CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of PCT/JP2021/003822, filed on Feb. 3, 2021, and claims priority to Japanese Patent Application No. 2020-019211, filed on Feb. 6, 2020, the entire contents of which are incorporated herein by reference.

TECHNICAL FIELD

The present invention relates to a method for producing aromatic heterocycle-substituted difluoroacetic acid derivatives.

BACKGROUND ART

Aromatic heterocycle-substituted difluoroacetic acid derivatives are useful as synthetic intermediates for pharmaceutical or agrochemical products.

As methods for producing aromatic heterocycle-substituted fluoroalkyl carboxylic acid derivatives, for example, Non-Patent Document 1 discloses the following methods:

a method of reacting various aromatic heterocycle N-oxides with hexafluoropropene (CF₂═CFCF₃) and methanol in N,N-dimethylformamide to produce methyl 2-(2-heteroaryl)perfluoropropionate in two steps (Scheme 5, Table 2),

a method of reacting various aromatic heterocycle N-oxides with hexafluoropropene (CF₂═CFCF₃) and an amine in N,N-dimethylformamide to produce 2-(2-heteroaryl)perfluoropropionamide in two steps (Scheme 12, 13), and

a method of reacting quinoline N-oxide with chlorotrifluoroethylene (CF₂═CFCl) and methanol in N,N-dimethylformamide at 100° C. to produce methyl 2-chloro-2-fluoro-2-(2-quinolyl)acetate (Scheme 17).

4

However, none of the documents describe productions of aromatic heterocycle-substituted difluoroacetic acid derivatives or reactions with tetrafluoroethylene (CF₂═CF₂).

DOCUMENT LIST
Non-Patent Document

Non-Patent Document 1: Chem. Eur. J. 2008, vol. 14, pp 2577-2589

SUMMARY OF THE INVENTION
Problems to be Solved by the Invention

6

The aim of the present invention is to provide a method capable of easily and inexpensively producing aromatic heterocycle-substituted difluoroacetic acid derivatives.

Means of Solving the Problems

7

The present inventors have conducted intensive studies in an attempt to solve the above-mentioned problems and found that by reacting an N-oxido aromatic heterocyclic compound having a partial structure represented by the following formula (I) with tetrafluoroethylene in the presence of a compound represented by the following formula (II) in a specific solvent, an aromatic heterocycle-substituted difluoroacetic acid derivative having a partial structure represented by the following formula (III) with few by-products can be easily and inexpensively produced in one step, which resulted in the completion of the present invention.

8

Accordingly, the present invention provides the following.

[1] A method for producing an aromatic heterocycle-substituted difluoroacetic acid derivative having a partial structure represented by the formula (III):

9

[Image Omitted]

10

wherein

R is a C_1-8alkyl group, a C_3-8cycloalkyl group, a C_7-16aralkyl group or a C_6-10aryl group, wherein the C_1-8alkyl group is optionally substituted by substituent(s) selected from a halogen atom, a cyano group, a C_1-6alkoxy group and a C_1-6haloalkoxy group, and the C_3-8cycloalkyl group, C_7-16aralkyl group and C_6-10aryl group are each optionally substituted by substituent(s) selected from a halogen atom, a cyano group, a C_1-6alkyl group, a C_1-6haloalkyl group, a C_1-6alkoxy group and a C_1-6haloalkoxy group,

Y is O, S or NR^Y, and

R^Yis a hydrogen atom or a C_1-8alkyl group, or R^Yand R are optionally taken together to form a nitrogen-containing heterocycle with the nitrogen atom to which they are bond (hereinafter, to be referred to as aromatic heterocycle-substituted difluoroacetic acid derivative (III)), which comprises reacting an N-oxido aromatic heterocyclic compound having a partial structure represented by the formula (I):

11

[Image Omitted]

12

(hereinafter, to be referred to as N-oxido aromatic heterocyclic compound (I)) with tetrafluoroethylene, in the presence of a compound represented by the formula (II): R—YH wherein each symbol in the formula is as defined above (hereinafter, to be referred to as compound (II)), in a solvent selected from an aromatic hydrocarbon solvent, an ester solvent and an ether solvent.

[2] The method according to the above [1], wherein the reaction is carried out at temperature in the range of 100 to 300° C.

[3] The method according to the above [1] or [2], wherein the reaction is carried out under pressure in the range of 0.1 to 10.0 MPa.

[4] The method according to any of the above [1] to [3], wherein the N-oxido aromatic heterocyclic compound having the partial structure represented by the formula (I) is an N-oxido aromatic heterocyclic compound represented by the formula (IA) or (IB):

13

[Image Omitted]

14

wherein

X^1ais CR^1aor N;

X^1bis CR^1bor N;

X^1cis CR^1cor N;

X^1dis CR^1dor N;

