WO2021002407A1 - Composé contenant un groupe fluoroalkyle et procédé de production associé - Google Patents

Composé contenant un groupe fluoroalkyle et procédé de production associé Download PDF

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WO2021002407A1
WO2021002407A1 PCT/JP2020/025910 JP2020025910W WO2021002407A1 WO 2021002407 A1 WO2021002407 A1 WO 2021002407A1 JP 2020025910 W JP2020025910 W JP 2020025910W WO 2021002407 A1 WO2021002407 A1 WO 2021002407A1
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general formula
group
compound represented
formula
following general
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岡添　隆
雄一郎 石橋
光介 相川
峻輝 三上
京子 野崎
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Ａｇｃ株式会社
国立大学法人 東京大学
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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
    • C07C227/18—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 involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
    • 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
    • C07C227/18—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 involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
    • C07C227/20—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 involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters by hydrolysis of N-acylated amino-acids or derivatives thereof, e.g. hydrolysis of carbamates
    • 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
    • C07C229/04—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 being acyclic and saturated
    • C07C229/20—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 being acyclic and saturated the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/317—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
    • C07C67/327—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups by elimination of functional groups containing oxygen only in singly bound form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
    • C07C69/716—Esters of keto-carboxylic acids or aldehydo-carboxylic acids
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a method for producing a fluoroalkyl group-containing compound, which is an amino acid in which a fluoroalkyl group is introduced into a side chain, and an intermediate thereof.
  • Fluorine-containing amino acids have been reported to exhibit unique bioactivity and are attracting attention. For example, 3,3,3-trifluoroalanine and its derivatives have been reported to act as a suicide inhibitor of pyridoxal enzyme (Non-Patent Document 1). In addition, it has been reported that alanine racemase of Gram-negative bacterium Salmonella typhimurium and Gram-positive bacterium Bacillus stearothermophilus is inactivated by 3,3,3-trifluoroalanine (Non-Patent Document 2). Fluorine-containing amino acids and peptides containing them are expected to be used in the pharmaceutical field as physiologically active substances.
  • Non-Patent Documents 3 and 4 A method for synthesizing optically active perfluoroalkylalanine by introducing a perfluoroalkyl group into optically active acrylamide.
  • Non-Patent Document 6 A method for synthesizing perfluoroalkylglycine via an oxazolone (Non-Patent Document 6).
  • Non-Patent Document 7 A method for synthesizing perfluoroalkylglycine via an oxazole ring (Non-Patent Document 7).
  • CAN cerium ammonium nitrate
  • the methods capable of stereoselectively synthesizing various fluorine-containing amino acids having optical activity by the conventional method are the method of Non-Patent Document 5 and the method of Non-Patent Document 1, 8 or 9.
  • Non-Patent Document 5 is useful as a method for synthesizing optically active perfluoroalkylalanine.
  • an equivalent amount of the optically active site of the substrate is required to obtain the optically active substance.
  • the perfluoroalkyl group has a long chain, the stereoselectivity is not high, and in order to carry out the reaction with good yield, a large excess amount of 10 equivalents of perfluoroalkyl iodide is required.
  • Non-Patent Document 1 The method of Non-Patent Document 1, 8 or 9 is useful as a method for synthesizing perfluoroalkylglycine.
  • the raw material imideyl iodide must be synthesized from perfluoroalkyl iodide and isonitrile, which is complicated (Non-Patent Document 10).
  • the synthesis of the optically active substance by the reported method is before deprotection by CAN, and it is unclear whether the optically active substance can be deprotected while maintaining the optical activity.
  • An object of the present invention is to provide a novel production method and an intermediate thereof capable of efficiently synthesizing a fluoroalkyl group-containing compound which is an amino acid in which a fluoroalkyl group is introduced into a side chain.
  • the present inventors have found a method for synthesizing a fluoroalkyl group-containing compound by a simple method using an oxalic acid diester as a starting material, and completed the present invention. That is, the present invention is as follows.
  • Rf is selected from the group consisting of at least two fluorine atoms are substituted with a further optionally substituted C 1-30 alkyl group (said C 1-30 alkyl group by a halogen atom other than a fluorine atom is C 2 When it is a -30 alkyl group, it may have 1 to 5 ether-bonding oxygen atoms between carbon atoms).
  • R 1 is the following general formula (p-1).
  • R 3 is a optionally substituted C 6-14 aryl group
  • R 4 and R 5 are independently hydrogen atoms or optionally substituted C 6-14 aryl groups, respectively.
  • the black circle means a bond), and is a protecting group selected from 2- (9,10-dioxo) anthrylmethyl group, benzyloxymethyl group, and phenacyl group).
  • the C 1-30 alkyl group (in which Rf is substituted with at least two fluorine atoms and may be further substituted with a halogen atom other than the fluorine atom) in the general formula (3) (in the formula).
  • the C 1-30 alkyl group is a C 2-30 alkyl group, it may have 1 to 5 ether-bonding oxygen atoms between carbon atoms).
  • R 1 is the general formula (p-1) (in the formula, R 3 is a optionally substituted C 6-14 aryl group, and R 4 and R 5 are independent hydrogen atoms or C 6-14 aryl group which may be substituted, black circle means bonder), 2- (9,10-dioxo) anthrylmethyl group, benzyloxymethyl group, and phenacyl.
  • a method for producing a compound represented by (which is a protecting group selected from the groups).
  • Rf is selected from the group consisting of at least two fluorine atoms are substituted with a further optionally substituted C 1-30 alkyl group (said C 1-30 alkyl group by a halogen atom other than a fluorine atom is C 2 When it is a -30 alkyl group, it may have 1 to 5 ether-bonding oxygen atoms between carbon atoms).
  • R 1 is the general formula (p-1) (in the formula, R 3 is a optionally substituted C 6-14 aryl group, and R 4 and R 5 are independent hydrogen atoms or C 6-14 aryl group which may be substituted, black circle means bonder), 2- (9,10-dioxo) anthrylmethyl group, benzyloxymethyl group, and phenacyl.
  • a method for producing a compound represented by (which is a protecting group selected from the groups).
  • the compound represented by the general formula (3) is produced by the production method according to any one of [1] to [5].
  • the compound represented by the general formula (3) is a compound represented by the following general formula (9) or (10).
