WO2015063659A1 - Process for the preparation of glycerol phenylbutyrate - Google Patents
Process for the preparation of glycerol phenylbutyrate Download PDFInfo
- 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
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- glycerol
- phenylbutyrate
- preparation
- glycerol phenylbutyrate
- chloride
- Prior art date
Links
- ZSDBFLMJVAGKOU-UHFFFAOYSA-N glycerol phenylbutyrate Chemical compound C=1C=CC=CC=1CCCC(=O)OCC(OC(=O)CCCC=1C=CC=CC=1)COC(=O)CCCC1=CC=CC=C1 ZSDBFLMJVAGKOU-UHFFFAOYSA-N 0.000 title claims abstract description 28
- 229960002815 glycerol phenylbutyrate Drugs 0.000 title claims abstract description 27
- 238000000034 method Methods 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims abstract description 43
- VQDQISMDUHBUFF-UHFFFAOYSA-N 4-phenylbutanoyl chloride Chemical compound ClC(=O)CCCC1=CC=CC=C1 VQDQISMDUHBUFF-UHFFFAOYSA-N 0.000 claims abstract description 20
- 239000002904 solvent Substances 0.000 claims abstract description 18
- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 9
- 150000007530 organic bases Chemical class 0.000 claims abstract description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 claims description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical group ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 6
- 238000004587 chromatography analysis Methods 0.000 claims description 5
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 3
- 238000003818 flash chromatography Methods 0.000 claims description 3
- IWDFHWZHHOSSGR-UHFFFAOYSA-N 1-ethylimidazole Chemical compound CCN1C=CN=C1 IWDFHWZHHOSSGR-UHFFFAOYSA-N 0.000 claims description 2
- 238000004440 column chromatography Methods 0.000 claims description 2
- 125000002883 imidazolyl group Chemical group 0.000 claims description 2
- 238000002953 preparative HPLC Methods 0.000 claims description 2
- 229950005499 carbon tetrachloride Drugs 0.000 claims 1
- OBKXEAXTFZPCHS-UHFFFAOYSA-N 4-phenylbutyric acid Chemical compound OC(=O)CCCC1=CC=CC=C1 OBKXEAXTFZPCHS-UHFFFAOYSA-N 0.000 description 19
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 229950009215 phenylbutanoic acid Drugs 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 208000028547 Inborn Urea Cycle disease Diseases 0.000 description 2
- YRYZGVBKMWFWGT-UHFFFAOYSA-N Methyl 4-phenylbutanoate Chemical compound COC(=O)CCCC1=CC=CC=C1 YRYZGVBKMWFWGT-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 231100001261 hazardous Toxicity 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 208000030954 urea cycle disease Diseases 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 102000015781 Dietary Proteins Human genes 0.000 description 1
- 108010010256 Dietary Proteins Proteins 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- GEXDMGACZSUNJN-UHFFFAOYSA-N [2-hydroxy-3-(4-phenylbutanoyloxy)propyl] 4-phenylbutanoate Chemical compound C=1C=CC=CC=1CCCC(=O)OCC(O)COC(=O)CCCC1=CC=CC=C1 GEXDMGACZSUNJN-UHFFFAOYSA-N 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 235000021245 dietary protein Nutrition 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000036267 drug metabolism Effects 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 239000003759 ester based solvent Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000003976 glyceryl group Chemical group [H]C([*])([H])C(O[H])([H])C(O[H])([H])[H] 0.000 description 1
- 230000005484 gravity Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000009469 supplementation Effects 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
Classifications
-
- 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%.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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)
| Publication Number | Publication Date |
|---|---|
| WO2015063659A1 true WO2015063659A1 (en) | 2015-05-07 |
Family
ID=51982661
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IB2014/065578 WO2015063659A1 (en) | 2013-10-30 | 2014-10-24 | Process for the preparation of glycerol phenylbutyrate |
Country Status (2)
| Country | Link |
|---|---|
| IN (1) | IN2013MU03442A (enrdf_load_stackoverflow) |
| WO (1) | WO2015063659A1 (enrdf_load_stackoverflow) |
Cited By (7)
| 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 |
| US9962359B2 (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)
| 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 |
-
2014
- 2014-10-24 IN IN3442MU2013 patent/IN2013MU03442A/en unknown
- 2014-10-24 WO PCT/IB2014/065578 patent/WO2015063659A1/en active Application Filing
Patent Citations (3)
| 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)
| 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)
| 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 |
| US10183003B2 (en) | 2011-09-30 | 2019-01-22 | 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 |
| US9962358B2 (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 |
| US10045958B1 (en) | 2011-09-30 | 2018-08-14 | 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 |
| US10183006B2 (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 |
| US10183004B2 (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 |
Also Published As
| Publication number | Publication date |
|---|---|
| IN2013MU03442A (enrdf_load_stackoverflow) | 2015-07-17 |
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