R^1a, R^1b, R^1cand R^1dare each independently a hydrogen atom, a halogen atom, a cyano group, a C_1-6alkyl group, a C_1-6haloalkyl group, a hydroxy group, a C_1-6alkoxy group, a C_1-6haloalkoxy group, a sulfanyl group, a C_1-6alkylsulfanyl group, an amino group, a mono-C_1-6alkylamino group, a di-C_1-6alkylamino group, a formyl group, a carboxy group, a C_1-6alkoxy-carbonyl group, a C_6-10aryl group or a C_7-16aralkyl group, or R^1aand R^1b, R^1band R^1c, or R^1cand R^1dare optionally taken together to form a C_6-10arene optionally substituted by substituent(s) selected from a halogen atom, a cyano group, a C_1-6alkyl group, a C_1-6haloalkyl group, a hydroxy group, a C_1-6alkoxy group, a C_1-6haloalkoxy group, a sulfanyl group, a C_1-6alkylsulfanyl group, an amino group, a mono-C_1-6alkylamino group, a di-C_1-6alkylamino group, a formyl group, a carboxy group, a C_1-6alkoxy-carbonyl group, a C_6-10aryl group and a C_7-16aralkyl group;

X^2ais CR^2a, N, NR^2a, S or O;

X^2bis CR^2bor N;

X^2cis OR²c, N, NR^2c, S or O; and

R^2a, R^2band R^2care each independently a hydrogen atom, a halogen atom, a cyano group, a C_1-6alkyl group, a C_1-6haloalkyl group, a hydroxy group, a C_1-6alkoxy group, a C_1-6haloalkoxy group, a sulfanyl group, a C_1-6alkylsulfanyl group, an amino group, a mono-C_1-6alkylamino group, a di-C_1-6alkylamino group, a formyl group, a carboxy group, a C_1-6alkoxy-carbonyl group, a C_6-10aryl group or a C_7-16aralkyl group, or R^2aand R^2b, or R^2band R^2care optionally taken together to form a C_6-10arene optionally substituted by substituent(s) selected from a halogen atom, a cyano group, a C_1-6alkyl group, a C_1-6haloalkyl group, a hydroxy group, a C_1-6alkoxy group, a C_1-6haloalkoxy group, a sulfanyl group, a C_1-6alkylsulfanyl group, an amino group, a mono-C_1-6alkylamino group, a di-C_1-6alkylamino group, a formyl group, a carboxy group, a C_1-6alkoxy-carbonyl group, a C_6-10aryl group and a C_7-16aralkyl group (hereinafter, to be referred to as N-oxido aromatic heterocyclic compound (IA) or (IB)).

[5] The method according to the above [4], wherein the N-oxido aromatic heterocyclic compound having the partial structure represented by the formula (I) is represented by the formula (IA), and R^1aand R^1b, R^1band R^1c, or R^1cand R^1din the formula are taken together to form a C_6-10arene optionally substituted by substituent(s) selected from a halogen atom, a cyano group, a C_1-6alkyl group, a C_1-6haloalkyl group, a hydroxy group, a C_1-6alkoxy group, a C_1-6haloalkoxy group, a sulfanyl group, a C_1-6alkylsulfanyl group, an amino group, a mono-C_1-6alkylamino group, a di-C_1-6alkylamino group, a formyl group, a carboxy group, a C_1-6alkoxy-carbonyl group, a C_6-10aryl group and a C_7-16aralkyl group.

[6] The method according to the above [4], wherein the N-oxido aromatic heterocyclic compound having the partial structure represented by the formula (I) is represented by the formula (IA), and R^1a, R^1b, R^1cand R^1din the formula are each independently a hydrogen atom, a halogen atom, a cyano group, a C_1-6alkyl group, a C_1-6haloalkyl group, a hydroxy group, a C_1-6alkoxy group, a C_1-6haloalkoxy group, a sulfanyl group, a C_1-6alkylsulfanyl group, an amino group, a mono-C_1-6alkylamino group, a di-C_1-6alkylamino group, a formyl group, a carboxy group, a C_1-6alkoxy-carbonyl group, a C_6-10aryl group or a C_7-16aralkyl group.

[7] The method according to the above [4], wherein the N-oxido aromatic heterocyclic compound having the partial structure represented by the formula (I) is represented by the formula (IB), and R^ea and R^2b, or R^2band R^2cin the formula are taken together to form a C_6-10arene optionally substituted by substituent(s) selected from a halogen atom, a cyano group, a C_1-6alkyl group, a C_1-6haloalkyl group, a hydroxy group, a C_1-6alkoxy group, a C_1-6haloalkoxy group, a sulfanyl group, a C_1-6alkylsulfanyl group, an amino group, a mono-C_1-6alkylamino group, a di-C_1-6alkylamino group, a formyl group, a carboxy group, a C_1-6alkoxy-carbonyl group, a C_6-10aryl group and a C_7-16aralkyl group.

[8] The method according to the above [4], wherein the N-oxido aromatic heterocyclic compound having the partial structure represented by the formula (I) is represented by the formula (IB), and R^2a, R^2band R^2cin the formula are each independently a hydrogen atom, a halogen atom, a cyano group, a C_1-6alkyl group, a C_1-6haloalkyl group, a hydroxy group, a C_1-6alkoxy group, a C_1-6haloalkoxy group, a sulfanyl group, a C_1-6alkylsulfanyl group, an amino group, a mono-C_1-6alkylamino group, a di-C_1-6alkylamino group, a formyl group, a carboxy group, a C_1-6alkoxy-carbonyl group, a C_6-10aryl group or a C_7-16aralkyl group.