  • R 2 is a protecting group for an amino group, and R 7 , R 8 and R 9 are independently C 6-14 aryl groups).
  • the following general formula (4) In the formula, R 1 and R f are the same as the general formula (3), and R 2 is the same as the general formula (9) or (10)).
  • the compound represented by the general formula (4) is subjected to a reduction reaction, and the following general formula (5) is applied.
  • R 1 , Rf, and R 2 are the same as those in the general formula (4).
  • Manufacture the compound represented by The protecting group R 2 of the compound represented by the general formula (5) is deprotected, which comprises preparing a compound represented by the general formula (6-1), the production method of the fluoroalkyl group-containing compound .. [7] The method for producing [6], wherein the R 2 is a tert-butoxycarbonyl group or a 9-fluorenylmethyloxycarbonyl group.
  • Rf is selected from the group consisting of at least two fluorine atoms are substituted with a further optionally substituted C 1-30 alkyl group (said C 1-30 alkyl group by a halogen atom other than a fluorine atom is C 2 In the case of a -30 alkyl group, it may have 1 to 5 ether-bonding oxygen atoms between carbon atoms))), which is a method for producing a compound represented by.
  • the compound represented by the general formula (6-1) is produced by the production method of [6] or [7].
  • the protecting group R 1 of the compound represented by the general formula (6-1) by deprotecting comprises producing a compound represented by the general formula (7), the production method of the fluoroalkyl group-containing compound ..
  • Rf is selected from the group consisting of at least two fluorine atoms are substituted with a further optionally substituted C 1-30 alkyl group (said C 1-30 alkyl group by a halogen atom other than a fluorine atom is C 2 In the case of a -30 alkyl group, it may have 1 to 5 ether-bonding oxygen atoms between carbon atoms), and R 2 is a protective group for amino groups).
  • the compound represented by the general formula (3) is produced by the production method according to any one of [1] to [5].
  • the compound represented by the general formula (3) is the compound represented by the general formula (9) or (10) (in the formula, R 2 is a protecting group for an amino group, and R 7 , R 8 and R 9 are respectively. independently, is reacted with a compound represented by C 6-14 aryl group), (4) (wherein, R 1 and Rf are the general formula (3) wherein the general formula is the same as, R 2 is the same as the general formula (9) or (10)).
  • the compound represented by the general formula (4) is subjected to a reduction reaction, and the general formula (5) (in the formula, R 1 , Rf, and R 2 are the same as the general formula (4)).
  • the C 1-30 alkyl group (in which Rf is substituted with at least two fluorine atoms and may be further substituted with a halogen atom other than the fluorine atom) in the general formula (7) (in the formula).
  • the C 1-30 alkyl group is a C 2-30 alkyl group, it may have 1 to 5 ether-bonding oxygen atoms between carbon atoms), and R 2 is amino.
  • the compound represented by the general formula (6-2) is produced by the production method of [9] or [10].
  • the protecting group R 2 of the compound represented by the general formula (6-2) by deprotecting comprises producing a compound represented by the general formula (7), the production method of the fluoroalkyl group-containing compound ..
  • the protecting group R 2 of the compound represented by deprotecting comprises producing an optically active compound represented by the general formula (6-3), optically active A method for producing a fluoroalkyl group-containing compound.
  • the general formula (6-3) (in the formula, the asterisk indicates that the absolute configuration of the asymmetric carbon atom with the asterisk is S or R, and Rf and R 1 are the general formula (6).
  • -1) is a method for producing an optically active compound represented by).
  • the compound represented by the general formula (6-1) is produced by the production method according to the above [6].
  • An optically active fluoroalkyl group-containing compound comprising the optical resolution of the compound represented by the general formula (6-1) to produce an optically active compound represented by the general formula (6-3). Manufacturing method.
  • R 1 and Rf are the general formula (3) wherein the general formula is the same as, R 2 is the same as the general formula (6-4)).
  • the compound represented by the general formula (4) is subjected to a reduction reaction, and the general formula (5-1) (in the formula, the asterisk has an asymmetric carbon atom with an asterisk in which the absolute configuration is S or R. Representing the above, R 1 , R f, and R 2 are the same as those in the general formula (4)) to produce an optically active compound.
  • Formula (5-1) the protecting group R 1 of a compound represented by deprotecting comprises producing an optically active compound represented by the general formula (6-4), optically active A method for producing a fluoroalkyl group-containing compound.
  • the general formula (6-4) (in the formula, the asterisk indicates that the absolute configuration of the asymmetric carbon atom with the asterisk is S or R, and Rf is the general formula (6-2).
  • R 2 is a method for producing an optically active compound represented by (), which is a protecting group for an amino group.
  • the compound represented by the general formula (6-2) is produced by the production method of the above [9].
  • An optically active fluoroalkyl group-containing compound comprising the optical resolution of the compound represented by the general formula (6-2) to produce an optically active compound represented by the general formula (6-4). Manufacturing method.
  • the general formula (7-1) (in the formula, the asterisk indicates that the absolute configuration of the asymmetric carbon atom with the asterisk is S or R, and Rf is the general formula (6-4).
  • An optically active compound represented by the general formula (6-4) is produced by the method of the above [15] or [16].
  • Formula (6-4) the protecting group R 2 of the compound represented by deprotecting comprises producing an optically active compound represented by the general formula (7-1), optically active A method for producing a fluoroalkyl group-containing compound.
  • the general formula (7-1) (in the formula, the asterisk indicates that the absolute configuration of the asymmetric carbon atom with the asterisk is S or R, and Rf is the same as the general formula (7).
  • the compound represented by the general formula (7) is produced by the method according to the above [8] or [11].
  • Rf 1 is substituted with at least two fluorine atoms, and more optionally substituted C 1-10 alkyl group (said C 1-10 alkyl group by a halogen atom other than a fluorine atom C When it is a 2-10 alkyl group, it may have 1 to 5 ether-bonding oxygen atoms between carbon atoms).
  • R 1 is the general formula (p-1) (in the formula, R 3 is a optionally substituted C 6-14 aryl group, and R 4 and R 5 are independent hydrogen atoms or C 6-14 aryl group which may be substituted, black circle means bonder), 2- (9,10-dioxo) anthrylmethyl group, benzyloxymethyl group, and phenacyl.
