WO2021002407A1 - Fluoroalkyl group-containing compound and production method therefor - Google Patents

Abstract

Provided is a novel production method by which a fluoroalkyl group-containing compound can be efficiently synthesized.　This method is for producing a compound represented by general formula (3) (Rf represents a C1-30 alkyl group substituted with at least two fluorine atoms, and R1 represents a protecting group selected from a group represented by –C(R4)(R5)-R3 (R3 represents a C6-14 aryl group which may be substituted, and R4 and R5 each independently represent a hydrogen atom or a C6-14 aryl group which may be substituted), a 2-(9,10-dioxo)anthrylmethyl group, a benzyloxymethyl group, and a phenacyl group, the method comprising: reacting a compound represented by general formula (2) with a compound represented by Rf-R6 (R6 represents a silyl protecting group) in the presence of a metal fluoride; and then subjecting the reactant to a dehydration reaction.

Description

Fluoroalkyl group-containing compounds and their production methods

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.

The following methods are known as methods for synthesizing fluorine-containing amino acids.
(1) A method for introducing a side chain containing fluorine (Non-Patent Documents 3 and 4).
(2) A method for synthesizing optically active perfluoroalkylalanine by introducing a perfluoroalkyl group into optically active acrylamide (Non-Patent Document 5).

(3) A method for synthesizing perfluoroalkylglycine via an oxazolone (Non-Patent Document 6). (4) A method for synthesizing perfluoroalkylglycine via an oxazole ring (Non-Patent Document 7). (5) A method for obtaining optically active fluorine-containing amino acids by asymmetric reduction via carbonylation of imidoyl iodide and then deprotection with cerium ammonium nitrate (CAN) (Non-Patent Documents 1, 8 and 9). ).

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.

The method of Non-Patent Document 5 is useful as a method for synthesizing optically active perfluoroalkylalanine. However, in principle, an equivalent amount of the optically active site of the substrate is required to obtain the optically active substance. Further, when 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.

The method of Non-Patent Document 1, 8 or 9 is useful as a method for synthesizing perfluoroalkylglycine. However, first, 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 (Non-Patent Document 9) is before deprotection by CAN, and it is unclear whether the optically active substance can be deprotected while maintaining the optical activity.

Therefore, it can be applied to both fluoroalkyl-substituted glycine and fluoroalkyl-substituted alanine, and various fluoroalkyl groups can be synthesized, and the optically active source is a catalytic amount of highly selectively optically active fluorine-containing amino acids. No simple synthetic method has been reported.

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.

[1] The following general formula (3)

(Wherein, 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).

(In the formula, R ³ is a optionally substituted C _6-14 aryl group, and 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). A method for producing a compound

The following general formula (2)

(In the formula, R ¹ is the same as the general formula (3).)
The compound represented by and the following general formula (8)

(Wherein, Rf is the same as in the general formula (3), ^{R 6} is a silyl protecting group)
The compound represented by is reacted in the presence of metal fluoride, and the following general formula (2-2)

(Wherein, ^{R 1} and Rf are the same as the general formula (3).)
Produce the compound represented by, and then
A method for producing a fluoroalkyl group-containing compound, which comprises subjecting the compound represented by the general formula (2-2) to a dehydration reaction to produce the compound represented by the general formula (3).

[2] 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). When 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).

The compound represented by the general formula (2) (in the formula, R ¹ is the same as the general formula (3)) and the general formula (8) (in the formula, R f is the general formula (3)). the same, R ⁶ is a compound represented by a silyl protecting group) is reacted in the presence of a metal fluoride, the following general formula (2-1)

(In the formula, R ¹ and R f are the same as those in the general formula (3), and R ⁶ is a silyl protecting group), and then the compound represented by the formula is produced.
A method for producing a fluoroalkyl group-containing compound, which comprises subjecting the compound represented by the general formula (2-1) to a dehydration reaction to produce the compound represented by the general formula (3).

[3] The method for producing [1] or [2], wherein R ¹ is a benzyl group.
[4] The C _1-10 alkyl group in which the Rf is substituted with at least two fluorine atoms and may be further substituted with a halogen atom other than the fluorine atom (the C _1-10 alkyl group is C _{2). In the} case of a _-10 alkyl group, it may have 1 to 5 ether-bonding oxygen atoms between carbon atoms)), which is the production method according to any one of [1] to [3] above. ..
[5] The compound represented by the general formula (2) and the compound represented by the general formula (8) are reacted in the presence of a metal fluoride to form the general formula (2-1) or the above. The production method according to any one of [1] to [4] above, wherein the reaction for producing the compound represented by the general formula (2-2) is carried out at a temperature of 10 ° C. or lower.