Effect of the Invention

15

According to the present invention, by an easy and inexpensive method of flowing tetrafluoroethylene into N-oxido aromatic heterocyclic compound (I) in the presence of compound (II) in a specific solvent, aromatic heterocycle-substituted difluoroacetic acid derivative (III) with few by-products can be produced in one step.

DESCRIPTION OF EMBODIMENTS

16

Hereinafter, the definitions of the groups used herein will be described in detail. Unless otherwise specified, the groups have the following definitions.

17

As used herein, the compound represented by the formula is indicated by adding the formula number to the “Compound”. For example, the compound represented by the formula (1) is indicated as “Compound (1)”.

As used herein, the numerical range represented by “to” or “-” means a numerical range in which the numbers before and after “to” or “-” are the lower and upper limits.

As used herein, when the name of arbitrary group is given the element symbol “C” and a numerical range by numbers before and after “-”, it means that the group has an integer number of carbon atoms whose the lower and upper limits are the numbers before and after the “-”. For example, an alkyl group having 1 to 3 carbon atoms may be referred to as a “C_1-3alkyl group”, which indicates each of —CH₃, —C₂H₅, —C₃H₇and the like. The same applies to other groups.

18

As used herein, the “halogen atom” means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

19

As used herein, the “C_1-8alkyl group” means a linear or branched saturated hydrocarbon group having 1 to 8 carbon atoms. Examples of the “C_1-8alkyl group” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neo-pentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, octyl and the like. The preferred is a C_1-4alkyl group.

20

As used herein, the “C_1-6alkyl group” means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms. Examples of the “C_1-6alkyl group” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neo-pentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl and the like. The preferred is a C_1-4alkyl group.

21

As used herein, the “C_1-4alkyl group” means a linear or branched saturated hydrocarbon group having 1 to 4 carbon atoms. Examples of the “C_1-4alkyl group” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.

22

As used herein, the “C_1-6alkoxy group” means a group represented by the formula R¹¹O— wherein R¹¹is a C_1-6alkyl group. Examples of the “C_1-6alkoxy group” include methoxy, ethoxy, propoxy, isopropoxy, butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy, pentyloxy, hexyloxy and the like. The preferred is a C_1-4alkoxy group.

23

As used herein, the “C_1-6haloalkyl group” means a group in which the one or more hydrogen atoms of the “C_1-6alkyl group” are replaced with halogen atoms. Examples of the “C_1-6haloalkyl group” include fluoromethyl, 2-fluoroethyl, 3-fluoropropyl, 4-fluorobutyl, trifluoromethyl, difluoromethyl, perfluoroethyl, perfluoropropyl, chloromethyl, 2-chloroethyl, bromomethyl, 2-bromoethyl, iodomethyl, 2-iodoethyl and the like. The preferred is trifluoromethyl.

24

As used herein, the “C_1-6haloalkoxy group” means a group in which the one or more hydrogen atoms of the “C_1-6alkoxy group” are replaced with halogen atoms. Examples of the “C_1-6haloalkoxy group” include bromomethoxy, 2-bromoethoxy, 3-bromopropoxy, 4-bromobutoxy, iodomethoxy, 2-iodoethoxy, 3-iodopropoxy, 4-iodobutoxy, fluoromethoxy, 2-fluoroethoxy, 3-fluoropropoxy, 4-fluorobutoxy, tribromomethoxy, trichloromethoxy, trifluoromethoxy, difluoromethoxy, perfluoroethoxy, perfluoropropoxy, perfluoroisopropoxy, 1,1,2,2-tetrafluoroethoxy and 2-chloro-1,1,2-trifluoroethoxy.

25

As used herein, the “C_1-6alkylsulfanyl group” means a group represented by the formula R¹¹S— wherein R¹¹is a C_1-6alkyl group. Examples of the “C_1-6alkylsulfanyl group” include methylsulfanyl, ethylsulfanyl, propylsulfanyl, isopropylsulfanyl, butylsulfanyl, isobutylsulfanyl, sec-butylsulfanyl, tert-butylsulfanyl, pentylsulfanyl, hexylsulfanyl and the like. The preferred is a C_1-4sulfanyl group.

26

As used herein, the “mono-C_1-6alkylamino group” means a group represented by the formula R¹¹NH— wherein R¹¹is a C_1-6alkyl group. Examples of the “mono-C_1-6alkylamino group” include methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino, tert-butylamino, pentylamino, hexylamino and the like. The preferred is a mono-C_1-4alkylamino group.

27

As used herein, the “di-C_1-6alkylamino group” means a group represented by the formula R¹¹₂N— wherein the two R¹¹are each independently a C_1-6alkyl group. Examples of the “di-C_1-6alkylamino group” include dimethylamino, diethylamino, N-ethyl-N-methylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, disec-butylamino, ditert-butylamino, dipentylamino, dihexylamino and the like. The preferred is a alkylamino group.

28

As used herein, the “C_1-6alkoxy-carbonyl group” means a group represented by the formula R¹¹O C(═O)— wherein R¹¹is a C_1-6alkyl group. Examples of the “C_1-6alkoxy-carbonyl group” include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl and the like. The preferred is a C_1-4alkoxy-carbonyl group.

