WO2015063659A1 - Process for the preparation of glycerol phenylbutyrate - Google Patents

Process for the preparation of glycerol phenylbutyrate Download PDF

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Publication number
WO2015063659A1
WO2015063659A1 PCT/IB2014/065578 IB2014065578W WO2015063659A1 WO 2015063659 A1 WO2015063659 A1 WO 2015063659A1 IB 2014065578 W IB2014065578 W IB 2014065578W WO 2015063659 A1 WO2015063659 A1 WO 2015063659A1
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WO
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Prior art keywords
glycerol
phenylbutyrate
preparation
glycerol phenylbutyrate
chloride
Prior art date
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PCT/IB2014/065578
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English (en)
French (fr)
Inventor
Sanket Pandurang JADHAV
Deepak Puna MAHAJAN
Sagar Purushottam Nehate
Himanshu Madhav Godbole
Girij Pal Singh
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Lupin Ltd
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Lupin Ltd
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Publication date
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Publication of WO2015063659A1 publication Critical patent/WO2015063659A1/en
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/14—Preparation of carboxylic acid esters from carboxylic acid halides

Definitions

  • the present invention relates to the process for the preparation of glycerol phenylbutyrate. Background of the invention:
  • Glycerol phenylbutyrate is a triglyceride containing three molecules of 4-phenylbutyric acid linked to a glycerol backbone, the chemical name of which is benzenebutanoic acid, ⁇ , , '- (1,2,3-propanetriyl) ester and the structural formula is:
  • US patent 5968979 covers glycerol phenylbutyrate generically. This patent merely states that the compounds of the invention can be produced by standard esterification procedures. There is no specific process disclosed for the preparation of glycerol phenylbutyrate in this patent.
  • IT 1317073 Bl describes preparation of glycerol phenylbutyrate in 75% yield by treatment of 4-phenylbutyric acid with 5-fold excess thionyl chloride to give 4-phenylbutyryl chloride, followed by removal of excess thionyl chloride and treatment of the 4-phenylbutyryl chloride with a stoichiometric amount of glycerol.
  • Kasumov et al (Drug Metabolism and Disposition, Volume: 32, Issue: 1, Pages: 10-19, 2004) describes preparation of glycerol phenylbutyrate by reacting glycerol with excess 4- phenylbutyryl chloride in the presence of pyridine and catalytic amounts of N,N- dimethylaminopyridine. The product was purified by flash column chromatography on silica.
  • Chang et al (Journal of Biotechnology, Volume: 127, Issue: 4, Pages: 694-702, 2007; Journal of Molecular Catalysis B: Enzymatic Volume 61, Issues 3-4, December 2009, Pages 117-122) describes preparation of glycerol phenylbutyrate from glycerol and 4- phenylbutyric acid by lipase-catalyzed esterification in a solvent-free system.
  • EP 2607366 Al describes preparation of 4-phenyl-butyric acid 2-hydroxy-3-(4-phenyl- butyryloxy)-propyl ester by reacting glycerol with 4-phenylbutyryl chloride. In this preparation glycerol phenylbutyrate is obtained as side product in 1.7 % yield.
  • the present invention relates to the process for the preparation of glycerol phenylbutyrate (I) by reacting 4-phenylbutyryl chloride (II) with glycerol (III) in presence of organic base in d- C 5 chlorinated hydrocarbon solvent.
  • Glycerol phenylbutyrate (I) prepared according the process of the present invention is having HPLC purity >99%.
  • the present invention relates to a process for the preparation of glycerol phenylbutyrate (I) comprising a) reacting 4-phenylbutyryl chloride (II) with glycerol (III) in presence of organic base in Q- C 5 chlorinated hydrocarbon solvent and
  • the step (a) is carried out at temperature in a range of -10 °C to 20 °C, preferably -5 °C to 5 °C.
  • the quantity of 4-phenylbutyryl chloride (II) is 3 to 4 molar equivalent of glycerol (III).
  • the organic base is selected from imidazole or 1-alkylimidazole such as 1-methylimidazole, 1 -ethylimidazole.
  • the quantity of organic base is 4 to 5 molar equivalent of glycerol (III).
  • the C 1 -C 5 chlorinated hydrocarbon solvent in step (a) is selected from chloroform, dichloromethane, carbon tetrachloride, ethylenedichloride.
  • the quantity of C 1 -C 5 chlorinated hydrocarbon solvent in step (a) is 15 to 25 volumes per weight of glycerol.
  • Glycerol phenylbutyrate (I) prepared according the process of the present invention is having HPLC purity >99%. We have studied this reaction using 1-methylimidazole in ethyl acetate as solvent, and found that reaction was very slow, the product glycerol phenylbutyrate (I) formed only upto 62 % in 11 hours. This shows that chlorinated hydrocarbons are better solvent for this reaction compared to ester solvents.
  • process for the preparation of 4-phenylbutyryl chloride (II) which comprises i) reacting 4-phenylbutyric acid with thionyl chloride in C 1 -C5 chlorinated hydrocarbon solvent and ii) isolating the 4-phenylbutyryl chloride (II) by removing the solvent using vacuum distillation.
  • the C 1 -C 5 chlorinated hydrocarbon solvent in step (i) is selected from chloroform, dichloromethane, carbon tetrachloride, ethylenedichloride.
  • the quantity of C 1 -C 5 chlorinated hydrocarbon solvent in step (i) is 1.2 to 2 volumes per weight of 4-phenylbutyric acid.
  • the quantity of thionyl chloride is 1.1 to 1.5 molar equivalent of 4-phenylbutyric acid.
  • the glycerol phenylbutyrate is isolated by chromatographic technique selected from column chromatography, flash column chromatography, preparative HPLC.
  • the crude glycerol phenylbutyrate (I) (10 g) was purified by Gravity column chromatographic technique using silica gel (100-200 mesh) as stationary phase and 0.5% - 3% ethyl acetate in cyclohexane as mobile phase. Ethyl acetate was gradually increased and fractions (500 ml each) were collected. Fractions containing any individual impurity less than 0.05 % were collected and solvent was distilled off under reduced pressure. Yield: 5.48 g, HPLC Purity - 99.81%.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
PCT/IB2014/065578 2013-10-30 2014-10-24 Process for the preparation of glycerol phenylbutyrate Ceased WO2015063659A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN3442/MUM/2013 2013-10-30
IN3442MU2013 IN2013MU03442A (enrdf_load_stackoverflow) 2013-10-30 2014-10-24