  • Rf is selected from the group consisting of at least two fluorine atoms are substituted with a further optionally substituted C 1-10 alkyl group by a halogen atom other than a fluorine atom (the C 1-10 alkyl group carbon atoms It may have 1 to 5 ether-bonding oxygen atoms in between).
  • R 1 is the general formula (p-1) (in the formula, R 3 is a optionally substituted C 6-14 aryl group, and R 4 and R 5 are independent hydrogen atoms or C 6-14 aryl group which may be substituted, black circle means bonder), 2- (9,10-dioxo) anthrylmethyl group, benzyloxymethyl group, and phenacyl. It is a protecting group selected from the groups, R 2A is the following general formula (p-2). (In the formula, R 10 is a optionally substituted C 1-6 alkyl group or an optionally substituted C 6-14 aryl-C 1-6 alkyl group, with black circles meaning binders). A compound represented by (which is a protecting group of an amino group represented by).
  • Rf 2 is -CF 3 , -CF 2 R 11 or -CFHR 11
  • R 11 is substituted with at least two fluorine atoms and further substituted with a halogen atom other than the fluorine atom.
  • C 1-9 alkyl group which may be used (when the C 1-9 alkyl group is a C 2-9 alkyl group, it has 1 to 5 ether-bonding oxygen atoms between carbon atoms.
  • R 1 is the general formula (p-1) (in the formula, R 3 is a optionally substituted C 6-14 aryl group, and R 4 and R 5 are independent hydrogen atoms or C 6-14 aryl group which may be substituted, black circle means bonder), 2- (9,10-dioxo) anthrylmethyl group, benzyloxymethyl group, and phenacyl. It is a protecting group selected from the groups, R 2A is the above-mentioned general formula (p-2) (in the formula, R 10 is a C 1-6 alkyl group which may be substituted or a C 6-14 aryl-C 1-6 alkyl which may be substituted. It is a group, and the black circle means a bonder), which is a protecting group for the amino group).
  • Rf 3 is -CF 2 R 11 or -CFHR 11
  • R 11 is substituted with at least two fluorine atoms, even if it is further substituted with a halogen atom other than the fluorine atom.
  • a good C 1-9 alkyl group when the C 1-9 alkyl group is a C 2-9 alkyl group, it may have 1 to 5 ether-bonding oxygen atoms between carbon atoms.
  • R 1 is the general formula (p-1) (in the formula, R 3 is a optionally substituted C 6-14 aryl group, and R 4 and R 5 are independent hydrogen atoms or C 6-14 aryl group which may be substituted, black circle means bonder), 2- (9,10-dioxo) anthrylmethyl group, benzyloxymethyl group, and phenacyl.
  • Rf 3 is -CF 2 R 11 or -CFHR 11
  • R 11 is substituted with at least two fluorine atoms, even if it is further substituted with a halogen atom other than the fluorine atom.
  • a good C 1-9 alkyl group when the C 1-9 alkyl group is a C 2-9 alkyl group, it may have 1 to 5 ether-bonding oxygen atoms between carbon atoms.
  • R 2A is the above-mentioned general formula (p-2) (in the formula, R 10 is a C 1-6 alkyl group which may be substituted or a C 6-14 aryl-C 1-6 alkyl which may be substituted. It is a group, and the black circle means a bonder), which is a protecting group for the amino group).
  • the deprotection of the carboxy group and the deprotection of the amino group proceed easily, so that the fluoroalkyl group-containing compound can be efficiently synthesized. Also, according to the present invention, there is provided a novel intermediate used in the above method.
  • C p1-p2 (p1 and p2 are positive integers satisfying p1 ⁇ p2) means that the group has p1 to p2 carbon atoms.
  • C 1-10 alkyl group is an alkyl group having 1 to 10 carbon atoms, and may be a straight chain or a branched chain.
  • the "C 2-10 alkyl group” is an alkyl group having 2 to 10 carbon atoms, and may be a straight chain or a branched chain.
  • C 1-10 alkyl groups include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, tert- Examples thereof include a pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group and a decyl group.
  • C 1-30 alkyl group is an alkyl group having 1 to 30 carbon atoms, and may be a straight chain or a branched chain.
  • the "C 2-30 alkyl group” is an alkyl group having 2 to 30 carbon atoms, and may be a straight chain or a branched chain.
  • C 1-30 alkyl groups include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, tert- Pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group, undecyl group, dodecyl group, tridecyl group, tetradecyl group, pentadecyl group, hexadecyl group, heptadecyl group, octadecyl group, nonadecil group, eicosyl group, heneicosyl group.
  • Docosyl group tricosyl group, tetracosyl group, pentacosyl group, hexacosyl group, heptacosyl group, octacosyl group, nonacosyl group, triacontyl group and the like.
  • C 1-6 alkyl group is an alkyl group having 1 to 6 carbon atoms, and may be a straight chain or a branched chain.
  • Examples of C 1-6 alkyl groups include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, tert- Examples include a pentyl group and a hexyl group.
  • the "C 6-14 aryl group” is an aromatic hydrocarbon group having 6 to 14 carbon atoms, and a C 6-12 aryl group is particularly preferable.
  • Examples of the C 6-14 aryl group include a phenyl group, a naphthyl group, an anthryl group, a 9-fluorenyl group and the like, and a phenyl group is particularly preferable.
  • the "optionally substituted C 6-14 aryl group” is one or more hydrogen atoms bonded to the carbon atom of the C 6-14 aryl group, preferably 1 to 1.
  • the substituents may be the same kind or different from each other. Examples of the substituent include a nitro group, a halogen atom (fluorine atom, chlorine atom, bromine atom, or iodine atom), a C 1-6 alkyl group, a C 1-6 alkoxy group, and a methylenedioxy group (-O-CH). 2- O-) and the like can be mentioned.
  • optionally substituted C 6-14 aryl groups are phenyl group, naphthyl group, anthryl group, 4-nitrophenyl group, 4-methoxyphenyl group, 2,4-dimethoxyphenyl group, 3, Examples thereof include 4-dimethoxyphenyl group, 4-methylphenyl group, 2,6-dimethylphenyl group, 3-chlorophenyl group, 1,3-benzodioxol-5-yl group and the like.
