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WO2012153991A2 - Procédé de préparation d'un α-aminonitrile chiral à l'aide d'un catalyseur pour une réaction de strecker - Google Patents

Procédé de préparation d'un α-aminonitrile chiral à l'aide d'un catalyseur pour une réaction de strecker Download PDF

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Publication number
WO2012153991A2
WO2012153991A2 PCT/KR2012/003666 KR2012003666W WO2012153991A2 WO 2012153991 A2 WO2012153991 A2 WO 2012153991A2 KR 2012003666 W KR2012003666 W KR 2012003666W WO 2012153991 A2 WO2012153991 A2 WO 2012153991A2
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Prior art keywords
formula
aminonitrile
cyanide
chiral
group
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Ceased
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PCT/KR2012/003666
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English (en)
Korean (ko)
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WO2012153991A3 (fr
Inventor
송충의
오중석
양하롱
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Sungkyunkwan University Foundation for Corporate Collaboration
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Sungkyunkwan University Foundation for Corporate Collaboration
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Publication of WO2012153991A2 publication Critical patent/WO2012153991A2/fr
Publication of WO2012153991A3 publication Critical patent/WO2012153991A3/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/32—Separation; Purification; Stabilisation; Use of additives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/22—Organic complexes
    • B01J31/2204—Organic complexes the ligands containing oxygen or sulfur as complexing atoms
    • B01J31/2208—Oxygen, e.g. acetylacetonates
    • B01J31/2213—At least two complexing oxygen atoms present in an at least bidentate or bridging ligand
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B57/00—Separation of optically-active compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/24—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the same saturated acyclic carbon skeleton
    • C07C255/25—Aminoacetonitriles
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/30—Addition reactions at carbon centres, i.e. to either C-C or C-X multiple bonds
    • B01J2231/32—Addition reactions to C=C or C-C triple bonds
    • B01J2231/322—Hydrocyanation
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/02—Compositional aspects of complexes used, e.g. polynuclearity
    • B01J2531/0261—Complexes comprising ligands with non-tetrahedral chirality
    • B01J2531/0266—Axially chiral or atropisomeric ligands, e.g. bulky biaryls such as donor-substituted binaphthalenes, e.g. "BINAP" or "BINOL"
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to a method for preparing chiral ⁇ -aminonitrile using a catalyst for a striker reaction, and more particularly, alkali metal cyanide alone or alkali metal cyanide in the presence of a catalyst derivatized with ethylene glycol. And a method for producing (S)-or (R) - ⁇ -aminonitrile having enantioselectivity through stereoselective stretcher reaction using a cyanide source which is a combination of a sulfonic acid alkali metal salt or sulfinic acid.
  • Alpha-amino acids play a very important role in vivo as the building blocks of proteins.
  • development of efficient and economical synthesis of non-natural amino acids widely used as components of pharmaceuticals and chiral catalysts is considered one of the most important research tasks for modern organic synthetic chemists.
  • the Strecker Synthesis reaction which is considered to be the most important in the synthesis of such alpha amino acids, is a method of producing alpha-amino acids by hydrolyzing iminonitrile obtained through the reaction of imine and hydrogen cyanide. This is one of the most commonly used methods.
  • the present inventors have used a catalyst derived from a small amount of chiral ethylene glycol composed of organic material to synthesize asymmetrical stretcher using cyanide source such as KCN, which is excellent in thermal stability, storage stability, economical and easy to use. It has been successful to obtain chiral aminonitrile, a synthetic precursor of chiral alpha amino acids, in high yield and high optical selectivity.
  • chiral ⁇ -aminonitrile of various structures can be synthesized from ⁇ -amido sulfone, which is a precursor of imine, which is a sensitive starting material, as well as a hydrolysis-sensitive starting material, in high yield and very high stereoselectivity.
  • ⁇ -amido sulfone which is a precursor of imine, which is a sensitive starting material, as well as a hydrolysis-sensitive starting material, in high yield and very high stereoselectivity.
  • the present invention comprises the step of using a cyanide source in the presence of a catalyst represented by the formula (1) or formula (2), and the cyanide source is (i) alkali metal cyanide; (ii) alkali metal cyanide and alkali metal salts of sulfinic acids represented by formula (6); And (iii) one selected from the group consisting of alkali metal cyanide and sulfinic acid represented by the formula (7).
  • R is halogen and n is 1-5.
  • M is an alkali metal
  • Ar 1 is a C 6-12 aryl group.