[6] The following general formula (6-1)

(Wherein, 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).

(In the formula, 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.

(In the formula, 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.

[8] The following general formula (7)

(Wherein, 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 ..

[9] The following general formula (6-2)

(Wherein, 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). Is a method of producing a compound

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)). Manufacture the compound represented by
The protecting group R ¹ of the compound represented by the general formula (5) is deprotected, which comprises preparing a compound represented by the general formula (6-2), the production method of the fluoroalkyl group-containing compound ..
[10] The production method according to the above [9], wherein R ² is a tert-butoxycarbonyl group or a 9-fluorenylmethyloxycarbonyl group.

[11] 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). When 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. A method for producing a compound represented by (which is a protective group of an atom).
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 ..

[12] The following general formula (6-3)

Optical (wherein asterisk denotes that the absolute configuration of the asymmetric carbon atoms marked with an asterisk is S or R, Rf and R ¹ are, for the general formula (3) the same as) represented by A method of producing an active compound
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 following general formula (5-1) is applied.

In (wherein asterisk denotes that the absolute configuration of the asymmetric carbon atoms marked with an asterisk is S or R, R ^1, Rf, and R ² are the same as the general formula (4)) Manufacture the optically active compound represented
Formula (5-1) 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.

[13] 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.

[14] The following 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 (6-3)). A method for producing various compounds
An optically active compound represented by the general formula (6-3) is produced by the production method of [12] or [13].
The protecting group R ¹ of the optically active compound represented by the general formula (6-3) by deprotecting comprises producing an optically active compound represented by the general formula (7-1), A method for producing an optically active fluoroalkyl group-containing compound.

[15] The following general formula (6-4)

(Wherein the asterisk denotes that the absolute configuration of the asymmetric carbon atoms marked with an asterisk is S or R, Rf is the same as the general formula (3), R ² is, protection of the amino group A method for producing an optically active compound represented by (based).
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 (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.

[16] 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.

[17] 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). A method for producing an optically active compound represented by (similar to).
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.

[18] 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). Is a method for producing an optically active compound represented by).
The compound represented by the general formula (7) is produced by the method according to the above [8] or [11].
Production of an optically active fluoroalkyl group-containing compound, which comprises optically resolving the compound represented by the general formula (7) to produce an optically active compound represented by the general formula (7-1). Method.

[19] The following general formula (3a)

(Wherein, 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. A compound represented by (which is a protecting group selected from the groups).

[20] The following general formula (4a)

(Wherein, 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).

[21] The following general formula (5a)

(In the formula, Rf ² is -CF ₃ , -CF ₂ R ¹¹ or -CFHR ¹¹ (In the formula, 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. It may be)) and
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).

[22] The following general formula (5-1a)

(In the formula, the asterisk indicates that the absolute configuration of the asymmetric carbon atom with the asterisk is S or R, and Rf ² is the same as the general formula (5a)). , The compound of the above [21].

[23] The following general formula (6-1a)

(In the formula, Rf ³ is -CF ₂ R ¹¹ or -CFHR ¹¹ (In the formula, 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. ) Is)
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 compound represented by (which is a protecting group selected from the groups).

[24] The following general formula (6-3a)

(In the formula, the asterisk indicates that the absolute configuration of the asymmetric carbon atom with the asterisk is S or R, and Rf ³ and R ¹ are the same as those in the general formula (6-1a)). The compound of the above [23], which is a compound to be used.

[25] The following general formula (6-2a)

(In the formula, Rf ³ is -CF ₂ R ¹¹ or -CFHR ¹¹ (In the formula, 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. ) Is)
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).

[26] The following general formula (6-4a)

(In the formula, the asterisk indicates that the absolute configuration of the asymmetric carbon atom with the asterisk is S or R, and Rf ³ and R ^2A are the same as those in the general formula (6-2a)). The compound of the above-mentioned [25], which is a compound to be used.

According to the method according to the present invention, 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.

