WO1997032835A1

WO1997032835A1 - Process for producing fluorine compounds

Info

Publication number: WO1997032835A1
Application number: PCT/JP1997/000706
Authority: WO
Inventors: Toshikazu Simizu; Atsusi Nagaoka; Mitsuo Oda; Chiaki Seki; Tsuneo Yamashita; Kazuhiro Shimokawa
Original assignee: Eisai Chemical Co., Ltd.; Daikin Industries, Ltd.
Priority date: 1996-03-07
Filing date: 1997-03-07
Publication date: 1997-09-12
Also published as: JPH09241190A; JP3759649B2

Abstract

A process for producing benzyl fluoride derivatives represented by general formula (II), wherein R1 represents hydrogen, lower alkyl, etc.; R2 represents hydrogen, piperazinyl, piperidyl, pyrrolidinyl, morpholinyl, amino or heteroaryl; and R?3 and R4¿ represent each hydrogen, halogeno, cyano, lower alkyl, or lower alkoxy, which comprises reacting a benzyl alcohol derivative represented by general formula (I), with N,N-diethyl-1,1,2,3,3,3-hexafluoropropylamine in the presence of a tertiary amine and hydrogen fluoride. This process permits fluorine compounds to be producedas efficiently as by the fluorination using DAST by inhibiting the formation of olefins and ethers as by-products.

Description

Specification

Manufacturing method of fluoro compounds Industrial application

The present invention relates to a fluoro compound useful as an intermediate of a drug (for example,

More specifically, the alcoholic hydroxyl group is fluorinated with N, N-getyl-1,1.2,3,3.3-hexafluoropropylamine or an analog thereof to obtain a fluoro compound. And a method for producing the same.

Conventional technology

Various fluorinating agents have been developed and used to obtain fluoro compounds by fluorinating various compounds. For example, fluorine (F ₂ ), hydrogen fluoride (HF), tetraalkylammonium fluoride (Bu ₄ N ⁺ F_, etc.), alkali metal fluorides (KF, CsF, etc.) have been used for a long time. Is a fluorinating agent. In recent years, monopyridine hydrofluoride (Olar reagent) and (C ₂ H ₅ ) ₂ NSF ₃ (DAST) have been widely used at the research stage because many compounds can be fluorinated efficiently.

For example, the following reaction formula:

It is known that the hydroxyl group can be replaced by a fluorine atom according to When DAST is used as a fluorination reagent for this fluorination, a product can be obtained with high selectivity. The force, and, SF ₄ is a non-which is the raw material of DAST It is always dangerous (highly toxic), it is difficult to secure enough DAST for industrial use, and it is very expensive. In addition, DAST is unstable at room temperature and produces explosive substances over time, which imposes many restrictions on the storage and use of DAS, which also limits its use on an industrial scale.

It is conceivable to use Ν, Ν-getyl-1,1,2,3,3,3-hexafluoropropylamine (so-called Ishikawa reagent) as a fluorinating reagent instead of DAST. In fact, when Ν. Ν-ethyl-1,1,2,3,3,3-hexafluoropropylamine is used in the above reaction, it does not proceed with hydrofluoric anhydride or hydrofluoric acid / amine reagent, or Even if it proceeds, the above fluorination reaction, in which side reactions take precedence, proceeds in high yield. In addition, Ν, Ν-Jetyl-1,1,2,3,3.3-hexafluoropropylamine is cheaper and more stable than DASΤ, so it can be fluorinated on an industrial scale. Suitable for. Furthermore, the selectivity of fluorinated products is higher than that of fluorinating agents other than DAST. However, even if the above reaction was carried out using Ν, Ν-getyl-1,1,2,3,3,3-hexafluoropropylamine, about 20% of the by-product olefin compound was produced, Hinders the reaction. It is also known that when the reaction is carried out using other starting materials, an ether form is formed together with the olefin form (Ishikawa et al., Bull.Chein. Soc. J APAN), 52 (11), 3377 ( 1979)].

