JP2019182800A - Manufacturing method of fluorine-containing methylthio substituted compound - Google Patents

Abstract

To provide a manufacturing method of a fluorine-containing methylthio substituted compound using a novel fluorine-containing methylthio group introduction agent.SOLUTION: A fluorine-containing methylthio introduction agent consisting of a bis(fluorine-containing methyl) zinc complex represented by the formula (1) Zn(CFR)L(1), wherein R represents a hydrogen atom or a fluoro group, and L represents an amine ligand, octathiocan, and quaternary ammonium salt or copper (I) salt, and a compound represented by the formula (2) Q-CH-X (2), wherein Q represents a substituted or unsubstituted hydrocarbon group in which a carbon atom bound to CH-X in the formula has SPhybrid orbital, and X represents a halogeno group, are reacted to manufacture a compound represented by the formula (3) Q-CH-SCFR (3), wherein Q and R represent same meaning as above.SELECTED DRAWING: None

Description

  The present invention relates to a method for producing a novel fluorine-containing methylthio-substituted compound.

Trifluoromethylthio group (CF ₃ S-) and difluoromethylthio group (CHF ₂ S-) are functional groups having strong electron withdrawing properties and high fat solubility, and are becoming increasingly important as partial structures of pharmaceuticals and agricultural chemicals. ing.

Various methods for introducing a trifluoromethylthio group into a substrate are known. For example, Non-Patent Document 1 reports that a secondary amino group in piperazine was trifluoromethylthiolated with trifluoromethanesulfenyl chloride (CF ₃ SCl). Non-Patent Document 2 reports that bis (methylsulfonyl) amine silver salt was trifluoromethylthiolated with CF ₃ SCl. Non-Patent Document 3 discloses the use of benzoyl (phenyliodonio) (trifluoromethanesulfonyl) methanide as an electrophilic trifluoromethylthiolation reagent. Non-Patent Document 4 reports a catalytic trifluoromethylthiolation reaction using N- (trifluoromethylthio) phthalimide.

Gupta et al., "(Trifluoromethyl) sulfeniy, (Trifluoromethyl) sulfinyl, and (Trifluoromethyl) sulfonyl Derivatives of Heterocyclic Amines" Inorg. Chem., Vol.24, No.14, 1985 2126-2129 Blaschette et al. "N-Sulfenyl-dimesylamine und (1-Sulfeny-4-dimethylaminopyridinium) -dimesylamide: Synthese neuer Verbindungen und Anwendung als Sulfenylierungsreagenzien" Chemiker-Zeitung, 115. Jahrgang (1991) Nr. 2 61-64 Shibata et al. "Trifluoromethanesulfonyl Hypervalent Iodonium Ylide for Copper-Catalyzed Trifluoromethylthiolation of Enamines, Indoles, and β-Keto Esters" J. Am. Chem. Soc., 2013, 135 (24), pp 8782-8785 Rueping et al. "Direct Catalytic Trifluoromethylthiolation of Boronic Acids and Alkynes Employing Electrophilic Shelf-Stable N- (trifluoromethylthio) phthalimide" Angew. Chem. Int. Ed. Vol.53, pp1650-1653, 2014

  An object of the present invention is to provide a method for producing a fluorine-containing methylthio-substituted compound using a novel fluorine-containing methylthio group-introducing agent.

  As a result of repeated studies to achieve the above object, the present invention including the following aspects has been completed.

[1] Formula (1)
Zn (CF ₂ R) ₂ L ₂ (1)
(In the formula, R represents a hydrogen atom or a fluoro group, and L represents an amine-based ligand.) A bis (fluorinated methyl) zinc complex, octathiocan, and a quaternary ammonium salt or copper ( I) a fluorine-containing methylthio group introducing agent comprising a salt;
Formula (2)
_Q-CH 2 -X (2)
(Wherein, Q is a carbon atom bonded to the CH 2 _-X in the formula is a carbon atom having a SP ² hybrid orbital, .X showing a substituted or unsubstituted hydrocarbon group, it shows a halogeno group. ) Is reacted,
Formula (3)
_{Q-CH 2 -SCF 2 R (} 3)
(Wherein Q and R have the same meanings as described above).
[2] The method according to [1] above, wherein the amine-based ligand is N, N′-dimethylpropyleneurea or tetramethylethylenediamine.

  The fluorine-containing methylthio group-introducing agent of the present invention can produce fluorine-containing methylthiolated hydrocarbons by reacting with easily available halogenated hydrocarbons.

