RU2795917C2 - Method for obtaining fluoromethyl derivative - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to a method for producing a fluorinated organic compound, described by the following formula (1):

in which R¹ means phenyl, optionally containing halogen or C_1-6 alkyl, R² means hydrogen or C_1-6 alkyl, R³ means hydrogen, L means alkanediyl, -CONR- or -CO-O-, where R in each occurrence independently is hydrogen or C_1-6 alkyl, R⁴ is hydroxyl or C_1-6 alkyl and R^X is fluoro, provided that when L is -CONR- and R is hydrogen or methyl, R⁴ is not methyl, and that if L is -CO-O-, R⁴ is neither methyl nor propyl, the process comprises an alkene reaction step A of the following formula (2):

with a source of fluorine, which is the source (3a) described by the formula MF_n in which M is H, a metal of group 1 of the Periodic Table of the Elements or a metal of group 2 of the Periodic Table of the Elements and n is 1 or 2, in the presence of an aromatic compound containing hypervalent iodine, or in the presence of an iodine-containing aromatic compound and an oxidant to fluorinate the alkene.

EFFECT: new method for obtaining a fluorinated organic compound which can provide a higher yield and high selectivity in obtaining the target compound.

4 cl, 41 ex

Description

The field of technology to which the invention belongs

[0001]

The present invention relates to a process for the preparation of a fluoromethyl derivative.

State of the art

[0002]

Typically, difluoromethyl derivatives are prepared using an expensive difluoromethylating regent (eg CHF ₂ SO ₂ Cl). As a method for producing a fluoromethyl derivative without using a difluoromethylating regent in PTL 1, a method for producing 2-fluoro-1,3-dicarbonyl with high yield and high selectivity is proposed. The method proposed in PTL 1 includes the reaction of 1,3-dicarbonyl represented by the following formula (1):

with a source of hydrogen fluoride and an oxidizing agent in the presence of an iodobenzene derivative in a catalytic amount to obtain a compound described by the following formula (3):

Bibliography

patent literature

[0003]

PTL 1: JP2014-201553A

The essence of the invention

Technical task

[0004]

The subject of the present invention is a new process for the preparation of a fluoromethyl derivative.

The solution of the problem

[0005]

The present invention includes the following object.

[0006]

Paragraph 1.

A method for producing a fluorinated organic compound having the formula (1):

in which R ¹ means an organic group, R ² means hydrogen, halogen or an organic group,

R ³ means hydrogen, halogen or an organic group,

L is a single bond, alkanediyl, -CO-, -CONR-, -NRCO-, -O-CO- or -CO-O-, where R in each case independently represents hydrogen or an organic group,

R ⁴ means hydrogen, halogen, hydroxyl or an organic group,

R ³ and R ⁴ can be connected to each other and

R ^X means hydrogen or fluorine,

with the proviso that if R ⁴ is hydrogen, L is -CO-, -CONR-, -NRCO-, -O-CO- or -CO-O-,

the method includes step A of the reaction of an alkene represented by the formula (2):

in which the steric configuration of the single bond, indicated by the wavy line, with respect to the double bond to which the single bond is linked, is the E configuration or the Z configuration, or a mixture of the E configuration and the Z configuration in any ratio, and the other letter designations are as defined above

with a source of fluorine, which is the source (3a) described by the formula MF _n in which M is H, a metal of group 1 of the Periodic Table of the Elements or a metal of group 2 of the Periodic Table of the Elements; and n is 1 or 2

in the presence of an aromatic compound containing hypervalent iodine (1a), or

in the presence of an iodine-containing aromatic compound (1b) and an oxidizing agent (A) to fluorinate the alkene.

Paragraph 2.

The production method according to paragraph 1, wherein R ¹ is an aliphatic hydrocarbon group optionally containing one or more substituents, an aromatic hydrocarbon group optionally containing one or more substituents, an aliphatic heterocyclic group optionally containing one or more substituents, or an aromatic heterocyclic a group optionally containing one or more substituents.

Paragraph 3.

The preparation method according to paragraph 2, wherein R ¹ is an aromatic hydrocarbon group optionally having one or more substituents, or an aromatic heterocyclic group optionally having one or more substituents.

Paragraph 4.

The method of obtaining according to any one of paragraphs 1-3, in which R ² means hydrogen.

Paragraph 5.

The method of obtaining according to any of paragraphs 1-4, in which R ³ means hydrogen.

Paragraph 6.

The method of obtaining according to any one of paragraphs 1-5, in which L means -[C(-R ^4a )(-R ^4b )] _m -,

R ^4a means hydrogen or an organic group,

R ^4b is hydrogen or an organic group and

m means an integer from 1 to 10.

Paragraph 7.

The method of obtaining according to paragraph 6, in which R ⁴ means hydroxyl.

Paragraph 8.

The production process according to any one of paragraphs 1-5, wherein L is -CO- and R ⁴ is hydrogen, halogen or an organic group.

Paragraph 9.

The production process according to paragraph 8, wherein R ⁴ is an aliphatic hydrocarbon group optionally containing one or more substituents, an aromatic hydrocarbon group optionally containing one or more substituents, an aliphatic heterocyclic group optionally containing one or more substituents, or an aromatic heterocyclic a group optionally containing one or more substituents.

Paragraph 10.

The production process according to any one of paragraphs 1-5, wherein L is -CO-O- and R ⁴ is hydrogen or an organic group.

Paragraph 11.

The method of obtaining according to paragraph 10, in which R ⁴ means C _1-10 aliphatic hydrocarbon group, optionally containing one or more substituents.

Paragraph 12.

The method of obtaining according to any one of paragraphs 1-11, in which R ^X means fluorine.

Paragraph 13.

The method of obtaining according to any of paragraphs 1-11, in which R ^X means hydrogen.

Paragraph 14.

The fluorinated organic compound represented by the formula (1-1):

wherein

Ar means an aromatic hydrocarbon group optionally containing one or more substituents, or an aromatic heterocyclic group optionally containing one or more substituents;

R ² means hydrogen, halogen or an organic group;

R ³ means hydrogen, halogen or an organic group;

R ⁴ means an aliphatic hydrocarbon group optionally containing one or more substituents, an aromatic hydrocarbon group optionally containing one or more substituents, an aliphatic heterocyclic group optionally containing one or more substituents, or an aromatic heterocyclic group optionally containing one or more deputies,

R ³ and R ⁴ can be connected to each other and

R ^X means hydrogen or fluorine.

Paragraph 15.

The fluorinated organic compound according to paragraph 14, in which R ^X means fluorine.

Paragraph 16.

The fluorinated organic compound of paragraph 14, wherein R ^X is hydrogen.

Useful effects of the invention

[0007]

The present invention relates to a new process for the preparation of a fluoromethyl derivative.

Description of Embodiments

[0008]

1. Terms

The designations and abbreviations in the present description can be understood in the sense commonly used in the technical field to which the present invention pertains, unless otherwise indicated.

In the present description, the terms "comprises" and "comprises" are used with the inclusion of the expression "consists mainly of" and "consists of".

Unless otherwise indicated, the steps, treatments and operations described herein can be carried out at room temperature.

In the present description, "room temperature" means a temperature in the range from 10 to 40°C.

In the present description, the expression "C _n -C _m " (n and m mean a number) indicates that the number of carbon atoms is n or more and m or more, as usually understood by a person skilled in the art.

[0009]

In the present description, the expression "organic compound" should be understood in the usual sense, and it may be a compound containing one or more carbon atoms and one or more hydrogen atoms.

In the present description, the expression "organic group" means a group containing one or more carbon atoms (or a group obtained by removing one hydrogen atom from an organic compound).

[0010]

In the present description, a fluorinated organic compound means a compound that can be obtained by fluorination of an organic compound, and it may not contain hydrogen atoms.

[0011]

In the present description, unless otherwise indicated, examples of halogen (groups) may include fluorine (group), chlorine (group), bromine (group), and iodine (group).

[0012]

In the present description, examples of aromatic rings include aromatic carbocyclic rings and aromatic heterocyclic rings. In the present description, "aromatic compound" means a compound containing one or more aromatic rings.

[0013]

As used herein, unless otherwise indicated, examples of aromatic carbocyclic rings include aromatic hydrocarbon rings having 6 to 14 carbon atoms, and specific examples include benzene, naphthalene, anthracene, phenanthrene, and biphenyl.