  • the "C 6-14 aryl-C 1-6 alkyl group” is a C 6-14 aryl group in which one hydrogen atom bonded to the carbon atom of the C 1-6 alkyl group is a C 6-14 aryl group. It is a group substituted with.
  • the C 6-14 aryl group in the C 6-14 aryl -C 1-6 alkyl group, a phenyl group, a naphthyl group, an anthryl group can be exemplified a 9-fluorenyl group, a phenyl group or a 9-fluorenyl group is particularly preferred ..
  • C 1-6 alkyl group in the C 6-14 aryl -C 1-6 alkyl group C 1-4 alkyl groups are preferred.
  • Examples of C 6-14 aryl-C 1-6 alkyl groups include benzyl group, diphenylmethyl group, triphenylmethyl group, 2-phenylethyl group, 9-anthrylmethyl group, 9-fluorenylmethyl group and the like. Can be mentioned.
  • halogen atom means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
  • the "halogen atom other than the fluorine atom” means a chlorine atom, a bromine atom, or an iodine atom.
  • a chlorine atom or a bromine atom is preferable, and a chlorine atom is particularly preferable.
  • C 1-6 alkoxy group refers to a group in which an oxygen atom is bonded to the bond end of a C 1-6 alkyl group having 1 to 6 carbon atoms.
  • the C 1-6 alkoxy group may be a straight chain or a branched chain.
  • Examples of the C 1-6 alkoxy group include a methoxy group, an ethoxy group, a propoxy group, a butoxy group, a tert-butoxy group, a pentyloxy group, a hexyloxy group and the like.
  • the "ether-bonded oxygen atom” is an oxygen atom that connects carbon atoms, and does not include an oxygen atom in which oxygen atoms are connected in series.
  • An alkyl group having Nc carbon atoms (Nc is an integer of 2 or more) can have a maximum of Nc-1 ether-bonding oxygen atoms.
  • Compound n means a compound represented by the formula (n).
  • the method for producing a fluoroalkyl group-containing compound according to the present invention is a method for producing a compound (fluorine-containing amino acid) in which a fluoroalkyl group is introduced into the side chain of an amino acid.
  • a fluoroalkyl group-containing compound one aspect of synthesizing from compound 2 is shown below.
  • Rf is a group in which at least two hydrogen atoms bonded to carbon atoms are substituted with fluorine atoms among C 1-30 alkyl groups, and one or more hydrogen atoms bonded to carbon atoms are present. , It may be further substituted with a halogen atom other than the fluorine atom.
  • a C 1-30 alkyl group of Rf a C 1-20 alkyl group is preferable, a C 1-10 alkyl group is more preferable, a C 2-10 alkyl group is further preferable, and a C 2-8 alkyl group is preferable. Even more preferable.
  • the C 1-30 alkyl group is a C 2-30 alkyl group, it may have 1 to 5 ether-bonding oxygen atoms between carbon atoms.
  • the number of hydrogen atoms substituted with fluorine atoms is not particularly limited as long as it is 2 or more, for example, 3 or more is preferable, 6 or more is more preferable, and 7 or more is further. preferable.
  • Rf examples include trifluoromethyl group, pentafluoroethyl group, heptafluoropropyl group, nonafluorobutyl group, perfluoropentyl group, perfluorohexyl group, perfluoroheptyl group, perfluorooctyl group, perfluorononyl group, perfluorodecyl group, Difluoromethyl group, 1,1-difluoroethyl group, 2,2-difluoroethyl group, 1,1,2,2-tetrafluoroethyl group, 1,1,2,2,3,3-hexafluoropropyl group, 1,1,2,3,3,3-hexafluoropropyl group, 1,1,2,2,3,3-hexafluorohexyl group, 1,1,2,2,3,3-hexafluorooctyl group , 1,1,2,2,3,3-hexafluorodecyl group, 1,1,2,2,3,
  • R 1 is a protecting group for a carboxy group, and specifically, a group represented by the following general formula (p-1), a 2- (9,10-dioxo) anthrylmethyl group, a benzyloxymethyl group, And a protecting group selected from the phenacyl group.
  • R 3 is a optionally substituted C 6-14 aryl group
  • R 4 and R 5 are independently hydrogen atoms or optionally substituted C. It is a 6-14 aryl group.
  • the black circle means a bond.
  • Examples of the protective group for the carboxy group represented by R 1 include a benzyl group, a diphenylmethyl group, a triphenylmethyl group, a 4-nitrobenzyl group, a 4-methoxybenzyl group, a 2,4-dimethoxybenzyl group, and 3,4-. Dimethoxybenzyl group, 4-methylbenzyl group, 2,6-dimethylbenzyl group, 3-chlorobenzyl group, 9-anthrylmethyl group, piperonyl group, 2- (9,10-dioxo) anthrylmethyl group, benzyloxy Examples thereof include a methyl group and a phenacyl group.
  • R 1 is preferably a benzyl group, a triphenylmethyl group, and more preferably a benzyl group in that it can be deprotected under mild conditions.
  • R 1 can be deprotected under mild conditions by using an aralkyl protecting group such as a benzyl group or a triphenylmethyl group as the carboxy protecting group R 1 , and the functional group of the amino acid is decomposed. It is advantageous in that it is possible to synthesize a fluorine-containing amino acid and a fluorine-containing peptide without having to do so.
  • an aralkyl protecting group such as a benzyl group or a triphenylmethyl group
  • R 6 is a silyl protecting group.
  • R 6 include a trimethylsilyl (TMS) group, a triethylsilyl (TES) group, a triisopropylsilyl (TIPS) group, a tert-butyldimethylsilyl (TBDMS) group, a tert-butyldiphenylsilyl (TBDPS) group and the like.
  • TMS trimethylsilyl
  • TES triethylsilyl
  • TIPS triisopropylsilyl
  • TDMS tert-butyldimethylsilyl
  • TDPS tert-butyldiphenylsilyl
  • R 6 is trimethylsilyl (TMS) groups.
  • R 2 is an amino protecting group.
  • As the protecting group of the amino group tert-butoxycarbonyl (Boc) group, 9-fluorenylmethyloxycarbonyl (Fmoc) group, benzyloxycarbonyl (Cbz) group, allyloxycarbonyl (Allloc) group, 2,2 Carbamate protecting groups such as 2-trichloroethoxycarbonyl (Troc) group can be mentioned.
