WO2021019555A1 - Procédé de préparation d'acide 4-amino-2-hydroxy-4-oxobutanoïque et produit préparé à partir de celui-ci - Google Patents

Procédé de préparation d'acide 4-amino-2-hydroxy-4-oxobutanoïque et produit préparé à partir de celui-ci Download PDF

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Publication number
WO2021019555A1
WO2021019555A1 PCT/IN2020/050639 IN2020050639W WO2021019555A1 WO 2021019555 A1 WO2021019555 A1 WO 2021019555A1 IN 2020050639 W IN2020050639 W IN 2020050639W WO 2021019555 A1 WO2021019555 A1 WO 2021019555A1
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WO
WIPO (PCT)
Prior art keywords
hydroxy
amino
compound
oxobutanoic acid
stirring
Prior art date
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PCT/IN2020/050639
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English (en)
Inventor
Sunita BHAGAT
S.B Sharma
Pankaj Sharma
Nikhil Khurana
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Indian Council Of Medical Research
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Application filed by Indian Council Of Medical Research filed Critical Indian Council Of Medical Research
Publication of WO2021019555A1 publication Critical patent/WO2021019555A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/08—Preparation of carboxylic acid amides from amides by reaction at nitrogen atoms of carboxamide groups

Definitions

  • the present invention relates to a novel process for the preparation of a synthetic alpha hydroxyl succinamic acid, which is useful as active pharmaceutical ingredient in controlling diabetes mellitus. More specifically, the present invention relates to an efficient process for the preparation of 4-amino-2-hydroxy-4- oxobutanoic acid and intermediates thereof, which are amenable to large scale commercial production and provides the required products with improved yield for the management of type 2 diabetes mellitus and its complications.
  • Diabetes is a metabolic disorder characterized by high blood sugar level in the blood which results in hyperglycemia, lipoprotein abnormalities and raised metabolic rate.
  • a broad range of chemical drugs and ayurvedic herbal formulations are known in the art for management of diabetes.
  • the synthetic methodology adopted in the present invention is unique as the designing of molecule requires basic understanding of retrosynthetic approach. Different plausible routes can be proposed to achieve the synthesis of this molecule, but an expertise understanding of optimizing the intermediates and final compound is important.
  • the structure of present compound has been confirmed by spectral data and has been fully explored for its anti-diabetic potential which was found to be at par with the herbal compound.
  • the present invention provides a process for the preparation of 4-amino-2- hydroxy-4-oxobutanoic acid, an active anti-hyperglycemic compound and intermediates thereof.
  • the process of the present invention facilitates the commercial availability of said anti-hyperglycemic compound and its intermediates with acceptable yield.
  • the invention provides a process the preparation of 4-amino-2-hydroxy-4-oxobutanoic acid, wherein the process comprises following steps:
  • the present invention provides a process the preparation of 4-amino-2-hydroxy-4-oxobutanoic acid, wherein stirring in step c) of process is carried out for 5 to 7 hours and 4-((benzyloxy)amino)-2-hydroxy-4-oxobutanoic acid obtained in step c) is having a melting point in the range of 79-82°C.
  • the present invention provides a process the preparation of 4-amino-2-hydroxy-4-oxobutanoic acid, wherein stirring in step d) of process is carried out for 6 to 8 hours under hydrogen atmosphere.
  • the present invention provides a process the preparation of 4-amino-2-hydroxy-4-oxobutanoic acid, wherein the 3-hydroxy-4-methoxy-4- oxobutanoic acid obtained in step a) of process is having a melting point in the range of 69-70°C.
  • the present invention provides a process the preparation of 4-amino-2-hydroxy-4-oxobutanoic acid, wherein the final stirring in reaction of step b) of process is carried out for 11 to 13 hours and the methyl 4- ((benzyloxy)amino)-2-hydroxy-4-oxobutanoate obtained in step b) of process is having a melting point in the range of 68-72°C.
  • the present invention provides a compound of formula 4- amino-2-hydroxy-4-oxobutanoic acid as obtained from the process as described herein.
  • the present invention provides a compound of formula 4- amino-2-hydroxy-4-oxobutanoic acid, wherein the compound is having anti- hyperglycemic, hypolipidemic, anti-oxidant and anti-atherosclerotic activities at par with herbal alpha-hydroxysuccinamic acid isolated from E Jambolana. DESCRIPTION OF THE ACCOMPANYING DRAWINGS
  • Figure 1 illustrates the fasting blood glucose level after treatment with herbal compound (Flic) and present synthetic compound at week 0 and week 6 of the study.
  • Figure2 illustrates the HbAlc levels after treatment with herbal compound (Flic) and present synthetic compound at week 0 and week 6 of the study.
  • Figure3 illustrates the total serum cholesterol levels after treatment with herbal compound (Flic) and present synthetic compound at week 0 and week 6 of the study.
  • Figure4 illustrates the total serum triglyceride levels after treatment with herbal compound (Flic) and present synthetic compound at week 0 and week 6 of the study.
  • Figure5 Illustrates the HDL-C levels after treatment with herbal compound (Flic) and present synthetic compound at week 0 and week 6 of the study.