[0014]

In the present description, unless otherwise indicated, examples of aromatic heterocyclic rings include 5- or 6-membered aromatic heterocyclic rings; and specific examples include furan ring, thiophene ring, pyrrole ring, oxazole ring, isoxazole ring, thiazole ring, isothiazole ring, imidazole ring, pyrazole ring, 1,2,3-oxadiazole ring, 1,2,4-oxadiazole ring, 1 ,3,4-oxadiazole ring, furazan ring, 1,2,3-thiadiazole ring, 1,2,4-thiadiazole ring, 1,3,4-thiadiazole ring, 1,2,3-triazole ring, 1,2 ,4-triazole ring, tetrazole ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring, and triazine ring.

[0015]

As used herein, unless otherwise indicated, other examples of aromatic heterocyclic rings include a fused ring of one or more 5- or 6-membered aromatic heterocyclic rings and one or more aromatic carbocyclic rings.

[0016]

Examples of organic groups include:

an alkyl group optionally containing one or more substituents,

an alkenyl group optionally containing one or more substituents,

an alkynyl group optionally having one or more substituents,

a cycloalkyl group optionally containing one or more substituents,

a cycloalkenyl group optionally containing one or more substituents,

a cycloalkadienyl group optionally containing one or more substituents,

an aryl group optionally containing one or more substituents,

an arylalkyl group optionally having one or more substituents,

a non-aromatic heterocyclic group optionally containing one or more substituents,

a heteroaryl group optionally containing one or more substituents,

cyano group,

aldehyde group,

R ^r O-,

R ^r CO-,

R ^r SO ₂ -,

R ^r OCO-, and

R ^r OSO ₂ -

(in these formulas, R ^r independently means

an alkyl group optionally containing one or more substituents,

an alkenyl group optionally containing one or more substituents,

an alkynyl group optionally having one or more substituents,

a cycloalkyl group optionally containing one or more substituents,

a cycloalkenyl group optionally containing one or more substituents,

a cycloalkadienyl group optionally containing one or more substituents,

an aryl group optionally containing one or more substituents,

an arylalkyl group optionally having one or more substituents,

a non-aromatic heterocyclic group optionally containing one or more substituents, or

a heteroaryl group optionally containing one or more substituents).

[0017]

In the present description, the organic group may be, for example, a hydrocarbon group optionally containing one or more substituents (one or more moieties selected from the group consisting of -NR ^o -, =N-, -N= , -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -S(=O)-, -S(=O) ₂ - , -S(=O) ₂ -NR ^o -, -NR ^o -S(=O) ₂ -, -S(=O)-, -S(=O)-NR ^o - and -NR ^o -S( =O)- (where R ^o independently means a hydrogen atom or an organic group)).

[0018]

As generally understood from the public knowledge in the field of chemistry, examples of hydrocarbon groups with a heteroatom thus introduced include non-aromatic heterocyclic groups and heteroaryl groups.

[0019]

In the present specification, the number of carbon atoms in a "hydrocarbon group" in a "hydrocarbon group optionally containing one or more substituents" may be, for example, 1 to 100, 1 to 80, 1 to 60, 1 to 40, 1 to 30, 1 to 20, or 1 to 10 (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10).

[0020]

In the present description, examples of substituents in "hydrocarbon group optionally containing one or more substituents", "alkyl group containing one or more substituents", "alkenyl group optionally containing one or more substituents", "alkynyl group optionally containing one or more substituents", "cycloalkyl group optionally containing one or more substituents", "cycloalkenyl group optionally containing one or more substituents", "cycloalkadienyl group optionally containing one or more substituents", "aryl group , optionally containing one or more substituents" and "arylalkyl group optionally containing one or more substituents" include a halide group, a nitro group, a cyano group, an oxo group, a thioxo group, a sulfo group, a sulfamoyl group, a sulfinamoyl group, and a sulfenomoyl group.

The number of substituents may range from 1 to the maximum possible number of substituents (eg 1, 2, 3, 4, 5 or 6).

[0021]

In the present specification, examples of hydrocarbon groups include an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, a cycloalkadienyl group, an aryl group, an arylalkyl group, and a group that is a combination of these groups.

[0022]

In the present description, unless otherwise indicated, examples of alkyl groups include linear or branched C ₁ -C ₁₀ alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl (n-butyl, isobutyl, sec-butyl, tert-butyl), pentyl (n-pentyl, isopentyl, neopentyl), hexyl, heptyl, octyl, nonyl and decyl.

[0023]

As used herein, a fluoroalkyl group means an alkyl group in which at least one hydrogen atom has been replaced by a fluorine atom.

As used herein, the number of fluorine atoms in the fluoroalkyl group may be one or more (eg, 1 to 3, 1 to 6, 1 to 12, or 1 to the maximum possible number of substituents).

[0024]

As one skilled in the art can understand, the prefix "perhalogen" means that all hydrogen atoms have been replaced by a halide group.

As one skilled in the art can understand, the prefix "perfluoro" means that all hydrogen atoms have been replaced by a fluoride group.

[0025]

The fluoroalkyl group includes a perfluoroalkyl group.

[0026]

A perfluoroalkyl group is an alkyl group in which all hydrogen atoms have been replaced by a fluorine atom. Specific examples of perfluoroalkyl groups include trifluoromethyl group (CF ₃ -) and pentafluoroethyl group (C ₂ F ₅ -).

[0027]

In the present description, the fluoroalkyl group may be, for example, a fluoroalkyl group containing 1 to 20, 1 to 12, 1 to 6, 1 to 4, 1 to 3, 6, 5, 4, 3, 2, or 1 carbon atom.

[0028]

As used herein, the fluoroalkyl group may be a linear or branched fluoroalkyl group.

In the present description, specific examples of fluoroalkyl groups include fluoromethyl group, difluoromethyl group, trifluoromethyl group (CF ₃ -), 2,2,2-trifluoroethyl group, pentafluoroethyl group (C ₂ F ₅ -), tetrafluoropropyl group (for example, HCF ₂ CF ₂ CH ₂ -), a hexafluoropropyl group (for example, (CF ₃ ) ₂ CH-), a nonafluorobutyl group, an octafluoropentyl group (for example, HCF ₂ CF ₂ CF ₂ CF ₂ CH ₂ -), a tridecafluorohexyl group, and 3,3,4,4 ,5,5,6,6,7,7,8,8,8-tridecafluorooctyl group (CF ₃ CF ₂ CF ₂ CF ₂ CF ₂ CF ₂ CH ₂ CH ₂ -).

[0029]

As used herein, unless otherwise indicated, examples of alkenyl groups include linear or branched C _2-10 alkenyl groups such as vinyl, 1-propen-1-yl, 2-propen-1-yl, isopropynyl, 2-butene-1 -yl, 4-penten-1-yl and 5-hexen-1-yl.

[0030]

As used herein, unless otherwise indicated, examples of alkynyl groups include linear or branched C ₂ -C ₁₀ alkynyl groups such as ethynyl, 1-propyn-1-yl, 2-propyn-1-yl, 4-pentyn-1- yl and 5-hexyn-1-yl.

[0031]

In the present specification, unless otherwise indicated, examples of cycloalkyl groups include C ₃ -C ₇ cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0032]

In the present specification, unless otherwise indicated, examples of cycloalkenyl groups include C ₃ -C ₇ cycloalkenyl groups such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and cycloheptenyl.

[0033]

In the present specification, unless otherwise indicated, examples of cycloalkadienyl groups include C ₄ -C ₁₀ cycloalkadienyl groups such as cyclobutadienyl, cyclopentadienyl, cyclohexadienyl, cycloheptadienyl, cyclooctadienyl, cyclononadienyl, and cyclodecadienyl.

In the present description, unless otherwise indicated, aromatic groups include an aryl group and a heteroaryl group.

[0034]

In the present description, unless otherwise indicated, the aryl group may be monocyclic, bicyclic, tricyclic or tetracyclic.

In the present description, unless otherwise indicated, the aryl group may be a C ₆ -C ₁₈ aryl group.

As used herein, unless otherwise indicated, examples of aryl groups include phenyl, 1-naphthyl, 2-naphthyl, 2-biphenyl, 3-biphenyl, 4-biphenyl, and 2-anthryl.

[0035]

As used herein, unless otherwise indicated, examples of arylalkyl groups include benzyl, phenethyl, diphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2,2-diphenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 2-biphenylylmethyl, 3 -biphenylylmethyl and 4-biphenylylmethyl.