  • R 2 is preferably a tert-butoxycarbonyl (Boc) group or a 9-fluorenylmethyloxycarbonyl (Fmoc) group in that it can be deprotected under mild conditions.
  • Step 1 Compound 2-2 can be obtained by reacting compound 2 and compound 8 in the presence of metal fluoride. Since the compound 8 represented by the general formula (8) Rf-R 6 can be synthesized from easily available Rf-I (fluoroalkyl iodide) in one step, the range of Rf groups that can be introduced is wide.
  • alkali metal fluorides such as cesium fluoride, lithium fluoride and sodium fluoride can be used, and cesium fluoride is preferable.
  • the reaction can be carried out in a solvent inert to the reaction.
  • the solvent include inert solvents such as tetrahydrofuran, dichloromethane, acetonitrile, benzene, toluene, diethyl ether, 1,4-dioxane, N, N-dimethylformamide, N, N-dimethylacetamide, and tetrahydrofuran is preferable.
  • the amount of compound 8 is preferably 0.5 to 10 mol with respect to 1 mol of compound 2.
  • the amount of metal fluoride is preferably 0.01 to 2 mol with respect to 1 mol of compound 2.
  • the reaction in step 1 is preferably carried out at a temperature of 10 ° C. or lower. By carrying out the reaction at a temperature of 10 ° C. or lower, compound 2-2 can be produced in high yield.
  • the reaction temperature is preferably ⁇ 78 ° C. to 10 ° C., more preferably ⁇ 50 ° C. to ⁇ 10 ° C., and particularly preferably ⁇ 40 ° C. to ⁇ 20 ° C.
  • the reaction time is preferably 1 to 48 hours, more preferably 6 to 36 hours.
  • Compound 2 can be produced by diesterizing oxalic acid by a known method, or a commercially available product may be used.
  • Step 1-1 In the reaction of step 1, (one compound protected with R 6 hydroxy groups) Compound 2-1, or a mixture of compounds 2-2 and compound 2-1 may be obtained. In that case, the silyl protecting group R 6 of compound 2-1 by deprotection, to give compound 2-2.
  • the reaction of step 1-1 can be carried out in the same manner as in step 1.
  • Step 1-2 The silyl protecting group R 6 of compound 2-1 by deprotection, to give compound 2-2.
  • Deprotection can be performed in the presence of fluoride salts such as tetrabutylammonium fluoride (TBAF), cesium fluoride and hydrofluoride salts, or acids such as hydrochloric acid, acetic acid and paratoluenesulfonic acid.
  • fluoride salts such as tetrabutylammonium fluoride (TBAF), cesium fluoride and hydrofluoride salts
  • acids such as hydrochloric acid, acetic acid and paratoluenesulfonic acid.
  • the reaction can be carried out in a solvent inert to the reaction.
  • the solvent include inert solvents such as tetrahydrofuran, dichloromethane, acetonitrile, benzene, toluene, diethyl ether, 1,4-dioxane, N, N-dimethylformamide, N, N-dimethylacetamide, and tetrahydrofuran is preferable. It is preferable to add acetic acid.
  • the amount of the fluoride salt is preferably 0.1 to 10 mol with respect to 1 mol of compound 2-1 (in the case of a mixture of compound 2-2 and compound 2-1).
  • the amount of acid is preferably 0.1 to 10 mol with respect to 1 mol of Compound 2-1 (in the case of a mixture of Compound 2-2 and Compound 2-1).
  • the reaction in step 1-2 is preferably carried out at a temperature of 50 ° C. or lower. By carrying out the reaction at a temperature of 50 ° C. or lower, compound 2-2 can be produced in high yield.
  • the reaction temperature is preferably ⁇ 80 ° C. to 50 ° C., more preferably ⁇ 40 ° C. to 30 ° C., and particularly preferably ⁇ 20 ° C. to 30 ° C.
  • the reaction time is preferably 1 to 48 hours, more preferably 6 to 36 hours.
  • Step 2 Compound 3 can be obtained by subjecting compound 2-2 to a dehydration reaction.
  • the dehydration reaction can be carried out in the presence of a dehydrating agent such as diphosphorus pentoxide, concentrated sulfuric acid, calcium chloride, sodium sulfate, magnesium sulfate, calcium sulfate, molecular sieve (synthetic zeolite), and silica gel.
  • a dehydrating agent such as diphosphorus pentoxide, concentrated sulfuric acid, calcium chloride, sodium sulfate, magnesium sulfate, calcium sulfate, molecular sieve (synthetic zeolite), and silica gel.
  • diphosphorus pentoxide is preferable.
  • the amount of the dehydrating agent is preferably 10 to 100% by weight based on 100% by weight of compound 2-2.
  • the dehydration reaction can be carried out by distilling compound 2-2 in the presence of a dehydrating agent.
  • Distillation is preferably carried out at a temperature of 30 ° C. to 150 ° C. If the distillation temperature is too high, compound 3 may decompose. If the distillation temperature is too low, compound 3 cannot be condensed and the recovery rate may decrease. Distillation can be carried out at any pressure of reduced pressure, normal pressure and pressure, and can be appropriately determined so that the boiling point of compound 3 falls within the above-mentioned preferable temperature range.
  • the pressure is preferably 0.1 mmHg to 5 atm (3800 mmHg).
  • Compound 4 can be obtained by reacting compound 3 with compound 9 or compound 10.
  • R 2 is a protecting group for an amino group as described above.
  • R 7 , R 8 and R 9 are independently C 6-14 aryl groups. Examples of the C 6-14 aryl group represented by R 7 , R 8 or R 9 include a phenyl group and a naphthyl group. Preferably, R 7 , R 8 and R 9 are phenyl groups, respectively.
  • the reaction can be carried out in a solvent inert to the reaction.
  • the solvent include inert solvents such as diethyl ether, tetrahydrofuran, dichloromethane, acetonitrile, benzene, toluene, 1,4-dioxane, N, N-dimethylformamide, N, N-dimethylacetamide, and diethyl ether is preferable.
  • the amount of compound 9 or compound 10 is preferably 0.5 to 10 mol with respect to 1 mol of compound 3.
  • the reaction temperature is preferably ⁇ 78 ° C. to 100 ° C., more preferably 0 ° C. to 40 ° C.
