WO2015111004A2 - Méthode améliorée de préparation de chlorophényl-trifluoroéthanone - Google Patents

Méthode améliorée de préparation de chlorophényl-trifluoroéthanone Download PDF

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Publication number
WO2015111004A2
WO2015111004A2 PCT/IB2015/050533 IB2015050533W WO2015111004A2 WO 2015111004 A2 WO2015111004 A2 WO 2015111004A2 IB 2015050533 W IB2015050533 W IB 2015050533W WO 2015111004 A2 WO2015111004 A2 WO 2015111004A2
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WO
WIPO (PCT)
Prior art keywords
formula
compound
chlorophenyl
process according
trifluoroethanone
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PCT/IB2015/050533
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English (en)
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WO2015111004A3 (fr
Inventor
Dhananjaya GUNDLA
Kondala Rao KOTA
Srinivasa Rao ALA
Prashanth MANNE
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Discovery Intermediates Private Limited
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Application filed by Discovery Intermediates Private Limited filed Critical Discovery Intermediates Private Limited
Publication of WO2015111004A2 publication Critical patent/WO2015111004A2/fr
Publication of WO2015111004A3 publication Critical patent/WO2015111004A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups

Definitions

  • the present invention relates to an improved process for the preparation of chlorophenyl trifluoroethanone of formula I. an intermediate used in the preparation of Efavirenz.
  • Efavirenz is an HIV-1 specific, non-nucleoside. reverse transcriptase inhibitor (NNRTI) which is used to treat human immunodeficiency virus (HIV ) infection.
  • NRTI reverse transcriptase inhibitor
  • Efavirenz has been marketed under the brand name SUSTIVA by Bristol Myers Squibb.
  • Efavirenz is chemically described as (4S )-6-chloiO-4-(cyclopi pylethynyl )- 1.4-dihydiO-4-(trifluoiOmethyl)-2H-3.1 - benzoxazin-2-one and is structurally below.
  • Efavirenz is first disclosed in US patent 5.519.021 and in EP patent 582 455.
  • R is halogenated 0,. 6 alkyl
  • X is a halogen
  • trifluoromethylated compounds like trifluoroacetyl group become high synthetic interest due to their exceptional properties and applicability as building blocks, hi recent times, trifluoromethyl-acetophenones with an additional amino substituent in ortho- position have become useful precursors for selective colorimetric sensing of anions, fluorinated benzoxazinones and quinolines. These molecules can also be used in anion recognition, which is stabilized by hydrogen bonding.
  • a well established method to form trifluoroacetyl group is the nucleophilic addition of TMS- CF 3 (Ruppert' s reagent) to esters or aldehydes, whereas the second reaction requires the oxidation of the intermediate trifluoromethylated alcohol.
  • the main objective of the present invention is to provide a process which is safe on industrial scale for the preparation of chlorophenyl trifluoroethanone of formula I.
  • Another objective of the present invention is to provide a commercially viable process for the preparation of chlorophenyl trifluoroethanone of formula I.
  • the present invention provides an improved process for the preparation of chlorophenyl trifluoroethanone of fomiula I which comprises the steps:
  • R H or X conventional amino protecting groups to provide compound of fomiula 3.
  • R H or X
  • PG amino-protecting grop ii. acetylating the compound of fomiula 3 to provide compound 4.
  • the present invention provides a process for the preparation of chlorophenyl trifluoroethanone of formula I. which comprises the steps:
  • PG amino-protecting group
  • X is halogen atom iii. acetylating the compound of fomiula 6 to provide compound 4.
  • the present invention provides a process for the preparation of chlorophenyl trifluoroethanone of formula I, which comprises the steps:
  • reaction of acetylation and deprotection can be carried out in one step.
  • reaction in another embodiment of the present invention can be carried in the presence or absence of basic ligands such as sodium, magnesium and lithium.
  • Suitable X represents a halogen selected from chlorine, bromine, fluorine and iodine.
  • Suitable amino protecting groups are trichloroethoxycarbonyl. benzyloxycarbonyl (Cbz), chloroacetyl. trifluoroacetyl. phenylacetyl. formyl. acetyl, benzoyl, tert-butoxycarbonyl (BOC). para-methoxybenzyloxycarbonyl. para-methoxybenzyl. para-nitrobenzyl diphenylmethoxycarbonyl. phthaloyl. succinyl, benzyl, diphenylmethyl. triphenylmethyl (trityl ). methanesulfonyl. para-toluenesulfonyl. pivaloyl. trimethylsilyl, triethylsilyl, triphenylsilyl and the like.
  • the protection is carried out in the presence or absence of a base and in a solvent.
  • the base is selected from sodium hydroxide, potassium hydroxide and carbonates such as potassium carbonates.
  • the organic solvent used in the reaction is selected from alcohols such as methanol, ethanol. butanol; hydrocarbons such as heptane; aromatic hydrocarbons such as toluene, xylene: halogenated solvents such as dichloromethane. chloroform. 1 ,2- dichloroethane; ethers such as diethyl ether. MTBE. 1.4 dioxane. THF; nit iles such as acetonitrile; esters such as ethylacetate; sulfoxides such as DMSO; amides such as DMF and water or mixtures thereof.
  • Acetylation is carried out using a acetylating agent which is selected from the group consisting of methyltrifluoroacetate. ethyltrifluoroacetate. trifluoroacetylchloride. trifluoroacetic anhydride and mixtures thereof.