Publications (1)

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WO2015063659A1 true WO2015063659A1 (en) 2015-05-07

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PCT/IB2014/065578 Ceased WO2015063659A1 (en) 2013-10-30 2014-10-24 Process for the preparation of glycerol phenylbutyrate

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IN (1) IN2013MU03442A (enrdf_load_stackoverflow)
WO (1) WO2015063659A1 (enrdf_load_stackoverflow)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106117045A (zh) * 2016-06-22 2016-11-16 北京阳光诺和药物研究有限公司 一种苯基丁酸的纯化方法
US9914692B2 (en) 2016-05-25 2018-03-13 Horizon Therapeutics, Llc Procedure for the preparation of 4-phenyl butyrate and uses thereof
US9962358B2 (en) 2011-09-30 2018-05-08 Horizon Therapeutics, Llc Methods of therapeutic monitoring of nitrogen scavenging drugs
WO2020070760A1 (en) * 2018-10-04 2020-04-09 Msn Laboratories Private Limited, R&D Center An improved process for the preparation of 1,2,3-propanetriyl tris(4-phenylbutanoate)
US10668040B2 (en) 2017-09-11 2020-06-02 Horizon Therapeutics, Llc Treatment of urea cycle disorders in neonates and infants
CN111787917A (zh) * 2017-09-08 2020-10-16 伊梅尔迪卡制药公司 疗尿素循环障碍的方法
CN113845420A (zh) * 2021-10-22 2021-12-28 安徽沃泰生物医药有限公司 苯丁酸甘油酯的合成工艺

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5968979A (en) 1995-02-07 1999-10-19 Brusilow Enterprises Llc Triglycerides and ethyl esters of phenylalkanoic acid and phenylalkenoic acid useful in treatment of various disorders
IT1317073B1 (it) 2000-12-12 2003-05-26 Mini Ricerca Scient Tecnolog Esteri dell'acido fenilbutirrico, procedimenti per la loro produzionee loro impiego terapeutico.
EP2607366A1 (en) 2011-12-21 2013-06-26 Lunamed AG Glycerol phenyl butyrate esters