In the present invention and the present specification, "C _p1-p2 " (p1 and p2 are positive integers satisfying p1 <p2) means that the group has p1 to p2 carbon atoms.

In the present invention and the present specification, the "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. Examples of 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.

In the present invention and the specification of the present application, the "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. Examples of 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.

In the present invention and the present specification, the "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.

In the present invention and the present specification, 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.

In the present invention and the present specification, 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. Three are groups substituted with other functional groups. When having two or more substituents, 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. Examples of " _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.

In the present invention and the present specification, 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 .. As the _{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.

In the present invention and the present specification, the "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. As an example of the "halogen atom other than the fluorine atom", a chlorine atom or a bromine atom is preferable, and a chlorine atom is particularly preferable.

In the present invention and the specification of the present application, the "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.

In the present invention and the present specification, 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.

In the following, "Compound n" means a compound represented by the formula (n).

<Synthetic reaction of compound 2 to compound 7>
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. Among the synthetic routes of compound 7 which is 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. Here, as the 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. When 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. In Rf, 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.

Examples of Rf 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, 1,1,2,2,3,3-hexafluorooctadecyl group, 1,1,2,2,3,3-hexafluorohexa Examples include a cosyl group.

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. In the general formula (p-1), R ³ is a optionally substituted C _6-14 aryl group, and 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.

In the production method, 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.

R ⁶ is a silyl protecting group. Examples of 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. Preferably, ^{R 6} is trimethylsilyl (TMS) groups.

R ² is an amino protecting group. The R ^2, if a protecting group for amino groups used in peptide synthesis is not particularly limited. 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.

As the metal fluoride, 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. Examples of 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.

The reaction can be carried out in a solvent inert to the reaction. Examples of 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. As the dehydrating agent, 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).

[Step 3]
Compound 4 can be obtained by reacting compound 3 with compound 9 or compound 10.

In the general formula (9), 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. Examples of 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.

In a preferred embodiment, 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.

[Step 4]
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.

(1) Method using a reducing agent Examples of the reducing agent 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. As the reducing agent, 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.

(2) Method of reduction in the presence of a metal catalyst Examples of the metal catalyst 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. 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) and the like, and 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. Examples of 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.
When R ² is a Boc group, it can be deprotected under acidic conditions. Examples of 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. Examples of 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. Examples of 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.

When R ² is an Fmoc group, it can be deprotected under basic conditions. Examples of 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. Examples of 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. When 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, in the presence of a metal catalyst. 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.

<Synthetic reaction of compound 4 to compound 7-1>
An optically active fluorine-containing amino acid (fluoroalkyl group-containing compound) can be synthesized by performing asymmetric reduction of imine (compound 4) represented by the general formula (4). In the following reaction formula, an asterisk (*) indicates that the absolute configuration of the asymmetric carbon atom with an asterisk is S or R. Further, Rf, R ¹ , and R ² are as defined above.

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.

[Step 7]
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.

As the asymmetric reduction catalyst, a transition metal complex in which an asymmetric ligand is coordinated with the transition metal can be used. Examples of the transition metal include palladium, rhodium, ruthenium, iridium, nickel, cobalt, platinum, iron and the like. Examples of 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. As optically active phosphine ligands, 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (BINAP), 2,2'-bis (diphenylphosphino) -5,5', 6 , 6 ', 7,7', 8,8'-octahydro-1,1'-binaphthyl _(H 8 -BINAP), 2,2'-bis (di -p- tolylphosphino) -1,1'-binaphthyl ( Tol-BINAP), 2,2'-bis [bis (3,5-dimethylphenyl) phosphino] -1,1'-binaphthyl (Xyl-BINAP), 2,2'-bis [bis (3,5-di) -Tert-Butyl-4-methoxyphenyl) phosphino] -1,1'-binaphthyl (DTBM-BINAP), 1,2-bis (anicil phosphino) ethane (DIPAMP), 2,3-bis (diphenylphosphino) ) Butane (CHIRAPHOS), 1-cyclohexyl-1,2-bis (diphenylphosphino) ethane (CYCPHOS), 1,2-bis (diphenylphosphino) propane (PROPHOS), 2,3-bis (diphenylphosphino) -5-Norbornene (NORPHOS), 2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis (diphenylphosphino) butane (DIOP), 1- [1', 2-bis (diphenylphos) Fino) ferrocenyl] ethylamine (BPPFA), 1- [1', 2-bis (diphenylphosphino) ferrocenyl] ethyl alcohol (BPPFOH), 2,4-bis- (diphenylphosphino) pentane (SKEWPHOS), 1,2 -Bis (substituted phosphorano) benzene (DuPHOS), 5,5'-bis (diphenylphosphino) -4,4'-bi-1,3-benzodioxol (SEGPHOS), 5,5'-bis [di (3,5-kisilyl) Phosphino] -4,4'-bi-1,3-benzodioxol (DM-SEGPHOS), 5,5'-bis [bis (3,5-di-tert-butyl-) 4-methoxyphenyl) phosphino] -4,4'-bi-1,3-benzodioxol (DTBM-SEGPHOS), 1- [2- (2-substituted phosphino) ferrocenyl] ethyl-2-substituted phosphin (Josiphos), Examples thereof include 1- [2- (2'-2 substituted phosphinophenyl) ferrocenyl] ethyl-2-substituted phosphin (Walphos).