Summary of the Invention

An object of the present invention is to produce a fluoro compound by fluorination using N, N-getyl-1,1,2,3,3,3-hexafluoropropylamine, which is a by-product, an olefin compound to an ether compound. An object of the present invention is to provide a method for suppressing the formation of fluorinated compounds and producing a fluoro compound as efficiently as fluorination using DAST. In the present invention, in order to achieve the above object, hydrogen fluoride and a tertiary amino acid are used together with a fluorinating agent, NN-ethyl-1,1,2.3,3.3-hexafluoropropylamine or an analog thereof. The fluorination is performed using

That is, according to a first aspect, the present invention provides a compound represented by the general formula (I):

(In the formula, R ¹ represents a hydrogen atom, a lower alkyl group, lower alkenyl group, halogenation lower alkyl group, a lower alkoxyalkyl group, a lower Arukokishikaru Boniruarukiru group, Shiano lower alkyl group or Ararukiru group: R ² is A hydrogen atom, an optionally substituted piperazinyl group, a piperidyl group, a pyrrolidinyl group, a morpholinyl group, an optionally substituted amino group or a heteroaryl group; R ³ and R ⁴ are the same or different and are each a hydrogen atom Represents a halogen atom, a cyano group, a lower alkyl group or a lower alkoxy group.) The benzyl alcohol derivative represented by the formula (1) is reacted with tertiary amine, especially triethylamine and hydrogen fluoride in the presence of N, N-ethyl-1,1, General formula (II) characterized by reacting with 1,2,3,3,3-hexafluoropropylamine.

(Wherein, RR ² , R ³ and R ⁴ are as defined above.)

To provide a method for producing a benzyl fluoride derivative represented by According to a second aspect, the present invention provides a compound represented by the general formula (III):

Ru _{R 1 2 R} i 3 _COH (ΙΠ)

(In the formula,! ^ Is the same or different, and represents a hydrogen atom or a halogen atom, an alkoxy group, an amino group, an amide group, a nitro group, a cyano group, a carbonyl group, a carboxyl group, a thiol group, An alkyl group having 1 to 20 carbon atoms, an alkenyl group having 2 to 20 carbon atoms, an allene group, an aryl group, a carbon atom having 6 to 6 carbon atoms, which may be substituted with a thioether group, a sulfonyl group, a sulfoxide group or a phosphonyl group. Represents an aryl group of 20 or a hetero ring containing N, 0 or S, provided that R ¹¹ and R ¹² may together form a saturated or unsaturated 3- to 8-membered ring, and R ¹³ is hydrogen Atom or halogen atom, alkoxy group, amino group, amide group, nitro group, cyano group, carbonyl group, carboxyl group, thiol group, thioether group, sulfonyl group, Represents an alkyl group, an alkenyl group, an allene group, an aryl group, an aryl group, or a heterocyclic ring containing N, 0 or S, having 1 to 20 carbon atoms, which may be substituted by a hydroxide group or a phosphonyl group. However, when R ¹¹ and R ¹² are both hydrogen atoms, R ¹³ is not a hydrogen atom, and R ¹³ forms a saturated or unsaturated 3- to 8-membered ring together with R ¹¹ and R ¹² May be.)

Reacting the alcohol represented by the formula (II) with Ν, Ν-diethyl-1,1,2,3,3,3-hexafluoropropylamine or its analog in the presence of hydrogen fluoride and tertiary amine. General formula (IV):

_R n _{R 1 2 R} i 3 _CF (IV)

(Wherein, R ¹ R ¹² and R ¹³ have the same meanings as described above.).

According to a third aspect, the present invention relates to N, N-Jetyl-1.1,2,3,3,3-hexafluoropropylamine or an analog thereof, hydrogen fluoride and Provided is a fluorinated reagent composition comprising gradeamine.