[0036]

As used herein, unless otherwise indicated, a non-aromatic heterocyclic group may be monocyclic, bicyclic, tricyclic, or tetracyclic.

In the present specification, unless otherwise indicated, a non-aromatic heterocyclic group may be, for example, a non-aromatic heterocyclic group which, in addition to a carbon atom, contains from 1 to 4 heteroatoms selected from the group consisting of an oxygen atom as the ring-forming atom(s). , a sulfur atom or a nitrogen atom.

In the present description, unless otherwise indicated, a non-aromatic heterocyclic group may be saturated or unsaturated.

As used herein, unless otherwise indicated, examples of non-aromatic heterocyclic groups include tetrahydrofuryl, oxazolidinyl, imidazolinyl (e.g., 1-imidazolinyl, 2-imidazolinyl, and 4-imidazolinyl), aziridinyl (e.g., 1-aziridinyl and 2-aziridinyl), azetidinyl ( e.g. 1-azetidinyl and 2-azetidinyl), pyrrolidinyl (e.g. 1-pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl), piperidinyl (e.g. 1-piperidinyl, 2-piperidinyl and 3-piperidinyl), azepanil (e.g. 1 -azepanil, 2-azepanil, 3-azepanil and 4-azepanil), azocanil (for example, 1-azocanil, 2-azokanil, 3-azokanil and 4-azocanil), piperazinil (for example, 1,4-piperazin-1-yl and 1,4-piperazin-2-yl), diazepinil (e.g. 1,4-diazepin-1-yl, 1,4-diazepin-2-yl, 1,4-diazepin-5-yl and 1,4- diazepin-6-yl), diazocanil (e.g. 1,4-diazocan-1-yl, 1,4-diazocan-2-yl, 1,4-diazocan-5-yl, 1,4-diazocan-6-yl , 1,5-diazocan-1-yl, 1,5-diazocan-2-yl and 1,5-diazocan-3-yl), tetrahydropyranyl (e.g. tetrahydropyran-4-yl), morpholinyl (e.g. 4-morpholinyl ), thiomorpholinyl (eg, 4-thiomorpholinyl), 2-oxazolidinyl, dihydrofuryl, dihydropyranyl, and dihydroquinolyl.

[0037]

As used herein, unless otherwise indicated, examples of heteroaryl groups include monocyclic aromatic heterocyclic groups (e.g., 5- or 6-membered monocyclic aromatic heterocyclic groups) and aromatic fused heterocyclic groups (e.g., 5- to 18-membered aromatic fused heterocyclic groups) .

[0038]

As used herein, unless otherwise indicated, examples of 5- or 6-membered monocyclic aromatic heterocyclic groups include pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl), furyl (e.g., 2-furyl and 3-furyl) , thienyl (e.g. 2-thienyl and 3-thienyl), pyrazolyl (e.g. 1-pyrazolyl, 3-pyrazolyl and 4-pyrazolyl), imidazolyl (e.g. 1-imidazolyl, 2-imidazolyl and 4-imidazolyl), isoxazolyl ( e.g. 3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl), oxazolyl (e.g. 2-oxazolyl, 4-oxazolyl and 5-oxazolyl), isothiazolyl (e.g. 3-isothiazolyl, 4-isothiazolyl and 5-isothiazolyl), thiazolyl (e.g. 2-thiazolyl, 4-thiazolyl and 5-thiazolyl), triazolyl (e.g. 1,2,3-triazol-4-yl and 1,2,4-triazol-3-yl), oxadiazolyl (e.g. 1 ,2,4-oxadiazol-3-yl and 1,2,4-oxadiazol-5-yl), thiadiazolyl (e.g. 1,2,4-thiadiazol-3-yl and 1,2,4-thiadiazol-5- yl), tetrazolyl, pyridyl (e.g. 2-pyridyl, 3-pyridyl and 4-pyridyl), pyridazinyl (e.g. 3-pyridazinyl and 4-pyridazinyl), pyrimidinyl (e.g. 2-pyrimidinyl, 4-pyrimidinyl and 5-pyrimidinyl ), and pyrazinyl.

[0039]

As used herein, unless otherwise indicated, examples of 5- to 18-membered aromatic fused heterocyclic groups include isoindolyl (e.g., 1-isoindolyl, 2-isoindolyl, 3-isoindolyl, 4-isoindolyl, 5-isoindolyl, 6-isoindolyl, and 7 -isoindolyl), indolyl (for example, 1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl and 7-indolyl), benzo[b]furanyl (for example, 2-benzo[b ]furanyl, 3-benzo[b]furanyl, 4-benzo[b]furanyl, 5-benzo[b]furanyl, 6-benzo[b]furanyl and 7-benzo[b]furanyl), benzo[c]furanyl ( e.g. 1-benzo[c]furanyl, 4-benzo[c]furanyl and 5-benzo[c]furanyl), benzo[b]thienyl (e.g. 2-benzo[b]thienyl, 3-benzo[b]thienyl , 4-benzo[b]thienyl, 5-benzo[b]thienyl, 6-benzo[b]thienyl and 7-benzo[b]thienyl), benzo[c]thienyl (e.g. 1-benzo[c]thienyl, 4-benzo[c]thienyl and 5-benzo[c]thienyl), indazolyl (e.g. 1-indazolyl, 2-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl and 7-indazolyl), benzimidazolyl (for example, 1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl and 5-benzimidazolyl), 1,2-benzisoxazolyl (for example, 1,2-benzisoxazol-3-yl, 1,2-benzisoxazol-4-yl, 1 ,2-benzisoxazol-5-yl, 1,2-benzisoxazol-6-yl and 1,2-benzisoxazol-7-yl), benzoxazolyl (e.g. 2-benzoxazolyl, 4-benzoxazolyl, 5-benzoxazolyl, 6-benzoxazolyl and 7-benzoxazolyl), 1,2-benzisothiazolyl (e.g. 1,2-benzisothiazol-3-yl, 1,2-benzisothiazol-4-yl, 1,2-benzisothiazol-5-yl, 1,2-benzisothiazol-6 -yl and 1,2-benzisothiazol-7-yl), benzothiazolyl (e.g. 2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl and 7-benzothiazolyl), isoquinolyl (e.g. 1-isoquinolyl, 3-isoquinolyl , 4-isoquinolyl and 5-isoquinolyl), quinolyl (e.g. 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl and 8-quinolyl), cinnolinyl (e.g. 3-cinnolinyl, 4-cinnolinyl, 5-cinnolinyl , 6-cinnolinyl, 7-cinnolinyl and 8-cinnolinyl), phthalazinyl (e.g. 1-phthalazinyl, 4-phthalazinyl, 5-phthalazinyl, 6-phthalazinyl, 7-phthalazinyl and 8-phthalazinyl), quinazolinyl (e.g. 2-quinazolinyl , 4-quinazolinyl, 5-quinazolinyl, 6-quinazolinyl, 7-quinazolinyl, and 8-quinazolinyl), quinoxalinyl (e.g., 2-quinoxalinyl, 3-quinoxalinyl, 5-quinoxalinyl, 6-quinoxalinyl, 7-quinoxalinyl, and 8-quinoxalinyl) , pyrazolo[1,5-a]pyridyl (e.g. pyrazolo[1,5-a]pyridin-2-yl, pyrazolo[1,5-a]pyridin-3-yl, pyrazolo[1,5-a]pyridine -4-yl, pyrazolo[1,5-a]pyridin-5-yl, pyrazolo[1,5-a]pyridin-6-yl and pyrazolo[1,5-a]pyridin-7-yl), imidazo[ 1,2-a]pyridyl (e.g. imidazo[1,2-a]pyridin-2-yl, imidazo[1,2-a]pyridin-3-yl, imidazo[1,2-a]pyridin-5- yl, imidazo[1,2-a]pyridin-6-yl, imidazo[1,2-a]pyridin-7-yl and imidazo[1,2-a]pyridin-8-yl).

[0040]

In the present description, unless otherwise indicated, examples of substituents in "non-aromatic heterocyclic group optionally containing one or more substituents" and "heteroaryl group optionally containing one or more substituents" include a hydrocarbon group optionally containing one or more substituents, a halogen atom, a nitro group, a cyano group, an oxo group, a thiooxo group, a sulfo group, a sulfamoyl group, a sulfinamoyl group, and a sulfenomoyl group.