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. Examples of 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.

<Synthetic reaction of compound 6-1 or compound 6-2 to compound 7-1>
The synthesis of optically active fluorine-containing amino acids (fluoroalkyl group-containing compounds) can also be carried out by the following reaction. In the following reaction formula, the asterisk indicates that the absolute configuration of the asymmetric carbon atom with the asterisk is S or R. Further, Rf, R ¹ , and R ² are as defined above.

[Step 10-1]
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.

(1) Method using a chiral column A racemate can be divided into optically active substances by liquid chromatography or supercritical fluid chromatography (SFC) using a chiral column. As the chiral column, CHIRALPAK (registered trademark) (Daicel Co., Ltd.), CHIRALCEL (registered trademark) (Daicel Co., Ltd.) and the like can be used.

(2) Method by crystallization 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. Examples of optically active amines include brucine, cinchonidine, cinchonine, 1-phenethylamine and the like. Examples of optically active acids include camphorsulfonic acid, tartaric acid, mandelic acid and the like.

(3) 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.

<New intermediate compound>
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. In the formula, 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. Further, 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. When 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. Here, as the C _1-10 alkyl group, a C _2-10 alkyl group is preferable, and a C _2-8 alkyl group is preferable. Examples of Rf ¹ 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 . Here, 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. 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. As the C _1-9 alkyl group in R ¹¹ , a C _1-7 alkyl group is more preferable. Examples of Rf ² 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. Examples of 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). 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. 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.

Hereinafter, the present invention will be described with reference to Examples, but the present invention is not limited to these Examples.

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.

The following abbreviations are used herein.
Bn: Benzyl Boc: t-butoxycarbonyl Et ₂ O: Diethyl ether Fmoc: 9-Fluorenylmethyloxycarbonyl THF: Tetrahydrofuran TMS: Trimethylsilyl C ₄ F ₉ : 1,1,2,2,3,3,4 4,4-Nonafluorobutyl

[Example 1]
2-((T-butoxycarbonyl) amino) -3,3,4,4,5,5,6,6,6-nonafluorocaproic acid was synthesized from trimethyl (nonafluorobutyl) silane and dibenzyl oxalate. ..

[Step 1]

Place the stir bar in an oven-dried 100 mL two-necked flask and add dibenzyl oxalate (5.41 g, 20.0 mmol), cesium fluoride (255 mg, 1.68 mmol), and THF (54 mL) under a nitrogen atmosphere. In addition, the mixture was stirred, cooled to −30 ° C., trimethyl (nonafluorobutyl) silane (4.50 mL, 20.2 mmol) was added, and stirring was continued at −30 ° C. for 24 hours. A saturated aqueous ammonium chloride solution (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic phases are dried over sodium sulfate, filtered off, and the filtrate is evaporated under reduced pressure to 2- (benzyloxy) -3,3,4,4,5,5,6,6,6-nonafluoro-. A mixed crude product of benzyl 2-((trimethylsilyl) oxy) caproate and benzyl 3,3,4,4,5,5,6,6-nonafluoro-2,2-dihydroxycaproate was obtained. The obtained crude product was used in the next step without purification.