Detailed description of the invention

In the present invention, the lower alkyl group is, for example, a carbon atom such as a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a t-butyl group, a pentyl group, and a hexyl group. It is an alkyl group of numbers 1 to 6.

The lower alkenyl group is, for example, an alkenyl group having 2 to 6 carbon atoms such as a vinyl group, a propenyl group and a butenyl group.

The halogenated lower alkyl group is, for example, a fluoroalkyl group, a difluoromethyl group, a trifluoromethyl group, a fluoroethyl group, a fluoropropyl group, a cyclobutyl group, a cyclopentyl group, etc., wherein the lower alkyl group is one or more halogen atoms. It is a substituted group.

The lower alkoxyalkyl group is a group in which the lower alkyl group such as a methoxymethyl group, a methoxyethyl group, a methoxypropyl group and the like is substituted by a lower alkoxy group having 1 to 6 carbon atoms.

The lower alkoxycarbonylalkyl group is an alkoxycarbonylalkyl group having 3 to 10 carbon atoms as a whole, such as a methoxycarbonylmethyl group, an ethoxyquincarbonylethyl group, a t-butoxycarbonylmethyl group, and the like.

The cyano lower alkyl group is a group in which the lower alkyl group is substituted with one or more cyano groups, such as a cyanomethyl group and a cyanoethyl group.

Examples of the aralkyl group include an aralkyl group having 7 to 16 carbon atoms such as a benzyl group, a methylbenzyl group, a phenyl group, and a phenylpropyl group. Examples of the piperazinyl group which may be substituted include, for example, 4- (t-butoxycarbonyl) piperazine-11-yl group, 4-benzyloxycarbonyl piperazine-11-yl group, 4-ethoxycarbonylpi Perezin 1-yl Group, 4-benzylpiperazine-l-yl group, 4-formylpiperazine-l-yl group, 4-acetylbiperazine-l-yl group, 4-benzylbiperazine-l-yl group, 4-l (p- Nitrobenzoyl) piperazine-1-yl group, 4-methanesulfonylbiperazine-11-yl group, 4- (p-toluenesulfonyl) piperazine-1-yl group, 4-arylpiperazine-11-yl group, 4 One-year-old xypiperazine-11-yl group, 4-trimethylsilylpiperazin-1-yl group and other piperazine-11-yl groups in which an atom group usually used as a protecting group for an amino group is bonded to the 4-position. is there.

Examples of the heteroaryl group include an imidazolyl group, a thiazolyl group, an oxazolyl group, a pyridyl group, and a virazyl group.

Examples of heterocycles containing N, 0 or S include:

Can be mentioned.

N, N—Jetyloo 1,1,2,3,3,3-hexafluorov mouth pyramine and its analogs are generally

Formula: XCFH—CF ₂ NR ₂

(In the formula, X represents a trifluoromethyl group or a halogen atom, particularly a fluorine atom or a chlorine atom, and R represents a lower alkyl group. However, two Rs are, together with the nitrogen atom to which they are bound, a ring May be formed.), Formula: R 'NS F ₃ (In the formula, R ′ represents a lower alkyl group. However, two R ′s may form a ring together with the nitrogen atom to which they are attached.)

Formula: R "SF ₃

(In the formula, R "represents a fluorine atom or an aryl group, preferably a phenyl group.)

Formula: R PF ₅ - _X

(In the formula, R ′ ″ represents an aryl group, preferably a phenyl group, and X represents 1, 2, or 3.)

Compound represented by

Or SeF ₄ .

N, N-Jetyl-1.1,2,3,3,3-hexafluoropropylamine or a tertiary amine used with an analog thereof is not particularly limited, and a wide range of known tertiary amines is used. You can choose from.

Particularly preferred tertiary amines are the amines shown below:

QL00 / L6d £ llDd SC8 / "Ο

Preferred examples of N, N-getyl-1,1,2,3,3,3-hexafluoropropylamine or analogs thereof are as follows:

d. £ 0j. One d >> "n,

dMd "

In the production method of the present invention, the proportions of N, N-ethyl-1,1,2,3,3,3-hexafluoropropylamine or its analogs, hydrogen fluoride and tertiary amine are as follows. It is as follows.