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5968979A (en) 1995-02-07 1999-10-19 Brusilow Enterprises Llc Triglycerides and ethyl esters of phenylalkanoic acid and phenylalkenoic acid useful in treatment of various disorders
IT1317073B1 (it) 2000-12-12 2003-05-26 Mini Ricerca Scient Tecnolog Esteri dell'acido fenilbutirrico, procedimenti per la loro produzionee loro impiego terapeutico.
EP2607366A1 (en) 2011-12-21 2013-06-26 Lunamed AG Glycerol phenyl butyrate esters

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CHANG ET AL., JOURNAL OF BIOTECHNOLOGY, vol. 127, no. 4, 2007, pages 694 - 702
JOURNAL OF MOLECULAR CATALYSIS B: ENZYMATIC, vol. 61, no. 3-4, December 2009 (2009-12-01), pages 117 - 122
KASUMOV ET AL., DRUG METABOLISM AND DISPOSITION, vol. 32, no. 1, 2004, pages 10 - 19
KASUMOV ET AL., DRUG METABOLISM AND DISPOSITION, vol. 32, no. 1, 2004, pages 10 - 19, XP002736935 *

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10183002B2 (en) 2011-09-30 2019-01-22 Horizon Therapeutics, Llc Methods of therapeutic monitoring of nitrogen scavenging drugs
US10183005B2 (en) 2011-09-30 2019-01-22 Horizon Therapeutics, Llc Methods of therapeutic monitoring of nitrogen scavenging drugs
US9962358B2 (en) 2011-09-30 2018-05-08 Horizon Therapeutics, Llc Methods of therapeutic monitoring of nitrogen scavenging drugs
US9962359B2 (en) 2011-09-30 2018-05-08 Horizon Therapeutics, Llc Methods of therapeutic monitoring of nitrogen scavenging drugs
US9999608B2 (en) 2011-09-30 2018-06-19 Horizon Therapeutics, Llc Methods of therapeutic monitoring of nitrogen scavenging drugs
US10045959B1 (en) 2011-09-30 2018-08-14 Horizon Therapeutics, Llc Methods of therapeutic monitoring of nitrogen scavenging drugs
US10045958B1 (en) 2011-09-30 2018-08-14 Horizon Therapeutics, Llc Methods of therapeutic monitoring of nitrogen scavenging drugs
US10183006B2 (en) 2011-09-30 2019-01-22 Horizon Therapeutics, Llc Methods of therapeutic monitoring of nitrogen scavenging drugs
US10183004B2 (en) 2011-09-30 2019-01-22 Horizon Therapeutics, Llc Methods of therapeutic monitoring of nitrogen scavenging drugs
US10183003B2 (en) 2011-09-30 2019-01-22 Horizon Therapeutics, Llc Methods of therapeutic monitoring of nitrogen scavenging drugs
US10617665B2 (en) 2011-09-30 2020-04-14 Horizon Therapeutics, Llc Methods of therapeutic monitoring of nitrogen scavenging drugs
US9914692B2 (en) 2016-05-25 2018-03-13 Horizon Therapeutics, Llc Procedure for the preparation of 4-phenyl butyrate and uses thereof
US10329236B2 (en) 2016-05-25 2019-06-25 Horizon Therapeutics, Llc Procedure for the preparation of 4-phenyl butyrate and uses thereof
US11014870B2 (en) 2016-05-25 2021-05-25 Horizon Therapeutics, Llc Procedure for the preparation of 4-phenyl butyrate and uses thereof
CN106117045A (zh) * 2016-06-22 2016-11-16 北京阳光诺和药物研究有限公司 一种苯基丁酸的纯化方法
CN111787917A (zh) * 2017-09-08 2020-10-16 伊梅尔迪卡制药公司 疗尿素循环障碍的方法
US10668040B2 (en) 2017-09-11 2020-06-02 Horizon Therapeutics, Llc Treatment of urea cycle disorders in neonates and infants
WO2020070760A1 (en) * 2018-10-04 2020-04-09 Msn Laboratories Private Limited, R&D Center An improved process for the preparation of 1,2,3-propanetriyl tris(4-phenylbutanoate)
CN113845420A (zh) * 2021-10-22 2021-12-28 安徽沃泰生物医药有限公司 苯丁酸甘油酯的合成工艺
CN113845420B (zh) * 2021-10-22 2024-04-16 安徽沃泰生物医药有限公司 苯丁酸甘油酯的合成工艺

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