Method for producing propionic acid derivative

Abstract

The present invention addresses the problem of providing a method for producing a propionic acid derivative with excellent productivity. This problem is solved by a method for producing a compound represented by formula (1), said method comprising: a step A in which a compound represented by formula (2) and a compound represented by formula (3) M (R1) n (in the formula, M is a cation, and n is an integer corresponding to the valence of M) are reacted with each other; the compound shown in the formula (4): R6-X-H reacts with the compound shown in the formula (4): R6-X-H; and a step B in which a compound represented by formula (5): MFn is separated by filtration from the mixture obtained by the reaction. (In the formula, R1 is a halogen atom or the like, R2 and R3 are each independently a hydrogen atom, a halogen atom, an organic group or the like, X is an oxygen atom or a sulfur atom, R4 and R5 are each independently a hydrogen atom, a halogen atom, a hydrocarbon group which may have one or more substituents or the like, and R6 is a hydrocarbon group which may have one or more substituents. )

Description

[0001] This application is a divisional application of Chinese invention patent application No. 202080067669.6, filed on September 29, 2020, entitled "Method for manufacturing propionic acid derivative". Technical Field

[0002] This disclosure relates to methods for manufacturing propionic acid derivatives, etc. Background Technology

[0003] Propionic acid derivatives such as 2,2-difluoropropionate are compounds that can be used as raw materials for pharmaceuticals, pesticides, etc. As a method for manufacturing 2,2-difluoropropionate, a method is known to be a reaction of 2,2,3,3-tetrafluorooxetane with alcohols or phenols in the presence of alkali metal halides (Patent Document 1).

[0004] Existing technical documents Patent documents Patent Document 1: Japanese Patent Application Publication No. 61-130254 Summary of the Invention

[0005] The technical problem that the invention aims to solve In the method of Patent Document 1, after the reaction, (a) the solvent is distilled off, (b) water is added, and (c) an organic solvent is added for separation. However, since the reaction solution contains a large amount of alkali metal fluorides, separation is difficult, resulting in poor productivity.

[0006] The purpose of this disclosure is to solve the above-mentioned problems and to provide a method for manufacturing propionic acid derivatives with excellent productivity.

[0007] Means for solving technical problems This disclosure includes the following aspects.

[0008] Item 1. A method for manufacturing a compound represented by formula (1):

Chemistry 1

[0009] (in the formula, R 1 It can be a halogen atom or SR (where R is a hydrogen atom or a hydrocarbon group). R 2 and R 3 Each is independently a hydrogen atom, a halogen atom, or an organic group, or R 2 and R 3 It can form a ring with the carbon atom at the β position. X is an oxygen atom or a sulfur atom. R 4 and R 5Each is independently a hydrogen atom, a halogen atom, or a hydrocarbon group that may have one or more substituents, or R 4 and R 5 It can form a ring with the carbon atom at the α position. R 6 (A hydrocarbon group that can have more than one substituent.) The manufacturing method includes: Step A, wherein the compound shown in formula (2) reacts with the compound shown in formula (3) and the compound shown in formula (4):

Chemistry 2

[0010] (where R is in the formula) 2 ~R 5 (This has the same meaning as mentioned above.) M(R 1 ) n (3) (In the formula, M is a cation, n is an integer corresponding to the valence of M, R) 1 (This has the same meaning as the one mentioned above.) R 6 -XH (4) (where R is in the formula) 6 "and X have the same meaning as described above." Step B, wherein the compound of formula (5) is separated from the mixture obtained by the above reaction by filtration: MF n (5) (In the formula, M and n have the same meaning as described above.)

[0011] Item 2. According to the manufacturing method described in item 1, the filtration is carried out at a temperature above 45°C.

[0012] Item 3. According to the manufacturing method described in item 1 or 2, the filtration is performed using filter material and filter aid.

[0013] Item 4. According to the manufacturing method of item 3, the filter aid is at least one selected from diatomaceous earth, filter sand, perlite and cellulose.

[0014] Item 5. According to the manufacturing method described in item 3 or 4, the average particle size of the filter aid is in the range of 0.5 to 200 μm.

[0015] Item 6. The manufacturing method according to any one of items 1 to 5 further includes: step C, wherein the filtrate obtained by the filtration is subjected to a separation process.

[0016] Item 7. The manufacturing method according to any one of items 1 to 6, wherein R 1 It can be a chlorine atom, a bromine atom, or an iodine atom.

[0017] Item 8. The manufacturing method according to any one of items 1 to 7, wherein R 1 It consists of bromine or iodine atoms.

[0018] Item 9. The manufacturing method according to any one of items 1 to 8, wherein R 2 and R 3 Each is independently a hydrogen atom, a halogen atom, an alkyl group, or a haloalkyl group.

[0019] Item 10. The manufacturing method according to any one of items 1 to 9, wherein R 2 and R 3 It is a hydrogen atom.

[0020] Item 11. The manufacturing method according to any one of items 1 to 10, wherein R 4 and R 5 Each is independently a hydrogen atom, a halogen atom, an alkyl group, or a haloalkyl group.

[0021] Item 12. The manufacturing method according to any one of items 1 to 11, wherein R 4 and R 5 It is a halogen atom.

