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WO2023097691A1 - Procédé d'obtention d'un acide aminé chiral à chaîne ramifiée b-chirale à haute sélectivité - Google Patents

Procédé d'obtention d'un acide aminé chiral à chaîne ramifiée b-chirale à haute sélectivité Download PDF

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Publication number
WO2023097691A1
WO2023097691A1 PCT/CN2021/135522 CN2021135522W WO2023097691A1 WO 2023097691 A1 WO2023097691 A1 WO 2023097691A1 CN 2021135522 W CN2021135522 W CN 2021135522W WO 2023097691 A1 WO2023097691 A1 WO 2023097691A1
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WIPO (PCT)
Prior art keywords
chiral
branched
amino acids
highly selective
obtaining highly
Prior art date
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Ceased
Application number
PCT/CN2021/135522
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English (en)
Chinese (zh)
Inventor
周章涛
叶伟平
费安杰
王杨
王道功
罗富元
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Guangdong Raffles Pharmatech Co Ltd
Original Assignee
Guangdong Raffles Pharmatech Co Ltd
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.)
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Publication date
Application filed by Guangdong Raffles Pharmatech Co Ltd filed Critical Guangdong Raffles Pharmatech Co Ltd
Priority to PCT/CN2021/135522 priority Critical patent/WO2023097691A1/fr
Publication of WO2023097691A1 publication Critical patent/WO2023097691A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/16—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions not involving the amino or carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C229/36—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton

Definitions

  • the invention belongs to the field of organic chemical synthesis, and in particular relates to a method for obtaining highly selective ⁇ -chiral branched-chain chiral amino acids.
  • ⁇ -branched chiral amino acid compounds are an important class of organic synthesis intermediates, which play an extremely important role in the field of biopharmaceuticals, especially in the stability of polypeptide molecules and the modification of spatial structure. Due to the construction of multiple chiral centers, in order to efficiently obtain a single-configuration product, the preparation process of ⁇ -branched chiral amino acid compounds is highly demanding.
  • the methods for preparing ⁇ -branched chiral amino acid compounds are limited, and there are mainly the following two schemes: 1) enzyme-catalyzed fermentation and 2) asymmetric catalytic hydrogenation.
  • the enzyme-catalyzed fermentation method has high requirements on the activity and selectivity of the enzyme catalyst, and is only applicable to certain types of chiral amino acids, which makes the process development difficult and relatively low in efficiency;
  • the asymmetric catalytic hydrogenation method although also suitable for the catalyst
  • the requirements for activity, cost and selectivity are high, but the types of catalysts and chiral ligands that can be selected are wide, the condition screening is flexible and changeable, and the feasibility of later scale-up production is high, which is the current key research direction.
  • the preparation of unnatural ⁇ -branched chiral amino acids has always been an important research direction in the pharmaceutical field, especially ⁇ -chiral branched chain amino acids with multiple chiral centers.
  • the present invention starts from latent chiral olefin compounds and constructs ⁇ -chiral branched-chain chiral amino acids in one step with high selectivity through asymmetric hydrogenation.
  • the present invention has developed a new process route, which has better applicability, specifically
  • the synthetic route and reaction conditions are as follows:
  • R 1 is alkyl or aryl
  • R 2 is alkyl or aryl
  • R 3 is alkyl
  • R 4 is benzoyl or acetyl
  • R 1 and R 2 can form a ring; because R 1 and R 2 are essentially is not the site where the reaction occurs, and whether R 1 and R 2 form a ring will not have a substantial impact on the reaction.
  • R1 is an alkyl group below C30, a cyclohydrocarbyl group below C40, or an aryl group below C40
  • R2 is an alkyl group below C30, a cyclohydrocarbyl group below C40, or an aryl group below C40
  • R3 is below C30 the alkyl group
  • R 1 and R 2 are methyl, ethyl, phenyl or cycloalkyl
  • R 3 is methyl, ethyl or benzyl
  • R 4 is benzoyl, acetyl or tert-butyloxycarbonyl carbonate .
  • the required metal catalyst is a monovalent ruthenium catalyst.
  • the monovalent ruthenium catalyst is Rh(COD) 2 BF 4 and/or [Rh(COD)Cl] 2 .
  • the desired chiral ligand is a chiral ligand based on a chiral ferrocenephosphine ligand; preferably, the chiral ligand based on a chiral ferrocenephosphine ligand
  • the ligands are Josiphos series commercial catalysts.
  • the required solvent is one of dichloromethane, methanol or ethanol.
  • R 1 is an alkyl group, a cycloalkyl group, an aryl group, such as an alkyl group below C30, a cycloalkyl group below C40, or an aryl group below C40;
  • R 2 is Alkyl, cycloalkyl, aryl, such as alkyl below C30, cyclohydrocarbyl below C40, or aryl below C40;
  • R3 is alkyl, such as alkyl below C30;
  • R4 is benzoyl or acetyl .
  • the desired metal catalyst is Rh(COD) 2 BF 4 , [Rh(COD)Cl] 2 , preferably Rh(COD) 2 BF 4 ;
  • the desired chiral ligand is a chiral phosphine ligand, preferably a chiral ligand based on a chiral ferrocene phosphine ligand, preferably a commercial catalyst of the Jos iphos series, more preferably (R)-1-[(SP)- 2-(diphenylphosphino) ferrocene] ethyl di-tert-butylphosphine, its structure is as follows;
  • the required solvent is dichloromethane, methanol, preferably dichloromethane;
  • the required hydrogen pressure is 30-50atm, preferably 30atm; the reaction can be effectively completed within the range of 30-50atm, but because the greater the pressure, the higher the requirements for the reactor and the higher the risk factor, so in meeting the process requirements Under the precursor of , the reaction conditions with less pressure are preferred.
  • the desired reaction temperature is 60-80°C, preferably 80°C.
  • choosing a higher temperature can increase the reaction rate and reduce the reaction time.
  • the beneficial effect of the present invention is that: adopting the method for preparing ⁇ -chiral branched-chain chiral amino acid compounds of the present invention can efficiently construct ⁇ -chiral branched-chain chiral amino acids with multiple chiral centers in one step, which is different from traditional enzymes Catalyzed fermentation process, this scheme has better substrate universality, lower cost, and is more environmentally friendly, and can prepare a variety of ⁇ -chiral branched-chain chiral amino acid compounds with complex structures.
  • Fig. 1 is the chiral HPLC spectrum of the compound 2a racemate prepared in the example of the present invention.
  • Fig. 2 is the chiral HPLC spectrum of the compound optical alcohol 2a prepared in the example of the present invention.
  • Fig. 3 is the hydrogen spectrum of compound 2a prepared in the embodiment of the present invention.
  • the synthetic route is as follows:

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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 un procédé d'obtention d'un acide aminé chiral à chaîne ramifiée β-chirale à haute sélectivité. La voie de synthèse du procédé d'obtention d'un acide aminé chiral à chaîne ramifiée β-chirale à haute sélectivité est la suivante : R1 représente un alkyle ou un aryle ; R2 représente un alkyle ou un aryle ; R3 représente un alkyle ; et R4 représente un benzoyle ou un acétyle. À l'aide du procédé de préparation d'un composé acide aminé chiral à chaîne ramifiée β-chirale, on peut construire efficacement en une étape un acide aminé chiral à chaîne ramifiée β-chirale comportant de nombreux centres chiraux. La solution de la présente invention est différente du procédé classique de fermentation à catalyse enzymatique et présente une meilleure généralité de substrat et un coût plus faible, il est plus respectueux de l'environnement et permet de préparer différents composés acides aminés chiraux à chaîne ramifiée β-chirale présentant des structures complexes.
PCT/CN2021/135522 2021-12-03 2021-12-03 Procédé d'obtention d'un acide aminé chiral à chaîne ramifiée b-chirale à haute sélectivité Ceased WO2023097691A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/CN2021/135522 WO2023097691A1 (fr) 2021-12-03 2021-12-03 Procédé d'obtention d'un acide aminé chiral à chaîne ramifiée b-chirale à haute sélectivité

