledipasvir or pharmaceutically acceptable salts thereof.
  • ledipasvir or pharmaceutically acceptable salts thereof may be prepared by the following steps:
  • Ri and R 2 are independently selected from halogen, wherein
  • X and Ri are selected from Br Formula 1 may be converted into a pharmaceutically acceptable salt by methods well known in the art.
  • pharmaceutically acceptable salts include acid addition salts, formed with inorganic acids such as hydrochloric acid, hydro bromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as glycolic acid, pyruvic acid, lactic acid, malonic acid, malic acid, inaleic acid, fumaric acid, tartaric acid, citric acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methane sulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4- chiorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluen
  • Pharmaceutically acceptable salts further include basic addition salts formed with the conjugate bases of any of the inorganic acids listed above, wherein the conjugate bases comprise a cationic component selected from among Na + , K + , Mg 2+ , Ca 2+ , and NHgR " 4 _ g + ; in which R is a Ci_ 3 alkyl and g is a number selected from among 0, 1, 2, 3, or 4. It should be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein, of the same acid addition salt.
  • the compound of formula 6 is treated with the compound of formula 5 to get compound of formula 4.
  • This reaction may be carried out in the presence of base and solvent.
  • the base employed may be an organic base.
  • suitable organic bases include, but are not limited to, pyridine, imidazole, methyl amine, ⁇ , ⁇ -diisopropylethylamine, triethylamine, tetramethylammonium hydroxide, tetrabutylammonium hydroxide, and mixtures thereof.
  • ⁇ , ⁇ -diisopropylethylamine was found to be a particularly useful base.
  • One of the skill in the art will recognize numerous well- known organic bases that may be useful within the context of this embodiment.
  • the solvent employed may be a polar aprotic solvent or an aromatic hydrocarbon.
  • suitable polar aprotic solvents include, but are not limited to, acetone, acetonitrile, dichloromethane, tetrahydrofuran, ethyl acetate, dimethylformamide, dimethyl sulfoxide, acetone, N-methylpyrrolidone, and mixtures thereof.
  • aromatic hydrocarbons include, but are not limited to, toluene, xylene, and mixtures thereof.
  • acetonitrile is used as the solvent.
  • the compound of formula 4 is then coupled with the compound of formula 3 to get compound of formula 2. This reaction may be carried out in the presence of base, metal catalyst, and solvent.
  • the metal catalyst employed may be selected from Pd(0) and Pd(II) compounds such as Pd(PPh 3 ) 4 , PdCl 2 (PPh 3 ) 2 , Pd(OAc) 2 , PdCl 2 (P(t-Bu) 2 Ph) 2 , and Pd(dppf) 2 Cl 2 .
  • the solvent employed may be selected from ester solvents such as isopropyl acetate, ethyl acetate, and butyl acetate; alcohols such as methanol, ethanol, isopropyl alcohol, and tert-amyl alcohol; ether solvents such as dimethoxy ethane and di(2-methoxyethyl) ether; and mixtures thereof.
  • ester solvents such as isopropyl acetate, ethyl acetate, and butyl acetate
  • alcohols such as methanol, ethanol, isopropyl alcohol, and tert-amyl alcohol
  • ether solvents such as dimethoxy ethane and di(2-methoxyethyl) ether
  • isopropyl acetate is used as the solvent.
  • the base employed in this step may be selected from a propionate salt such as potassium propionate; acetates such as sodium acetate, potassium acetate, and cesium acetate; phosphates such as sodium phosphate and potassium phosphate; carbonates such as sodium carbonate and potassium carbonate; and mixtures thereof.
  • potassium phosphate is used as base.
  • the compound of formula 3 is prepared in situ, thereby allowing subsequent coupling step to proceed.
  • the process comprises contacting the compound of formula (7)
  • the borylation reagent is selected from bis(pinacolato)diboron and bis(neopentylglycolato)diboron;
  • the palladium source employed may be selected from Pd(0) and Pd(II) compounds such as Pd(PPh 3 ) 4 , PdCl 2 (PPh 3 ) 2 , Pd(OAc) 2 , PdCl 2 (P(t-Bu) 2 Ph) 2 , and Pd(dppf) 2 Cl 2 ;