29

As used herein, the “C_3-8cycloalkyl group” means a cyclic saturated hydrocarbon group having 3 to 8 carbon atoms. Examples of the “C_3-8cycloalkyl group” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

30

As used herein, the “C_6-10aryl group” means a hydrocarbon group having 6 to 10 carbon atoms and having aromaticity. Examples of the “C_6-10aryl group” include phenyl, 1-naphthyl and 2-naphthyl. The preferred is phenyl.

31

As used herein, the “C_7-16aralkyl group” means the “C_1-6alkyl group” substituted by the “C_6-10aryl group”. Examples of the “C_7-16aralkyl group” include benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, (1-naphthyl)methyl, (2-naphthyl)methyl and the like. The preferred is benzyl.

32

As used herein, the “C_6-10arene” means a hydrocarbon ring having 6 to 10 carbon atoms and having aromaticity. Examples of the “C_6-10arene” include benzene and naphthalene. The preferred is benzene.

As used herein, Examples of the substituent of the “optionally substituted C_6-10arene” include a halogen atom, a cyano group, a C_1-6alkyl group, a hydroxy group, a C_1-6alkoxy group, a sulfanyl group, a C_1-6alkylsulfanyl group, an amino group, a mono-C_1-6alkylamino group, a di-C_1-6alkylamino group, a formyl group, a carboxy group, a C_1-6alkoxy-carbonyl group, a C_6-10aryl group and a C_7-16aralkyl group.

33

As used herein, the “nitrogen-containing heterocycle” include a ring containing at least one nitrogen atom, and optionally further containing hetero atom(s) selected from a nitrogen atom, an oxygen atom and a sulfur atom. Examples of the “nitrogen-containing heterocycle” include aziridine, azetidine, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine and the like. The preferred is a 3- to 8-membered nitrogen-containing heterocycle, and the more preferred is a 5- or 6-membered nitrogen-containing heterocycle.

34

Hereinafter, the production method of the present invention is explained.

In the present invention, aromatic heterocycle-substituted difluoroacetic acid derivative (III) is produced by reacting N-oxido aromatic heterocyclic compound (I) with tetrafluoroethylene, in the presence of compound (II), in a solvent selected from an aromatic hydrocarbon solvent, an ester solvent and an ether solvent. The reaction mechanism is as follows.

35

[Image Omitted]

36

Specific examples of N-oxido aromatic heterocyclic compound (I) include the following N-oxido aromatic heterocyclic compounds (IA) and (IB):

37

[Image Omitted]

38

wherein

X^1ais CR^1aor N;

X^1bis CR^1cor N;

X^1cis CR^1cor N;

X^1dis CR^1dor N;

R^1a, R^1b, R^1cand R^1dare each independently a hydrogen atom, a halogen atom, a cyano group, a C_1-6alkyl group, a C_1-6haloalkyl group, a hydroxy group, a C_1-6alkoxy group, a C_1-6haloalkoxy group, a sulfanyl group, a C_1-6alkylsulfanyl group, an amino group, a mono-C_1-6alkylamino group, a di-C_1-6alkylamino group, a formyl group, a carboxy group, a C_1-6alkoxy-carbonyl group, a C_6-10aryl group or a C_7-16aralkyl group, or R^1aand R^1b, R^1band R^1c, or R^1cand R^1dare optionally taken together to form a C_6-10arene optionally substituted by substituent(s) selected from a halogen atom, a cyano group, a C_1-6alkyl group, a C_1-6haloalkyl group, a hydroxy group, a C_1-6alkoxy group, a C_1-6haloalkoxy group, a sulfanyl group, a C_1-6alkylsulfanyl group, an amino group, a mono-C_1-6alkylamino group, a di-C_1-6alkylamino group, a formyl group, a carboxy group, a C_1-6alkoxy-carbonyl group, a C_6-10aryl group and a C_7-16aralkyl group;

X^2ais CR^2a, N, NR^2a, S or O;

X^2bis CR^2bor N;

X^2cis OR^2c, N, NR^2c, S or O; and

R^2a, R^2band R^2care each independently a hydrogen atom, a halogen atom, a cyano group, a C_1-6alkyl group, a C_1-6haloalkyl group, a hydroxy group, a C_1-6alkoxy group, a C_1-6haloalkoxy group, a sulfanyl group, a C_1-6alkylsulfanyl group, an amino group, a mono-C_1-6alkylamino group, a di-C_1-6alkylamino group, a formyl group, a carboxy group, a C_1-6alkoxy-carbonyl group, a C_6-10aryl group or a C_7-16aralkyl group, or R^2aand R^2b, or R^2band R^2care optionally taken together to form a C_6-10arene optionally substituted by substituent(s) selected from a halogen atom, a cyano group, a C_1-6alkyl group, a C_1-6haloalkyl group, a hydroxy group, a C_1-6alkoxy group, a C_1-6haloalkoxy group, a sulfanyl group, a C_1-6alkylsulfanyl group, an amino group, a mono-C_1-6alkylamino group, a di-C_1-6alkylamino group, a formyl group, a carboxy group, a C_1-6alkoxy-carbonyl group, a C_6-10aryl group and a C_7-16aralkyl group.

R^1b, R^1cand R^1dare preferably each independently a hydrogen atom, a cyano group or a C_1-6alkyl group, or R^1aand R^1b, R^1band R^1c, or R^1cand R^1dare optionally taken together to form a C_6-10arene optionally substituted by C_1-6alkoxy-carbonyl group(s).