[0022] Item 13. The manufacturing method according to any one of items 1 to 12, wherein R 4 and R 5 It is a fluorine atom.

[0023] Item 14. The manufacturing method according to any one of items 1 to 13, wherein R 6 It is an alkyl or haloalkyl group.

[0024] Item 15. The manufacturing method according to any one of items 1 to 14, wherein R 6 C 1-6 Alkyl or halogenated C 1-6 alkyl.

[0025] Item 16. The manufacturing method according to any one of items 1 to 15, wherein X is an oxygen atom.

[0026] Item 17. The manufacturing method according to any one of items 1 to 16, wherein M is a metal.

[0027] Item 18. The manufacturing method according to any one of items 1 to 17, wherein M is an alkali metal or an alkaline earth metal.

[0028] Item 19. The manufacturing method according to any one of items 1 to 18, wherein M is an alkali metal.

[0029] Item 20. A composition comprising a compound of formula (1) and a compound of formula (5):

Transformation 3

[0030] (in the formula, R 1 It can be a halogen atom or SR (where R is a hydrogen atom or a hydrocarbon group). R 2 and R 3 Each is independently a hydrogen atom, a halogen atom, or an organic group, or R 2 and R 3 It can form a ring with the carbon atom at the β position. X is an oxygen atom or a sulfur atom. R 4 and R 5 Each is independently a hydrogen atom, a halogen atom, or a hydrocarbon group that may have one or more substituents, or R 4 and R 5 It can form a ring with the carbon atom at the α position. R 6 (A hydrocarbon group that can have more than one substituent.) MF n (5) (In the formula, M represents an alkali metal, and n is an integer corresponding to the valence of M.) The concentration of fluoride ions in the composition is greater than 0 mg / L and less than 1000 mg / L.

[0031] Item 21. The composition according to item 20, wherein R 1 It can be a chlorine atom, a bromine atom, or an iodine atom.

[0032] Item 22. The composition according to item 20 or 21, wherein R 1 It consists of bromine or iodine atoms.

[0033] Item 23. The composition according to any one of items 20 to 22, wherein R 2 and R 3 Each is independently a hydrogen atom, a halogen atom, an alkyl group, or a haloalkyl group.

[0034] Item 24. The composition according to any one of items 20 to 23, wherein R 2 and R 3 It is a hydrogen atom.

[0035] Item 25. The composition according to any one of items 20 to 24, wherein R 4 and R 5 Each is independently a hydrogen atom, a halogen atom, an alkyl group, or a haloalkyl group.

[0036] Item 26. The composition according to any one of items 20 to 25, wherein R 4 and R 5 It is a halogen atom.

[0037] Item 27. The composition according to any one of items 20 to 26, wherein R 4 and R 5 It is a fluorine atom.

[0038] Item 28. The composition according to any one of items 20 to 27, wherein R 6 It is an alkyl or haloalkyl group.

[0039] Item 29. The composition according to any one of items 20 to 28, wherein R 6 C 1-6 Alkyl or halogenated C 1-6 alkyl.

[0040] Item 30. The composition according to any one of items 20 to 29, wherein X is an oxygen atom.

[0041] Item 31. The composition according to any one of items 20 to 30, wherein M is a metal.

[0042] Item 32. The composition according to any one of items 20 to 31, wherein M is an alkali metal or an alkaline earth metal.

[0043] Item 33. The composition according to any one of items 20 to 32, wherein M is an alkali metal.

[0044] In addition, this disclosure also includes ethyl 2,2-difluoro-3-iodopropionate (ICH2CF2COOEt).

[0045] Invention Effects According to this disclosure, a method for manufacturing a propionic acid derivative with excellent productivity is provided. Attached Figure Description

[0046] Figure 1 It shows ICH2CF2COOEt 1 A diagram of H-NMR spectrum.

[0047] Figure 2 It shows ICH2CF2COOEt 19 Figure of F-NMR spectrum. Detailed Implementation

[0048] The foregoing summary of this disclosure is not intended to describe all possible embodiments or forms of this disclosure.

[0049] The following description of this disclosure illustrates the implementation of the examples in more detail.

[0050] In many places in this specification, guidance is provided by way of example, and such examples can be used in a wide variety of combinations.

[0051] In each case, the exemplified group can serve as a non-exclusive representative group.

[0052] All publications, patents and patent applications cited in this specification are incorporated herein by reference in their entirety.

[0053] <Terminology> Unless otherwise specified, the references and abbreviations used in this specification are to be understood in the context of this specification as commonly used in the technical field to which this disclosure pertains.

[0054] In this specification, the phrase “contains” is intended to be used to include the phrases “essentially composed of” and “composed of”.

[0055] Unless otherwise specified, the steps, processes, or operations described in this instruction manual may be performed at room temperature.

[0056] In this instruction manual, room temperature can refer to a temperature within the range of 10~40℃.

[0057] In this instruction manual, the symbol "C" is used. n-m (Here, n and m are each numbers) as commonly understood by those skilled in the art, means that the number of carbon atoms is more than n and less than m.

[0058] In this specification, unless otherwise specified, examples of fluorine, chlorine, bromine, and iodine atoms can be cited as "halogen atoms".