[Step 1-2]

Put the stir bar in a 100 mL two-necked flask dried in an oven, and under a nitrogen atmosphere, the total amount of the crude material obtained in step 1 and tetrabutylammonium fluoride (TBAF) 1 mol / L THF solution (10.5 mL, 10. 5 mmol), acetic acid (1 mL), and THF (50 mL) were added and stirred at 0 ° C. Then, the temperature was raised to room temperature, and after stirring for 24 hours, saturated aqueous sodium hydrogen carbonate (30 mL) was added for quenching, and the mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with water (50 mL) and saturated brine (50 mL), dried over sodium sulfate, filtered off, and the filtrate was evaporated under reduced pressure to 3,3,4,5,4,5,5. A crude product of benzyl 6,6,6-nonafluoro-2,2-dihydroxyhexanoate was obtained. The obtained crude product was used in the next step without purification.

^{1 1} H NMR (400 MHz, CDCl ₃ ) δ7.39 (brs, 5H), 5.37 (s, 2H). ¹⁹ F NMR (376 MHz, CDCl ₃ ) δ-80.79 (brs, 3F), -121.09 (brs, 2F), -121.24-121.26 (m, 2F), -126.12-126 .21 (m, 2F).

[Step 2]

The stirrer was placed in a 20 mL flask dried in an oven, and the total amount of the crude material obtained in step 2 and phosphorus pentoxide (22% by weight of the crude material) were added under a nitrogen atmosphere, and distillation was performed under reduced pressure. Fractions obtained at 2 mmHg, 77 ° C. were collected to give benzyl 3,3,4,4,5,5,6,6,6-nonafluoro-2-oxohexanoate as a colorless liquid (from step 1). Yield 73% through step 3).

^{1 1} H NMR (400 MHz, CDCl ₃ ) δ7.41 (brs, 5H), 5.40 (s, 2H). _{^{19 F NMR (376MHz, CDCl 3}} ) δ-80.79 (brs, 3F), - 117.78-117.850 (t, 2F, J F-F = 13Hz), - 122.01 (brs, 2F) , -125.58 (brs, 2F).

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%.

[Step 3]

Place the stir bar in an oven-dried 30 mL Schlenk flask and place in a nitrogen atmosphere under benzyl 3,3,4,4,5,6,6,6-nonafluoro-2-oxohexanoate (1 g, 2. 6 mmol), t-butyl (triphenylphosphaneiraidene) carbamate (2.6 mmol), and Et ₂ O (10 mL) were added. The reaction mixture was stirred at room temperature for 1 hour, filtered, and the filtrate was washed with Et ₂ O (2 × 2 mL). The combined organic phases were distilled off under reduced pressure to obtain a crude product of benzyl 2-((t-butoxycarbonyl) imino) -3,3,4,5,5,6,6,6-nonafluorohexaneate. It was. The obtained crude product was purified by silica gel chromatography (Et ₂ O / hexane = 1/4) and 2-((t-butoxycarbonyl) imino) -3,3,4,4,5,5,6. Benzyl 6,6-nonafluorohexaneate was obtained as a colorless liquid (yield 87%).

^{1 1} H NMR (400 MHz, CDCl ₃ ) δ7.410-7.352 (m, 5H), 5.350 (s, 2H), 1.504 (s, 9H). _{^{19 F NMR (376MHz, CDCl 3}} ) δ-80.76-80.78 (t, 3F, J F-F = 9Hz), - 112.37 (brs, 2F), - 121.0 (brs, 2F) , -125.36 (brs, 2F).

[Step 4]

Place the stir bar in an oven-dried 30 mL Schlenk flask and place in a nitrogen atmosphere, 2-((t-butoxycarbonyl) imino) -3,3,4,5,5,6,6-nona. Benzyl fluorohexanoate (0.2 g, 0.42 mmol) was dissolved in Et ₂ O (15 mL) and stirred at 0 ° C. Sodium borohydride (0.46 mmol) was added in 3 portions at 0 ° C., then the temperature was raised to room temperature and the mixture was stirred for 24 hours. Ice water was added for quenching, and 1 mol / L hydrochloric acid was added to bring the pH below 7. The aqueous phase was extracted with Et ₂ O (2 × 10 mL), and the combined organic phase was distilled off under reduced pressure to 2-((t-butoxycarbonyl) amino) -3,3,4,5,4,5,6. , 6,6-Nonafluorocaproate benzyl crude was obtained. The obtained crude product was purified by silica gel chromatography (ethyl acetate / hexane = 1/4) and 2-((t-butoxycarbonyl) amino) -3,3,4,4,5,5,6,6. , Benzyl 6-Nonafluorohexaneate was obtained as a colorless liquid (yield 61%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ7.40-7.33 (m, 5H), 5.41-5.39 (d, 2H, J H-H = 10Hz), 5.28-5.20 ( m, 3H), 1.45 (s, 9H). _{^{19 F NMR (376MHz, CDCl 3}} ) δ-80.86-80.89 (t, 3F, J F-F = 9Hz), - 115.36-118.55 (m, 2F), - 121.50- 123.17 (m, 2F), -125.00-126.77 (m, 2F).