N, N Jethyl, 1, 1.2, 3.3, 3-hexa Fluoropropylamine or an analog thereof can be used in an amount of 1 to 10 equivalents. N-N-Jetyl-1,1,2,3,3,3-hexafluoropropylamine or its analogs consist of hydrogen fluoride and tertiary amine per mole of the analog The complex can be used in an amount of 0.3 to 30 mol, preferably 1 to 20 mol. The molar ratio between hydrogen fluoride and tertiary amine is 10: 1 to 1: 1 and preferably 5: 1 to 1: 1.

Among the benzyl alcohols represented by the formula (I) used as a starting material in the first production method of the present invention, preferred are compounds in which R ¹ is a lower alkyl group and R ² is an optionally substituted piperazinyl. Or a piperidyl group, benzyl alcohol of the formula (I) wherein R ³ is a hydrogen atom, a halogen atom or a lower alkyl group, and R ⁴ is a hydrogen atom, a halogen atom or a lower alkoxy group.

Further preferred compounds are those of formula (I) wherein R ¹ is a lower alkyl group, R ² is an optionally substituted piperazinyl group, and R ³ and R ⁴ are the same or different halogen atoms. Jil alcohol.

The most preferred compounds are those in which R ¹ is an ethyl group, R ² is a 4- (t-butoxy) carborylbiperazine-1-yl group, R ³ is a bromine atom, and R ⁴ is a chlorine atom. A benzyl alcohol of the formula (I). The most preferred compound is a benzyl alcohol of the formula (I) in which R ¹ is an optically active substance consisting of an atomic group selected from other than a hydrogen atom. It has been difficult to stereospecifically obtain a desired benzyl fluoride derivative reflecting the optical purity of the raw material by the conventional fluorination technology of secondary benzyl alcohol. That is, a decrease in the optical purity due to the reaction was inevitable. However, in the present invention, the benzyl fluoride derivative can be stereospecifically obtained without racemization by almost completely reversing the configuration of the alcohol. Among the alcohols represented by the formula (ΠΙ) used as starting materials in the second production method of the present invention, preferred alcohols are the following alcohols:

The reaction conditions in the production method of the present invention are as follows.

The reaction is preferably performed in the absence of moisture.

The reaction temperature depends on the reactivity of the starting materials, and is preferably between 100 ° C and 150 ° C, preferably between 78 ° C and 100 ° C, more preferably between 78 ° C and 50 ° C. You can choose from a range.

The reaction pressure depends on the state of the starting material at the reaction temperature (either solid or gaseous) and can be used from depressurization to pressurization, but atmospheric pressure or pressurization due to the simplicity of the reactor. For example, pressures up to 10 atmospheres are preferred.

The reaction can be performed either in the presence or absence of a solvent. When a solvent is used, hydrocarbons, ethers, halogenated hydrocarbons, nitriles, amides, alkylsulfoxides, etc. can be used. Preferred solvents are pentane, hexane, benzene, toluene, xylene, petroleum benzene, petroleum ether. , Dimethyl ether, isopropyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, chloroform, methylene chloride, trichloroethylene, acetonitrile, Ν, Ν-dimethylformamide, dimethylsulfoxide, hexamethylphosphonamide. .

ADVANTAGE OF THE INVENTION According to the manufacturing method of this invention, generation | occurrence | production of the by-product olefin body-ether form is suppressed, and a fluoro compound can be manufactured as efficiently as the fluorination using DAST. Further, since the fluorinated reagent composition of the present invention is very inexpensive, very stable and has no danger in handling, the use of the fluorinated reagent composition is safe and industrially desirable on a industrial scale. Compounds can be manufactured.

Example

Hereinafter, the present invention will be described specifically with reference to Examples.