[0059] In this specification, "organic group" refers to a group formed by removing one hydrogen atom from an organic compound.

[0060] Examples of this "organic group" include: Hydrocarbon groups that can have more than one substituent Non-aromatic heterocyclic groups that may have one or more substituents Heteroaryl groups that can have one or more substituents cyano, Aldehyde group QO-、 QS-、 QCO-、 QSO2-、 QOCO-、and QOSO2- (In these formulas, Q is independently:) Hydrocarbon groups that can have more than one substituent Non-aromatic heterocyclic groups that may have one or more substituents, or Heteroaryl groups may have one or more substituents.

[0061] Examples of "substituents" include halogen atoms, cyano groups, amino groups, alkoxy groups, and alkylthio groups. It should be noted that two or more substituents can be the same or different from each other. The number of substituents can be selected from, for example, one to the maximum number that can be substituted, and can be one, two, three, or four.

[0062] In this specification, unless otherwise specified, examples of "hydrocarbon group" include alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cyclodienyl, aryl, and aralkyl.

[0063] In this specification, unless otherwise specified, "alkyl" can refer to linear or branched C-aryl groups such as methyl, ethyl, propyl (n-propyl, isopropyl), butyl (n-butyl, isobutyl, sec-butyl, tert-butyl), pentyl, and hexyl. 1-20 alkyl.

[0064] In this specification, unless otherwise specified, "halogenated alkyl" refers to an alkyl group that can be substituted with one or more halogen atoms. Examples of halogenated alkyl groups include, for instance, fluoromethyl, difluoromethyl, trifluoromethyl (perfluoromethyl), 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 1,1,2,2-tetrafluoroethyl, pentafluoroethyl (perfluoroethyl), and groups obtained by substituting some or all of the fluorine atoms in these groups with other halogen atoms, such as straight-chain or branched halogenated C groups. 1-20 alkyl.

[0065] In this specification, unless otherwise specified, "alkoxy" can refer to linear or branched C-type compounds such as methoxy, ethoxy, propoxy (n-propoxy, isopropoxy), butoxy (n-butoxy, isobutoxy, sec-butoxy, tert-butoxy), pentoxy, and hexoxy. 1-20 Alkyl group.

[0066] In this specification, unless otherwise specified, "alkathioyl" can refer to linear or branched C-type groups such as methylthio, ethylthio, propylthio (n-propylthio, isopropylthio), butylthio (n-butylthio, isobutylthio, sec-butylthio, tert-butylthio), pentylthio, and hexylthio. 1-20 Alkylthio group.

[0067] In this specification, unless otherwise specified, "alkenyl" can refer to linear or branched C-aryl groups such as vinyl, 1-propen-1-yl, 2-propen-1-yl, isopropenyl, 2-buten-1-yl, 4-penten-1-yl, and 5-hexen-1-yl. 2-20 Alkenyl group.

[0068] In this specification, unless otherwise specified, "alkynyl" can refer to linear or branched C-terminal groups such as ethynyl, 1-propyn-1-yl, 2-propyn-1-yl, 4-pentyn-1-yl, and 5-hexyn-1-yl. 2-20 Alkyne group.

[0069] In this specification, unless otherwise specified, "cycloalkyl" can refer to, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. 3-10 Cycloalkyl.

[0070] In this specification, unless otherwise specified, examples of cycloalkenyl groups, such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and cycloheptenyl, can be used as "cycloalkenyl". 3-10 Cycloalkenyl.

[0071] In this specification, unless otherwise specified, examples of cyclodienyl groups, such as cyclobutadienyl, cyclopentadienyl, cyclohexadienyl, cycloheptadienyl, cyclooctadienyl, cyclononadienyl, and cyclodecadienyl, can be used as "cyclodienyl". 4-10 Cycloalkyldienyl.

[0072] In this specification, unless otherwise specified, "aryl" can be monocyclic, bicyclic, tricyclic, or tetracyclic.

[0073] In this specification, unless otherwise specified, "aryl" can be C 6-18 Aryl.

[0074] In this specification, unless otherwise specified, examples of aryl groups include phenyl, 1-naphthyl, 2-naphthyl, 2-biphenyl, 3-biphenyl, 4-biphenyl, and 2-anthrayl.

[0075] In this specification, unless otherwise specified, "halogenated aryl" refers to an aryl group that can be replaced by one or more halogen atoms.

[0076] In this specification, unless otherwise specified, "aryl" can be exemplified by, for example, benzyl, phenethyl, diphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2,2-diphenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 2-biphenylmethyl, 3-biphenylmethyl and 4-biphenylmethyl.

[0077] In this specification, unless otherwise specified, "halogenated aralkyl" refers to an aralkyl group that can be substituted by one or more halogen atoms.

[0078] In this specification, "non-aromatic heterocyclic group" refers to a group formed by removing one hydrogen atom from a non-aromatic heterocycle.

[0079] In this specification, unless otherwise specified, "non-aromatic heterocyclic group" can be monocyclic, bicyclic, tricyclic, or tetracyclic.

[0080] In this specification, unless otherwise specified, "non-aromatic heterocyclic group" may be saturated or unsaturated.

[0081] In this specification, unless otherwise specified, "non-aromatic heterocyclic group" can be, for example, a 5- to 18-membered non-aromatic heterocyclic group.

