WO2001066509A1

WO2001066509A1 - PROCESS FOR PRODUCING α,α-DIFLUORO- β -KETOESTER

Info

Publication number: WO2001066509A1
Application number: PCT/JP2001/001103
Authority: WO
Inventors: Katsuhiko Iseki; Yoshichika Kuroki; Yuko Sakamaki
Original assignee: Daikin Industries Ltd.
Priority date: 2000-03-07
Filing date: 2001-02-15
Publication date: 2001-09-13
Also published as: JP2001247514A

Abstract

An acid halide represented by general formula [1] is reacted with a difluoroketene silyl acetal represented by general formula [2] preferably in the presence of a transition metal catalyst to obtain an α, α -difluoro- β -ketoester represented by general formula [3]. According to need, the β - ketoester is subjected to an asymmetric hydrogenation reaction with the aid of a hydrogenation catalyst to induce the corresponding optically active α, α - difluoro- β -hydroxyester. (In general formulae, R?1, R2, R3, R4, and R5¿ each represents, e.g., alkyl; and X1 represents halogeno.) The process enables the α, α - difluoro- β -ketoester to be mass-produced in high yield. Also provided are: a process for producing the difluoroketene silyl acetal usable as an intermediate in that process; and a process for efficiently mass-producing an optically active α,αdifluoro-β-hydroxyester from the β-ketoester.

Description

Details ^:

-Difluoro-β-ketoester production method

i¾ の

The present invention relates to a method for producing a difluoro /?-Ketoester useful as a physiologically active substance such as a medicine or a pesticide, and a method for producing difluoroketene silyl acetal useful as a synthetic intermediate thereof. Also, the present invention relates to a method for producing optically active aniline, difluoro-5-hydroxy ester.

of

In general, a compound obtained by replacing a hydrogen atom with a fluorine atom from a known compound having a function or a physiological activity has a function or a physiological activity enhanced by a specific electronic effect of the fluorine atom, Alternatively, it is known to exhibit new functions and physiological activities.

For this reason, fluorinated building blocks having a structure similar to the raw materials of known compounds have been designed [“Fluorine Physiologically Active Substances in the 1990s”, supervised by Nobuo Ishikawa, published by CMC (1991), Latest Trends in Materials ”edited by Masaaki Yamabe and Hitoshi Matsuo, published by CMC (1994)].

One typical example is H, H-difluoro /?-Ketoester. It is known primarily as an important synthetic intermediate for making pharmaceuticals and pesticides.

Insistence of invention However, the production method of this compound has problems to be improved as described below.

For example, a method of oxidizing a di-difluoro /?-Hydroxy ester corresponding to a target product, a method of fluorinating a keto ester, and the like are known.

However, these methods have a problem that reagents such as an oxidizing agent and a fluorinating agent, which are indispensable for use, are expensive and the reaction yield is low (J. 0rg, Chem. 1989, 54, 661). J. Am. Chem. Soc. 1990, 112,8563). Also, the applicant has already disclosed in Japanese Patent Application No. 11-333932 that difluoroketene silyl acetate is reacted with acid chloride in the presence of a base such as triethylamine. Provided a method.

Although this production method has been improved in terms of mass productivity and the like, it is desired to further improve the reaction yield, and there remains a problem in the generality of the reaction substrate.

In addition, there is a synthetic method using mono-trimethylsilyl mono- or di-fluoroacetate, but the reaction yield is low and its generality is unknown (J. Org. Chem. 1994, 64, 6717).

The present invention has been made in order to improve the above circumstances, and its object is to collect a thiophene, a thiofluoride mono /?-Ketoester and a derivative thereof, and a synthetic intermediate thereof by a general method. An object is to provide a method for efficiently synthesizing.

Structure of the invention

That is, the method of the present invention for producing a monodifluoro-5-ketoester comprises an acid halide represented by the following general formula [1] and a difluoroketene silyl acetal represented by the following general formula [2]. And non-catalytic conditions or metal-based The reaction is carried out in the presence of a catalyst to obtain a fluorinated / fluoroketoester represented by the following general formula [3].