The same reaction as in Step 4 was carried out using the solvent and reducing agent (equivalent) shown in Table 1 instead of Et ₂ O and sodium borohydride. The yields are shown in Table 1. In the table, "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.).

[Step 5-2]

Place the stir bar in an oven-dried 25 mL two-necked flask and place 2-((t-butoxycarbonyl) amino) -3,3,4,4,5,5,6,6-nonafluorohexanoic acid. Benzyl (73.6 mg, 0.15 mmol), palladium / carbon (Pd 5%, about 55% water-wet product, 20 mg), ethyl acetate (1 mL), and ethanol (7 mL) were added, and the temperature was room temperature under a hydrogen atmosphere under normal pressure. Was stirred with. After stirring at room temperature for 24 hours, Celite filtration was performed, the filtrate was washed with ethanol (3 x 5 mL), and the combined organic phase was distilled off under reduced pressure to 2-((t-butoxycarbonyl) amino) -3,3 A crude product of 4,4,5,5,6,6,6-nonafluorohexanoic acid was obtained. The obtained crude product was purified by silica gel chromatography (ethyl acetate / hexane = 1/1) and 2-((t-butoxycarbonyl) amino) -3,3,4,4,5,5,6,6. , 6-Nonafluorocaproic acid was obtained as a colorless liquid (yield 86%).

^{1 1} H NMR (400 MHz, CDCl ₃ ) δ7.72 (br, 1H), 5.49-5.47 (d, 2H, _JH-H = 10 Hz), 5.24-5.15 (m, 1H) , 1.45 (s, 9H). ¹⁹ F NMR (376 MHz, CDCl ₃ ) δ-80.30 (brs, 3F), 114.64-118.03 (m, 2F), -120.70-122.40 (m, 2F), -124 .52-126.22 (m, 2F).

[Step 5-1]

A stir bar was placed in a 25 mL two-necked flask dried in an oven, and Boc-RfAA-OBn (376 mg, 0.78 mmol), 4M HCl, and 1,4-dioxane solution (3 mL) were added at 0 ° C. After stirring at room temperature for 18 hours, a saturated aqueous sodium carbonate solution was added to adjust the pH to be higher than 7, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over sodium sulfate. The organic phase was filtered and the filtrate was evaporated under reduced pressure to give the hydrochloride salt of HRfAA-OBn as a white solid (yield 78%).

^{1 1} H NMR (400 MHz, D ₂ O) δ7.31 (brs, 2H), 6.81-6.77 (m, 5H), 5.27 (m, 1H), 3.71-3.67 (m) , 2H). ¹⁹ F NMR (376 MHz, D ₂ O) δ-80.38 (t, 3F), 118.29-121.00 (m, 2F), -121.00-123.80 (m, 2F),- 126.12-128.12 (m, 2F).

The present invention provides a novel production method capable of efficiently synthesizing a fluoroalkyl group-containing compound such as a fluorine-containing amino acid. According to the production method according to the present invention, 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. Further, according to the present invention, a novel intermediate used in the above-mentioned production method is provided.
The entire contents of the specification, claims and abstract of Japanese Patent Application No. 2019-124015 filed on July 02, 2019 are cited here and incorporated as disclosure of the specification of the present invention. Is.

Claims (26)

1. The following general formula (3)
   

   

   (Wherein, 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).
   