[0082] In this specification, unless otherwise specified, a “non-aromatic heterocyclic group” can be, for example, a non-aromatic heterocyclic group that contains, in addition to a carbon atom, 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen atoms as cyclic atoms.

[0083] In this specification, unless otherwise specified, examples of "non-aromatic heterocyclic groups" include, for instance, tetrahydrofuranyl, oxazolinyl, imidazolinyl (e.g., 1-imidazolinyl, 2-imidazolinyl, 4-imidazolinyl), aziridine (e.g., 1-aziridine, 2-aziridine), pyrrolidine (e.g., 1-pyrrolidine, 2-pyrrolidine, 3-pyrrolidine), piperidinyl (e.g., 1-piperidinyl, 2-piperidinyl, 3-piperidinyl), aziridine-heptyl (e.g., 1-aziridine-heptyl, 2-aziridine-heptyl, 3-aziridine-heptyl, 4-aziridine-heptyl), aziridine-octyl (e.g., 1-aziridine-octyl, 2-aziridine-octyl, 3-aziridine-octyl, 4-aziridine-octyl), and piperazine (e.g., 1,4-piperazin-1-yl, 1,4-piperidine-1-yl). Azine-2-yl), diazacycloheptatrienyl (e.g., 1,4-diazacycloheptatrien-1-yl, 1,4-diazacycloheptatrien-2-yl, 1,4-diazacycloheptatrien-5-yl, 1,4-diazacycloheptatrien-6-yl), diazacyclooctyl (e.g., 1,4-diazacyclooctane-1-yl, 1,4-diazacyclooctane-2-yl, 1,4-diazacyclooctane-5-yl) Examples of dihydropyranyl compounds include 1,4-diazacyclooctane-6-yl, 1,5-diazacyclooctane-1-yl, 1,5-diazacyclooctane-2-yl, 1,5-diazacyclooctane-3-yl), tetrahydropyranyl (e.g., tetrahydrofuran-4-yl), morpholinyl (e.g., 4-morpholinyl), thiomorpholinyl (e.g., 4-thiomorpholinyl), 2-oxazolylyl, dihydrofuranyl, dihydropyranyl, and dihydroquinolinyl.

[0084] In this specification, unless otherwise specified, "heteroaryl" can be monocyclic, bicyclic, tricyclic, or tetracyclic.

[0085] In this specification, unless otherwise specified, "heteroaryl" can be, for example, a heteroaryl group of 5 to 18 nucleotides.

[0086] In this specification, unless otherwise specified, "heteroaryl" can be, for example, a heteroaryl group containing, in addition to a carbon atom, 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen atoms as cyclic atoms.

[0087] In this specification, unless otherwise specified, "heteroaryl" includes both "monocyclic heteroaryl" and "aromatic fused heterocyclic".

[0088] In this specification, unless otherwise specified, examples of "monocyclic heteroaryl groups" include pyrrole (e.g., 1-pyrrole, 2-pyrrole, 3-pyrrole), furanyl (e.g., 2-furanyl, 3-furanyl), thiophene (e.g., 2-thiophene, 3-thiophene), pyrazolyl (e.g., 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), imidazole (e.g., 1-imidazolyl, 2-imidazolyl, 4-imidazolyl), isoxazolyl (e.g., 3-isooxazolyl, 4-isooxazolyl, 5-isooxazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), and isothiazolyl (e.g., 3-isothhiazolyl, 4-isooxazolyl). Thiazolyl, 5-isothiazolyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), triazolyl (e.g., 1,2,3-triazol-3-yl, 1,2,4-triazol-4-yl), oxadiazolyl (e.g., 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl), thiazolyl (e.g., 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl), tetrazolyl, pyridinyl (e.g., 2-pyridinyl, 3-pyridinyl, 4-pyridinyl), pyrazinyl (e.g., 3-pyrazinyl, 4-pyrazinyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), and pyrazinyl, etc.