  • the reaction is carried out in the presence of Grignard reagent in a solvent.
  • the Grignard reagent is selected from methyl magnesium bromide/chloride, ethyl magnesium bromide/chloride. isopropyl magnesium bromide/chloride. n-butyl magnesium bromide/chloride.
  • the solvent is selected from toluene, xylene, diethylether. diisopropylether. MTBE. tetrahydrofuran. and the like.
  • the deprotection step comprises the single-step removal of the protecting groups.
  • the deprotection is carried out either by using an acid or a base or by catalytic hydrogenation in the presence of a hydrogenation catalyst, optionally in the presence of an acid, under high pressure or by catalytic transfer hydrogenation (CTH ) in the presence of a catalytic transfer hydrogenation reagent, and optionally in the presence of an acid.
  • CTH catalytic transfer hydrogenation
  • Suitable acids used for deprotection are selected from mineral acids such as hydrochloric acid, viz. methanolic HC1. Ethanolic HC1. 1.4-dioxane HC1. IPA HC1; sulphuric acid; acetic acid and the like.
  • the reaction is carried out in a solvent selected from methanol, ethanol. isopropanol or any other suitable solvent.
  • Halogenation is carried out using suitable halogenating reagents for the preparation of corresponding bromides, chlorides, iodides or fluorides include for example NBS. Bi acetic acid. HBr/acetic acid. aqueous HBr. l,3-dibi mo-5.5-dimethylhydantoin, tetrabutylammonium bromide. N-bromoacetamide. NCS. SO 2 CK hydrogen fluoride, tetra- butylammonium fluoride, pyridinium hydrofluoride. potassium iodide, sodium iodide or lithium iodide and the like.
  • the reaction is carried out in a solvent selected from dichloromethane. dichloroehtane, chloroform, carbon tetrachloride, MTBE. acetonitrile, toluene, acetic acid, sulfuric acid, hydrochloric acid or water and the like.
  • Step 1 Synthesis of N-(4-chlorophenyl)pivalamide 2 from p-chloroaniline:
  • Step 3 Synthesis of l -(2-amino-5-chlorophenyl)-2,2.2-trifluoi ethanone hydrochloride from N-(2-bromo-4-chloiOphenyl)pivalamide:
  • the crude compound was added to a mixture of acetic acid (4 vol. ) and HC1 (2 vol. ) and slowly heated to 75°C and stirred for 4 h at the same temperature.
  • the reaction mixture was cooled to 0-5°C and filtered, washed with ethyl acetate ( 1 vol. ) to afford 40 of the title compound.
  • Step 1 Synthesis of N-(4-chlorophenyl)pivalamide 2 from p-chloroaniline:
  • Step 3 Synthesis of l -(2-amino-5-chlorophenyl)-2,2.2-trifluoiOethanone hydrochloride from N-(2-bromo-4-chloiOphenyl)pivalamide:
  • Step 1 Synthesis of N-(4-chlorophenyl)pivalamide 2 from p-chloroaniline:
  • Step 2 Synthesis of N-(2-bromo-4-chloiOphenyl (pivalamide from N-(4- chlorophenyl )pivalamide: Bromine ( 1.2 mmol) was added dropwise to a solution of N-(4-chlorophenyl )pivalamide ( 1 mmol ) in acetic acid (2 vol. ) at room temperature. The reaction was stirred at the same temperature for lh. After completion of the reaction the reaction mixture was poured into crushed ice to get precipitate. The precipitate was filtered and washed with water to yield 90% N-(2-biOmo-4-chlorophenyl)pivalamide.
  • Step 3 Synthesis of l -(2-amino-5-chlorophenyl)-2,2.2-trifluoi ethanone hydrochloride from N-(2-biOmo-4-chlorophenyl)pivalamide:
  • Step 1 Synthesis of N-(4-chlorophenyl)pivalamide 2 from p-chloroaniline:
  • Step 3 Synthesis of l -(2-amino-5-chloi'ophenyl)-2.2.2-trifluoi'oethanone hydrochloride from N-(2-biOmo-4-chlorophenyl)pivalamide:
  • Step 1 Synthesis of N-(4-chlorophenyl (pivalamide 2 from p-chloroaniline:
  • Step 2 Synthesis of N-(2-bromo-4-chloiOphenyl (pivalamide from N-(4- chlorophenyl )pivalamide:
  • Step 3 Synthesis of l -(2-amino-5-chloi phenyl)-2,2.2-trifluoiOethanone hydrochloride from N-(2-biOmo-4-chlorophenyl)pivalamide:
  • Sodamide (3.2 mmol ) was added to a solution of N-(2-bromo-4-chloiOphenyl) pivalamide ( 1 mmol ) & lithium chloride (0.25mmol) in THF (4 vol. ) at 20°C under inert atmosphere.
  • the reaction mixture was maintained at 25°C for 6hrs and cooled to - 15°C.
  • ethyltrifluoroacetate ( 1.4 mmol) was added at - 15°C.
  • the reaction mixture was warmed to room temperature and stirred for another 30 min. After completion of the starting material the reaction was quenched with aqueous ammonium chloride solution (50 ml ) and extracted with MTBE (2X50 nil ).
  • Step 1 Synthesis of N-(4-chlorophenyl)pivalamide 2 from p-chloroaniline:
  • Step 2 Synthesis of N-(2-biOmo-4-chlorophenyl )pivalamide from N-(4- chlorophenyl)pivalamide:
  • Step 3 Synthesis of l -(2-aniino-5-chloi phenyl)-2,2.2-trifluoiOethanone hydrochloride from N-(2-biOnio-4-chlorophenyl)pivalamide: Magnesium (2.3 mmol ) was added to a solution of N-(2-bromo-4-chloiOphenyl ) pivalamide ( 1 mmol ) & lithium chloride (0.25mmol) in THF (4 vol. ) at 20°C under inert atmosphere. The reaction mixture was maintained at 25°C for 6hrs and cooled to - 15°C.
  • Step 1 Synthesis of 4-chloi -2-bromo phenyl pivalamide
  • Step 2 Synthesis of l-(2-amino-5-chloi phenyl )-2.2.2.-trifluoroethanone hydrochloride from 4-chloro-2-biomo phenyl pivalamide.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne une méthode améliorée de préparation de chlorophényl-trifluoroéthanone de formule I, un intermédiaire utilisé dans la préparation de l'éfavirenz. Formule I
PCT/IB2015/050533 2014-01-24 2015-01-24 Méthode améliorée de préparation de chlorophényl-trifluoroéthanone WO2015111004A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN304/CHE/2014 2014-01-24
IN304CH2014 IN2014CH00304A (fr) 2014-01-24 2015-01-24