   

   (In the formula, R ³ is a optionally substituted C _6-14 aryl group, and 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). A method for producing a compound
   The following general formula (2)
   

   

   (In the formula, R ¹ is the same as the general formula (3).)
   The compound represented by and the following general formula (8)
   

   

   (Wherein, Rf is the same as in the general formula (3), ^{R 6} is a silyl protecting group)
   The compound represented by is reacted in the presence of metal fluoride, and the following general formula (2-2)
   

   

   (Wherein, ^{R 1} and Rf are the same as the general formula (3).)
   Produce the compound represented by, and then
   A method for producing a fluoroalkyl group-containing compound, which comprises subjecting the compound represented by the general formula (2-2) to a dehydration reaction to produce the compound represented by the general formula (3).
2. The following general formula (3)
   

   

   (Wherein, 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).
   

   

   (In the formula, R ³ is a optionally substituted C _6-14 aryl group, and 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). A method for producing a compound
   The following general formula (2)
   

   

   (In the formula, R ¹ is the same as the general formula (3))
   The compound represented by and the following general formula (8)
   

   

   (Wherein, Rf is the same as in the general formula (3), ^{R 6} is a silyl protecting group)
   The compound represented by is reacted in the presence of metal fluoride, and the following general formula (2-1)
   

   

   (In the formula, R ¹ and R f are the same as those in the general formula (3), and R ⁶ is a silyl protecting group), and then the compound represented by the formula is produced.
   A method for producing a fluoroalkyl group-containing compound, which comprises subjecting the compound represented by the general formula (2-1) to a dehydration reaction to produce the compound represented by the general formula (3).
3. The production method according to claim 1 or 2, wherein R ¹ is a benzyl group.
4. Wherein Rf is substituted with at least two fluorine atoms, further optionally substituted _{C 1-10} alkyl group (said _{C 1-10} alkyl group _{C 2-10} alkyl with a halogen atom other than a fluorine atom The production method according to any one of claims 1 to 3, wherein when it is a group, it may have 1 to 5 ether-bonding oxygen atoms between carbon atoms).
5. The compound represented by the general formula (2) and the compound represented by the general formula (8) are reacted in the presence of a metal fluoride to form the general formula (2-1) or the general formula (2). The production method according to any one of claims 1 to 4, wherein the reaction for producing the compound represented by 2-2) is carried out at a temperature of 10 ° C. or lower.
6. The following general formula (6-1)
   

   

   (Wherein, 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).
   

   

   (In the formula, R ³ is a optionally substituted C _6-14 aryl group, and 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). A method for producing a compound
   The compound represented by the general formula (3) is produced by the production method according to any one of claims 1 to 5.
   The compound represented by the general formula (3) is a compound represented by the following 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 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.
   

   

   (In the formula, 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 production method according to claim 6, wherein R ² is a tert-butoxycarbonyl group or a 9-fluorenylmethyloxycarbonyl group.
8. The following general formula (7)
   

   

   (Wherein, 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 according to claim 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 ..
9. The following general formula (6-2)
   

   

   (Wherein, 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). Is a method of producing a compound
   The compound represented by the general formula (3) is produced by the production method according to any one of claims 1 to 5.
   The compound represented by the general formula (3) is a compound represented by the following 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 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.
   

   

   (In the formula, 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 ¹ of the compound represented by the general formula (5) is deprotected, which comprises preparing a compound represented by the general formula (6-2), the production method of the fluoroalkyl group-containing compound ..
10. The production method according to claim 9, wherein R ² is a tert-butoxycarbonyl group or a 9-fluorenylmethyloxycarbonyl group.
11. The following general formula (7)
    

    

    (Wherein, 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). Is a method of producing a compound
    The compound represented by the general formula (6-2) is produced by the production method according to claim 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 ..
12. The following general formula (6-3)
    

    

    Optical (wherein asterisk denotes that the absolute configuration of the asymmetric carbon atoms marked with an asterisk is S or R, Rf and R ¹ are, for the general formula (3) the same as) represented by A method of producing an active compound
    The compound represented by the general formula (3) is produced by the production method according to any one of claims 1 to 5.
    The compound represented by the general formula (3) is a compound represented by the following 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 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 (5-1) is applied.
    