General formula [1]:

0

General formula (: 3)

(However, in the general formulas (1), (2) and (3), R ¹ represents an alkyl group, an aryl group, an aralkyl group, an alkenyl group, an alkynyl group, an alkyloxy group, an aryloxy group, an alkenyloxy group, R ² represents an alkyl group, an aryl group, an aralkyl group, an alkenyl group or an alkynyl group; R ³ , R ⁴ and R ⁵ are the same or different groups; And an alkyl group, an aryl group, an aralkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an aryloxy group, an alkenyloxy group, an alkynyloxy group or an aralkyloxy group which may form a cyclic group together with each other. represents a group, also X ¹ is off Tsu atom, a chlorine atom, a bromine atom (hereinafter the same) a halogen atom shown .) The manufacturing method of difluoromethane O Roque Ten silyl § Se evening Ichiru of the present invention will / JPO 1/1103

The present invention is characterized in that a difluoroketene silyl acetal represented by the following general formula [2] is produced using a difluoroacetic acid ester represented by the general formula [4], zinc and trialkyl halosilane.

General formula [2]:

General formula [4]: X ² CF ₂ C0 ₂ R ²

(However, in the general formulas (2) and (4), R ² represents an alkyl group, an aryl group, an aralkyl group, an alkenyl group or an alkynyl group, and R ³ , R ⁴ and R ⁵ are the same as each other. Or an alkyl group, aryl group, aralkyl group, alkenyl group, alkynyl group, alkoxy group, aryloxy group, alkenyloxy group, alkynyloxy group or And X ² represents a chlorine atom, a bromine atom or an iodine atom (the same applies hereinafter). In addition, the method for producing the mono- or mono-difluoro-hydroxy ester of the present invention is as follows. An acid halide represented by the formula [1] and a difluoroketene silyl acetal represented by the following general formula [2] are reacted under non-catalytic conditions or with a metal. The reaction is carried out in the presence of a catalyst to obtain a difluoro /?-Ketoester represented by the following general formula [3]. Further, the di-difluoro-^-ketoester is subjected to asymmetric reaction using a hydrogenation catalyst. It is characterized in that it is converted into an optically active compound represented by the following general formula [5] by hydrogenation reaction.

General formula (1)

c o n

General formula (2) X

F

2 \ R '

F OR General formula (3)

CF ₂ — C-OR 'General formula [5]:

OH

CH CF 2 one C — OR '

(However, in the above general formulas (1), (2), (3) and (5), R ¹ is an alkyl group, an aryl group, an aralkyl group, an alkenyl group, an alkynyl group, an alkyloxy group, an aryloxy group, an alkenyl R ² represents an alkyl group, an aralkyl group, an aralkyl group, an alkenyl group or an alkynyl group; R ³ , R ⁴ and R ⁵ represent the same or different groups; An alkyl group, an aryl group, an aralkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an aryloxy group, an alkenyloxy group, an alkynyloxy group or an aralkyloxy group which may form a cyclic group together with each other. X ¹ Represents a halogen atom, and * C represents a chiral carbon atom. According to the present invention, the acid halide represented by the general formula [1] and the difluoroketene silyl acetal represented by the general formula [2] are reacted under non-catalytic conditions or in the presence of a metal-based catalyst. Because of the reaction, it is possible to mass-produce para-difluoro-5-ketoester, which is useful, for example, as an intermediate for pharmaceuticals and agricultural chemicals in higher yields than in the case of conventional techniques, and to broaden the selection range of substrates to be used. can do.

In the above reaction, difluoroketene silyl acetate can serve as an intermediate for the synthesis of di-difluoro-/-keto-esters. It can be produced efficiently using the difluoroacetate represented by the formula [4], zinc and trialkylhalosilane.

The difluoroketene silyl acetal produced in this way can be reacted with the acid halide to form the dihydroketene silyl acetal in situ without isolation and purification. You. In other words, difluoroketene silyl acetal can be used in the system without isolation in the process of obtaining the desired product without isolation, and not only does not cause any problem, but also greatly contributes to the efficiency of the process. Was issued. On the other hand, according to the present invention, an optically active substance can be further produced from the above-mentioned difluoro- / di-ketoester.

That is, an asymmetric hydrogenation reaction is carried out in the presence of a hydrogenated catalyst using the above-mentioned difluoro-/?-Ketoester to obtain optically-enriched difluoro-/?-Hydroxyester. It can be mass-produced efficiently.

Hereinafter, the present invention will be described more specifically based on embodiments. In the present invention, the alkyl group (or alkyl) represented by the general formula [1], [2], [3] or [4] has a linear, branched or cyclic structure. An alkyl group such as a methyl group, an ethyl group, a propyl group, or a butyl group, which may have a heteroatom or a halogen atom and may have a substituent and has 1 to 30 carbon atoms; Or a cycloalkyl group having an equivalent number of carbon atoms.