[Fluorine-containing methylthio group introduction agent]
The fluorine-containing methylthio group introducing agent of the present invention has the formula (1)
Zn (CF ₂ R) ₂ L ₂ (1)
(In the formula, R represents a hydrogen atom or a fluoro group, and L represents an amine-based ligand.) A bis (fluorinated methyl) zinc complex, octathiocan, and a quaternary ammonium salt or copper (I ) Made of salt.

  The bis (fluorinated methyl) zinc complex represented by the formula (1) of the present invention reacts a dialkylzinc, trifluoromethyl halide or difluoromethyl halide, and an amine-based ligand in an organic solvent for a predetermined time. Then, the solid obtained by filtering the residue or distilling off the solvent is produced by washing with a solvent such as diethyl ether inert to the bis (fluorinated methyl) zinc complex and drying. As a specific production method, the method described in Non-Patent Document 1 can be exemplified.

As the amine-based ligand used in the present invention, N, N-dimethylformamide (hereinafter sometimes referred to as “DMF”), N, N′-dimethylpropylene urea (hereinafter referred to as “DMPU”). And tetramethylethylenediamine (hereinafter sometimes referred to as “TMEDA”).
DMPU or TMEDA is preferable.

The quaternary ammonium salt used in the present invention can be represented by the following formula (A).
R ₄ N ⁺ X ⁻ (A)
In formula (A), each R independently represents a C1-8 alkyl group or a benzyl group. X ⁻ represents an anion.
As C1-8 alkyl group, methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, s-butyl group, i-butyl group, t-butyl group, n-pentyl group, n -A hexyl group, n-heptyl group, n-octyl group, etc. can be mentioned.
Examples of the anion include a fluoride anion, a chloride anion, a bromide anion, an iodide anion, an acetate anion, a borate anion, a sulfate anion, a phosphate anion, and a thiocyanate anion.

  Specific examples include tetrabutylammonium acetate, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium fluoride, tetrabutylammonium iodide, and tetrabutylammonium thiocyanate.

  Specific examples of the copper (I) salt used in the present invention include copper acetate (I), copper (I) bromide, copper (I) chloride, copper (I) iodide, and copper (I) thiocyanate. Can be mentioned.

  When using a copper (I) salt, a nitrogen-containing bidentate ligand can be further added. The nitrogen-containing bidentate ligand that can be added is not limited as long as it is a nitrogen-containing compound that is bidentately coordinated to the copper (I) salt. Specifically, 2,2′-bipyridyl, 4,4′-t-butyl-2,2′-bipyridyl, 1,10-phenanthroline, methylenebisoxazoline, N, N′-tetramethylethylenediamine and the like can be mentioned. .

[Compound represented by Formula (2)]
The compound used as the raw material of the present invention is a compound represented by the following formula (2).
_Q-CH 2 -X (2)

Q represents a substituted or unsubstituted hydrocarbon group in which the carbon atom bonded to CH ₂ —X in the formula is a carbon atom having an SP ² hybrid orbital.
X represents a halogeno group such as a fluoro group, a chloro group, a bromo group, or an iodo group.

Examples of the carbon atom having an SP ² hybrid orbital include a carbon atom of a carbonyl group, a carbon atom in an aromatic ring, and a carbon atom in a vinyl group.
Examples of the hydrocarbon group having such a carbon atom include C6-10 aryl groups such as phenyl and naphthyl groups; styryl groups; C6-10 arylcarbonyl groups such as benzoyl groups; C1 such as acetyl groups and propionyl groups. -6 alkylcarbonyl groups; C2-6 alkenylcarbonyl groups such as acrylic groups and methacryl groups; C1-6 alkoxycarbonyl groups such as methoxycarbonyl groups and t-butoxycarbonyl groups; and the like.