The number of substituents may range from 1 to the maximum possible number of substituents (eg 1, 2, 3, 4, 5 or 6).

[0041]

2. Method for producing a fluorinated organic compound

One embodiment of the present invention is a process for producing a fluorinated organic compound represented by formula (1):

wherein

R ¹ means an organic group,

R ² means hydrogen, halogen or an organic group,

R ³ means hydrogen, halogen or an organic group,

L is a single bond, alkanediyl, -CO-, -CONR-, -NRCO-, -O-CO- or -CO-O-, where R in each case independently represents hydrogen or an organic group,

R ⁴ means hydrogen, halogen, hydroxyl or an organic group,

R ³ and R ⁴ can be connected to each other and

R ^X means hydrogen or fluorine,

with the proviso that if R ⁴ is hydrogen, L is -CO-, -CONR-, -NRCO-, -O-CO- or -CO-O-,

the method includes step A of the reaction of an alkene represented by the formula (2):

in which the steric configuration of the single bond, indicated by the wavy line, with respect to the double bond to which the single bond is linked, is the E configuration or the Z configuration, or a mixture of the E configuration and the Z configuration in any ratio, and the other letter designations are as defined above

with a source of fluorine, which is the source (3a) described by the formula MF _n in which M is H, a metal of group 1 of the Periodic Table of the Elements or a metal of group 2 of the Periodic Table of the Elements; and n is 1 or 2

in the presence of an aromatic compound containing hypervalent iodine (1a), or

in the presence of an iodine-containing aromatic compound (1b) and an oxidizing agent (A) to fluorinate the alkene.

[0042]

R ¹ is preferably an aliphatic hydrocarbon group optionally containing one or more substituents, an aromatic hydrocarbon group optionally containing one or more substituents, an aliphatic heterocyclic group optionally containing one or more substituents, or an aromatic heterocyclic group optionally containing one or more the number of substitutes.

[0043]

R ¹ more preferably means an aromatic hydrocarbon group optionally containing one or more substituents, or an aromatic heterocyclic group optionally containing one or more substituents.

[0044]

R ¹ even more preferably means C _6-14 aromatic hydrocarbon group, optionally containing one or more substituents, or

A 5- to 14-membered aromatic heterocyclic group optionally containing one or more substituents.

[0045]

R ¹ is even more preferably a C _6-14 aryl group optionally having one or more substituents selected from the group consisting of halo, C _1-6 alkyl, C _1-6 alkoxy, and nitro (e.g., 1, 2, 3, 4, 5 or 6 substituents), or a 5- to 14-membered aromatic heterocyclic group optionally containing one or more substituents selected from the group consisting of halogen, C _1-6 alkyl, C _1-6 alkoxy and nitro (for example, 1, 2, 3, 4, 5 or 6 substituents).

[0046]

R ² preferably means hydrogen or C _1-6 alkyl.

[0047]

R ³ preferably means hydrogen.

[0048]

If R ³ and R ⁴ are bonded to each other, any atom in R ³ (for example, an atom at the end or an internal atom) and any atom in R ⁴ (for example, an atom at the end or an internal atom) can be bonded to an atom in the other R .

When R ³ and R ⁴ are linked to each other, the "R ³ -CCLR ⁴ " moiety in formula (1) may be a ring optionally containing one or more substituents.

The ring may optionally contain one or more substituents.

One or more substituents may be formed from the structure or part of the structure of R ³ , L and/or R ⁴ (eg substituents).

The ring may be, for example, a monocyclic, bicyclic or tricyclic ring.

The ring may be, for example, a 5- to 14-membered ring, a 5- to 10-membered ring, a 6- to 14-membered ring, a 6- to 10-membered ring, or a 5- or 6-membered ring.

[0049]

In one embodiment, preferably

L means -[C(-R ^4a )(-R ^4b )] _m -,

R ^4a means hydrogen or an organic group,

R ^4b is hydrogen or an organic group and

m means an integer from 1 to 10.

[0050]

More preferably,

L means -[C(-R ^4a )(-R ^4b )] _m -,

R ^4a means hydrogen or C _1-6 alkyl,

R ^4b is hydrogen or C _1-6 alkyl and

m means an integer from 1 to 6.

[0051]

Even more preferably,

L means -[C(-R ^4a )(-R ^4b )] _m -,

R ^4a means hydrogen,

R ^4b is hydrogen, and

m equals 1.

[0052]

R ⁴ is more preferably C _1-10 alkoxy or hydroxyl. R ⁴ is even more preferably hydroxyl.

[0053]

In another embodiment, preferably

L stands for -CO-, and

R ⁴ means hydrogen, halogen or an organic group.

[0054]

R ⁴ is preferably an aliphatic hydrocarbon group optionally containing one or more substituents, an aromatic hydrocarbon group optionally containing one or more substituents, an aliphatic heterocyclic group optionally containing one or more substituents, or an aromatic heterocyclic group optionally containing one or more the number of substitutes.

[0055]

R ⁴ is more preferably a C _1-6 alkyl group, a phenyl group optionally containing one or more substituents, a naphthyl group optionally containing one or more substituents, or a thiophenyl group optionally containing one or more substituents.

R ⁴ is even more preferably a C _1-3 alkyl group or a phenyl group optionally containing one or more substituents.

[0056]

In another embodiment, preferably

L stands for -CO-O-, and

R ⁴ means hydrogen or an organic group.

[0057]

R ⁴ is preferably an aliphatic hydrocarbon group optionally containing one or more substituents, an aromatic hydrocarbon group optionally containing one or more substituents, an aliphatic heterocyclic group optionally containing one or more substituents, or an aromatic heterocyclic group optionally containing one or more the number of substitutes.

[0058]

R ⁴ is more preferably a C _1-10 alkyl group. R ⁴ is even more preferably a C _1-6 alkyl group.

[0059]

In one embodiment, R ^X is preferably fluorine. A compound in which R ^X is fluorine (this compound may be referred to as the "difluoro form") can be obtained with higher selectivity by increasing the reaction temperature, increasing the reaction time, increasing the amount of fluorine source, or any combination thereof in step A.

In another embodiment, R ^X is preferably hydrogen. The compound in which R ^X is hydrogen (this compound may be referred to as the "monofluoro form") can be obtained with higher selectivity by lowering the reaction temperature, reducing the reaction time, reducing the amount of fluorine source, or any combination thereof in step A.

The difluoro-containing form and the monofluoro-containing form, if desired, can be isolated by a conventional purification procedure.

[0060]

In one embodiment of the present invention,

preferably,

R ¹ means an aromatic hydrocarbon group, optionally containing one or more substituents, or an aromatic heterocyclic group, optionally containing one or more substituents;

R ² means hydrogen or C _1-6 alkyl;

R ³ means hydrogen;

L means -[C(-R ^4a )(-R ^4b )] _m -,

R ^4a means hydrogen or an organic group,

R ^4b means hydrogen or an organic group,

m means an integer from 1 to 10,

R ⁴ means hydroxyl, and

R ^X means fluorine or hydrogen.

[0061]

In this embodiment, more preferably,

R ¹ is a C _6-14 aryl group optionally having one or more substituents (eg 1, 2, 3, 4, 5 or 6 substituents) selected from the group consisting of halo, C _1-6 alkyl, C _{1- 6} alkoxy and a nitro group or a 5- to 14-membered aromatic heterocyclic group optionally having one or more substituents (eg 1, 2, 3, 4, 5 or 6 substituents) selected from the group consisting of halogen, C _1-6 alkyl, C _1-6 alkoxy and nitro;

R ² means hydrogen or C _1-6 alkyl;

R ³ means hydrogen;

L means -CH ₂ -;

R ⁴ means hydroxyl; And

R ^X means fluorine or hydrogen.

[0062]

In another embodiment of the present invention,

R ¹ means an aromatic hydrocarbon group, optionally containing one or more substituents, or an aromatic heterocyclic group, optionally containing one or more substituents;

R ² means hydrogen;

R ³ means hydrogen;

L stands for -CO-,

R ⁴ means hydrogen, halogen or an organic group.

In the preferred embodiment

R ¹ means a phenyl group, optionally containing one or more substituents;

R ² means hydrogen;

R ³ means hydrogen;

L means -CO-; And

R ⁴ means a phenyl group, optionally containing one or more substituents.