  • the base employed for this step may be selected from a propionate salt such as potassium propionate; acetates such as sodium acetate, potassium acetate, and cesium acetate; phosphates such as sodium phosphate and potassium phosphate; carbonates such as sodium carbonate and potassium carbonate; and mixtures thereof.
  • Scheme-I Another embodiment of the present invention provides a process for preparation of ledipasvir or its pharmaceutically acceptable salts, which is shown in scheme-II.
  • L is amino protecting group
  • Ri and R 2 are independently selected from halogen
  • Another embodiment the present invention provides a process for the preparation of ledipasvir or its pharmaceutically acceptable salts, which is as shown in
  • Another embodiment of the present invention provides a process for preparation of ledipasvir or its pharmaceutically acceptable salts, which is shown in scheme-IV.
  • the compound of formula 6 may be prepared by the following process.
  • he compound of formula 7 may be prepared by the following process:
  • reaction conditions e.g., reaction time and temperature
  • reaction time and temperature may be adjusted to achieve appropriate yield without undertaking undue experimentation and without departing from the scope of the present disclosure.
  • various separation and isolation techniques may be applied to isolate the final ledipasvir product or any intermediate disclosed above. For example, such techniques as thin layer chromatography, high performance liquid chromatography, filtration, distillation, and crystallization may be employed.
  • the ledipasvir generated using the methods of the present invention may be administered to patients who are suffering from a chronic hepatitis C virus infection.
  • Ledipasvir or its pharmaceutically acceptable salts produced by the methods of the present invention may be included in a pharmaceutical dosage form, including oral pharmaceutical dosage forms such as a tablet or capsule.
  • Ledipasvir may be included as the only active pharmaceutical ingredient, or it may be combined with other bioactive drugs, such as sofosbuvir.
  • pharmaceutical excipients may also be included. Suitable pharmaceutical excipients for tablet formulation of ledipasvir include colloidal silicon dioxide, copovidone, croscarmellose sodium, lactose monohydrate, magnesium stearate, and microcrystalline cellulose.
  • Tablets so formulated may be film-coated with materials such as dyes, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide.
  • ledipasvir When included in pharmaceutical dosage forms, ledipasvir may be present in a pharmaceutically effective amount, such as 90 milligrams.
  • a pharmaceutically effective amount such as 90 milligrams.
  • reaction mass was allowed to 25-30 °C, acetonitrile was added and then cooled to 0-5 °C, maintained for 2 hours, and then filtered to get 3-(6-bromo-lH-benzoimidazol-2- yl)-2-aza-bicyclo[2.2. l]heptane.
  • reaction mass was allowed to 25-30 °C and maintained until TLC complied (-16 hours). Ethyl acetate (175 mL) and water (175 mL) were then charged to the reaction mass. The organic layer was separated and washed with water (2 x 175 mL) followed by 5% sodium bicarbonate washing (175 mL) then again washed with water (2 x 175 mL).
  • the aqueous layer was pH adjusted to 1.0 with HC1 solution at 10-20 °C, followed by extracted with dichloromethane (MDC) (2 x 175 mL).
  • MDC dichloromethane
  • the MDC layer was distilled under reduced pressure and the compound (S)-5-azaspiro[2.4]heptane-6-carboxylic acid, 5-[(2S)-2- [(methoxycarbonyl)amino] -3 -methyl- 1-oxobutyl] was isolated.
  • the compound of formula 4a (2.5 g) and degassed K 3 P0 4 solution (4.2 g in 24 mL water) were charged at 20-25 °C, maintained for 2 hrs at 65-72 °C, and then cooled to 20-25 °C. Layers were separated and the organic layer was diluted with isopropyl acetate (IPA) (30 mL) followed by washing with 5% NaCl solution (2 x 37.5 mL). To the organic layer, N-aetyl-L-cysteine (1.0 g) was charged at 20-25 °C and maintained for 18 hours at 20-25 °C. Hyflo (0.25 g) and sodium hydroxide solution (0.25 g in 25 mL water) were charged.
  • IPA isopropyl acetate
  • Hyflo (0.25 g
  • sodium hydroxide solution (0.25 g in 25 mL water