Such hydrocarbon groups may be substituted. Examples of groups that can be “substituents” are given below.
C1-6 such as methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, s-butyl group, i-butyl group, t-butyl group, n-pentyl group and n-hexyl group An alkyl group;
Vinyl group, 1-propenyl group, 2-propenyl group (allyl group), 1-butenyl group, 2-butenyl group, 3-butenyl group, 1-methyl-2-propenyl group, 2-methyl-2-propenyl group, etc. A C2-6 alkenyl group of
C2-6 alkynyl groups such as ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, 1-methyl-2-propynyl group;

A C3-8 cycloalkyl group such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a cubanyl group;
A C6-10 aryl group such as a phenyl group or a naphthyl group;
A C6-10 aryl C1-6 alkyl group such as a benzyl group or a phenethyl group;
A 3-6 membered heterocyclyl group;
A 3-6 membered heterocyclyl C1-6 alkyl group;

C1-6 alkoxy groups such as methoxy group, ethoxy group, n-propoxy group, i-propoxy group, n-butoxy group, s-butoxy group, i-butoxy group, t-butoxy group;
C6-10 aryloxy groups such as phenoxy group and naphthoxy group;
A C6-10 aryl C1-6 alkoxy group such as a benzyloxy group or a phenethyloxy group;
5- to 6-membered heteroaryloxy group such as thiazolyloxy group and pyridyloxy group;
5- to 6-membered heteroaryl C1-6 alkyloxy group such as thiazolylmethyloxy group, pyridylmethyloxy group;

Formyloxy group;
A C1-6 alkylcarbonyloxy group such as an acetyloxy group or a propionyloxy group;
C1-6 alkoxycarbonyl groups such as methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, i-propoxycarbonyl group, n-butoxycarbonyl group, t-butoxycarbonyl group;
A C1-6 alkoxycarbonyloxy group such as a methoxycarbonyloxy group, ethoxycarbonyloxy group, n-propoxycarbonyloxy group, i-propoxycarbonyloxy group, n-butoxycarbonyloxy group, t-butoxycarbonyloxy group;

Halogeno groups such as fluoro, chloro, bromo and iodo groups;
C1-6 haloalkyl groups such as chloromethyl group, chloroethyl group, trifluoromethyl group, 1,2-dichloro-n-propyl group, 1-fluoro-n-butyl group, perfluoro-n-pentyl group;
A C1-6 haloalkoxy group such as a trifluoromethoxy group, a 2-chloro-n-propoxy group, or a 2,3-dichlorobutoxy group;

Formylamino group;
A C1-6 alkylcarbonylamino group such as an acetylamino group, a propanoylamino group, a butyrylamino group, an i-propylcarbonylamino group;
A C1-6 alkoxycarbonylamino group such as a methoxycarbonylamino group, an ethoxycarbonylamino group, an n-propoxycarbonylamino group, an i-propoxycarbonylamino group;
An aminocarbonyl group having no substituent or a substituent such as an aminocarbonyl group, a dimethylaminocarbonyl group, a phenylaminocarbonyl group, an N-phenyl-N-methylaminocarbonyl group;

C1-6 alkylthio groups such as methylthio group, ethylthio group, n-propylthio group, i-propylthio group, n-butylthio group, i-butylthio group, s-butylthio group, t-butylthio group;
A C1-6 haloalkylthio group such as a trifluoromethylthio group or a 2,2,2-trifluoroethylthio group;
A C1-6 alkylsulfonyl group such as a methylsulfonyl group, an ethylsulfonyl group, a t-butylsulfonyl group;
A C1-6 haloalkylsulfonyl group such as a trifluoromethylsulfonyl group or a 2,2,2-trifluoroethylsulfonyl group;

A tri-C1-6 alkyl-substituted silyl group such as a trimethylsilyl group, a triethylsilyl group, or a t-butyldimethylsilyl group;
A tri-C6-10 aryl-substituted silyl group such as a triphenylsilyl group;
Cyano group; nitro group;

  In these “substituents”, any hydrogen atom in the substituent may be substituted with a group having a different structure. In this case, examples of the substituent include a C1-6 alkyl group, a C1-6 haloalkyl group, a C1-6 alkoxy group, a C1-6 haloalkoxy group, a halogeno group, a cyano group, and a nitro group.

In addition, the “3 to 6-membered heterocyclyl group” includes 1 to 4 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom as ring constituent atoms. The heterocyclyl group may be monocyclic or polycyclic. In the polycyclic heterocyclyl group, when at least one ring is a hetero ring, the remaining ring may be a saturated alicyclic ring, an unsaturated alicyclic ring or an aromatic ring. Examples of the “3-6 membered heterocyclyl group” include a 3-6 membered saturated heterocyclyl group, a 5-6 membered heteroaryl group, a 5-6 membered partially unsaturated heterocyclyl group, and the like.
Examples of the 3-6 membered saturated heterocyclyl group include aziridinyl group, epoxy group, pyrrolidinyl group, tetrahydrofuranyl group, thiazolidinyl group, piperidyl group, piperazinyl group, morpholinyl group, dioxolanyl group, dioxanyl group and the like.
Examples of 5-membered heteroaryl groups include pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, etc. be able to.
Examples of the 6-membered heteroaryl group include a pyridyl group, a pyrazinyl group, a pyrimidinyl group, a pyridazinyl group, and a triazinyl group.