  • Ar 2 is a C 6-12 aryl group.
  • the present invention includes the steps of a stretcher reaction of an imine of formula 3 or an ⁇ -amido sulfone of formula 4 with a cyanide source in an organic solvent in the presence of a catalyst represented by formula 1 or formula 2
  • the cyanide source is (i) an alkali metal cyanide; (ii) alkali metal cyanide and alkali metal salts of sulfinic acids represented by formula (6); And (iii) one selected from the group consisting of alkali metal cyanide and sulfinic acid represented by the general formula (7).
  • R is halogen and n is 1-5.
  • R 3 is selected from the group consisting of C 1-30 alkyl group, C 3-30 cycloalkyl group, C 6-30 aryl group, and C 4-30 heteroaryl group, wherein the alkyl group, cycloalkyl group , Aryl group and heteroaryl group are unsubstituted or substituted with halogen, nitrogen, oxygen or sulfur, P is an amine protecting group, Ar is a C 6-12 aryl group or C 4-12 heteroaryl group.
  • M is an alkali metal
  • Ar 1 is a C 6-12 aryl group.
  • Ar 2 is a C 6-12 aryl group.
  • the present invention provides chiral ⁇ -aminonitrile prepared according to the method of the present invention.
  • the present invention provides a method for producing a chiral ⁇ -amino acid by hydrolyzing chiral ⁇ -aminonitrile prepared according to the method of the present invention with an acid.
  • the present invention provides chiral ⁇ -amino acids prepared according to the process of the invention.
  • the present invention also provides a catalyst for a striker reaction selected from the following table.
  • R is halogen
  • the chiral ⁇ -aminonitrile can be produced in high optical yield by using a cyanide source according to the present invention in the presence of a catalyst represented by the following formula (1) or (2).
  • the term "stretcher reaction” is well known for the synthesis of ⁇ -aminonitrile, a precursor useful in amino acid synthesis, and is generally a compound having an imine group or a precursor of ⁇ -amidosulfone and cyanide. It means a process occurring under the action of a specific catalyst under this organic solvent. Since the term itself includes the definition of a substance that participates in a striker reaction, it is not necessary to specifically limit the substance that reacts with the cyanide source, i.e., a compound having an imine group or a precursor of imine.
  • the imine of formula (3) or (alpha) -amido sulfone of formula (4) is added in an organic solvent with the catalyst represented by formula (1) or formula (2) and the cyanide source of the invention
  • a chiral ⁇ -aminonitrile of Formula 5 of high enantiomeric excess can be prepared by carrying out a stretcher reaction such as Scheme 1 or Scheme 2.
  • chiral ⁇ -aminonitriles of the formula (5) can be obtained with very high optical selectivity under optimized conditions of cyanation reactions, especially with enantiomeric excess of more than 90%.
  • the catalyst used in the present invention is a compound represented by Formula 1 or Formula 2 wherein ethylene glycol is derivatized:
  • R is halogen and n is 1-5.
  • R is Cl, Br or I, and n is 1-4.
  • R is Br or I and n is 2 or 3.
  • R is I and n is 2.
  • the catalyst represented by the formula (1) or (2) may be used by those skilled in the art based on the imine of the formula (3) or the ⁇ - amido sulfone of the formula (4), but in terms of optical purity In an amount of preferably 0.01 to 100 mol%, particularly preferably 1 to 30 mol%.
  • R 3 is selected from the group consisting of C 1-30 alkyl group, C 3-30 cycloalkyl group, C 6-30 aryl group and C 4-30 heteroaryl group, wherein the alkyl group, cycloalkyl group, The aryl group and heteroaryl group are unsubstituted or substituted with halogen, nitrogen, oxygen or sulfur, P is an amine protecting group, Ar is a C 6-12 aryl group or a C 4-12 heteroaryl group.
  • the term 'amine protecting group' refers to a functional group capable of protecting the nitrogen atom of the amine during the reaction
  • suitable amine protecting groups are known in the art, for example, Green, the entire teachings of which are incorporated by reference. And Protecting Groups in Organic Synthesis, Wuts, John Wiley and Sons, 1991 and Protecting Groups in Organic Synthesis, Green and Wuts, John Wiley and Sons, 2007. Therefore, the amine protecting group can use a well-known amine protecting group without limitation.
  • Examples of the amine protecting group include methyloxycarbonyl group, benzyloxycarbonyl group, p-methoxybenzyloxy carbonyl group, t-butyloxycarbonyl group (Boc), 9-fluorenylmethyloxycarbonyl group (FMOC), allyloxycarbonyl (Alloc), Benzoyl group (Bz), benzyl (Bn) group, p-methoxybenzyl group (PMB), 3,4-dimethoxybenzyl group (DMPM), p-methoxyphenyl group (PMP), tosyl group (Ts), trimethyl Silylethyloxy carbonyl group (Teoc), benzhydryl, triphenylmethyl (Trityl), (4-methoxyphenyl) diphenylmethyl (Mmt), dimethoxytrityl (DMT), diphenylphosphino group and the like. have.
  • Ar is phenyl or tolyl.
  • P is an amine protecting group, and a methyloxycarbonyl group, benzyloxycarbonyl group, p-methoxybenzyloxy carbonyl group, t-butyloxycarbonyl group (Boc), and 9-fluorenylmethyloxycarbonyl group (FMOC) It is preferably selected from the group consisting of.