[0063]

In another embodiment of the present invention, preferably

R ¹ means an aliphatic hydrocarbon group optionally containing one or more substituents, an aromatic hydrocarbon group optionally containing one or more substituents, an aliphatic heterocyclic group optionally containing one or more substituents, or an aromatic heterocyclic group optionally containing one or more deputies;

R ² means hydrogen;

R ³ means hydrogen;

L means -CO-;

R ⁴ means an aliphatic hydrocarbon group optionally containing one or more substituents, an aromatic hydrocarbon group optionally containing one or more substituents, an aliphatic heterocyclic group optionally containing one or more substituents, or an aromatic heterocyclic group optionally containing one or more deputies; And

R ^X means fluorine or hydrogen.

[0064]

In another embodiment of the present invention,

R ¹ means an aromatic hydrocarbon group, optionally containing one or more substituents, or an aromatic heterocyclic group, optionally containing one or more substituents;

R ² means hydrogen;

R ³ means hydrogen;

L means -CO-O-; And

R ⁴ means hydrogen or an organic group.

[0065]

In another embodiment of the present invention, preferably

R ¹ means an aliphatic hydrocarbon group optionally containing one or more substituents, an aromatic hydrocarbon group optionally containing one or more substituents, an aliphatic heterocyclic group optionally containing one or more substituents, or an aromatic heterocyclic group optionally containing one or more deputies;

R ² means hydrogen;

R ³ means hydrogen;

L means -CO-O-;

R ⁴ means an aliphatic hydrocarbon group optionally containing one or more substituents, an aromatic hydrocarbon group optionally containing one or more substituents, an aliphatic heterocyclic group optionally containing one or more substituents, or an aromatic heterocyclic group optionally containing one or more deputies; And

R ^X means fluorine or hydrogen.

[0066] tosylate

The source of fluorine for use in step A is described by the formula MF _n , where M is H, a metal of group 1 of the Periodic Table of the Elements, or a metal of group 2 of the Periodic Table of the Elements; and n is 1 or 2. M may preferably be H, Li, Na, K, Ca, or Cs; more preferably H, Na, K or Ca; and even more preferably H. The source of fluorine may preferably be a source of hydrogen fluoride.

Examples of the fluorine source include anhydrous hydrofluoric acid, an aqueous solution of hydrofluoric acid (for example, an aqueous solution of hydrofluoric acid at a concentration of 10 to 70% by weight), and a mixture of hydrofluoric acid, an organic base and an inorganic base.

This mixture of hydrofluoric acid and an organic base, in particular, may contain, for example, salts such as hydrogen fluoride salt-triethylamine [Et ₃ N(nHF (n=1 to 5)], hydrogen fluoride salt-pyridine [Py( nHF (n=1 to 10)] and hydrogen fluoride salt-tetraethylammonium fluoride salt [Et4NF(nHF (n=1 to 10)]; or it may be formed from it.

This mixture of hydrofluoric acid and an inorganic base may in particular contain, for example, HF-KF(KHF ₂ ); or it may be formed from it.

These fluorine sources may be used alone or in combination of two or more.

[0067]

The amount of hydrogen fluoride source, for example in the form of hydrogen fluoride, can generally be in the range of 0.5 to 100 moles, preferably in the range of 1 to 80 moles, more preferably in the range of 2 to 60 moles, and even more preferably in the range of 3 to 50 moles, per 1 mole of the organic compound (2) which is the substrate.

[0068]

Aromatic compound containing hypervalent iodine (1a)

Specific examples of hypervalent iodine-containing aromatic compounds (1a) include iodosylbenzene, 2-iodosyltoluene, 3-iodosyltoluene, 4-iodosyltoluene, 2,4,6-trimethyliodosylbenzene,

2-ethyliodosylbenzene, 3-ethyliodosylbenzene, 4-ethyliodosylbenzene, 2-iodosylanisole, 3-iodosylanisole, 4-iodosylanisole, 1-chloro-2-iodosylbenzene, 1-chloro-3-iodosylbenzene, 1-chloro-4-iodosylbenzene, 1, 2-diiodosylbenzene,

1,3-diiodosylbenzene, 1,4-diiodosylbenzene, 1-iodosyl-2-nitrobenzene, 1-iodosyl-3-nitrobenzene, 1-iodosyl-4-nitrobenzene, 1-iodosyl-2-cyanobenzene, 1-iodosyl-3- cyanobenzene and 1-iodosyl 4-cyanobenzene. These hypervalent iodine-containing aromatic compounds may be used alone or in combination of two or more.

[0069]

The amount of hypervalent iodine-containing aromatic compound (1a) can generally be 0.1 to 50 mol, and preferably 0.2 to 30 mol, per 1 mol of compound (2).

[0070]

In step A, the hypervalent iodine-containing aromatic compound (1a) is preferably used in the absence of an oxidizing agent.

"No oxidizing agent" when used in the present invention means that the amount of oxidizing agent in the reaction system in step A is 0.1 mol or less per 1 mol of the organic compound (1).

[0071]

Iodine-containing aromatic compound (1b) and oxidizing agent (A)

Examples of the iodine-containing aromatic compound (1b) include iodobenzene, 2-iodotoluene, 3-iodotoluene, 4-iodotoluene, 2,4,6-trimethyliodobenzene, 2-ethyliodobenzene, 3-ethyliodobenzene, 4-ethyliodobenzene, 2-iodanisole, 3-iodanisole , 4-iodanisole, 1-chloro-2-iodobenzene, 1-chloro-3-iodobenzene, 1-chloro-4-iodobenzene, 1,2-diiodobenzene, 1,3-diiodobenzene, 1,4-diiodobenzene, 1-iodine -2-nitrobenzene, 1-iodine-3-nitrobenzene, 1-iodine-4-nitrobenzene, 1-iodine-2-cyanobenzene, 1-iodine-3-cyanobenzene, 1-iodine-4-cyanobenzene, 1-iodine-4 -(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl)benzene, p-iodobenzoic acid, 2-iodopyridine, 3-iodopyridine, 4-iodopyridine, 3 -iodopyrazole, and 4-iodopyrazole. These aromatic compounds containing iodine can be used alone or in combination of two or more.

[0072]

The amount of hypervalent iodine-containing aromatic compound (1b) can generally be 0.1 to 50 mol, and preferably 0.2 to 30 mol, per 1 mol of compound (2).

[0073]

In step A, an iodine-containing aromatic compound (1b) is used together with an oxidizing agent (A).

The oxidizing agent (A) may preferably be, for example, one or more selected from the group consisting of:

(i) a compound represented by the formula: R ^X COOOM

in which R ^X means a hydrocarbon group, optionally containing one or more substituents, and

M means a hydrogen atom or a metal atom;

(ii) a compound represented by the formula: R ^X OOM

in which R ^X means a hydrogen atom or a hydrocarbon group, optionally containing one or more substituents, and

M means a hydrogen atom or a metal atom; And

(iii) metal oxide.

Examples of the oxidizing agent (A) include metachloroperbenzoic acid, hydrogen peroxide, peracetic acid, perbenzoic acid, tert-butyl hydroperoxide, cumene hydroperoxide, potassium persulfate, potassium hydrogen persulfate-potassium hydrogen sulfate-potassium sulfate, permanganic acid, dichromic acid, tungsten oxide, ruthenium oxide, antimony oxide, osmium oxide and sulfur trioxide.

Preferred examples of the oxidizing agent (A) include metachloroperbenzoic acid, hydrogen peroxide, peracetic acid, perbenzoic acid, tert-butyl hydroperoxide, cumene hydroperoxide, potassium persulfate, and potassium hydrogen persulfate-potassium hydrogen sulfate-potassium sulfate.

More preferred examples of the oxidizing agent (A) include m-chloroperbenzoic acid.

They can be used singly or in combination of two or more.

[0074]

The amount of oxidizing agent to be used in step A can generally be 0.1 to 40 mol, and preferably 0.5 to 30 mol, per 1 mol of compound (2).