R^2a, R^2band R^2care preferably each independently a hydrogen atom, a C_1-6alkyl group or a C_7-16aralkyl group, or R^2aand R^2b, or R^2band R^2care optionally taken together to form a C_6-10arene.

39

In the formula (IB), one of the bond R^2a-R^2band the bond R^2b-R^2cis a single bond, and the other is a double bond. Provided that when X^2ais S or O, then the bond R^2a-R^2bis a single bond, and the bond R^2b-R^2cis a double bond. Also, provided that when X^2cis S or O, then the bond R^2a-R^2bis a double bond, and the bond R^2b-R²c is a single bond.

40

Specific examples of N-oxido aromatic heterocyclic compound (IA) include the following N-oxido aromatic heterocyclic compounds (IA-a)-(IA-e).

41

[Image Omitted]

42

wherein each symbol in the formula is as defined above.

Among them, the preferred are (IA-a), (IA-b) and (IA-d).

Preferable specific examples of N-oxido aromatic heterocyclic compound (IA) include the following compounds.

43

[Image Omitted]

44

wherein

R^1aa, R^1bb, R^1ccand R^1ddare each independently a hydrogen atom, a halogen atom, a cyano group, a C_1-6alkyl group, a C_1-6haloalkyl group, a hydroxy group, a C_1-6alkoxy group, a C_1-6haloalkoxy group, a sulfanyl group, a C_1-6alkylsulfanyl group, an amino group, a mono-C_1-6alkylamino group, a di-C_1-6alkylamino group, a formyl group, a carboxy group, a C_1-6alkoxy-carbonyl group, a C_6-10aryl group or a C_7-16aralkyl group;

R^1eein the number of n are each independently a halogen atom, a cyano group, a C_1-6alkyl group, a C_1-6haloalkyl group, a hydroxy group, a C_1-6alkoxy group, a C_1-6haloalkoxy group, a sulfanyl group, a C_1-6alkylsulfanyl group, an amino group, a mono-C_1-6alkylamino group, a di-C_1-6alkylamino group, a formyl group, a carboxy group, a C_1-6alkoxy-carbonyl group, a C_6-10aryl group or a C_7-16aralkyl group; and n is an integer of 0 to 4.

R^1aa, R^1bb, R^1ccand R^1ddare preferably each independently a hydrogen atom, a cyano group or a C_1-6alkyl group;

R^1eein the number of n are preferably each independently a C_1-6alkoxy-carbonyl group; and

n is 0 or 1.

45

Specific examples of N-oxido aromatic heterocyclic compound (IB) include the following N-oxido aromatic heterocyclic compounds (IB-a)-(IB-ff).

46

[Image Omitted]

47

48

wherein each symbol in the formula is as defined above.

Among them, the preferred are (IB-e), (IB-u) and (IB-w).

Preferable specific examples of N-oxido aromatic heterocyclic compound (IB) include the following compounds.

49

[Image Omitted]

50

wherein

R^2aa, R^2bband R^2ccare each independently a hydrogen atom, a halogen atom, a cyano group, a C_1-6alkyl group, a C_1-6haloalkyl group, a hydroxy group, a C_1-6alkoxy group, a C_1-6haloalkoxy group, a sulfanyl group, a C_1-6alkylsulfanyl group, an amino group, a mono-C_1-6alkylamino group, a di-C_1-6alkylamino group, a formyl group, a carboxy group, a C_1-6alkoxy-carbonyl group, a C_6-10aryl group or a C_7-16aralkyl group;

R^2eein the number of n are each independently a halogen atom, a cyano group, a C_1-6alkyl group, a C_1-6haloalkyl group, a hydroxy group, a C_1-6alkoxy group, a C_1-6haloalkoxy group, a sulfanyl group, a C_1-6alkylsulfanyl group, an amino group, a mono-C_1-6alkylamino group, a di-C_1-6alkylamino group, a formyl group, a carboxy group, a C_1-6alkoxy-carbonyl group, a C_6-10aryl group or a C_7-16aralkyl group; and n is an integer of 0 to 4.

R^2aa, R^2bband R^2ccare preferably each independently a hydrogen atom, a C_1-6alkyl group or a C_7-16aralkyl group; and n is 0.

51

N-Oxido aromatic heterocyclic compound (I) may be commercially available, or can be produced according to a method known per se.

52

Tetrafluoroethylene (CF₂═CF₂) can be produced according to a known method. Since tetrafluoroethylene is in a gaseous state at room temperature under atmospheric pressure, it is added to the reaction system by inflow. In this case, tetrafluoroethylene diluted with nitrogen gas may be flowed into the reaction system. The amount of the tetrafluoroethylene to be used is generally 1 to 100 mol, preferably 1 to 10 mol, per 1 mol of N-oxido aromatic heterocyclic compound (I).

53

The reaction is carried out in the presence of compound (II). R in compound (II) is preferably a C_1-8alkyl group optionally substituted by substituent(s) selected from a halogen atom, a cyano group, a C_1-6alkoxy group and a C_1-6haloalkoxy group; a C_7-16aralkyl group or a C_6-10aryl group, which of each is optionally substituted by substituent(s) selected from a halogen atom, a cyano group, a C_1-6alkyl group, a C_1-6haloalkyl group, a C_1-6alkoxy group and a C_1-6haloalkoxy group, more preferably a C_1-6alkyl group.