  • R 3 and P are as defined in formula (3) and (4).
  • the cyanide source which is a nucleophile for the striker reaction, comprises: (i) alkali metal cyanide; (ii) alkali metal cyanide and alkali metal salts of sulfinic acids represented by formula (6); And (iii) an alkali metal cyanide and sulfinic acid represented by the formula (7).
  • M is an alkali metal
  • Ar 1 is a C 6-12 aryl group, preferably phenyl or tolyl.
  • Ar 2 is a C 6-12 aryl group, preferably phenyl or tolyl.
  • potassium cyanide As an alkali metal cyanide, it is preferable to use potassium cyanide or sodium cyanide, and especially potassium cyanide is used.
  • cyanide sources for the striker reaction include hydrogen cyanide (HCN), acetone cyanohydrin, trimethylsilyl cyanide (TMSCN), alkali metal cyanide and the like.
  • HCN hydrogen cyanide
  • TMSCN trimethylsilyl cyanide
  • the preparation method according to the present invention makes it possible to effectively carry out the stretcher reaction using an easy-to-handle alkali metal cyanide in place of the highly toxic hydrogen cyanide, acetone cyanohydrin and trimethylsilyl cyanide among known cyanide sources. This is because the structure of the catalyst represented by the formula (1) or (2) according to the present invention contributes to the reactivity of the cyanide source participating in the striker reaction.
  • the ether group possessed by the catalyst of the present invention acts as a Lewis base with respect to the alkali metal cation to release a counteranion and to improve the solubility of the alkali metal salt, and also has a hydroxyl present at the terminal. It is based on the fact that the group (-OH) can stabilize the transition state by activating an electrophile through hydrogen bonding.
  • the cyanide source of the present invention may be selected and used by the person skilled in the art for an imine of formula (3) or ⁇ -amido sulfone of formula (4), but preferably 1 to 50 equivalents, more preferably 1 to 10 It can be used in the equivalent amount, most preferably 1 to 2 equivalents.
  • an aprotic solvent may be used, and methyl t-butyl ether, diethyl ether, diisopropyl ether, tetrahydrofuran, acetonitrile, chloroform, dichloromethane, dichloroethane, carbon Preference is given to tetrachloride, benzene, toluene, methylcyclohexane and mixtures thereof, in particular dichloromethane, dichloroethane, benzene, toluene and mixtures thereof.
  • the conditions of the production method of the present invention that is, the reaction conditions of the striker can be appropriately selected according to a known method, but in the production method of the present invention, it is preferable that the reaction is carried out at a temperature of -70 ° C to 30 ° C. . Preferably it can be carried out at -20 °C to 30 °C, most preferably -20 °C to 20 °C. Since such a temperature range includes a temperature range of 0 ° C to room temperature, it can be said that it is very useful for industrialization for mass production.
  • the present invention also provides a process for preparing chiral ⁇ -amino acids by hydrolyzing chiral ⁇ -amino nitriles prepared according to the process of the present invention with acids.
  • Acid hydrolysis reactions for synthesizing chiral ⁇ -amino acids from ⁇ -aminonitrile are known in the art and thus detailed discussions are omitted.
  • Chiral ⁇ -amino acids are very important compounds in the pharmaceutical industry in that they provide an important structure for the preparation of various pharmaceutical products. According to the present invention, non-natural ⁇ -amino acids can be easily prepared according to the present invention. Natural ⁇ -amino acids can also be used as pharmaceuticals through mass production.
  • chiral ⁇ -aminonitrile of various structures can be synthesized with very high stereoselectivity in a short time from not only imine which is sensitive to hydrolysis but also ⁇ -amido sulfone, which is a precursor of imine which is a stable starting material.
  • ⁇ -amido sulfone which is a precursor of imine which is a stable starting material.
  • the (R) -form ⁇ -aminonitrile of the (R) -form which is a precursor of the non-natural amino acid (R) - ⁇ -amino acid, can be produced with high optical purity, it can be said that the industrial utility is greater.
  • the preparation method of the present invention is an alkali metal cyanide that is excellent in thermal stability, storage property, and low cost and easy to use instead of toxic hydrogen cyanide (HCN), acetone cyanohydrin and trimethylsilyl cyanide (TMSCN) as a cyanide source.
  • HCN toxic hydrogen cyanide
  • TMSCN trimethylsilyl cyanide
  • the imine of formula 3 or ⁇ -amido sulfone of formula 4 was dissolved in an organic solvent, and then the result of the stretcher reaction by adding 10 mol% of the catalyst of formula 1 or formula 2 and 1.05 equivalents of cyanide source is shown in Table 1 below. Indicated.
  • the prepared ⁇ -aminonitrile was analyzed by high performance liquid chromatography (HPLC) and gas chromatography (GC) to determine enantiomeric excess.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Materials Engineering (AREA)
  • Inorganic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