[0089] In this specification, unless otherwise specified, examples of "aromatic fused heterocyclic groups" include isoindolyl (e.g., 1-isoindolyl, 2-isoindolyl, 3-isoindolyl, 4-isoindolyl, 5-isoindolyl, 6-isoindolyl, 7-isoindolyl), indolyl (e.g., 1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), and benzo[b]furanyl (e.g., 2-benzo[b]furanyl, 3 ... Benzofuryl, 4-benzo[b]furanyl, 5-benzo[b]furanyl, 6-benzo[b]furanyl, 7-benzo[b]furanyl), benzo[c]furanyl (e.g.: 1-benzo[c]furanyl, 4-benzo[c]furanyl, 5-benzo[c]furanyl), benzo[b]thiophenyl (e.g.: 2-benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4-benzo[b]thiophenyl, 5-benzo[b]thiophenyl, 6-benzo[b]thiophenyl, 7-benzo[b]thiophenyl ), benzo[c]thiophene (e.g., 1-benzo[c]thiophene, 4-benzo[c]thiophene, 5-benzo[c]thiophene), indazole (e.g., 1-indazole, 2-indazole, 3-indazole, 4-indazole, 5-indazole, 6-indazole, 7-indazole), benzimidazole (e.g., 1-benzimidazole, 2-benzimidazole, 4-benzimidazole, 5-benzimidazole), 1,2-benzisoxazole (e.g., 1,2-benzisoxazole-3-yl, 1,2-benzimid ... Benzo[a]oxazol-4-yl, 1,2-benzisoxazol-5-yl, 1,2-benzisoxazol-6-yl, 1,2-benzisoxazol-7-yl), benzo[a]oxazolyl (e.g., 2-benzisoxazolyl, 4-benzisoxazolyl, 5-benzisoxazolyl, 6-benzisoxazolyl, 7-benzisoxazolyl), 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, 1,2-Benzisothiazolyl-7-yl), benzothiazolyl (e.g., 2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, 4-isoquinolinyl, 5-isoquinolinyl), quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl, 5-quinolinyl, 8-quinolinyl), cenolinyl ( For example: 3-terpinel, 4-terpinel, 5-terpinel, 6-terpinel, 7-terpinel, 8-terpinel), phthalazinyl (e.g.: 1-phthalazinyl, 4-phthalazinyl, 5-phthalazinyl, 6-phthalazinyl, 7-phthalazinyl, 8-phthalazinyl), quinazolinyl (e.g.: 2-quinazolinyl, 4-quinazolinyl, 5-quinazolinyl, 6-quinazolinyl, 7-quinazolinyl, 8-quinazolinyl), quinoxalinyl (e.g.: 2-Quinoxolinyl, 3-Quinoxolinyl, 5-Quinoxolinyl, 6-Quinoxolinyl, 7-Quinoxolinyl, 8-Quinoxolinyl), 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]pyridin-4-yl, pyrazolo[1,5-a]pyridin-5-yl, pyrazolo[1,5-a]pyridin-6-yl) The compounds include imidazo[1,5-a]pyridin-7-yl and imidazo[1,2-a]pyridinyl (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).

[0090] <Method for manufacturing the compound shown in formula (1)> In one embodiment, a method for manufacturing the compound represented by formula (1) includes: Step A, wherein the compound shown in formula (2) reacts with the compound shown in formula (3) and the compound shown in formula (4):

Chemistry 4

[0091] (in the formula, R 1 It can be a halogen atom or SR (where R is a hydrogen atom or a hydrocarbon group). R 2 and R 3 Each is independently a hydrogen atom, a halogen atom, or an organic group, or R 2 and R 3 It can form a ring with the carbon atom at the β position. X is an oxygen atom or a sulfur atom. R 4 and R5 Each is independently a hydrogen atom, a halogen atom, or a hydrocarbon group that may have one or more substituents, or R 4 and R 5 It can form a ring with the carbon atom at the α position. R 6 (A hydrocarbon group that can have more than one substituent.)

Transformation 5

[0092] (where R is in the formula) 2 ~R 5 (This has the same meaning as mentioned above.) M(R 1 ) n (3) (In the formula, M is a cation, n is an integer corresponding to the valence of M, R) 1 (This has the same meaning as mentioned above.) R 6 -XH (4) (where R is in the formula) 6 "and X have the same meaning as described above." Step B, wherein the compound represented by formula (5) is separated from the mixture obtained by the aforementioned reaction by filtration: MF n (5) (In the formula, M and n have the same meaning as described above.)

[0093] The compound shown in formula (1) Regarding R 1 , Preferably, it contains halogen atoms, mercapto groups, or alkylthio groups; More preferably, halogen atoms; Further preferred are fluorine atoms, chlorine atoms, bromine atoms, or iodine atoms; More preferably, bromine or iodine atoms; Iodine atoms are particularly preferred.

[0094] R 2 and R 3 Each independent, Preferably, it is a hydrogen atom, a halogen atom, an alkyl group, or a haloalkyl group; More preferably, hydrogen atoms, halogen atoms, and C atoms. 1-4 Alkyl or halogenated C 1-4 alkyl; Further preferred are hydrogen atoms or halogen atoms; More preferably, hydrogen atoms or fluorine atoms; Hydrogen atoms are particularly preferred.

[0095] R 2 and R 3 There are no particular restrictions on the ring formed together with the carbon atom at the β position. It can be, for example, a 5- to 8-membered aliphatic ring or heterocycle (e.g., nitrogen-containing heterocycle, oxygen-containing heterocycle, sulfur-containing heterocycle) that may have one or more substituents.

[0096] R 4 and R 5 Each independent, Preferably, it is a hydrogen atom, a halogen atom, an alkyl group, or a haloalkyl group; More preferably, hydrogen atoms, halogen atoms, and C atoms. 1-4 Alkyl or halogenated C 1-4 alkyl; Further preferred are halogen atoms; Fluorine atoms are particularly preferred.

[0097] R 4 and R 5 There are no particular restrictions on the ring formed together with the carbon atom at the α position. It can be, for example, a 5- to 8-membered aliphatic ring or heterocycle (e.g., nitrogen-containing heterocycle, oxygen-containing heterocycle, sulfur-containing heterocycle) that may have one or more substituents.