Y in compound (II) is preferably O or NR^Y, more preferably O.

R^Yin compound (II) is preferably a hydrogen atom or a C_1-6alkyl group, or R^Yand R are taken together to form a 5- or 6-membered nitrogen-containing heterocycle (e.g., morpholine) with the nitrogen atom to which they are bond.

Preferable specific examples of compound (II) include butanol, morpholine and the like.

The amount of compound (II) to be used can be appropriately selected, and is preferably 0.05 to 0.5 times the volume of the solvent described below.

54

The reaction may be carried out in the presence of an additive.

55

The reaction is carried out in a solvent selected from an aromatic hydrocarbon solvent, an ester solvent and an ether solvent. The use of such solvent allows for good dissolution of tetrafluoroethylene and thus the production of aromatic heterocycle-substituted difluoroacetic acid derivative (III) with few by-products.

Examples of the aromatic hydrocarbon solvent include toluene, xylene, nitrobenzene and the like.

Examples of the ester solvent include butyl acetate, octyl acetate and the like.

Examples of the ether solvent include dibutyl ether, cyclopentyl methyl ether and the like.

The solvent used in the reaction is preferably a solvent having a boiling point of 80° C. or higher, more preferably a solvent having a boiling point of 100° C. or higher, particularly preferably a solvent having a boiling point of 110° C. or higher, from the aspect of the reaction temperature. Examples of such solvents include toluene, xylene, nitrobenzene, butyl acetate, octyl acetate, dibutyl ether, cyclopentyl methyl ether and the like. Among them, the preferred are toluene and butyl acetate.

The amount of the solvent to be used is generally 100 to 1000 times, preferably 100 to 200 times the volume of N-oxido aromatic heterocyclic compound (I).

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The reaction may be carried out in a flow system while flowing tetrafluoroethylene into a mixture of N-oxido aromatic heterocyclic compound (I), compound (II) and a solvent. Alternatively, the reaction may be carried out in a sealed system after flowing tetrafluoroethylene into a mixture of N-oxido aromatic heterocyclic compound (I), compound (II) and a solvent. The reaction is carried out preferably in a sealed system, more preferably under pressure in the range of 0.1 to 100.0 MPa, particularly preferably in the range of 0.1 to 10.0 MPa, from the aspect of the reaction efficiency and reduction of by-products.

When N-oxido aromatic heterocyclic compound (I) is represented by the formula (IA), and R^1aand R^1b, R^1band R^1c, or R^1cand R^1dare taken together to form the above C_6-10arene, then the reaction is carried out preferably under pressure in the range of 0.1 to 10.0 MPa, more preferably in the range of 0.1 to 1.0 MPa, particularly preferably in the range of 0.1 to 0.5 MPa, from the aspect of ease of the reaction progress and increase in the reaction rate.

On the other hand, when N-oxido aromatic heterocyclic compound (I) is represented by the formula (IA), and does not form the above C_6-10arene, then the reaction may be carried out under pressure in the above range. From the aspect of ease of the reaction progress and increase in the reaction rate, the reaction may be carried out preferably under pressure in the range of 0.1 to 30.0 MPa, more preferably in the range of 1.5 to 3.0 MPa, particularly preferably in the range of 2.0 to 2.5 MPa.

Prior to the inflow of tetrafluoroethylene, the reaction system is preferably degassed in advance. The reaction is also carried out preferably under nitrogen atmosphere.

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The reaction is carried out generally at 100° C. or higher, preferably at temperature in the range of 100 to 300° C.

When N-oxido aromatic heterocyclic compound (I) is represented by the formula (IA), and R^1aand R^1b, R^1band R^1c, or R^1cand R^idare taken together to form the above C_6-10arene, then the reaction is carried out preferably at temperature in the range of 100 to 200° C., particularly preferably in the range of 100 to 150° C., from the aspect of ease of the reaction progress and increase in the reaction rate.

On the other hand, when N-oxido aromatic heterocyclic compound (I) is represented by the formula (IA), and does not form the above C_6-10arene, then the reaction may be carried out at temperature in the above range. From the aspect of ease of the reaction progress and increase in the reaction rate, the reaction may be carried out preferably at temperature in the range of 200 to 300° C., particularly preferably in the range of 200 to 250° C.

The reaction time varies depending on the kinds of N-oxido aromatic heterocyclic compound (I) and compound (II), and the reaction temperature, and it is generally 12 to 120 hr, preferably 24 to 48 hr.

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After the completion of the reaction, the objective aromatic heterocycle-substituted difluoroacetic acid derivative (III) can be isolated and purified from the reaction mixture according to conventional method, for example, a separation means such as concentration, crystallization, recrystallization, distillation, solvent extraction, fractional distillation, column chromatography and the like.

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The container used for the reaction of tetrafluoroethylene and N-oxido aromatic heterocyclic compound (I) is not limited as long as it does not adversely affect the reaction. For example, metal containers and the like can be used. Since olefin in a gaseous state under the reaction condition is handled in the present invention, the use of air-sealing, pressure-resistant containers is preferable. Moreover, since the compound generated as the reaction progresses may become a reaction inhibitor by reacting with the metal of the reaction container, the use of containers lined with resin such as PFA or glass is preferable.