    

    In (wherein asterisk denotes that the absolute configuration of the asymmetric carbon atoms marked with an asterisk is S or R, R ^1, Rf, and R ² are the same as the general formula (4)) Manufacture the optically active compound represented
    Formula (5-1) 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.
13. The following 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 same as those in the general formula (6-1)). A method for producing optically active compounds
    The compound represented by the general formula (6-1) is produced by the production method according to claim 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.
14. The following 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 (6-3)). A method for producing various compounds
    The optically active compound represented by the general formula (6-3) is produced by the production method according to claim 12 or 13.
    The protecting group R ¹ of the optically active compound represented by the general formula (6-3) by deprotecting comprises producing an optically active compound represented by the general formula (7-1), A method for producing an optically active fluoroalkyl group-containing compound.
15. The following general formula (6-4)
    

    

    (Wherein the asterisk denotes that the absolute configuration of the asymmetric carbon atoms marked with an asterisk is S or R, Rf is the same as the general formula (3), R ² is, protection of the amino group A method for producing an optically active compound represented by (based).
    The compound represented by the general formula (3) is produced by the production method according to any one of claims 1 to 5.
    The compound represented by the general formula (3) is a compound represented by the following 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 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 (6-4)).
    The compound represented by the general formula (4) is subjected to a reduction reaction, and the following general formula (5-1) is applied.
    

    

    In (wherein asterisk denotes that the absolute configuration of the asymmetric carbon atoms marked with an asterisk is S or R, R ^1, Rf, and R ² are the same as the general formula (4)) Manufacture the optically active compound represented
    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.
16. The following general formula (6-4)
    

    

    (Wherein the asterisk denotes that the absolute configuration of the asymmetric carbon atoms marked with an asterisk is S or R, Rf is the same as the general formula (6-2), R ² is an amino group It is a method for producing an optically active compound represented by) (which is a protecting group of).
    The compound represented by the general formula (6-2) is produced by the production method according to claim 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.
17. The following 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 (6-4)). A method for producing various compounds
    The optically active compound represented by the general formula (6-4) is produced by the method according to claim 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.
18. The following 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)). Is a method of manufacturing
    The compound represented by the general formula (7) is produced by the method according to claim 8 or 11.
    A method for producing an optically active fluoroalkyl group-containing compound, which comprises optically resolving the compound represented by the general formula (7) to produce an optically active compound represented by the above (7-1).
19. The following general formula (3a)
    

    

    (Wherein, 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 following 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 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). Compound.
20. The following general formula (4a)
    

    

    (Wherein, 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).
    

    

    (In the formula, R ³ is a optionally substituted C _6-14 aryl group, and R ⁴ and R ⁵ are independently hydrogen atoms or optionally substituted C _6-14 aryl groups, respectively. The black circle is a protective group selected from a group represented by (), a 2- (9,10-dioxo) anthrylmethyl group, a benzyloxymethyl group, and a phenacyl group.
    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).
21. The following general formula (5a)
    

    

    (In the formula, Rf ² is -CF ₃ , -CF ₂ R ¹¹ or -CFHR ¹¹ (In the formula, 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. It may be)) and
    R ¹ is the following 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 independently hydrogen atoms or optionally substituted C _6-14 aryl groups, respectively. The black circle is a protective group selected from a group represented by (), a 2- (9,10-dioxo) anthrylmethyl group, a benzyloxymethyl group, and a phenacyl group.
    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).
22. The following general formula (5-1a)
    

    

    (In the formula, the asterisk indicates that the absolute configuration of the asymmetric carbon atom with the asterisk is S or R, and Rf ² is the same as the general formula (5a)). , The compound according to claim 21.
23. The following general formula (6-1a)
    

    

    (In the formula, Rf ³ is -CF ₂ R ¹¹ or -CFHR ¹¹ (In the formula, 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. ) Is)
    R ¹ is the following 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 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). Compound.
24. The following general formula (6-3a)
    

    

    (In the formula, the asterisk indicates that the absolute configuration of the asymmetric carbon atom with the asterisk is S or R, and Rf ³ and R ¹ are the same as those in the general formula (6-1a)). The compound according to claim 23, which is a compound to be used.
25. The following general formula (6-2a)
    

    

    (In the formula, Rf ³ is -CF ₂ R ¹¹ or -CFHR ¹¹ (In the formula, 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. ) Is)
    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).
26. The following general formula (6-4a)
    

    

    (In the formula, the asterisk indicates that the absolute configuration of the asymmetric carbon atom with the asterisk is S or R, and Rf ³ and R ^2A are the same as those in the general formula (6-2a)). The compound according to claim 25, which is a compound to be used.