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2021/135522 WO2023097691A1 (fr) 2021-12-03 2021-12-03 Procédé d'obtention d'un acide aminé chiral à chaîne ramifiée b-chirale à haute sélectivité

Publications (1)

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WO2023097691A1 true WO2023097691A1 (fr) 2023-06-08

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PCT/CN2021/135522 Ceased WO2023097691A1 (fr) 2021-12-03 2021-12-03 Procédé d'obtention d'un acide aminé chiral à chaîne ramifiée b-chirale à haute sélectivité

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1950354A (zh) * 2004-05-11 2007-04-18 默克公司 N－磺酰化－氨基酸衍生物的制备方法
CN114105793A (zh) * 2021-12-03 2022-03-01 广东莱佛士制药技术有限公司 一种获得高选择性β-手性支链手性氨基酸的方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1950354A (zh) * 2004-05-11 2007-04-18 默克公司 N－磺酰化－氨基酸衍生物的制备方法
CN114105793A (zh) * 2021-12-03 2022-03-01 广东莱佛士制药技术有限公司 一种获得高选择性β-手性支链手性氨基酸的方法

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
BLASER, HANS-ULRICH ET AL.: "(R)-1-[(1R)-1-(Dicyclohexylphosphino) ethyl]-2-(diphenylphosphino)-ferrocene and (2S)-1-[(1R)-1-(Dicyclohexylphosphino) ethyl]-2-(diphenylphosphino)- ferrocene (Josiphos)", ENCYCLOPEDIA OF REAGENTS FOR ORGANIC SYNTHESIS, 14 March 2008 (2008-03-14), XP009546942 *
BUERGLER, JONAS F. ET AL.: "P-Stereogenic Trifluoromethyl Derivatives of Josiphos: Synthesis, Coordination Properties, and Applications in Asymmetric Catalysis", CHEMISTRY - A EUROPEAN JOURNAL, vol. 18, 8 December 2011 (2011-12-08), XP071834580, DOI: 10.1002/chem.201102390 *
CHANGYOU ZHOU, MARGARETA GARCIA-CALVO, SHIRLY PINTO, MATTHEW LOMBARDO, ZHE FENG, KATE BENDER, KELLYANN D. PRYOR, URMI R. BHATT, RE: "Design and Synthesis of Prolylcarboxypeptidase (PrCP) Inhibitors To Validate PrCP As A Potential Target for Obesity", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, vol. 53, no. 19, 14 October 2010 (2010-10-14), pages 7251 - 7263, XP055096999, ISSN: 00222623, DOI: 10.1021/jm101013m *
MOLINARO CARMELA, SCOTT JEREMY P., SHEVLIN MICHAEL, WISE CHRISTOPHER, MÉNARD ALAIN, GIBB ANDREW, JUNKER ELLYN M., LIEBERMAN DAVID: "Catalytic, Asymmetric, and Stereodivergent Synthesis of Non-Symmetric β,β-Diaryl-α-Amino Acids", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, AMERICAN CHEMICAL SOCIETY, vol. 137, no. 2, 21 January 2015 (2015-01-21), pages 999 - 1006, XP093071455, ISSN: 0002-7863, DOI: 10.1021/ja511872a *
TOGNI, ANTONIO ET AL.: "A Novel Easily Accessible Chiral Ferrocenyldiphosphine for Highly Enantioselective Hydrogenation, Allylic Alkylation, and Hydroboration Reactions", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 116, no. 9, 31 December 1994 (1994-12-31), XP001056531, DOI: 10.1021/ja00088a047 *
YOSHIKAWA NAOKI, TAN LUSHI, MCWILLIAMS J. CHRISTOPHER, RAMASAMY DEEPA, SHEPPARD RUTH: "Catalytic Enantioselective Hydrogenation of N -Alkoxycarbonyl Hydrazones: A Practical Synthesis of Chiral Hydrazines", ORGANIC LETTERS, AMERICAN CHEMICAL SOCIETY, US, vol. 12, no. 2, 15 January 2010 (2010-01-15), US , pages 276 - 279, XP093071456, ISSN: 1523-7060, DOI: 10.1021/ol902602c *

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