[0098] Regarding R 6 , Preferably, it is an alkyl group having one or more substituents, an aryl group having one or more substituents, or an aralkyl group having one or more substituents; More preferably, it is alkyl, haloalkyl, aryl, haloaryl, aralkyl, or haloaralkyl; Further preferred are alkyl or haloalkyl groups; C is particularly preferred 1-6 Alkyl or halogenated C 1-6 alkyl.

[0099] X is preferably an oxygen atom.

[0100] Step A R in equation (2) 2 ~R 5 Each can be R in equation (1) 2 ~R 5 The corresponding functional group.

[0101] Examples of compounds represented by formula (2) include 2,2-difluorooxetanes, with 2,2,3,3-tetrafluorooxetane being a typical example. Compounds represented by formula (2) may be used alone or in combination of two or more.

[0102] R in equation (3) 1 It can be R in equation (1)1 The corresponding functional group.

[0103] As the cation represented by M in formula (3), as long as it is R 1 There are no specific limitations on the counter ions; examples include hydrogen, metals, and ammonium.

[0104] Specific examples of the metal may include alkali metals and alkaline earth metals.

[0105] Examples of alkali metals include lithium, sodium, potassium, and cesium.

[0106] Examples of alkaline earth metals include magnesium and calcium.

[0107] Specific examples of ammonium may include primary to quaternary ammonium.

[0108] Examples of primary ammonium compounds include methylamine, ethylamine, propylamine (n-propylamine, isopropylamine), and butylamine. 1-6 Alkylamines, aniline, etc.

[0109] Examples of secondary ammonium compounds include dimethylamine, diethylamine, ethylmethylamine, and dipropylamine. 1-6 Alkylamines, pyrrolidines, imidazoles, piperidines, morpholines, etc.

[0110] Examples of tertiary ammonium compounds include trimethylamine and triethylamine. 1-6 Alkylamines, pyridines, quinolines, etc.

[0111] Examples of quaternary ammonium compounds include tetramethylammonium and tetraethylammonium. 1-6 Alkyl ammonium, etc.

[0112] M is preferably a metal, more preferably an alkali metal or an alkaline earth metal, and even more preferably an alkali metal.

[0113] n can be chosen appropriately based on the valence of M, for example, it can be 1 or 2.

[0114] Examples of compounds represented by formula (3) include NaI, KI, CsI, MgI2, CaI2, NaBr, KBr, CsBr, MgBr2, CaBr2, NaCl, KCl, CsCl, MgCl2, CaCl2, etc.

[0115] The compound shown in formula (3) can be used alone or in combination of two or more.

[0116] The lower limit of the amount of compound used in formula (3) can be, for example, 0.1 moles, preferably 0.5 moles, and more preferably 0.9 moles, relative to 1 mole of the compound shown in formula (2).

[0117] The upper limit of the amount of compound used in formula (3) can be, for example, 10 moles, preferably 5 moles, and more preferably 3 moles, relative to 1 mole of the compound shown in formula (2).

[0118] The amount of compound used in formula (3) can be, for example, 0.1 to 10 moles, preferably 0.5 to 5 moles, and more preferably 0.9 to 3 moles, relative to 1 mole of the compound shown in formula (2).

[0119] R in equation (4) 6 X and R can each be R in equation (1) 6 The group corresponding to X.

[0120] Specific examples of compounds shown in formula (4) may include alcohols, phenols, and thiols. Examples of alcohols include methanol, ethanol, propanol (n-propanol, isopropanol), butanol, etc. 1-6 Alkyl alcohols, etc. Examples of phenols include phenol, cresol, and naphthol. Examples of thiols include methanethiol, ethanethiol, propanethiol (n-propanethiol, isopropanethiol), and butanethiol. 1-6 Alkyl thiols, etc.

[0121] The compound shown in formula (4) can be used alone or in combination of two or more.

[0122] The lower limit of the amount of compound used in formula (4) can be, for example, 0.1 moles, preferably 0.5 moles, and more preferably 0.9 moles, relative to 1 mole of the compound shown in formula (2).

[0123] The upper limit of the amount of compound used in formula (4) can be, for example, 10 moles, preferably 5 moles, and more preferably 3 moles, relative to 1 mole of the compound shown in formula (2).

[0124] The amount of compound used in formula (4) can be, for example, 0.1 to 10 moles, preferably 0.5 to 5 moles, and more preferably 0.9 to 3 moles, relative to 1 mole of the compound shown in formula (2).

[0125] In the reaction of step A, the compound shown in formula (4) can be used as a solvent, or other components besides the compound shown in formula (4) can be used as a solvent. When the compound shown in formula (4) is used as a solvent, it is preferable to use 10 moles or more relative to 1 mole of the compound shown in formula (2).

[0126] Other than the compounds shown in formula (4), examples of components include aliphatic hydrocarbons (e.g., hexane), aromatic hydrocarbons (e.g., toluene, xylene), halogenated hydrocarbons (e.g., dichloromethane, dichloroethane, chloroform), ethers (e.g., diethyl ether, tetrahydrofuran), ketones (e.g., acetone, methyl ethyl ketone), nitriles (e.g., acetonitrile), esters (e.g., ethyl acetate), and amides (e.g., dimethylformamide (DMF), dimethylacetamide (DMAc)).

[0127] In addition to the compound shown in formula (4), one or more components may be used alone or in combination.

