WO2003104180A1 - Procede de preparation d'acide 4-(4-fluorobenzoyl) butyrique - Google Patents

Procede de preparation d'acide 4-(4-fluorobenzoyl) butyrique Download PDF

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Publication number
WO2003104180A1
WO2003104180A1 PCT/IN2003/000159 IN0300159W WO03104180A1 WO 2003104180 A1 WO2003104180 A1 WO 2003104180A1 IN 0300159 W IN0300159 W IN 0300159W WO 03104180 A1 WO03104180 A1 WO 03104180A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
fluorobenzene
preparation
improved process
Prior art date
Application number
PCT/IN2003/000159
Other languages
English (en)
Inventor
Muddasani Pulla Reddy
Original Assignee
Natco Pharma Limited
Venkaiah Chowdary Nannapaneni
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 Natco Pharma Limited, Venkaiah Chowdary Nannapaneni filed Critical Natco Pharma Limited
Priority to AU2003237593A priority Critical patent/AU2003237593A1/en
Priority to US10/516,770 priority patent/US20050250961A1/en
Publication of WO2003104180A1 publication Critical patent/WO2003104180A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/083—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid anhydrides

Definitions

  • the present invention relates to an improved process for the preparation of 4-(4- fluorobenzoyl)butyric acid.
  • the 4-(4-fluorobenzoyl)butyric acid has the formula-I given below.
  • the 4-(4-fluorobenzoyl)butyric acid has the formula-I is a key raw material for the synthesis of anti-hyperlipoproteinemetic drug ezetimibe (US 5767115, Schering).
  • the main criticality in making the compound of formula-I lies in controlling the desfluoro analogue impurity (4-benzoylbutyric acid) at an acceptable level ( ⁇ 0.05% w/w by HPLC).
  • the main objective of the present invention is, therefore, to provide an improved process for the preparation of compound of formula-I as defined above overcoming all the disadvantages present in the hitherto known processes.
  • Another objective of the present invention is to provide an improved process for the preparation of compound of formula-I as defined above which is simple and economical.
  • Another objective of the present invention is to provide an improved process for the preparation of compound of formula-I as defined above which does not have any mixing problem when the process is used on any scale of operation
  • Another objective of the present invention is to provide an improved process for the preparation of compound of formula-I as defined above which does not have reaction quenching problem when the process is used on any scale of operation
  • Still another objective of the present invention is to provide an improved process for the preparation of compound of formula-I as defined above which does not require high quality fluorobenzene
  • Another objective of the present invention is to provide an improved process for the preparation of compound of formula-I as defined above which does not require fluorobenzene as solvent medium to carry out the Friedel-Crafts reaction SUMARY OF INVENTION
  • the present invention provides an improved process for the preparation of compound (4-4(fluorobenzoyl)butyric acid) of the formula-I
  • I which comprises: (a) Preparing a solution of normal quality fluorobenzene, glutaric anhydride and halogenated solvent, the amount of fluorobenzene used being in a molar ratio of 0.5 to 0.7 molar equivalent with regard to the amount of glutaric anhydride used. (b) Preparing a mixture of aluminum chloride, normal quality fluorobenzene and halogenated solvent, the amount of fluorobenzene used being in a molar ratio of 0.5 to 0.6 molar equivalent with regard to the amount of glutaric anhydride used and the amount of halogenated solvent used being at least 4-6 times (w/v) with regard to the amount of glutaric anhydride used.
  • step (c) Adding the solution obtained in step (a) to the mixture obtained in step (b) at a • temperature in the range of 10 to 25°C.
  • step (g) Filtering and washing the residue with the same halogenated solved used in step (b) above to obtain the compound of the formula-I.
  • the normal quality of fluorobenzene used in step (a) refers to the impurity level of benzene.
  • the benzene content in fluorobenzene may be between 300-700ppm.
  • the halogenated solvent used in step (b) may be selected form methylene chloride, ethylene dichloride, 1,1,2,2-tetrachloroethane.
  • the base used in step (h) may be selected from sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, and ammonia.
  • the acid used in step (h) may be selected from hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, and propionic acid.
  • the solvent used for recrystallization in step (j) may be selected from acetone, methyl ethyl ketone, methyl isobutyl ketone, toluene, acetonitrile, methanol, ethanol, ethyl acetate, hexane or a mixture of these solvents.
  • Tnto a 3L three-necked RB flnsk were charged 500ml of methylene chloride, 250 ⁇ r of aluminum chloride and 45gr of fluorobenzene (benzene content 700ppm) under nitrogen atmosphere.
  • the reaction mixture was cooled to 10°C and a solution of lOOgr of glutaric anhydride, 45gr of fluorobenzene (benzene content 700ppm) and 500ml of methylene chloride was added slowly over a period of 3hrs between 10-15°C.
  • the reaction mixture was maintained for another one hour at the same temperature.
  • the reaction mixture was slowly poured onto a mixture of crushed ice (700gr) and cone. HC1 (300ml) below 10°C.
  • the reaction mass temperature was allowed to reach 25°C and methylene chloride distilled off from the reaction mixture below 50°C. After cooling the reaction mixture to 20°C, solids were filtered off and washed with 500ml of water.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un procédé amélioré de préparation d'acide 4-(4-fluorobenzoyl)butyrique, qu'on prépare à l'échelle commerciale au moyen de fluorobenzène de qualité standard (ayant une teneur en benzène comprise entre 300 et 700 ppm) et d'un niveau acceptable d'impureté d'analogue desfluoro (moins d'environ 0,1% par CLHP). L'acide 4-(4-fluorobenzoyl)butyrique représenté par la formule (I) est un matériau clé pour la synthèse d'un médicament à effet similaire à l'hyperlipoprotéinémie appelé l'ezetimibe. Formule (I)
PCT/IN2003/000159 2002-06-05 2003-04-16 Procede de preparation d'acide 4-(4-fluorobenzoyl) butyrique WO2003104180A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU2003237593A AU2003237593A1 (en) 2002-06-05 2003-04-16 Process for the preparation of 4-(4-fluorobenzoyl) butyric acid
US10/516,770 US20050250961A1 (en) 2002-06-05 2003-04-16 Process for the preparation of 4-(4-fluorobenzoyl) butyric acid