[Compound represented by Formula (3)]
The compound represented by the following formula (3) corresponds to the fluorine-containing methylthio-substituted compound obtained by the production method of the present invention.
_{Q-CH 2 -SCF 2 R (} 3)

  In the formula, Q and R have the same meaning as described above.

[Method for producing fluorine-containing methylthio-substituted compound]
The fluorine-containing methylthio group introducing agent used in the present invention comprises a bis (fluorinated methyl) zinc complex represented by the above formula (1), octathiocan, and a quaternary ammonium salt or copper (I) salt.
If the fluorine-containing methylthio group introducing agent is in a state where the compounds constituting the fluorine-containing methylthio group introducing agent coexist in the reaction system, the target fluorine-containing methylthio-substituted compound can be produced.
Therefore, it is only necessary to previously mix the compound constituting the fluorine-containing methylthio group introducing agent in the reaction system.

The amount of the compound used is as follows.
The amount of the bis (fluorinated methyl) zinc complex used is, for example, in the range of 1.0 to 4.0 mol with respect to 1 mol of the compound represented by the formula (2) of the raw material, preferably 2 The range is from 0.0 to 3.2 mol.
The amount of octathiocan used is, for example, in the range of 1.0 to 2.0 mol, preferably in the range of 1.0 to 1.2 mol, with respect to 1 mol of the bis (fluorinated methyl) zinc complex. is there.
The amount of the quaternary ammonium salt or copper (I) salt to be used is, for example, in the range of 0.1 to 1.0 mol, preferably 0, per 1 mol of the compound represented by the formula (2). The range is from 2 to 0.5 mol.
When a nitrogen-containing bidentate ligand is further added when using the copper (I) salt, the amount of the nitrogen-containing bidentate ligand used is, for example, 1.0 mol per 1 mol of the copper (I) salt. The range of -2.0 mol is mentioned, Preferably, it is the range of 1.0-1.2 mol.

The reaction can be performed without using a solvent if the compound represented by the formula (2) as a raw material is liquid, but considering the operability, the reaction is preferably performed in an organic solvent. The organic solvent is not particularly limited as long as it is inert to the compound represented by the formula (2). For example, ethers such as diethyl ether, diisopropyl ether, diethylene glycol dimethyl ether (product name: diglyme), tetrahydrofuran (abbreviation: THF); halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane (abbreviation: DCE) Aliphatic hydrocarbons such as pentane, hexane, cyclohexane, heptane and octane; Aromatic hydrocarbons such as toluene and xylene; N, N-dimethylformamide (abbreviation: DMF), N, N′-dimethylpropylene Aprotic polar solvents such as urea (abbreviation: DMPU) and hexamethylphosphoric triamide (abbreviation: HMPA) can be given.
The amount of the organic solvent used is 10 to 500 parts by weight with respect to 1 part by weight of the compound represented by the formula (2).

The reaction is carried out by preparing a mixed solution of the compound constituting the fluorine-containing methylthio group introducing agent and the compound represented by the formula (2), and stirring the mixture at 40 ° C. to 80 ° C. for 6 to 24 hours. Can do. Considering the stability of the bis (fluorinated methyl) zinc complex, the reaction temperature is preferably in the range of 50 ° C to 70 ° C. The reaction system is preferably an inert gas atmosphere.
After completion of the reaction, a difluoromethyl-substituted compound having a desired purity can be obtained by purification according to a conventional method.

  Hereinafter, the present invention will be described more specifically with reference to examples. In addition, this invention is not limited by the following Example.