  • the reaction time is preferably 1 minute to 24 hours, more preferably 10 minutes to 4 hours.
  • the protecting group R 2 of the amino group, tert- butoxycarbonyl group by the use of carbamate protecting groups such as 9-fluorenylmethyloxycarbonyl group, the deprotection of R 2 under mild conditions It is possible to synthesize fluorine-containing amino acids while suppressing decomposition and racemization of compounds.
  • Compound 5 can be obtained by subjecting compound 4 to a reduction reaction.
  • the reduction reaction can be carried out by a method using a reducing agent or a method of reducing in the presence of a metal catalyst.
  • a reducing agent examples include sodium borohydride, zinc borohydride, sodium cyanoborohydride, lithium triethylborohydride, lithium borohydride (sec-butyl), and try hydride.
  • a boron borohydride reagent such as potassium boron (sec-butyl), lithium boron borohydride, and sodium triacetoxyborohydride can be used.
  • sodium borohydride or zinc borohydride is preferable, and sodium borohydride is more preferable.
  • the amount of the reducing agent is preferably 0.5 to 10 mol with respect to 1 mol of the compound 4.
  • the reaction can be carried out in a solvent inert to the reaction.
  • Solvents include diethyl ether, dichloromethane, hydrochlorofluorocarbon (HCFC) (eg, Asahiclin® AK-225 (3,3-dichloro-1,1,1,2,2-pentafluoropropane and 1,1). 3-Dichloro-1,1,2,2,3-pentafluoropropane mixture, AGC Co., Ltd.)), dichloromethane, acetonitrile, 1,4-dioxane, N, N-dimethylformamide, N, N-dimethylacetamide, etc.
  • Inert solvent is mentioned, and diethyl ether is preferable.
  • the reaction temperature is preferably ⁇ 78 ° C. to 100 ° C., more preferably ⁇ 10 ° C. to 40 ° C.
  • the reaction time is preferably 1 to 48 hours, more preferably 6 to 36 hours.
  • metal catalyst examples include palladium catalysts (eg, palladium carbon, palladium hydroxide, Pearlman catalyst, Lindler catalyst, silica gel-supported palladium catalyst, alumina-supported palladium catalyst, palladium oxide) and nickel.
  • palladium catalysts eg, palladium carbon, palladium hydroxide, Pearlman catalyst, Lindler catalyst, silica gel-supported palladium catalyst, alumina-supported palladium catalyst, palladium oxide
  • nickel nickel
  • Catalyst eg, lane nickel
  • platinum catalyst eg, platinum carbon, platinum oxide, silica gel-supported platinum catalyst, alumina-supported platinum catalyst
  • rhodium catalyst eg, rhodium carbon, alumina-supported rhodium catalyst, rhodium oxide
  • ruthenium catalyst eg, rhodium oxide
  • Luthenium carbon alumina-supported ruthenium catalyst, ruthenium oxide
  • cobalt catalyst eg, lane cobalt
  • palladium catalyst is preferable.
  • the amount of the metal catalyst is preferably 0.0001 to 0.1 mol, more preferably 0.0005 to 0.02 mol, based on 1 mol of the compound 4.
  • the reaction can be carried out in a solvent inert to the reaction.
  • the solvent include inert solvents such as methanol, ethanol, isopropanol, diethyl ether, tetrahydrofuran, ethyl acetate, dichloromethane, acetonitrile, 1,4-dioxane, N, N-dimethylformamide, N, N-dimethylacetamide and the like.
  • the reduction reaction is carried out in the presence of hydrogen gas.
  • the reduction reaction may be carried out under normal pressure or under pressure.
  • the pressure of hydrogen gas is preferably 0.5 atm to 10 atm.
  • the reaction temperature is preferably 0 ° C. to 100 ° C., more preferably 10 ° C. to 50 ° C.
  • the reaction time is preferably 1 to 48 hours, more preferably 6 to 36 hours.
  • Step 5-1 The protecting group R 2 of Compound 5 by deprotection, to give compound 6-1.
  • Deprotection can be carried out according to the type of the protecting group R 2.
  • R 2 is a Boc group, it can be deprotected under acidic conditions.
  • the acid used include trifluoroacetic acid and hydrochloric acid.
  • the amount of acid is preferably 1 to 1000 mol with respect to 1 mol of Compound 5.
  • the reaction can be carried out in a solvent inert to the reaction.
  • the solvent include inert solvents such as diethyl ether, tetrahydrofuran, dichloromethane, acetonitrile, benzene, toluene, 1,4-dioxane, N, N-dimethylformamide, N, N-dimethylacetamide, and dichloromethane, N, N. -Dimethylformamide is preferred.
  • An acid can also be used as a solvent.
  • the solvent include inorganic acids such as hydrochloric acid, acetic acid and trifluoroacetic acid, and organic acids, and trifluoroacetic acid is preferable.
  • the reaction temperature is preferably ⁇ 78 ° C. to 50 ° C., more preferably 0 ° C. to 40 ° C.
  • the reaction time is preferably 1 to 48 hours, more preferably 6 to 36 hours.
  • R 2 When R 2 is an Fmoc group, it can be deprotected under basic conditions.
  • the base used include secondary amines such as piperidine, morpholine and pyrrolidine.
  • the amount of base is preferably 1 to 100 mol with respect to 1 mol of compound 5.
  • the reaction can be carried out in a solvent inert to the reaction.
  • the solvent include inert solvents such as diethyl ether, tetrahydrofuran, dichloromethane, acetonitrile, benzene, toluene, 1,4-dioxane, N, N-dimethylformamide and N, N-dimethylacetamide.
  • the reaction temperature is preferably ⁇ 20 ° C. to 80 ° C., more preferably 0 ° C. to 40 ° C.
  • the reaction time is preferably 1 minute to 24 hours, more preferably 5 minutes to 2 hours.
  • Step 6-1 The protecting group R 1 of the compound 6-1 by deprotection to give compound 7.
  • Deprotection can be carried out according to the type of the protecting group R 1.
  • R 1 is a benzyl group, a triphenylmethyl group, a 9-anthrylmethyl group, a piperonyl group, a 2- (9,10-dioxo) anthrylmethyl group, a benzyloxymethyl group, or a phenacyl group
  • Deprotection can be achieved by the method of reducing with.