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WO2015111004A2 true WO2015111004A2 (fr) 2015-07-30
WO2015111004A3 WO2015111004A3 (fr) 2017-05-11

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105777610A (zh) * 2015-10-16 2016-07-20 浙江沙星医药化工有限公司 一种制备4-氯-2-(三氟乙酰基)苯胺盐酸盐水合物的方法
CN106518636A (zh) * 2016-10-18 2017-03-22 浙江天宇药业股份有限公司 4‑氯‑2‑（三氟乙酰基）苯胺盐酸盐水合物及其游离碱的制备方法
CN108821938A (zh) * 2018-08-06 2018-11-16 江苏沙星化工有限公司 一种制备4-氯-2-（三氟乙酰）-苯胺盐酸盐副产物的分离方法
CN108997150A (zh) * 2018-08-31 2018-12-14 江苏沙星化工有限公司 一种依法韦仑中间体的制备方法

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ATE527243T1 (de) * 2005-03-09 2011-10-15 Merck Sharp & Dohme Calciumkanal-antagonisten vom typ chinazolinon t

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105777610A (zh) * 2015-10-16 2016-07-20 浙江沙星医药化工有限公司 一种制备4-氯-2-(三氟乙酰基)苯胺盐酸盐水合物的方法
CN105777610B (zh) * 2015-10-16 2018-10-09 浙江沙星科技有限公司 一种制备4-氯-2-(三氟乙酰基)苯胺盐酸盐水合物的方法
CN106518636A (zh) * 2016-10-18 2017-03-22 浙江天宇药业股份有限公司 4‑氯‑2‑（三氟乙酰基）苯胺盐酸盐水合物及其游离碱的制备方法
CN108821938A (zh) * 2018-08-06 2018-11-16 江苏沙星化工有限公司 一种制备4-氯-2-（三氟乙酰）-苯胺盐酸盐副产物的分离方法
CN108997150A (zh) * 2018-08-31 2018-12-14 江苏沙星化工有限公司 一种依法韦仑中间体的制备方法
CN108997150B (zh) * 2018-08-31 2021-01-12 江苏沙星化工有限公司 一种依法韦仑中间体的制备方法

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WO2015111004A3 (fr) 2017-05-11

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