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For aromatic heterocycle-substituted difluoroacetic acid derivative (III) thus obtained, for example, aromatic heterocycle-substituted difluoroacetic acid derivative (III) wherein Y is O can be led to a difluoromethyl-substituted aromatic heterocyclic compound having a partial structure represented by the formula (IV):

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[Image Omitted]

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which is useful as a synthetic intermediate for pharmaceutical or agrochemical products, by a known method, for example, hydrolysis, followed by decarboxylation.

EXAMPLES

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The present invention is explained in detail in the following by referring to Examples, which are not to be construed as limitative.

[Analysis Method]

The present invention is explained in detail in the following by referring to Examples, which are not to be construed as limitative. Nuclear magnetic resonance spectrum (NMR) was measured using JNM-AL300 manufactured by JEOL Ltd. ¹H NMR was measured at 300 MHz using tetramethylsilane as standard.

Mass spectrometry (LC-MS) was measured using liquid chromatograph mass spectrum system (LCMS6120B) manufactured by Agilent Technologies. Mass spectrometry (GC-MS) was determined by electron ionization (EI) using gas chromatograph mass spectrometer (GCMS-QP5000V2 or GCMS-QP2010Ultra) manufactured by Shimadzu Corporation.

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Example 1

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[Image Omitted]

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A SUS reactor having a volume of 25 cm³was charged with butyl acetate (10 ml) and 1-butanol (1 ml), and the mixture was stirred, and kept at 25° C. Then, quinoline N-oxide (109 mg, 0.751 mmol, Compound 1) was added thereto, and the mixture was degassed under reduced pressure. Tetrafluoroethylene diluted to 50% with nitrogen gas was refilled until the reactor pressure reached 0.1 MPa, and the mixture was kept stirred under heating at 140° C. for one week. By measuring ¹H-NMR and LC-MS of the crude solution after the completion of the reaction, it was found that Compound 2 was obtained in a yield of 89%.

The reaction solution was concentrated as it is. Compound 2 (20 mg, 0.0677 mmol) was dissolved in methanol (0.2 ml), 1N aqueous potassium carbonate solution (0.2 ml) was added thereto, and the mixture was stirred, and kept stirred at 25° C. for 18 hr. Then, 5% aqueous hydrochloric acid solution (1 ml) was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was separated, and washed with saturated brine. The organic layer was concentrated, and the obtained crude product was dissolved in N,N-dimethylformaldehyde (1 ml). Sodium fluoride (23 mg) was added thereto, and the mixture was kept stirred under heating at 170° C. for 1 hr. By measuring ¹H-NMR and GC-MS of the crude solution after the completion of the reaction, it was found that Compound 3 was obtained in a yield of 92%.

¹H-NMR and LC-MS of the above Compound (2) are shown below.

¹H-NMR (CDCl₃) δ 8.35 (d, 1H), 8.15 (d, 1H), 7.89 (d, 1H), 7.72-7.81 (m, 2H), 7.63 (t, 1H), 4.36 (t, 2H), 1.67 (tt, 2H), 1.35 (tt, 2H), 0.88 (t, 3H)

LC-MS:[M+1]=280

¹H-NMR and GC-MS of the above Compound (3) are shown below.

¹H-NMR (CDCl₃) δ 8.34 (d, 1H), 8.15 (d, 1H), 7.90 (d, 1H), 7.80 (dd, 1H), 7.74 (d, 1H), 7.65 (dd, 1H), 6.79 (t, 1H) GC-MS (EI): [M+]=179

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Reference Example 1

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[Image Omitted]

A crude solution containing Compounds 2 and 3 was obtained from Compound 1 in the same procedure as in Example 1, except that butyl acetate were not used. By measuring ¹H-NMR and GC-MS of the crude solution after the completion of the reaction, it was found that Compound 2 was obtained in a yield of 13%.

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Example 2

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[Image Omitted]

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A SUS reactor having a volume of 25 cm³was charged with toluene (7 ml) and morpholine (0.3 ml), and the mixture was stirred, and kept at 25° C. Then, quinoline N-oxide (109 mg, 0.751 mmol, Compound 1) was added thereto, and the mixture was degassed under reduced pressure. Tetrafluoroethylene diluted to 50% with nitrogen gas was refilled until the reactor pressure reached 0.1 MPa, and the mixture was kept stirred under heating at 140° C. for 12 hr. By measuring ¹H-NMR and LC-MS of the crude solution after the completion of the reaction, it was found that Compound 4 was obtained in a yield of 37%.

¹H-NMR and LC-MS of the above Compound (4) are shown below.

¹H-NMR (CDCl₃) δ 8.33 (d, 1H), 8.11 (d, 1H), 7.88 (d, 1H), 7.82-7.74 (m, 2H), 7.63 (t, 1H), 3.76 (s, 4H), 3.64 (t, 2H), 3.57 (t, 2H).

LC-MS: [M+1]=293

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Example 3

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[Image Omitted]

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A crude solution containing Compound 6 was obtained from Compound 5 in the same procedure as in Example 1. By measuring ¹H-NMR and LC-MS of the crude solution after the completion of the reaction, it was found that Compound 6 was obtained in a yield of 61%.