[0075]

The hypervalent iodine-containing aromatic compound (1a) is preferably the compound represented by the formula (p1):

wherein

Ar means aromatic ring,

R ^p1 in each case independently means

an alkyl group

alkoxy group,

group: -O-(CH ₂ ) _q -NR ₃ X, in which q is a number greater than or equal to 1; R means H or C ₁ -C ₂₀ alkyl group; and X is a halogen atom, an arylsulfonyloxy group or an alkylsulfonyloxy group,

a group: -(CH ₂ ) _q -NR ₃ X, in which q is a number greater than or equal to 1; R means H or C ₁ -C ₂₀ alkyl group; and X is a halogen atom, an arylsulfonyloxy group or an alkylsulfonyloxy group,

halogen atom,

cyano group,

nitro group,

a carboxylic acid group or

a sulfonic acid group;

R ^p2 in each case independently means

an alkyl group

alkoxy group,

group: -O-(CH ₂ ) _q -NR ₃ X, in which q is a number greater than or equal to 1; R means H or C ₁ -C ₂₀ alkyl group; and X is a halogen atom, an arylsulfonyloxy group or an alkylsulfonyloxy group,

a group: -(CH ₂ ) _q -NR ₃ X, in which q is a number greater than or equal to 1; R means H or C ₁ -C ₂₀ alkyl group; and X is a halogen atom, an arylsulfonyloxy group or an alkylsulfonyloxy group,

halogen atom,

cyano group,

nitro group,

carboxylic acid group

sulfonic acid group,

a hydroxy group or

a phosphoryloxy group; or

two R ^p2 groups bonded together to one iodine atom together optionally form ═O;

n1 is a number greater than or equal to 0;

n2 is a number greater than or equal to 1; And

the sum of n1 and n2 is in the range from 1 to 11.

[0076]

The iodine-containing aromatic compound (1b) is preferably the compound represented by the formula (p1'):

wherein

Ar means aromatic ring;

R ^p1 in each case independently means

an alkyl group

alkoxy group,

group: -O-(CH ₂ ) _q -NR ₃ X, in which q is a number greater than or equal to 1; R at each occurrence is independently H or a C ₁ -C ₂₀ alkyl group; and X is a halogen atom, an arylsulfonyloxy group or an alkylsulfonyloxy group,

a group: -(CH ₂ ) _q -NR ₃ X, in which q is a number greater than or equal to 1; R means H or C ₁ -C ₂₀ alkyl group; and X is a halogen atom, an arylsulfonyloxy group or an alkylsulfonyloxy group,

halogen atom,

cyano group,

nitro group,

a carboxylic acid group or

a sulfonic acid group;

n1 is from 0 to the maximum possible number of substituents (eg, a number from 0 to 5); And

n2 is a number between 1 and 6.

As one skilled in the art can generally understand, the maximum possible number of substituents for n1 varies with n2.

[0077]

In the structural formula (p1), R ^p1 at each occurrence is independently preferably an alkyl group optionally substituted with one or more fluorine atoms, an alkoxy group optionally substituted with one or more fluorine atoms, halogen atoms, a carboxylic acid group, or a sulfonic acid group.

In the structural formula (p1'), R ^p1 at each occurrence is independently preferably an alkyl group optionally substituted with one or more fluorine atoms, an alkoxy group optionally substituted with one or more fluorine atoms, halogen atoms, a carboxylic acid group or a sulfonic acid group.

The number of fluorine atoms as substituents may range from 1 to the maximum possible number of substituents. Specific examples of the number of fluorine atoms as substituents include 1, 2, 3, 4, 5, 6, 7, 8 and 9.

[0078]

In the structural formula (p1), R ^p2 at each occurrence is independently preferably a halogen atom, an acetic acid group, a trifluoroacetic acid group, a p-toluenesulfonic acid group, a hydroxy group, a phosphoryloxy group, a trifluoromethanesulfonic acid group, a propionic acid group, a 3,3,3 group -trifluoropropionic acid, a perfluoropropionic acid group, a perfluorobutyric acid group, or a methanesulfonic acid group.

[0079]

As used herein, the term "acid group" means an atom or group of atoms formed by removing one hydrogen atom, which can be ionized as a hydrogen ion, from an organic or inorganic acid molecule. In particular, the carboxylic acid group, for example, may include an acetic acid group; and the acetic acid group in the present description may be -OCOCH ₃ (acetyloxy).

[0080]

The reaction in step A can be carried out in the presence or absence of a solvent. The solvent may be a non-polar solvent or a polar solvent. A preferred example of a solvent may be a non-polar solvent or a polar solvent. The solvent may be an aromatic compound, an alcohol, an ether, a nitrogen-containing polar organic compound, a nitrile, a halogenated hydrocarbon, an aliphatic hydrocarbon, a fluorine-based solvent, other solvents, or a combination of these solvents.

[0081]

Examples of aromatic compounds as such a solvent include anisole, benzene, toluene, xylene and ethylbenzene. Preferred examples include benzene and toluene.

[0082]

Examples of alcohols as such a solvent include methanol, ethanol, n-propanol, isopropanol, n-butanol, pentanol, hexanol, ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, polyethylene glycol, propylene glycol, dipropylene glycol, tripropylene glycol, polypropylene glycol, trimethylene glycol, and hexane triol. Preferred examples include methanol and ethanol.

[0083]

Examples of ethers as such a solvent include diethyl ether, dibutyl ether, tetrahydrofuran, tetrahydropyran, dioxane, dimethoxyethane, diethylene glycol diethyl ether, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, propylene glycol monomethyl ether (PGME; other the name is 1-methoxy-2-propanol), propylene glycol monoethyl ether, triethylene glycol dimethyl ether, triethylene glycol diethyl ether, tetraethylene glycol dimethyl ether and tetraethylene glycol diethyl ether. Preferred examples include diethyl ether and tetrahydrofuran.

[0084]

Examples of nitrogen-containing polar organic compounds as such a solvent include N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, 2-pyrrolidone and 1,3-dimethyl-2-imidazolidinone. Preferred examples include N,N-dimethylformamide, N,N-dimethylacetamide and N-methyl-2-pyrrolidone.

[0085]

Examples of nitriles as such a solvent include acetonitrile, propionitrile, butyronitrile, isobutyronitrile, benzonitrile and adiponitrile. Preferred examples include acetonitrile.

[0086]

Examples of halogenated hydrocarbons as such a solvent include dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrachloroethane, trichloroethane, chlorobenzene, dichlorobenzene and chlorotoluene. Preferred examples include dichloromethane and chloroform.

[0087]

Examples of aliphatic hydrocarbons as such a solvent include hexane, cyclohexane, heptane, octane, nonane, decane, undecane, dodecane, and mineral spirits. Preferred examples include cyclohexane and heptane.

[0088]

Examples of fluorine-based solvents include perfluorobenzene, trifluorotoluene, ditrifluorobenzene, and trifluoroethanol. Preferred examples include perfluorobenzene and trifluoroethanol.

[0089]

Examples of other solvents include acetic acid, dimethyl sulfoxide, sulfolane and water.

These solvents may be used singly or in combination of two or more.

[0090]

The amount of solvent may be, for example, usually 0 to 200 parts by weight, preferably 0 to 100 parts by weight. and more preferably from 0 to 50 wt.part. per 1 wt. an organic compound (1) which is a substrate in the production process of the present invention.

[0091]

The temperature in step A can generally be -78 to 200°C, preferably -10 to 100°C, and more preferably 0 to 100°C.

[0092]

The time period in step A can generally be from 0.1 to 72 hours, preferably from 0.1 to 48 hours, more preferably from 0.2 to 24 hours, and even more preferably from 0.5 to 12 hours.

[0093]

The production method of the present invention can achieve a conversion rate of the starting material, preferably 10% or more, more preferably 20% or more, and even more preferably 30% or more.

The production method of the present invention can provide a target compound selectivity of preferably 50% or more, and more preferably 60% or more.

The production method of the present invention can achieve a yield of the target compound, preferably 10% or more, more preferably 20% or more, and even more preferably 30% or more.

[0094]

2. Fluorinated organic compound

One embodiment of the present invention is a fluorinated organic compound represented by the formula (1-1):

wherein

Ar means an aromatic hydrocarbon group optionally containing one or more substituents, or an aromatic heterocyclic group optionally containing one or more substituents;

R ² means hydrogen, halogen or an organic group;

R ³ means hydrogen, halogen or an organic group;

R ⁴ means an aliphatic hydrocarbon group optionally containing one or more substituents, an aromatic hydrocarbon group optionally containing one or more substituents, an aliphatic heterocyclic group optionally containing one or more substituents, or an aromatic heterocyclic group optionally containing one or more deputies; And

R ^X means hydrogen or fluorine.

[0095]

Preferred embodiments of this compound can be understood from the preferred embodiments given for the preparation method.

[0096]

In one embodiment, R ^X is preferably fluorine. In another embodiment, R ^X is preferably hydrogen.