La présente invention concerne un procédé de préparation d'un α-aminonitrile chiral par une réaction de Strecker par utilisation d'une source de cyanure sous un catalyseur ayant la Formule Chimique 1 ou la Formule Chimique 2 de dérivés d'éthylène glycol. Selon la présente invention, des α-aminonitriles chiraux ayant diverses structures et une stéréosélectivité élevée peuvent être synthétisés. De plus, un α-aminonitrile de type (R), qui est un précurseur d'un acide aminé pouvant être obtenu de manière synthétique, un acide (R)-α-aminé, peut être synthétisé pour avoir une pureté optique élevée. Comme source de cyanure, un cyanure de métal alcalin ayant une bonne stabilité thermique, de bonnes propriétés de stockage, un faible coût et des propriétés de facilité d'utilisation, peut être utilisé seulement, ou une combinaison du cyanure de métal alcalin et d'un sulfinate de métal alcalin ou d'acide sulfinique peut être utilisée. Le procédé selon la présente invention est très utile en développement industriel, très économique et simple.
PCT/KR2012/003666 2011-05-12 2012-05-10 Procédé de préparation d'un α-aminonitrile chiral à l'aide d'un catalyseur pour une réaction de strecker Ceased WO2012153991A2 (fr)

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KR20110044666 2011-05-12

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WO2012153991A3 WO2012153991A3 (fr) 2013-03-21

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016158458A1 (fr) * 2015-03-30 2016-10-06 三菱瓦斯化学株式会社 Matière de base pour photorésine, composition de photorésine et procédé de formation d'un motif de photorésine
US10294183B2 (en) 2014-03-13 2019-05-21 Mitsubishi Gas Chemical Company, Inc. Compound, resin, material for forming underlayer film for lithography, underlayer film for lithography, pattern forming method, and method for purifying the compound or resin
US10303055B2 (en) 2014-03-13 2019-05-28 Mitsubishi Gas Chemical Company, Inc. Resist composition and method for forming resist pattern
US10747112B2 (en) 2015-03-30 2020-08-18 Mitsubishi Gas Chemical Company, Inc. Compound, resin, and purification method thereof, material for forming underlayer film for lithography, composition for forming underlayer film, and underlayer film, as well as resist pattern forming method and circuit pattern forming method

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR820000624B1 (ko) * 1977-12-15 1982-04-19 쟝-클로드 꽁발뒤으 α-아미노산의 제조방법

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10294183B2 (en) 2014-03-13 2019-05-21 Mitsubishi Gas Chemical Company, Inc. Compound, resin, material for forming underlayer film for lithography, underlayer film for lithography, pattern forming method, and method for purifying the compound or resin
US10303055B2 (en) 2014-03-13 2019-05-28 Mitsubishi Gas Chemical Company, Inc. Resist composition and method for forming resist pattern
WO2016158458A1 (fr) * 2015-03-30 2016-10-06 三菱瓦斯化学株式会社 Matière de base pour photorésine, composition de photorésine et procédé de formation d'un motif de photorésine
JPWO2016158458A1 (ja) * 2015-03-30 2017-04-27 三菱瓦斯化学株式会社 レジスト基材、レジスト組成物及びレジストパターン形成方法
CN107533290A (zh) * 2015-03-30 2018-01-02 三菱瓦斯化学株式会社 抗蚀基材、抗蚀剂组合物及抗蚀图案形成方法
US10642156B2 (en) 2015-03-30 2020-05-05 Mitsubishi Gas Chemical Company, Inc. Resist base material, resist composition and method for forming resist pattern
US10747112B2 (en) 2015-03-30 2020-08-18 Mitsubishi Gas Chemical Company, Inc. Compound, resin, and purification method thereof, material for forming underlayer film for lithography, composition for forming underlayer film, and underlayer film, as well as resist pattern forming method and circuit pattern forming method
CN107533290B (zh) * 2015-03-30 2021-04-09 三菱瓦斯化学株式会社 抗蚀基材、抗蚀剂组合物及抗蚀图案形成方法

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KR101430116B1 (ko) 2014-08-14
KR20120127276A (ko) 2012-11-21

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