[0128] In step A, there are no particular restrictions on the reaction temperature and reaction time, as long as the reaction can proceed.

[0129] The lower limit of the reaction temperature can be, for example, -70°C, preferably -20°C, and more preferably 0°C.

[0130] The upper limit of the reaction temperature can be, for example, 150°C, preferably 100°C, and more preferably 80°C.

[0131] The reaction temperature can be, for example, -70 to 150°C, preferably -20 to 100°C, and more preferably 0 to 80°C.

[0132] The lower limit of the reaction time can be, for example, 0.5 hours, preferably 1 hour, and more preferably 1.5 hours.

[0133] The upper limit of the reaction time can be, for example, 12 hours, preferably 10 hours, and more preferably 5 hours.

[0134] The reaction time can be, for example, 0.5 to 12 hours, preferably 1 to 10 hours, and more preferably 1.5 to 5 hours.

[0135] Step B In step B, the compound represented by formula (5) can be highly removed from the reaction mixture in step A.

[0136] M and n in equation (5) can correspond to M and n in equation (3), respectively.

[0137] Examples of compounds represented by formula (5) include NaF, KF, CsF, CaF2, etc.

[0138] The compound represented by formula (5) may be a compound with low solubility in water and / or organic solvents. The solubility at 20°C may be, for example, less than 100 g / L, preferably less than 80 g / L, and more preferably less than 50 g / L.

[0139] There are no particular limitations on the filtration method. It can generally be carried out using filter materials, and preferably using filter materials and filter aids. The method of using filter materials and filter aids can be, for example, pre-coat filtration (a method of filtration using a material on which a layer of filter aids is formed) or body feed filtration (a method of filtration by adding filter aids to the reaction mixture of step A).

[0140] As a filter material, it can be made of materials such as paper, metal (e.g., stainless steel), polymer (e.g., cellulose, polypropylene, polyester, polyamide), glass, ceramics, cloth, etc.

[0141] The filter material is preferably porous, such as a porous membrane or a porous filter.

[0142] The average pore size of the filter material is not particularly limited and can be, for example, 0.01 to 20 μm, preferably 0.01 to 15 μm, and more preferably 0.01 to 10 μm.

[0143] Examples of filter aids include diatomaceous earth (e.g., CELITE (trademark)), filter sand (e.g., manganese sand, manganese zeolite, activated carbon, anthracite, ceramic sand), perlite, and cellulose. A single filter aid can be used, or two or more can be used in combination. Diatomaceous earth is preferred as a filter aid.

[0144] The average particle size of the filter aid can be, for example, 0.5 to 200 μm, preferably 1 to 150 μm, and more preferably 1 to 100 μm.

[0145] There are no particular limitations on the filtration temperature (the internal temperature of the reaction mixture used for filtration). From the viewpoint of filtration efficiency, filtration is preferably carried out at room temperature or above.

[0146] The lower limit of the filtration temperature is preferably 45°C, more preferably 50°C, 55°C, 60°C, or 65°C.

[0147] The upper limit of the filtration temperature is preferably 90°C, more preferably 85°C, and even more preferably 80°C.

[0148] The filtration temperature is preferably above 45°C, and more preferably in the range of 45~90°C.

[0149] Filtration can be carried out under atmospheric pressure, under pressure, or under pressure, and can be carried out in a range of, for example, -2 to 2 MPa, preferably -1 to 1 MPa.

[0150] Step C The method for producing the compound shown in formula (1) preferably further includes step C, wherein the filtrate obtained by the aforementioned filtration is subjected to a liquid-liquid separation process. By combining steps B and C, the compound shown in formula (5) can be further removed.

[0151] Liquid separation typically includes the steps of adding water and organic solvent to the filtrate, separating the filtrate into an aqueous phase and an organic phase, and recovering the organic phase.

[0152] Examples of organic solvents used in liquid-liquid separation processes include aliphatic hydrocarbons (e.g., hexane), aromatic hydrocarbons (e.g., toluene, xylene), halogenated hydrocarbons (e.g., dichloromethane, dichloroethane), ethers (e.g., diethyl ether, tetrahydrofuran), ketones (e.g., methyl ethyl ketone), and esters (e.g., ethyl acetate).

[0153] One organic solvent may be used alone or in combination of two or more. Ethers are preferred as organic solvents.

[0154] The method for producing the compound shown in formula (1) may further include any other steps. Examples of other steps include, for instance, distillation, concentration, washing, or combinations of two or more of them.

[0155] <A composition containing the compound shown in formula (1) and the compound shown in formula (5)> In one embodiment, the composition is a composition containing the compound shown in formula (1) and the compound shown in formula (5), wherein the concentration of fluoride ions is greater than 0 mg / L and less than 1000 mg / L.

[0156] The upper limit of the concentration of fluoride ions can preferably be 900 mg / L, 800 mg / L, 700 mg / L, 600 mg / L, 500 mg / L, 400 mg / L, 300 mg / L, 200 mg / L, or 150 mg / L.

[0157] The lower limit of the concentration of fluoride ions contained is usually the detection limit or 0.001 mg / L.

[0158] The concentration of fluoride ions contained therein can be, for example, in the range of 0.001 to 1000 mg / L.

[0159] The composition may further contain the compound shown in formula (4).