¹H-NMR and LC-MS of the above Compound (6) are shown below.

¹H-NMR (CDCl₃) δ 9.23 (s, 1H), 8.10-8.22 (m, 2H), 7.80-7.92 (m, 2H), 4.36 (t, 2H), 1.70 (tt, 2H), 1.38 (tt, 2H), 0.92 (t, 3H) LC-MS: [M+1]=281

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Example 4

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A crude solution containing Compound 8 was obtained from Compound 7 in the same procedure as in Example 1. By measuring ¹H-NMR and LC-MS of the crude solution after the completion of the reaction, it was found that Compound 8 was obtained in a yield of 41%.

¹H-NMR and LC-MS of the above Compound (8) are shown below. ¹H-NMR (CDCl₃) δ9.58 (1H, s), 8.46 (1H, m), 7.77-8.09 (3H, m), 4.48 (2H, t), 1.73 (2H, tt), 1.44 (2H, tt), 0.95 (3H, t).

LC-MS: [M+1]=281

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Example 5

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[Image Omitted]

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A PFA-lined SUS reactor having a volume of 300 cm³was charged with butyl acetate (30 ml) and butanol (3 ml), and the mixture was stirred, and kept at 25° C. Then, pyridine N-oxide (336.4 mg, 3.54 mmol, Compound 9) was added thereto, and the mixture was degassed under freezing. Tetrafluoroethylene diluted to 50% with nitrogen gas was refilled until the reactor pressure reached 0.3 MPa, and the mixture was kept stirred under heating at 250° C. for 8 hr. By measuring ¹H-NMR and LC-MS of the crude solution after the completion of the reaction, it was found that Compound 10 was obtained in a yield of 28%.

¹H-NMR and LC-MS of the above Compound (10) are shown below.

¹H-NMR (ACETN) δ8.69 (d, 1H), 8.08 (ddd, 1H), 7.84 (ddd, 1H), 7.60-7.63 (m, 1H), 4.33 (t, 2H), 1.65 (tt, 2H), 1.35 (tt, 2H), 0.89 (t, 3H)

LC-MS: [M+1]=230

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Example 6

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A crude solution containing Compound 12 was obtained from Compound 11 in the same procedure as in Example 1. By measuring ¹H-NMR and LC-MS of the crude solution after the completion of the reaction, it was found that Compound 12 was obtained in a yield of 42%.

¹H-NMR and LC-MS of the above Compound (12) are shown below.

¹H-NMR (CDCl₃) δ8.15 (1H, d), 7.97 (1H, d), 7.54 (2H, dt), 4.44 (2H, t), 1.59 (2H, tt), 1.34 (2H, tt), 0.94 (3H, t).

LC-MS: [M+1]=286

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Example 7

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A crude solution containing Compound 14 was obtained from Compound 13 in the same procedure as in Example 1. By measuring ¹H-NMR and LC-MS of the crude solution after the completion of the reaction, it was found that Compound 14 was obtained in a yield of 55%.

¹H-NMR and LC-MS of the above Compound (14) are shown below.

¹H-NMR (CDCl₃) δ 7.31-7.36 (m, 2H), 7.09 (dd, 2H), 4.81 (s, 2H), 4.35 (t, 2H), 2.10 (s, 3H), 1.97 (s, 3H), 1.72 (tt, 2H), 1.41 (tt, 2H), 0.93 (t, 3H)

LC-MS: [M+1]=337

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Example 8

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A crude solution containing Compound 16 was obtained from Compound 15 in the same procedure as in Example 1. By measuring ¹H-NMR and GC-MS of the crude solution after the completion of the reaction, it was found that Compound 16 was obtained in a yield of 25%.

¹H-NMR and GC-MS of the above Compound (16) are shown below.

¹H-NMR (CDCl₃) δ 8.50 (d, 1H), 7.72 (d, 1H), 7.09 (s, 1H), 3.90 (t, 2H), 1.59 (tq, 2H), 1.35 (s, 9H), 1.34 (m, 2H), 0.94 (t, 3H)

GC-MS (EI): [M+]=285

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Example 9

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[Image Omitted]

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A crude solution containing Compound 18 was obtained from Compound 17 in the same procedure as in Example 1. By measuring ¹H-NMR and GC-MS of the crude solution after the completion of the reaction, it was found that Compound 18 was obtained in a yield of 26%.

¹H-NMR and GC-MS of the above Compound (18) are shown below.

¹H-NMR (CDCl₃) δ 8.95 (d, 1H), 8.02 (s, 1H), 7.60 (d, 1H), 3.90 (t, 2H), 1.59 (d, 2H), 1.34 (tq, 2H), 0.94 (t, 3H),

GC-MS (EI): [M+]=254

INDUSTRIAL APPLICABILITY

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According to the present invention, by an easy and inexpensive method of flowing tetrafluoroethylene into N-oxido aromatic heterocyclic compound (I) in the presence of compound (II) in a specific solvent, aromatic heterocycle-substituted difluoroacetic acid derivative (III) with few by-products can be produced in one step.

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This application is based on patent application No. 2020-019211 filed on Feb. 6, 2020 in Japan, the contents of which are encompassed in full herein.