Example 1 1-Fluoro-1-phenylpropane

Hexafluoropropene-Jethylamine (200 mg, 0.46 mmo 1) and Triethylfluorinated triethylamine (5 66 mg, 3.52 mmol) and double-mouthed form (1. Oml) were added and stirred under ice-cooling. To this was added 60 mg (0.44 mmo 1) of 1-phenyl-1-propanol, and the mixture was stirred for 3 hours. After terminating the reaction by adding water, the reaction solution is washed with saturated saline, dried over sodium sulfate, and dried with sodium fluoride in a yield of 81%, methylstyrene in a yield of 4%, methylstyrene in a yield of 4%, and a yield of 6%. With this, di (1-phenylpropane-1-yl) ether was obtained. The yield was determined from the integrated value of ¹⁹ F—NM R.

1-Fluoro-1-phenylpropane

'H-NMRCCDC, TMS): 7.39 (s.5H), 5.46 (ddd, 1 H, J FH1 = 56.7H z), 1.92 (m, 2H), 0.91 (t, 3 H. J = 8. 0 Hz ).

^{_{19 F-NMR (CDC1 3,}} F - 11):. -173 0 (ddd, 1 F, J FH1 = 56.7H z, J FH 2 = 26.5H z, J FH3 = 23.7 H z).

Example 2 (1-Fluoroethyl) benzene

Sec monophenethyl alcohol (54 mg (0.44 mmo 1)) was used to produce (1-fluoroethyl) benzene in a yield of 94% in the same manner as in Example 1.

(1—Fluoroethyl) Benzene

^ -NMRCCDC, TMS): 7.36 (s, 5H), 5.63 (qd, 1H, J FH, = 47.4 Hz, J = 7.2 Hz), 1.65 (dd, 3H), 0.9 l (t,

¹⁹ F-NMR (CDCI3, F-11):-167.5 (qd, 1H, J FHI =

Example 3-Fluent mouth

Same as Example 1 from benzyl alcohol 48 mg (0.44 mmo 1) As a result, α-fluorotoluene was obtained at a yield of 83%, and dibenzyl ether was obtained at a yield of 9%.

a-Fluoro toluene

'H-NMRCCDCls. TMS): 7.39 (s, 5H), 5.36 (d, 2H,

^{_{19 F-NMR (CDC1 3,}} F - 1 1): - 207.2 (t, 1 F, J F "= 47. 7Hz).

Comparative Examples 1-3

In each of Examples 1 to 3, the same operation was carried out except that only hexafluoropropenediethylamine (200 mg, 0.46 mmo 1) was used as the fluorinating agent, and the yields of fluorinated compounds and ethers were obtained. I asked.

Table 1 shows the results of Examples 1 to 3 and Comparative Examples 1 to 3.

table 1

Notes: 1) Ishikawa's reagent: N, N—Jetyl, 1,1,2,3,3,3-hexafluorolob pyramine

Examples 4 to 9 and Comparative Example 4

1- [3-Bromo-5- (4-tert-butoxycarbylbiperazine-1-inole) -1 2-Chlorophenyl] -1 1-Fluoropropane

The reactor is charged with the molar equivalent of tris-fluoric acid described in Table 2 and the molar equivalent of hexafluoropropene-getylamine (Ishikawa reagent) described in Table 2 is added thereto and cooled on ice (about 0 ° C). did. Reaction of 3- (3-bromo-5- (4-tert-butoxycarbonylpiperazine-1-11-yl) -1-2-chlorophenyl) -11-propanol dissolved in chloroform (3 times volume (vZv)) from dropping funnel The solution was dripped slowly so that the temperature inside the vessel did not rise. After completion of the dropwise addition, the mixture was stirred under ice cooling for 3 hours. A small amount of sample was collected, water was added thereto, and the separated organic layer was analyzed by TLC (n-hexane: ethyl acetate = 3: 1, Kieselgel 60F ₂₅₄ , UV = 254 nm). When the completion of the reaction was confirmed, methanol was slowly added from the dropping funnel under ice cooling so that the temperature inside the reactor did not rise. The temperature was returned to room temperature, and water was added while stirring so as not to generate heat. The organic layer was separated, washed once each with 1 to 3 volumes of water, a saturated aqueous solution of sodium hydrogen carbonate, and a saturated saline solution, and dried over sodium sulfate. After filtration, the solvent was distilled off. [3-Promo 5- (4-tert-butoxycarbylbiperazine-11-inole) -12-chloropropenyl] -11-propene (compound (3)) was obtained. Each production ratio was determined by the integrated value of ¹ H-NMR. Table 2 shows the results.