  • Figure 6 illustrates the LDL-C levels after treatment with herbal compound (Flic) and present synthetic compound at week 0 and week 6 of the study.
  • Figure 7 illustrates the VLDL-C levels after treatment with herbal compound (Flic) and present synthetic compound at week 0 and week 6 of the study.
  • the articles“a”,“an” and“the” are used to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article.
  • the present invention provides a process the preparation of 4-amino-2-hydroxy-4-oxobutanoic acid, wherein stirring in step c) of process is carried out for 5 to 7 hours and 4-((benzyloxy)amino)-2-hydroxy-4-oxobutanoic acid obtained in step c) of process is having a melting point in the range of 79-82°C.
  • the present invention provides a process the preparation of 4-amino-2-hydroxy-4-oxobutanoic acid, wherein stirring in step d) of process is carried out for 6 to 8 hours under hydrogen atmosphere.
  • the present invention provides a process the preparation of 4-amino-2-hydroxy-4-oxobutanoic acid, wherein the 3-hydroxy-4-methoxy-4- oxobutanoic acid obtained in step a) of process is having a melting point in the range of 69-70°C.
  • the present invention provides a process the preparation of 4-amino-2-hydroxy-4-oxobutanoic acid, wherein the final stirring in reaction of step b) of process is carried out for 11 to 13 hours and the methyl 4- ((benzyloxy)amino)-2-hydroxy-4-oxobutanoate obtained in step b) of process is having a melting point in the range of 68-72°C.
  • a process for preparing 4-amino-2-hydroxy-4-oxobutanoic acid wherein the process is a simple work-up procedure with optimum conditions for good yield of 4-amino-2-hydroxy- 4-oxobutanoic acid and is easily adapted on commercial scale as efficient and convenient process.
  • a process for preparing 4-amino-2-hydroxy-4-oxobutanoic acid as described herein wherein thin- layer chromatography is preferably used to monitor the progress of the reaction and the crude compound of the process are purified by column chromatography, thereby making the process simpler and more adaptable for large scale commercial production.
  • a therapeutic doze of 20mg/kg of body weight of herbal compound (Flic) and present synthetic compound of formula 6 are administered to Group C and Group D experimental animals respectively.
  • Glibenclamide a standard drug at a dose of 600pg/kg was given to Group E experimental animals.
  • the animals of the groups were assessed for various parameters namely fasting blood glucose level, HbAlc (%) level, total cholesterol level; serum triglycerides level; HDL-C, LDL-C and VLDL-C level, serum insulin levels, MDA levels and experimental data recorded was analyzed by statistical methods. Values are mean ⁇ S.D was calculated for below mentioned experimental groups. Difference was assumed to be significant at the level of p ⁇ 0.05.
  • the results of present synthetic compound of formula 6 are compared with herbal compound (Flic) as shown in Figures 1 to 7.
  • Trifluoroacetic anhydride 45 mL was added to L-malic (compound 1) acid (10.0 g, 1.0 eq), at 0°C and allowed to stir at room temperature. After 1.5 hours, excess of TFAA and TFA were distilled off on rotary evaporator at temperature ⁇ 30°C. The white crystalline compound obtained was cooled to 0°C and anhydrous methanol (50 mL) was added portion wise. The reaction mixture was further allowed to stir at room temperature for 3hours. The progress of reaction was monitored by TLC and after the completion of reaction; excess methanol was distilled off under reduced pressure.
  • Step 2 Synthesis of methyl 4-((benzyloxy) amino)-2-hydroxy-4-oxobutanoate (compound 4)
  • Step 3 Synthesis of 4-((benzyloxy) amino)-2-hydroxy-4-oxobutanoic acid (compound 5)
  • Step 4 Synthesis of 4-amino-2-hydroxy-4-oxobutanoic acid (compound 6)
  • Table 1 showing fasting blood glucose levels of healthy control and STZ+ NAD induced diabetic albino rats after treatment with anti-diabetic herbal comp (Flic) and present compound 4-amino-2-hydroxy-4-oxobutanoic acid (compound 6)at week 0 and week 6 of the study.
  • Table 2 showing HbAlc levels after treatment with herbal compound (Flic) and present compound 6at week 0 and week 6 of the study.
  • Table 3 showing Total cholesterol levels and serum triglycerides after treatment with herbal compound (Flic) and present compound 6at week 0 and week 6 of the study.
  • Table 4 showing serum HDL-C levels after treatment with herbal compound (Flic) and present compound 6at week 0 and week 6 of the study.
  • HDL-C levels showed no significant difference at week 0 in any of the study groups as compared with healthy control, although it has showed difference at week 6.
  • HDL-C levels in (group B) has decreased at 6 weeks (p ⁇ 0.001) as compared to healthy control (group A) while HDL-C levels had shown improvement in Flic treated (group C), present compound of formula 6 treated (group D) and glibenclamide treated (group E) as compared to diabetic control (group D) (p ⁇ 0.001).
  • group C Flic treated
  • group D present compound of formula 6 treated
  • group E glibenclamide treated
  • Table 5 showing serum LDL-C& VLDL-C levels after treatment with herbal compound (Flic) and present compound (6) at week 0 and week 6 of the study
  • Table 6 showing serum insulin and MDA levels after treatment with herbal compound (Flic) and present compound 6 at week 0 and week 6 of the study
  • diabetic control rats (group B) showed a significant increase in MDA levels (p ⁇ 0.001).
  • group C diabetic control rats
  • group D present compound 6