Examples of the aryl group (or aryl) shown in each of the above general formulas include a phenyl group which may have a substituent, a naphthyl group, an anthryl group, a heterocyclic aromatic group having a hetero atom or a halogen atom, and the like. Can be exemplified. Examples of the substituent include an alkyl group having 1 to 10 carbon atoms which may be branched, an alkoxy group, an amino group and the like. Examples of the aralkyl group (or aralkyl) include a benzyl group, a p-methylbenzyl group, a naphthylmethyl group, a furfuryl group, and a polyphenyl group.

Examples of the alkenyl group (or alkenyl) include a vinyl group,? -Styryl group, 1-probenyl group, 1-butenyl group, 1-hexenyl group, 1-decenyl group, cyclohexenyl group, aryl group, Examples thereof include a cinnamyl group, a 2-butenyl group and a 2-decenyl group. Examples of the alkynyl group (or alkynyl) include an ethynyl group, a phenylethynyl group, and a 2-propyl group.

The solvent used in each of the production methods of the present invention is not particularly limited, but preferred are 1,3-dimethyl-2-imidazolidinone (DMI), acetonitrile, tetrahydrofuran (THF), dimethylformamid Non-protonic solvents such as amide (DMF) and dimethoxetane (DME). In the method of the present invention, the reaction proceeds even under non-catalytic conditions, but the reaction rate is extremely slow. Generally, it is preferable to use a metal catalyst. However, the term “metal-based catalyst” as used herein means not only a metal catalyst but also a metal compound catalyst.

As the metal catalyst, a transition metal catalyst is preferable. Specific examples include, for example, cuprous chloride, cupric chloride, tetrakis (triphenylphosphine) palladium (0), and among them, cuprous chloride is preferable.

The amount of the metal-based catalyst used in the present invention can be appropriately selected from the range of 0.0001 to 100 equivalents to the acid halide, and among them, 0.1 to 2.0 equivalents. A range is preferred.

The reaction temperature in the production method of the present invention can be appropriately selected from the range of —100X; to 200 ° C., and is preferably in the range of 0 ° C. to 100 ° C.

Further, the difluoroketene silyl acetal produced by this method can be isolated and purified alone, but as described above, in the step of producing a-difluoro-/-ketoester, It is preferable to use it as is without purification.

Next, according to the present invention, it is possible to efficiently and efficiently produce not only H, H-difluoro-/-ketoester but also H, H-difluoro-/-H-hydroxy ester which is particularly rich in optical activity. That is, the acid halide represented by the general formula [1] and the difluoroketene silyl acetal represented by the general formula [2] are reacted under non-catalytic conditions, preferably in the presence of the metal-based catalyst. The reaction is carried out below to synthesize the di- and di-fluoro-ketoesters represented by the general formula [3], and the 5-ketoester is subjected to an asymmetric hydrogenation reaction using a hydrogenation catalyst. Then, the target substance can be efficiently obtained in a large amount.

Here, the hydrogenation catalyst is replaced by Even if 0.001 to 10 mol% is used, the reaction proceeds. The amount of the hydrogenation catalyst used is more preferably 0.01 to 1 mol%, for example, 0.1 mol% or around 0.1 mol%.

As such a hydrogenation catalyst, a metal complex represented by the general formula [6] is preferably used.

General formula [6]:

M (L)

(However, in the general formula [6], M represents a metal atom, and L represents an optically active phosphine ligand.)

Here, the metal atom is Ru, Rh, Pd, Ir or Ni, and the ligand (optically active phosphine ligand) combined therewith is (R) or (S) —BI NAP, (R) or (S) —T ol—BI NAP, (R) or (S) —Xy l—BI NAP, (R, R) or (S, S) —Me—D uphos, (R , R) or (S, S) —Me—BPE, (R, R) or

(S, S) — Di PAMP, (R, R) or (S, S) — CH I RAPH 0 S, (R, R) or (S, S) — B PPM, (R, R) or ( (S, S) -NORPHO S, or (R, R) or (S, S) —DIOP, etc. For example, the following (R) —BIN AP as a ligand Ru C ₁₂

[(R) — BI NAP], RuBr _? [(R) _BINAP], and the like.

(R) -BINAP EuCl ₂ [(E) -BINAP] RuBr ₂ C (R) -BINAP] According to the production method of the present invention, the ketoester of the general formula [3] can be efficiently synthesized, and the hydroxyester of the general formula [5] can be synthesized from the ketoester in a large amount even with a small amount of a catalyst. It is possible to obtain highly selective difluoro-1-hydroxy ester. Incidentally, the hydroxy ester of the general formula [5] obtained by the production method of the present invention is useful as a synthetic intermediate for pharmaceuticals, agricultural chemicals and the like.