Examples

[0097]

The present invention is described in more detail with reference to examples. However, the present invention is not limited to the examples.

In the examples, the term "output" means the output obtained, unless otherwise indicated.

[0098]

The designations and abbreviations used in the examples are given below.

TEA: triethylamine

DCM: dichloromethane

Ph: phenyl

Ac: acetyl

Py: pyridine

m-CPBA: meta-chloroperbenzoic acid

[0099]

Example 1a:

Fluorination reaction 1

PhIO (1.3 equiv.), Py∙HF (25 equiv.), and CH ₂ Cl ₂ were placed in a vessel and stirred at room temperature. (E)-chalcone (1 mmol) and CH ₂ Cl ₂ were added thereto at room temperature, and the mixture was stirred at room temperature for 7 hours. The reaction mixture was then neutralized with an aqueous solution of sodium hydrogen carbonate, then the aqueous layer was extracted three times with CH ₂ Cl ₂ . The resulting organic layer was dried over Na ₂ SO ₄ and evaporated. Then column chromatography was carried out on silica gel, and thus the target product, 3,3-difluoro-1,2-diphenylpropan-1-one, was isolated in 82% yield.

[0100]

Example 1b

The procedure of Example 1a was repeated with the difference that the starting material (E)-chalcone was replaced by (E)-4-phenylbut-3-en-2-one, thus obtaining 4,4-difluoro-3-phenylbutan-2-one with a yield of 67%.

[0101]

Example 1c

The procedure of example 1a was repeated with the difference that the starting material (E)-chalcone was replaced by (E)-4,4-dimethyl-1-phenylpent-1-en-3-one, thus obtaining 1,1-difluoro-4 ,4-dimethyl-2-phenylpentan-3-one in 80% yield.

[0102]

Example 1d

The procedure of example 1a was repeated with the difference that the starting material (E)-chalcone was replaced by (E)-1-(4-nitrophenyl)-3-phenylprop-2-en-1-one, thus obtaining 3,3-difluoro -1-(4-nitrophenyl)-2-phenylpropan-1-one in 86% yield.

[0103]

Example 1e

The procedure of example 1a was repeated with the difference that the starting material (E)-chalcone was replaced by (E)-1-(4-methoxyphenyl)-3-phenylprop-2-en-1-one, thus obtaining 3,3-difluoro -1-(4-methoxyphenyl)-2-phenylpropan-1-one in 71% yield.

[0104]

Example 1f

The procedure of example 1a was repeated with the difference that the starting material (E)-chalcone was replaced by (E)-1-(naphthalene-2-yl)-3-phenylprop-2-en-1-one, thus obtaining 3.3 -difluoro-1-(naphthalene-2-yl)-2-phenylpropan-1-one in 63% yield.

[0105]

Example 1g

The procedure of Example 1a was repeated with the difference that the starting material (E)-chalcone was replaced by (E)-3-phenyl-1-(thiophen-2-yl)prop-2-en-1-one, thus obtaining 3, 3-difluoro-2-phenyl-1-(thiophen-2-yl)propan-1-one in 80% yield.

[0106]

Example 1h

The procedure of Example 1a was repeated with the difference that the starting material (E)-chalcone was replaced by 3-(4-chlorophenyl)-1-(4-methoxyphenyl)prop-2-en-1-one, thus obtaining 2-(4 -chlorophenyl)-3,3-difluoro-1-(4-methoxyphenyl)propan-1-one in 66% yield.

[0107]

Example 1i

The procedure of example 1a was repeated with the difference that the starting material (E)-chalcone was replaced by 1-phenylnon-1-en-3-one, thus obtaining 1,1-difluoro-2-phenylnonan-3-one with a yield of 67% .

[0108]

Example 1j

The procedure of Example 1a was repeated with the difference that the starting material (E)-chalcone was replaced by 1-(4-chlorophenyl)-3-phenylprop-2-en-1-one, thus obtaining 1-(4-chlorophenyl)-3 ,3-difluoro-2-phenylpropan-1-one in 86% yield.

[0109]

Example 1k

The procedure of Example 1a was repeated with the difference that the starting material (E)-chalcone was replaced by N-(4-cinnamoylphenyl)acetamide, thus obtaining N-(4-(3,3-difluoro-2-phenylpropanoyl)phenyl)acetamide with yield 77%.

[0110]

Example 1l

The procedure of Example 1a was repeated with the difference that the starting material (E)-chalcone was replaced by 1-phenyl-3-(p-tolyl)prop-2-en-1-one, thus obtaining 3,3-difluoro-1- phenyl-2-(p-tolyl)propan-1-one with a yield of 52%.

[0111]

Example 1m

The procedure of Example 1a was repeated with the difference that the starting material (E)-chalcone was replaced by 3-(4-chlorophenyl)-1-phenylprop-2-en-1-one, thus obtaining 2-(4-chlorophenyl)-3 ,3-difluoro-1-phenylpropan-1-one in 80% yield.

[0112]

Example 1n

The procedure of Example 1a was repeated with the difference that the starting material (E)-chalcone was replaced by 3-(4-fluorophenyl)-1-phenylprop-2-en-1-one, thus obtaining 3,3-difluoro-2-( 4-fluorophenyl)-1-phenylpropan-1-one in 81% yield.

[0113]

Example 1o

The procedure of Example 1a was repeated with the difference that the starting material (E)-chalcone was replaced by 1-(4-chlorophenyl)-3-(p-tolyl)prop-2-en-1-one, thus obtaining 1-(4 -chlorophenyl)-3,3-difluoro-2-(p-tolyl)propan-1-one in 58% yield.

[0114]

Example 1p

The procedure of example 1a was repeated with the difference that the starting material (E)-chalcone was replaced by 1,3-diphenylbut-2-en-1-one, thus obtaining 3,3-difluoro-2-methyl-1,2-diphenylpropane -1-one with 72% yield.

[0115]

Example 1q

The procedure of Example 1a was repeated with the difference that the starting material (E)-chalcone was replaced by 1-phenyl-3-(p-tolyl)but-2-en-1-one, thus obtaining 3,3-difluoro-2- methyl-1-phenyl-2-(p-tolyl)propan-1-one in 60% yield.

[0116]

Example 1r

The procedure of Example 1a was repeated with the difference that the starting material (E)-chalcone was replaced by 7-phenyl-8,9-dihydro-5H-benzo[7]annulen-5-one, thus obtaining 2-(difluoromethyl)-2 -phenyl-3,4-dihydronaphthalene-1(2H)-one in 49% yield.

[0117]

Example 2a:

Fluorination reaction 2

4-Iodotoluene (20 mol%), mCPBA (1.3 eq.), and CH ₂ Cl ₂ were placed in a vessel. To these were added Py∙HF (40 eq.) and CH ₂ Cl ₂ then stirred at room temperature for 15 min. To these were added (E)-chalcone (0.5 mmol) and CH ₂ Cl ₂ at room temperature, and the mixture was stirred at room temperature for 24 hours. The aqueous layer was then extracted three times with CH ₂ Cl ₂ . The organic layer was dried over Na ₂ SO ₄ and evaporated. Column chromatography was carried out on silica gel and thus the target product, 3,3-difluoro-1,2-diphenylpropan-1-one, was isolated in 68% yield.

[0118]

Example 2b

The procedure of Example 1a was repeated with the difference that the starting material (E)-chalcone was replaced by (E)-4-phenylbut-3-en-2-one, thus obtaining 4,4-difluoro-3-phenylbutan-2-one with a yield of 32%.

[0119]

Example 2c

The procedure of example 1a was repeated with the difference that the starting material (E)-chalcone was replaced by (E)-4,4-dimethyl-1-phenylpent-1-en-3-one, thus obtaining 1,1-difluoro-4 ,4-dimethyl-2-phenylpentan-3-one in 73% yield.

[0120]

Example 2d

The procedure of example 1a was repeated with the difference that the starting material (E)-chalcone was replaced by (E)-1-(4-nitrophenyl)-3-phenylprop-2-en-1-one, thus obtaining 3,3-difluoro -1-(4-nitrophenyl)-2-phenylpropan-1-one in 67% yield.

[0121]

Example 2e

The procedure of example 1a was repeated with the difference that the starting material (E)-chalcone was replaced by (E)-1-(4-methoxyphenyl)-3-phenylprop-2-en-1-one, thus obtaining 3,3-difluoro -1-(4-methoxyphenyl)-2-phenylpropan-1-one in 62% yield.