1 i (3- promoter 5-(4 - tert butoxycarbonyl two Rubiperajin - 1-I le) one 2- Kurorofuweniru) Single 1 over unloading Reo Ropuro c ⁰ down

'H-NMRCDMSO-d 6, TMS): 7.30 (d.1 H), 7.04 (d, 1H), 5.70 (ddd, 1H, J _FH , = 46.8Hz), 3.45 (brd t.4H), 3.13 (brd t.4H), 1.90 (m, 2H), 1.45 (s, 9H) , 1.00 (t, 3H, J = 6. OH z).

¹⁹ F-NMR (DMS 0- d 6, F-11):-179.0 (ddd, 1 F,

1- (3-promote 5- (4-tert e-r-butoxycarborbiperazine-1-inole) 1-2-chlorophenyl) 1-1-propene

^ -NMRCDMS 0- d 6, TMS): 7.20 (d.1 H), 7.11 (d, 1 H), 6.65 (d, lH), 6.37 (m, 1 H), 3.46 (brdt .4 H), 3.12 (brd t.4H), 1.83 (d, 3H), 1.44 (s, 9H).

Table 2

Example 10 2-Fluorobornane

2-Fluorobornane in a yield of 82% and 1-camphene in a yield of 7% were obtained from borneol 68 mg (0.44 mmo I) in the same manner as in Example 1.

2—Fluorobornan

¹⁹ F-NMR (CDC 13. F—11): −13.1 (brddd, 1 F). Example 11 1-Fluoronolpournan

From 1 norborneol 6 Omg (0.44 mmo 1), 1-fluoronorpornane was obtained in a yield of 80% in the same manner as in Example 1.

1 Fluoro Norbornan

One _{NMR (CDC1 3, TMS):} 4.52 (dd, 1H), 3.35 (m, 1 H), 2.43 (s, 1H), 2.36 (brdt, 1 H), 1.61 (s, 1 H), 1.6 0- 1.27 (m, 4H), 0.94 (m, 2H).

¹⁹ F-NMR (CDC 13, F-11):-160.6 (m, 1 F).

Example 12 2-Fluoroadamantane

2-Fluoroadamanone was obtained from 68 mg (0.44 mmo 1) of 2-adamantanol in the same manner as in Example 1 with a yield of 76% and adamanten with a yield of 4%.

2—Fluoroadamantane

'H-NMRCCDCU, TMS): 4.63 (d, 1 H, J

H z), 2.05 (br d.4H ), 1.90 - 1.56 (m, 8H), 1.50 (d, 2H) 19 F-NMR (CDC 1 a, F- 11): -. 174.4 (brdqd, 1 F,

Example 13 3-Fluoro-4-heptane

4-Methyl-heptane-20-ol 52mg (0.44mmo) From the same procedure as in Example 1, 3-fluoro-41-heptane was obtained in a yield of 53.3%.

3-Fluoro-41

¹⁹ F-NMR (CDC 1 a, F-11):-143.9 (qd .1 F, J _FH 1

Comparative Examples 5 to 8

In each of Examples 10 to 13, the same operation was carried out except that only hexafluoropropene-jetylamine (20 Omg, 0.46 mmo 1) was used as the fluorinating agent, and the yields of the fluorinated product and the olefin compound were determined. Was.