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Diabetes (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Obesity (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Hematology (AREA)
  • Emergency Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Endocrinology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Procédé de préparation d'acide 4-amino-2-hydroxy-4-oxobutanoïque et d'intermédiaires de celui-ci. Le composé préparé par le présent procédé est utile dans la gestion du diabète. Le présent procédé permet de produire 0,35 gm, 63 % du composé souhaité. La structure du composé préparé par le présent procédé est confirmée par des données spectrales et son potentiel anti-diabétique se révèle être au moins égal au composé à base d'herbes (FIIc), un composé anti-diabétique actif isolé de pulpe de fruit d'Eugenia jambolana. Le procédé de la présente invention est simple, peu coûteux et rentable, et peut être facilement adopté pour une production commerciale avec un degré élevé de consistance et de reproductibilité.
PCT/IN2020/050639 2019-07-26 2020-07-24 Procédé de préparation d'acide 4-amino-2-hydroxy-4-oxobutanoïque et produit préparé à partir de celui-ci WO2021019555A1 (fr)

Applications Claiming Priority (2)

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IN201911030346 2019-07-26
IN201911030346 2019-07-26

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WO2021019555A1 true WO2021019555A1 (fr) 2021-02-04

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2716243B2 (ja) * 1990-05-15 1998-02-18 鐘淵化学工業株式会社 Ｎ―ベンジル―３―ヒドロキシスクシンアミド酸およびその製造法
CN104311442A (zh) * 2014-09-27 2015-01-28 张远强 卤代萘环的丁二酸酰胺衍生物、其制备方法及用途

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2716243B2 (ja) * 1990-05-15 1998-02-18 鐘淵化学工業株式会社 Ｎ―ベンジル―３―ヒドロキシスクシンアミド酸およびその製造法
CN104311442A (zh) * 2014-09-27 2015-01-28 张远强 卤代萘环的丁二酸酰胺衍生物、其制备方法及用途

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
KHURANA NIKHIL, SHARMA PANKAJ, BHAGAT SUNITA, SHARMA SUMAN BALA: "Effect of a novel succinamic acid derivative as potential anti-diabetic agent in experimental diabetic rats", JOURNAL OF DRUG DELIVERY AND THERAPEUTICS, vol. 8, no. 6S, 15 December 2018 (2018-12-15), pages 57 - 62, XP055789223, DOI: 10.22270/jddt.v8i6-s.2080 *
TANWAR REENU SINGH, SHARMA SUMAN BALA, SINGH USHA RANI, PRABHU KRISHNA MADHAVA: "Antiatherosclerotic Potential of Active Principle Isolated from Eugenia jambolana in Streptozotocin-Induced Diabetic Rats", vol. 2011, 7 April 2011 (2011-04-07), pages 1 - 9, XP055789224, DOI: 10.1155/2011/127641 *

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