[0122]

Example 2f

The procedure of example 1a was repeated with the difference that the starting material (E)-chalcone was replaced by (E)-1-(naphthalene-2-yl)-3-phenylprop-2-en-1-one, thus obtaining 3.3 -difluoro-1-(naphthalene-2-yl)-2-phenylpropan-1-one in 26% yield.

[0123]

Example 2g

The procedure of Example 1a was repeated with the difference that the starting material (E)-chalcone was replaced by (E)-3-phenyl-1-(thiophen-2-yl)prop-2-en-1-one, thus obtaining 3, 3-difluoro-2-phenyl-1-(thiophen-2-yl)propan-1-one in 85% yield.

[0124]

Example 2h

The procedure of Example 1a was repeated with the difference that the starting material (E)-chalcone was replaced by (E)-3-(4-chlorophenyl)-1-(4-methoxyphenyl)prop-2-en-1-one, thus obtaining 2-(4-chlorophenyl)-3,3-difluoro-1-(4-methoxyphenyl)propan-1-one in 56% yield.

[0125]

Example 3a:

Fluorination reaction 3

PhIO (1.3 equiv.), Py∙HF (20 equiv.), and CH ₂ Cl ₂ were placed in a vessel and stirred at room temperature. Ethyl cinnamate (1 mmol) and CH ₂ Cl ₂ were then added thereto at room temperature, and the mixture was stirred at room temperature for 7 hours. The reaction product was then neutralized with an aqueous sodium hydrogen carbonate solution, and the aqueous layer was extracted with CH ₂ Cl ₂ . The organic layer was dried over Na ₂ SO ₄ and evaporated. Then column chromatography was carried out on silica gel, and thus the target product, ethyl 3,3-difluoro-2-phenylpropanoate, was isolated in a yield of 77%.

[0126]

Example 3b

The procedure of Example 3a was repeated with the difference that the starting material ethyl cinnamate was replaced by ethyl-(E)-3-(p-tolyl)acrylate, thus obtaining ethyl 3,3-difluoro-2-(p-tolyl)propanoate with the yield 80%.

[0127]

Example 3c

The procedure of Example 3a was repeated with the difference that the starting material ethyl cinnamate was replaced by ethyl-(E)-3-(o-tolyl)acrylate, thus obtaining ethyl 3,3-difluoro-2-(o-tolyl)propanoate with the yield 85%.

[0128]

Example 3d

The procedure of Example 3a was repeated with the difference that the starting material ethyl cinnamate was replaced by ethyl-(E)-3-(4-fluorophenyl)acrylate, thus obtaining ethyl 3,3-difluoro-2-(4-fluorophenyl)propanoate with the yield 77%.

[0129]

Example 4a:

Fluorination reaction 4

PhIO (1.4 eq.), Py∙HF (20 eq.), and CH ₂ Cl ₂ were stirred at room temperature. Then, (E)-3-phenylprop-2-en-1-ol (1 mmol) and CH ₂ Cl ₂ were added thereto at room temperature, followed by stirring at -45°C for 2 hours. Then, the reaction product was neutralized with an aqueous solution sodium bicarbonate, then the aqueous layer was extracted three times with CH ₂ Cl ₂ . The resulting organic layer was dried over Na ₂ SO ₄ and then evaporated. Column chromatography was then carried out on silica gel, and thus the target product, 3,3-difluoro-2-phenylpropan-1-ol, was isolated in 52% yield.

[0130]

Example 4b

The procedure of Example 4a was repeated with the difference that (E)-3-phenylprop-2-en-1-ol was replaced by (E)-3-(o-tolyl)prop-2-en-1-ol, thus 3,3-difluoro-2-(o-tolyl)propan-1-ol was obtained in this manner in 47% yield.

[0131]

Example 4c

The procedure of Example 4a was repeated with the difference that (E)-3-phenylprop-2-en-1-ol was replaced by (E)-3-(4-fluorophenyl)prop-2-en-1-ol, thus 3,3-difluoro-2-(4-fluorophenyl)propan-1-ol was obtained in this manner in 38% yield.

[0132]

Example 4d

The procedure of example 4a was repeated with the difference that the starting material (E)-3-phenylprop-2-en-1-ol was replaced by (E)-3-phenylbut-2-en-1-ol, thus obtaining 3.3 -difluoro-2-phenylbutan-1-ol with a yield of 54%.

[0133]

Example 5a

PhIO (1.4 equiv.), Py∙HF (20 equiv.), and CH ₂ Cl ₂ were placed in a vessel and stirred at -45°C. Then, 3-(o-tolyl)prop-2-en-1-ol (1 mmol) was added thereto, followed by stirring at -45°C for 2 h. Then, the reaction product was neutralized with an aqueous solution of sodium hydrogen carbonate, then the aqueous layer was extracted with CH ₂ Cl ₂ . The organic layer was dried over Na ₂ SO ₄ and evaporated. Then column chromatography was carried out on silica gel, and thus the target product, 3,3-difluoro-2-(o-tolyl)propan-1-ol, was isolated in 47% yield.

[0134]

Example 5b

The procedure of Example 5a was repeated with the difference that the starting material 3-(o-tolyl)prop-2-en-1-ol was replaced by 3-(p-tolyl)prop-2-en-1-ol, thus obtaining 3 ,3-difluoro-2-(p-tolyl)propan-1-ol in 38% yield.

[0135]

Example 5c

The procedure of Example 5a was repeated with the difference that the starting material 3-(o-tolyl)prop-2-en-1-ol was replaced by 3-(4-fluorophenyl)prop-2-en-1-ol, thus obtaining 3 ,3-difluoro-2-(4-fluorophenyl)propan-1-ol in 38% yield.

[0136]

Example 5d

The procedure of Example 5a was repeated with the difference that the starting material 3-(o-tolyl)prop-2-en-1-ol was replaced by 3-(4-chlorophenyl)prop-2-en-1-ol, thus obtaining 2 -(4-chlorophenyl)-3,3-difluoropropan-1-ol in 48% yield.

[0137]

Example 5e

The procedure of Example 5a was repeated with the difference that the starting material 3-(o-tolyl)prop-2-en-1-ol was replaced by 3-(4-bromophenyl)prop-2-en-1-ol, thus obtaining 2 -(4-bromophenyl)-3,3-difluoropropan-1-ol in 33% yield.

[0138]

Example 5f

The procedure of Example 5a was repeated with the difference that the starting material 3-(o-tolyl)prop-2-en-1-ol was replaced by 3-phenylbut-2-en-1-ol, thus obtaining 3,3-difluoro- 2-phenylbutan-1-ol with a yield of 54%.

Claims (23)

1. Process for producing a fluorinated organic compound having the formula (1)

wherein R ¹ means phenyl, optionally containing halogen or C _1-6 alkyl, R ² means hydrogen or C _1-6 alkyl, R ³ means hydrogen, L means alkanediyl, -CONR- or -CO-O-, where R in each case independently means hydrogen or C _1-6 alkyl, R ⁴ means hydroxyl or C _1-6 alkyl and R ^X means fluorine, with the proviso that if L is --CONR- and R is hydrogen or methyl, R ⁴ is not methyl, and that if L is -CO-O-, R ⁴ is neither methyl nor propyl, the method comprises an alkene reaction step A of formula (2)

in which the steric configuration of the single bond, indicated by the wavy line, with respect to the double bond to which the single bond is linked, is the E-configuration, or the Z-configuration, or a mixture of the E-configuration and the Z-configuration in any ratio, and other letter designations are as defined above with the source of fluorine, which is the source (3a) described by the formula MF _n in which M is H, a metal of group 1 of the Periodic Table of the Elements or a metal of group 2 of the Periodic Table of the Elements and n is 1 or 2 in the presence of an aromatic compound containing hypervalent iodine, or in the presence of an iodine-containing aromatic compound and an oxidant to fluorinate the alkene. 2. The method of production according to claim 1, in which R ² means hydrogen. 3. The method of obtaining according to claim 1 or 2, in which L means -[C(-R ^4a )(-R ^4b )] _m -, R ^4a means hydrogen, R ^4b is hydrogen and m means an integer equal to 1. 4. The method of preparation according to claim 3, in which R ⁴ means hydroxyl. 5. Process according to claim 1 or 2, wherein L is -CO-O- and R ⁴ is C _1-6 alkyl.