Example 1
Preparation of 2-((trifluoromethylthio) methyl) naphthalene

In a reaction vessel equipped with a stir bar at room temperature under an argon atmosphere, Zn (CF ₃ ) ₂ (DMPU) ₂ (96 mg, 0.2 mmol), octathiocan (6.4 mg, 0.2 mmol), tetrabutylammonium acetate ( 12.0 mg, 0.04 mmol), dichloroethane (1.0 mL), and 2-bromomethylnaphthalene (22 mg, 0.1 mmol) were added.
Then, the obtained mixture was stirred at 70 ° C. for 6 hours, and triethylamine (1 mL) was added to stop the reaction. After stopping the reaction, the mixture was further stirred at 70 ° C. for 1 hour, and water (5 mL) was added. After separating the organic layer, the remaining aqueous layer was further subjected to liquid separation treatment with ether (5 mL) three times. The ether layer and the organic layer were combined, washed with brine (10 mL), and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain a crude product. The crude yield determined by ¹⁹ FNMR using trifluoromethylbenzene as an internal standard was 82%. The crude product was produced by silica gel chromatography (solvent: pentane) to obtain the desired product (84%, 20.3 mg).
¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.85-7.82 (m, 4H), 7.51-7.42 (m, 3H), 4.29 (s, 2H).
¹⁹ F-NMR (282 MHz, CDCl ₃ ) δ -41.5 (s, 3F).

  The following compounds were produced by the same method.

Trifluoromethylthiomethylbenzene Crude yield: 83%, isolated yield: 81%
¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.36-7.30 (m, 5H), 4.12 (s, 2H).
¹⁹ F-NMR (282 MHz, CDCl ₃ ) δ -41.7 (s, 3F).

4-t-butyl- (trifluoromethylthio) methylbenzene Crude yield: 57%, isolated yield: 57%
¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.37 (d, J = 8.4 Hz, 2H), 7.27 (d, J = 7.9 Hz, 2H), 4.11 (s, 2H), 1.32 (s, 9H).
¹⁹ F-NMR (282 MHz, CDCl ₃ ) δ -41.7 (s, 3F).

2-trifluoromethylthio-4 ′-(trifluoromethyl) acetophenone Crude yield: 51%, isolated yield: 42%
¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.07 (d, J = 8.0 Hz, 2H), 7.79 (d, J = 8.2 Hz, 2H), 4.50 (s, 2H).
¹⁹ F-NMR (282 MHz, CDCl ₃ ) δ -41.4 (s, 3F, SCF ₃ ), -63.0 (s, 3F, CF ₃ ).

Benzyl 2- (trifluoromethylthio) acetate Crude yield: 52%, isolated yield: 49%
¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.89-7.35 (m, 5H), 5.21 (s, 2H), 3.71 (s, 2H).
¹⁹ F-NMR (282 MHz, CDCl ₃ ) δ -42.7 (s, 3F).

Example 2
Production of 2- (difluoromethylthio) -4′-methoxyacetophenone

In a reaction vessel equipped with a stir bar at room temperature, octathiocan (9.6 mg, 0.3 mmol), copper iodide (3.8 mg, 0.02 mmol), 1,10-phenanthroline (3.6 mg, 0.02 mmol). ), 2-bromo-4′-methoxyacetophenone (23 mg, 0.1 mmol), and Zn (CF ₂ H) ₂ (TMEDA) ₂ (0.30 to 0.40 M dichloroethane solution, 0.8 to 1.0 mL, 0.3 mmol) was added.
Then, the obtained mixture was stirred at 50 ° C. for 6 hours, and water (5 mL) was added to stop the reaction. After stopping the reaction, liquid separation treatment was performed with ether (5 mL), and the aqueous layer was further subjected to liquid separation treatment with ether (5 mL) three times. The ether layer was washed with brine (10 mL) and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain a crude product. The crude yield determined by ¹⁹ FNMR using trifluoromethylbenzene as an internal standard was 41%.
¹⁹ F-NMR (282 MHz, C ₆ D ₆ ) δ -94.6 (d, J = 56.0 Hz, 2F).

Claims (2)

Formula (1)
Zn (CF ₂ R) ₂ L ₂ (1)
(In the formula, R represents a hydrogen atom or a fluoro group, and L represents an amine-based ligand.) A bis (fluorinated methyl) zinc complex, octathiocan, and a quaternary ammonium salt or copper ( I) a fluorine-containing methylthio group introducing agent comprising a salt;
Formula (2)
_Q-CH 2 -X (2)
(Wherein, Q is a carbon atom bonded to the CH 2 _-X in the formula is a carbon atom having a SP ² hybrid orbital, .X showing a substituted or unsubstituted hydrocarbon group, it shows a halogeno group. ) Is reacted,
Formula (3)
_{Q-CH 2 -SCF 2 R (} 3)
(Wherein Q and R have the same meanings as described above).   The method according to claim 1, wherein the amine-based ligand is N, N'-dimethylpropyleneurea or tetramethylethylenediamine.