Table 3 shows the results of Examples 10 to 13 and Comparative Examples 5 to 8.

CO

Example 14

(R) — 1- [3-Promo 5— (4-tert-butoxycarbonylpyrazine-11-yl) 1-2-chlorophenyl] 1-1-Fluoropropane tris-fluoramine (30.0 g, 186. Ommol) ) And Hexaf (S) -1 was dissolved in a mixture of fluoropropene-Jetiramine (10.8 g, 48.4 mmol) in ice-cooled (approx. 0.C) lower bottom form (30.0 ml). -[3-Bromo-5- (4-tert-butoxycarbylbiperazin-1-yl) -12-chlorophenyl] -11-propanol (10.0 g, 23.lmmo 1, 94% ee) Dripped. The residue obtained by treating in the same manner as in Example 4 was purified by silica gel chromatography to give (R) -111- [3-bromo-5- (4-tert-butoxycarbonyl piperazine-11-yl). [2-Chlorophenyl] -1-fluoropropane (7.9 g, 18.2 mmol, 79%, 76% ee) was obtained.

Optical purity measurement method:

Appropriate amount of (R) — 1- [3-promo 5- (4-tert-butoxycarbonylbiperazine-1 1-yl) 12-chloro-openil] 1-1-1 Fluorop After the conversion into Boc, it was converted into NZ by ZC1, and this was used as a measurement sample.

Measurement condition:

Column CHIRALPAK AD (Daicel Chemical) 04. 6x 250 mm mobile phase ethanol

Flow and speed 0.5 m 1 / m i n

ι out UV = 254 nm

Retention time; S-form 17-19 min, R-form 20-21 min

Comparative Example 9

(S) — 1— [3-Bromo-5— (4-tert-butoxycarbonylpyrazine-111) -2-chlorophenyl] -1-propanol (18.0 g, 41.5 mmo 1, 94 % ee) in chloroform (90 ml) solution under ice-cooling (about 0 ° C). 9.4 g, 83. Ommo 1) was added dropwise, and the mixture was stirred for 2 hours. Water (80 ml) was added to the reaction solution for partition. The organic layer was washed with brine (60 ml), the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography to give (R) -1-1 [3-promo 5- (4-tert). —Butoxycarbylbiperazine—11-yl) -1-2-chlorophenyl) —1-fluoropropane (11.2 g, 25.8 mmol, 62%, 55% ee) was obtained.

Comparative Example 10

(S) —1— [3—Promo-5— (4-tert-butoxy) in a solution of getylaminosulfur trifluorofluoride (6.15 g, 38. Ommo 1) in dichloromethane (15 ml) at 70 ° C A solution of carbonylbiperazine-11-yl) -2-chlorophenyl] -11-propanol (15.0 g, 34.6 mmol, 94% ee) in dichloromethane (30 ml) was added dropwise, and the mixture was stirred for 1 hour. The reaction solution was cooled to room temperature, neutralized with saturated aqueous sodium hydrogen carbonate, extracted with dichloromethane (45 ml), and the organic layer was washed with water (60 ml). The solvent was distilled off under reduced pressure to obtain a residue. Purification by silica gel chromatography (R)-1-[3-bromo-15- (4-tert-butoxycarbonylbiperazine-1 -yl)-1-2-chlorophenyl]-1 -fluoropropane (12.5g, 28.8mmol, 83%, 34% ee)

Claims

The scope of the claims

General formula (I)

(In the formula, R ¹ represents a hydrogen atom, a lower alkyl group, lower alkenyl group, halogenation lower alkyl group, a lower alkoxyalkyl group, a lower Arukokishikaru Boniruarukiru group, Shiano lower alkyl group or Ararukiru group; R ² is A hydrogen atom, an optionally substituted piperazinyl group, a piperidyl group, a pyrrolidinyl group, a morpholinyl group, an optionally substituted amino group or a heteroaryl group; R ³ and R ⁴ are the same or different and are each a hydrogen atom , A halogen atom, a cyano group, a lower alkyl group or a lower alkoxy group.) In the presence of triethylamine and hydrogen fluoride in the presence of triethylamine 1.1,2,3 , 3,3-hexafluorop, characterized by reacting with pyramine, having the general formula (II):

(Wherein RR \ R ³ and R ⁴ are as defined above.)