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Virology (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (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

Procédés synthétiques chimiques utiles pour la synthèse de ledipasvir et de sels pharmaceutiquement acceptables de celui-ci.
PCT/IN2016/050198 2015-06-26 2016-06-24 Procédé de préparation de ledipasvir WO2016207915A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
IN3237/CHE/2015 2015-06-26
IN3237CH2015 2015-06-26
IN4204CH2015 2015-08-12
IN4204/CHE/2015 2015-08-12
IN5207/CHE/2015 2015-09-29
IN5207CH2015 2015-09-29

Publications (1)

Publication Number Publication Date
WO2016207915A1 true WO2016207915A1 (fr) 2016-12-29

Family

ID=56686856

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2016/050198 WO2016207915A1 (fr) 2015-06-26 2016-06-24 Procédé de préparation de ledipasvir

Country Status (1)

Country Link
WO (1) WO2016207915A1 (fr)

Cited By (1)

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

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011050146A1 (fr) * 2009-10-23 2011-04-28 Glaxosmithkline Llc Composés chimiques
WO2013184702A1 (fr) * 2012-06-05 2013-12-12 Gilead Sciences, Inc. Synthèse de composé antiviral
WO2016103232A1 (fr) * 2014-12-24 2016-06-30 Granules India Limited Procédé amélioré de préparation d'inhibiteur du vhc

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011050146A1 (fr) * 2009-10-23 2011-04-28 Glaxosmithkline Llc Composés chimiques
WO2013184702A1 (fr) * 2012-06-05 2013-12-12 Gilead Sciences, Inc. Synthèse de composé antiviral
WO2016103232A1 (fr) * 2014-12-24 2016-06-30 Granules India Limited Procédé amélioré de préparation d'inhibiteur du vhc

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
NZ754364A (en) Compositions and methods for inhibiting arginase activity
US20070191395A1 (en) Heterocyclic compounds having antifungal activity
JP2018533582A (ja) アルギナーゼ活性を阻害する組成物及び方法
NO330810B1 (no) N-benzyl-4-metylenamino-3-hydroksy-2-pyridoner som antimikrobielle midler
FR2620451A1 (fr) Nouveaux inhibiteurs de la renine, leur preparation et leur utilisation comme medicaments
WO2018165250A1 (fr) Promédicaments à base de glucuronide de tofacitinib
JP2008526897A (ja) ロスバスタチンのジアステレオマー精製
CN109651396B (zh) 氟代烷基磺酸烷基酯的烷基化
JP2016513103A (ja) アルビシジン誘導体、その使用および合成
KR20200010440A (ko) 야누스 키나아제 저해제의 글루쿠로니드 프로드러그
EP0552060B1 (fr) Dérivés d'imidazole à activité anti-HIV
WO2016207915A1 (fr) Procédé de préparation de ledipasvir
JP7106453B2 (ja) Ｎｒｆ２活性化化合物およびその使用
KR20050055793A (ko) 항미생물제로서의엔-설포닐-4-메틸렌아미노-3-하이드록시-2-피리돈
CS225816B2 (en) The production process of the alkoxyphenylpyrrolidone with the cyclic substituents and with the nitrogen on the end of the aliphatic chain
JP3160941B2 (ja) カルバゾール誘導体および免疫抑制剤
WO2009074020A1 (fr) Amides n-substitués par alpha-amino, composition pharmaceutique les contenant et leurs utilisations
WO2023078410A1 (fr) Composé ayant une activité de dégradation de gspt1 et son application
EP2874628A2 (fr) Sels et hydrates de composés antipsychotiques
WO2021250174A1 (fr) Synthèse d'acide (2s,5r)-5-(2-chlorophényl)-1-(2'-méthoxy-[1,1'-biphényl]-4-carbonyl)pyrrolidine-2-carboxylique
US11708320B2 (en) Environmentally-friendly hydroazidation of olefins
EP4077278A1 (fr) Procédé de préparation de brivaracétam
Fu et al. Development of a cyclosporin A derivative with excellent anti-hepatitis C virus potency
KR20220070489A (ko) 티아졸 카복사미드 화합물 및 미코박테리아 감염의 치료를 위한 이의 용도
WO2019082209A1 (fr) Prémélange de (2r,3r)-2,3-dihydroxysuccinate d'octanamide stable de n-((1r,2r)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl) et son procédé de préparation

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: 16751671

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: 16751671

Country of ref document: EP

Kind code of ref document: A1