  • the reduction reaction can be carried out in the same manner as the method of reducing in the presence of the metal catalyst in step 4.
  • Step 5-2 The protecting group R 1 of Compound 5 by deprotection, to give compound 6-2. Deprotection can be performed in the same manner as in step 6-1.
  • Step 6-2 The protecting group R 2 of the compound 6-2 by deprotection to give compound 7. Deprotection can be performed in the same manner as in step 5-1.
  • R 1 In the production method, by using an aralkyl protecting group such as a benzyl group or a triphenylmethyl group as the carboxy protecting group R 1 , R 1 can be deprotected under mild conditions and the optical activity is maintained. It is advantageous in that it is possible to synthesize a fluorine-containing amino acid and a fluorine-containing peptide.
  • an aralkyl protecting group such as a benzyl group or a triphenylmethyl group
  • Compound 5-1 can be obtained by subjecting compound 4 to an asymmetric reduction reaction.
  • the asymmetric reduction reaction can be carried out by reducing compound 4 in the presence of an asymmetric reduction catalyst.
  • a transition metal complex in which an asymmetric ligand is coordinated with the transition metal can be used.
  • the transition metal include palladium, rhodium, ruthenium, iridium, nickel, cobalt, platinum, iron and the like.
  • the transition metal complex include a palladium complex, a rhodium complex, a ruthenium complex, an iridium complex, and a nickel complex.
  • Asymmetric ligands include dpen (1,2-diphenylethylenediamine), daipen (1,1-di (4-anicil) -2-isopropyl-1,2-ethylenediamine), and optically active phosphine ligands. Can be mentioned.
  • the amount of the asymmetric reduction catalyst is preferably 0.0001 to 0.1 mol, more preferably 0.0005 to 0.02 mol, based on 1 mol of the compound 4.
  • the reaction can be carried out in a solvent inert to the reaction.
  • the solvent include inert solvents such as methanol, ethanol, isopropanol, diethyl ether, tetrahydrofuran, ethyl acetate, dichloromethane, acetonitrile, 1,4-dioxane, N, N-dimethylformamide, N, N-dimethylacetamide and the like.
  • the reduction reaction is carried out in the presence of hydrogen gas.
  • the reduction reaction may be carried out under normal pressure or under pressure.
  • the pressure of hydrogen gas is preferably 0.5 atm to 10 atm.
  • the reaction temperature is preferably 0 ° C. to 100 ° C., more preferably 10 ° C. to 50 ° C.
  • the reaction time is preferably 1 to 48 hours, more preferably 6 to 36 hours.
  • Step 8-1 The protecting group R 2 of the compound 5-1 by deprotection to give compound 6-3. Deprotection can be performed in the same manner as in step 5-1.
  • Step 9-1 The protecting group R 1 of the compound 6-3 by deprotection to give compound 7-1. Deprotection can be performed in the same manner as in step 6-1.
  • Step 8-2 The protecting group R 1 of the compound 5-1 by deprotection to give compound 6-4. Deprotection can be performed in the same manner as in step 6-1.
  • Step 9-2 The protecting group R 2 of the compound 6-4 by deprotection to give compound 7-1. Deprotection can be performed in the same manner as in step 5-1.
  • Compound 6-3 can be obtained by optically resolving compound 6-1.
  • the optical resolution can be performed by a known method. For example, it can be carried out by a method using a chiral column, a method by crystallization, a diastereomer method or the like.
  • a racemate can be divided into optically active substances by liquid chromatography or supercritical fluid chromatography (SFC) using a chiral column.
  • SFC supercritical fluid chromatography
  • CHIRALPAK registered trademark
  • CHIRALCEL registered trademark
  • a salt of a racemate and an optically active amine or an optically active acid is formed and induced into a crystalline diastereomer salt for fractional crystallization. By repeating recrystallization, a single diastereomer salt can be obtained. If necessary, the diastereomeric salt is neutralized to obtain a free optically active substance.
  • optically active amines include brucine, cinchonidine, cinchonine, 1-phenethylamine and the like.
  • optically active acids include camphorsulfonic acid, tartaric acid, mandelic acid and the like.
  • Diastereomer method A racemic mixture is reacted with an optically active reagent to obtain a mixture of diastereomers, which is separated by fractional crystallization and chromatography to separate a single diastereomer. The optically active reagent moiety is removed from the resulting single diastereomer to obtain the desired optical isomer.
  • Step 11-1 The protecting group R 1 of the compound 6-3 by deprotection to give compound 7-1. Deprotection can be performed in the same manner as in step 6-1.
  • Step 10-2 Compound 6-4 can be obtained by optically resolving compound 6-2.
  • the optical resolution can be performed in the same manner as in step 10-1.
  • Step 11-2 The protecting group R 2 of the compound 6-4 by deprotection to give compound 7-1. Deprotection can be performed in the same manner as in step 5-1.
  • Step 12 Compound 7-1 can be obtained by optically resolving compound 7.
  • the optical resolution can be performed in the same manner as in step 10-1.
  • the present invention relates to the general formula (3a), the general formula (4a), the general formula (5a), the general formula (5-1a), the general formula (6-1a), the general formula (6-3a), and the general formula (6).
  • -2a) or a novel compound represented by the general formula (6-4a) is provided.
  • the asterisk indicates that the absolute configuration of the asymmetric carbon atom with the asterisk is S or R.
  • These compounds are useful as intermediates in the method for producing the fluoroalkyl group-containing compound.
  • the compound represented by the general formula (6-1a), the general formula (6-3a), the general formula (6-2a), or the general formula (6-4a) produces a peptide containing a fluorine-containing amino acid. Can be used to
  • Rf 1 is a C 1-10 alkyl group in which at least two hydrogen atoms bonded to a carbon atom are substituted with a fluorine atom, and one or more hydrogen atoms bonded to the carbon atom. However, it may be further substituted with a halogen atom other than the fluorine atom.
  • the C 1-10 alkyl group is a C 2-10 alkyl group, it may have 1 to 5 ether-bonding oxygen atoms between carbon atoms.
  • a C 2-10 alkyl group is preferable, and a C 2-8 alkyl group is preferable.