[0160] The lower limit of the content of the compound represented by formula (4) in the composition may be, for example, the detection limit or 0.01 by mass.

[0161] The upper limit of the content of the compound represented by formula (4) in the composition can be, for example, 5% by mass, preferably 3% by mass.

[0162] The content of the compound represented by formula (4) in the composition can be, for example, less than 5% by mass, or in the range of 0.01 to 5% by mass.

[0163] Example The following describes one embodiment of the present disclosure in further detail through examples, but the present disclosure is not limited thereto.

[0164] [Example 1] Under ice-cold conditions, a solution of tetrafluorooxetine (75 wt% chloroform solution, 80 g, 0.462 mol) in ethanol (18.8 g) was added dropwise over 1 hour to a suspension of sodium iodide (69.3 g, 0.462 mol) in ethanol (60 g). After the addition, the mixture was heated to 50 °C and stirred for 2 hours. The resulting reaction mixture (internal temperature 50 °C) was filtered through a paper filter (average pore size 4.0 μm) and a filter aid (CELITE (trademark), average particle size 12–20 μm), and the ethanol was distilled off to obtain ICH₂CF₂COOEt (yield 90.8%).

[0165] ICH2CF2COOEt 1 H-NMR and 19 The F-NMR spectra are shown in the figures below. Figure 1 and Figure 2 .

[0166] [Comparative Example 1] Instead of filtration, water and diethyl ether were added to the reaction mixture for separation; otherwise, ICH2CF2COOEt was obtained by the same procedure as in Example 1.

[0167] [Example 2] After filtration, water and diethyl ether were added to the filtrate for separation; otherwise, ICH2CF2COOEt was obtained by the same procedure as in Example 1.

[0168] The concentration of F ions in the products of Example 1, Comparative Example 1 and Example 2 was determined by the following method.

[0169] 1. Weigh 1g of the sample in a plastic container.

[0170] 2. Weigh 1g of KOH into a plastic container and add distilled water to bring the total amount to 100g.

[0171] 3. Add 5g of the 1% KOH aqueous solution prepared in step 2 to the plastic container in step 1.

[0172] 4. Cover the plastic container from step 3 with the lid, mix, let stand, and then filter the supernatant into a disposable syringe equipped with a filter (0.45μm pore size).

[0173] 5. Take 1g of the filtrate obtained in step 4, add 5mL of distilled water to it, stir, extract 4mL of the upper layer, transfer it to another centrifuge precipitate tube, add 4mL of TISAB (Total Ionic Strength Adjustment Buffer) (Merck), stir and measure with an F ion meter.

[0174] The results of the F ion concentration determination are shown in the table below.

[0175] Table 1

[0176] [Example 3] Methanol was used instead of ethanol in Example 1; otherwise, the same operation as in Example 1 was performed to obtain ICH2CF2COOMe (yield 81.5%).

[0177] [Example 4] Sodium bromide was used instead of sodium iodide in Example 1, and the same procedures as in Example 1 were performed to obtain BrCH2CF2COOEt (yield 61.1%).

[0178] [Examples 5-8] 100g of the reaction mixture obtained in Example 1 was filtered under the conditions shown in Table 2. The filtration time is shown in Table 2.

[0179] Table 2

[0180] 1) Paper-based, average pore size 4.0 μm 2) CELITE (trademark), average particle size 12~20μm.

Claims

1. Method for manufacturing the compound shown in formula (1): In equation (1), R 1 It is an iodine atom; R 2 and R 3 It is a hydrogen atom; X is an oxygen atom; R 4 and R 5 It is a fluorine atom; R 6 C 1-6 alkyl, The manufacturing method includes: Step A, wherein the compound shown in formula (2) reacts with the compound shown in formula (3) and the compound shown in formula (4): In equation (2), R 2 ~R 5 This has the same meaning as the above. MR 1 (3) In equation (3), M is an alkali metal, R 1 This has the same meaning as the above. R 6 -X-H (4) In equation (4), R 6 X has the same meaning as described above; Step B, wherein the compound of formula (5) is separated from the mixture obtained from the above reaction by filtration: MF (5) In equation (5), M has the same meaning as described above; and Step C, wherein the filtrate obtained through filtration is subjected to a liquid-liquid separation process. The filtration is carried out at a temperature above 55°C. The separation process includes the steps of adding water and organic solvent to the filtrate, separating it into an aqueous phase and an organic phase, and recovering the organic phase.

2. The manufacturing method according to claim 1, wherein, The filtration is performed using filter media and filter aids.

3. The manufacturing method according to claim 2, wherein, The filter aid is selected from at least one of diatomaceous earth, filter sand, perlite and cellulose.

4. The manufacturing method according to claim 2, wherein, The average particle size of the filter aid is in the range of 0.5~200μm.

5. A composition comprising a compound of formula (1) and a compound of formula (5), wherein, The concentration of fluoride ions contained is greater than 0 mg / L and less than 150 mg / L. In equation (1), R 1 It is an iodine atom; R 2 and R 3 It is a hydrogen atom; X is an oxygen atom; R 4 and R 5 It is a fluorine atom; R 6 C 1-6 alkyl, MF(5) In equation (5), M is an alkali metal.

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