The method for producing a benzyl fluoride derivative represented by the formula:

2. R ¹ is a lower alkyl group, R ² is an optionally substituted piperazinyl group or a piberidyl group, R ³ is a hydrogen atom, a halogen atom or a lower alkyl group, R ⁴ is a hydrogen atom, Halogen atom or lower alcohol 2. The production method according to claim 1, which is a xy group.

3. The production method according to claim 2, wherein R ¹ is a lower alkyl group, R ² is an optionally substituted piperazinyl group, and R ³ and R ⁴ are the same or different halogen atoms.

4. R ¹ is an ethyl group, R ² is a 4- (t-butoxy) carbonylpyrazine-1-yl group, R ³ is a bromine atom, and R ⁴ is a chlorine atom. Item 4. The production method according to Item 3.

5. The benzyl alcohol derivative (I) wherein R ¹ is an optically active substance comprising an atomic group selected from other than hydrogen atoms, and the benzyl alcohol derivative (II) is stereospecifically obtained. The production method described in 1.

6. General formula (ΠΙ):

_R ll _R 12 _R 13 _COH (HI)

(In the formula, R ¹¹ and R ¹² are the same or different and each represents a hydrogen atom, a halogen atom, an alkoxy group, an amino group, an amide group, a nitro group, a cyano group, a carbonyl group, a carboxyl group, a thiol group, a thioether group. Which may be substituted with a sulfonyl group, a sulfoxide group or a phosphonyl group, an alkyl group having 1 to 20 carbon atoms, an alkenyl group having 2 to 20 carbon atoms, an allene group, an aryl group, and a group having 6 to 20 carbon atoms. Represents an aryl group or a heterocyclic ring containing N, 0 or S, provided that R ¹¹ and R ¹² may together form a saturated or unsaturated 3- to 8-membered ring, R ¹³ is a hydrogen atom, Or a halogen atom, an alkoxy group, an amino group, an amide group, a nitro group, a cyano group, a carbonyl group, a carboxyl group, a thiol group, a thioether group, a sulfonyl group, a sulfonyl group, Represents an alkyl group, an alkenyl group, an allene group, an aryl group, an aryl group, or a heterocyclic ring containing N, 0 or S, having 1 to 20 carbon atoms, which may be substituted with a kind group or a phosphonyl group. However, both R ¹¹ and R ¹² are hydrogen If it is a child, R ¹³ is not a hydrogen atom. R ¹³ may form a saturated or unsaturated 3- to 8-membered ring together with R ¹¹ and R ¹² . )

Reacting the alcohol represented by with N, N-diethyl-1,1,2,3,3,3_hexafluoropropylamine or its analog in the presence of hydrogen fluoride and tertiary amine General formula (IV):

_R 11 _R 12 _R 13 _CF (IV)

(Wherein, R ¹¹ R ¹² and R ¹³ are as defined above.)

A method for producing a fluorine compound represented by the formula:

7. A fluorinated reagent composition comprising N, N-getyl-1,1,2,3,3,3-hexafluoropropylamine or an analog thereof, hydrogen fluoride and tertiary amine.

8. Complex consisting of hydrogen fluoride and tertiary amine per mole of N, N-getyl-1,1,2,3,3,3-hexafluoropropylamine or its analog 0.3 8. The fluorinated reagent composition according to claim 7, comprising up to 30 moles.

9. The fluorinating reagent composition according to claim 7, wherein the molar ratio of hydrogen fluoride to tertiary amine is 10: 1 to 1: 1.