  • Rf 1 examples include pentafluoroethyl group, heptafluoropropyl group, nonafluorobutyl group, perfluoropentyl group, perfluorohexyl group, perfluoroheptyl group, perfluorooctyl group, perfluorononyl group, perfluorodecyl group, 1,1- Difluoroethyl group, 2,2-difluoroethyl group, 1,1,2,2-tetrafluoroethyl group, 1,1,2,2,3,3-hexafluoropropyl group, 1,1,2,3 Examples thereof include a 3,3-hexafluoropropyl group.
  • Rf 2 is -CF 3 , -CF 2 R 11 , or -CFHR 11 .
  • R 11 is a group in which at least two of the hydrogen atoms bonded to the carbon atom of the C 1-9 alkyl group are substituted with a fluorine atom, and one or more of the C 1-9 alkyl groups are bonded to the carbon atom.
  • the hydrogen atom of is further substituted with a halogen atom other than the fluorine atom.
  • the C 1-9 alkyl group is a C 2-9 alkyl group, it may have 1 to 5 ether-bonding oxygen atoms between carbon atoms.
  • a C 1-7 alkyl group is more preferable.
  • Rf 2 examples include -CF 3 , pentafluoroethyl group, heptafluoropropyl group, nonafluorobutyl group, perfluoropentyl group, perfluorohexyl group, perfluoroheptyl group, perfluorooctyl group, perfluorononyl group, perfluorodecyl group, Examples thereof include 1,1,2,2-tetrafluoroethyl group, 1,1,2,2,3,3-hexafluoropropyl group, 1,1,2,3,3,3-hexafluoropropyl group and the like. ..
  • Rf 3 is -CF 2 R 11 or -CFHR 11 .
  • -CF 2 R 11 and -CFHR 11 are the same as Rf 2, and the C 1-9 alkyl group in R 11 is more preferably the C 1-7 alkyl group.
  • Rf 3 include pentafluoroethyl group, heptafluoropropyl group, nonafluorobutyl group, perfluoropentyl group, perfluorohexyl group, perfluoroheptyl group, perfluorooctyl group, perfluorononyl group, perfluorodecyl group, 1,1 Examples thereof include 2,2-tetrafluoroethyl group, 1,1,2,2,3,3-hexafluoropropyl group and 1,1,2,3,3,3-hexafluoropropyl group.
  • R 2A is a protecting group for an amino group represented by the following general formula (p-2).
  • R 10 is a optionally substituted C 1-6 alkyl group or an optionally substituted C 6-14 aryl-C 1-6 alkyl group.
  • the black circle means a bond.
  • the "optionally substituted C 1-6 alkyl group" represented by R 10 is composed of a nitro group, a halogen atom (fluorine atom, chlorine atom, bromine atom, or iodine atom), and a C 1-6 alkoxy group. It means a C 1-6 alkyl group which may be substituted with 1 to 3 substituents of choice.
  • Examples of the "optionally substituted C 1-6 alkyl group” represented by R 10 include a tert-butyl group and a 2,2,2-trichloroethyl group.
  • the "optionally substituted C 6-14 aryl-C 1-6 alkyl group” represented by R 10 is a nitro group, a halogen atom (fluorine atom, chlorine atom, bromine atom, or iodine atom), C 1 C 6-14 aryl-which may be substituted with 1 to 3 substituents selected from -6 alkyl groups, C 1-6 alkoxy groups, and methylenedioxy groups (-O-CH 2- O-). It means a C 1-6 alkyl group.
  • Examples of the "optionally substituted C 6-14 aryl-C 1-6 alkyl group” represented by R 10 include a 9-fluorenylmethyl group and a benzyl group.
  • the amino protecting group represented by R 2A is preferably a tert-butoxycarbonyl (Boc) group or a 9-fluorenylmethyloxycarbonyl (Fmoc) group in that it can be deprotected under mild conditions.
  • the NMR apparatus used for the analysis of Examples and Comparative Examples was JNM-ECZ400S (400 MHz) manufactured by JEOL Ltd., and tetramethylsilane was set to 0 PPM in 1 H NMR and C 6 F 6 was set to 162 PPM in 19 F NMR. did.
  • Step 1 Benzyl 3,3,4,4,5,5,6,6,6-nonafluoro-2-oxohexanoate was added in the same manner as in Steps 1 and 2, except that the temperature in Step 1 was changed to 0 ° C. Obtained as a colorless liquid. The yield from step 1 to step 2 was 69%.
  • AK225 refers to "Asahiclean® AK-225" (3,3-dichloro-1,1,1,2,2-pentafluoropropane and 1,3-dichloro-1,1, A mixture of 2,2,3-pentafluoropropane, AGC Inc.).
  • the present invention provides a novel production method capable of efficiently synthesizing a fluoroalkyl group-containing compound such as a fluorine-containing amino acid.
  • a fluoroalkyl group-containing compound such as a fluorine-containing amino acid.
  • the deprotection of the carboxy group and the deprotection of the amino group proceed easily, so that the fluoroalkyl group-containing compound can be efficiently synthesized.
  • a novel intermediate used in the above-mentioned production method is provided.

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Abstract

L'invention concerne un nouveau procédé de production permettant de synthétiser efficacement un composé contenant un groupe fluoroalkyle.　Ce procédé est destiné à la production d'un composé représenté par la formule générale (3) (Rf représente un groupe alkyle en C1-30 substitué par au moins deux atomes de fluor, et R1 représente un groupe protecteur choisi dans un groupe représenté par –C(R4)(R5)-R3 ; (R3 représente un groupe alkyle en C6-14 qui peut être substitué, et R4 et R5 représentent chacun d'une manière indépendante un atome d'hydrogène ou un groupe aryle en C6-14 qui peut être substitué), un groupe 2-(9,10-dioxo)anthrylméthyle, un groupe benzyloxyméthyle et un groupe phénacyle, le procédé consistant : à faire réagir un composé représenté par la formule générale (2) avec un composé représenté par Rf-R6 ; (R6 représente un groupe protecteur silyle) en présence d'un fluorure métallique ; puis à soumettre le réactif à une réaction de déshydratation.
PCT/JP2020/025910 2019-07-02 2020-07-01 Composé contenant un groupe fluoroalkyle et procédé de production associé WO2021002407A1 (fr)

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WO2023048236A1 (fr) 2021-09-22 2023-03-30 Ａｇｃ株式会社 Peptide

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