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN427/MAS/2002 2002-06-05
IN427CH2002 2002-06-05

Publications (1)

Publication Number Publication Date
WO2003104180A1 true WO2003104180A1 (fr) 2003-12-18

Family

ID=29727194

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2003/000159 WO2003104180A1 (fr) 2002-06-05 2003-04-16 Procede de preparation d'acide 4-(4-fluorobenzoyl) butyrique

Country Status (2)

Country Link
AU (1) AU2003237593A1 (fr)
WO (1) WO2003104180A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020131807A1 (fr) * 2018-12-17 2020-06-25 Vertex Pharmaceuticals Incorporated Inhibiteurs d'apol1 et leurs procédés d'utilisation
US11801234B2 (en) 2020-03-06 2023-10-31 Vertex Pharmaceuticals Incorporated Methods of treating APOL-1 dependent focal segmental glomerulosclerosis
US11866446B2 (en) 2020-08-26 2024-01-09 Vertex Pharmaceuticals Incorporated Inhibitors of APOL1 and methods of using same

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000034240A1 (fr) * 1998-12-07 2000-06-15 Schering Corporation Procede relatif a la synthese d'azetidinones
US6207822B1 (en) * 1998-12-07 2001-03-27 Schering Corporation Process for the synthesis of azetidinones
WO2001038305A2 (fr) * 1999-11-25 2001-05-31 Fournier Industrie Et Sante Nouveaux antagonistes des recepteurs de l'il-8

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000034240A1 (fr) * 1998-12-07 2000-06-15 Schering Corporation Procede relatif a la synthese d'azetidinones
US6207822B1 (en) * 1998-12-07 2001-03-27 Schering Corporation Process for the synthesis of azetidinones
WO2001038305A2 (fr) * 1999-11-25 2001-05-31 Fournier Industrie Et Sante Nouveaux antagonistes des recepteurs de l'il-8

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BAENS, NICOLE P. ET AL: "Synthesis of 2,5-substituted piperidines: transposition of 1,4-substitution pattern for the analgesic drug R6582", TETRAHEDRON (1993), 49(15), 3193-202, XP002022790 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020131807A1 (fr) * 2018-12-17 2020-06-25 Vertex Pharmaceuticals Incorporated Inhibiteurs d'apol1 et leurs procédés d'utilisation
CN113453760A (zh) * 2018-12-17 2021-09-28 弗特克斯药品有限公司 Apol1抑制剂及其使用方法
US11618746B2 (en) 2018-12-17 2023-04-04 Vertex Pharmaceuticals Incorporated Inhibitors of APOL1 and methods of using same
CN113453760B (zh) * 2018-12-17 2024-05-24 弗特克斯药品有限公司 Apol1抑制剂及其使用方法
US11801234B2 (en) 2020-03-06 2023-10-31 Vertex Pharmaceuticals Incorporated Methods of treating APOL-1 dependent focal segmental glomerulosclerosis
US11866446B2 (en) 2020-08-26 2024-01-09 Vertex Pharmaceuticals Incorporated Inhibitors of APOL1 and methods of using same

Also Published As

Publication number Publication date
AU2003237593A1 (en) 2003-12-22
AU2003237593A8 (en) 2003-12-22

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