That is, for example, a compound of the general formula (5)

0H

With respect to _R ¹ CF _r, C0 ₂ Et can be used as intermediates for pharmaceuticals, U.S. Patent No. 4,857, the following compounds in the 507 Patent has been reported to be active as Renin Inhibitor.

OH

Boc-Phe-Leu-HN CF people

Bani ° ²

IC ₅₀ = 10 nM Next, in the reaction for synthesizing the hydroxy ester of the general formula [5], the reaction solvent is not particularly limited, but alcohols, particularly Me OH (methyl alcohol), Et 0 H (Ethyl alcohol) is preferred. The reaction temperature may be between 0 ° C. and 200 ° C., with around 100 ° C. being particularly preferred.

The pressure may be from 1 to: L 50 atm, but is especially preferred around lOOatm.

Available items % "In a sword, the fjij nil-acid halide represented by the general formula [1] and the difluoroketene silyl acetal represented by the general formula [1] are used under non-catalytic conditions or in the presence of a gold-based catalyst. Therefore, it is possible to produce a large amount of Nakawa Takahi, a difluoro-5-ketoester at a high yield, for example, as a cross-linking agent for pharmaceuticals.

The difluoroketene silyl acetate represented by the general formula [2] can be produced from difluoro w steep ester represented by the general formula [4], lead and trialkylhalosilane. Further, the acetal can be supplied in a form that is efficiently preferable for the production process of the above-mentioned di-difluoro-/-ketoester and does not require separation and purification.

rnmm

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto.

Example 1

(Synthesis of 2,2-difluoro-13-oxododecanoic acid ethyl ester) To a suspension of cuprous chloride (198 mg, 2.Ommol) in DMI (2 ml) was added dodecanoic chloride (374 mg, 1.8 mmo 1) at 50 ° C, difluoroketenethyl trimethylsilyl acetal (392 mg, 2.0 mg, 1.8 mmol) was added dropwise at 50 ° C. After stirring for 30 minutes, the temperature was returned to room temperature, methylene chloride (15 ml) was added, and the precipitate was filtered through celite. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography to obtain 436 mg of the target compound (87% yield).

An analysis of the target compound is shown below. 1H-NMR (CDC13) (5 (ppm): 0.88 (t, J = 6.6 Hz, 3H), 1.22-1.38 (m, 12H),

1.35 (t, J = 7.1Hz, 3H), 1.55-1.73 (m, 2H), 2.68-2.78 (m, 2H), 4.37 (q, J = 7.1Hz, 2H) .19F-NMR (CDC13) (5 (ppm):-114.17 (s, 2F).

IR (neat) cm-1: 2927,2856,1781,1748,1314,1140.

Example 2

(Synthesis of 2,2-difluoro-3-oxo-1-3-phenylpropionate)

Method 1) The target compound was obtained in the same manner as in Example 1 except that benzoyl-cuff light was used instead of dodecanoic acid-cure light (369 mg, 90% yield) .

Method 2) In a suspension of zinc dust (654 mg, 10 mmo1) in acetonitrile (2.5 ml), add 1,2-promoen (0.06 ml) and trimethylsilyl chloride (0.06 ml) at 40 ° C and stirred for 10 minutes. At the same temperature, trimethylsilyl chloride (1.27 ml, 10 mmo1) was further added, and ethyl bromodifluoroacetate (0.64 ml) was added. 1, 5. Ommol) was added dropwise. After stirring at the same temperature for 20 minutes, the supernatant of the suspension was added to a previously prepared suspension of cuprous chloride (495 ml, 5.0 mmol) in DMI (5 ml). Benzoyl chloride (0.58 m1, 5.0 mmo 1) was added at room temperature, and the mixture was stirred at 80 ° C. for 2 hours. The reaction solution was returned to room temperature, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain 681.2 mg (60% yield) of the target compound. In the above suspension, difluoroketene silyl acetal, which is an intermediate, is generated. The identification data is shown below. 19F-NMR (THF) ((ppm): -126.76 (d, J = 106 Hz), -128.19 (d, J = 106 Hz). Method 3) Benzoyl-capped mouth (0.2 ml, 1.8 mmol) To a DMI (2 ml) solution at 50 ° C. was added difluoroketenethyl trimethylsilyl acetate (392 mg, 2.Ommol) and stirred for 30 minutes. The reaction mixture was poured into an aqueous solution of 0.5 NHC 1 and extracted. After drying, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain 119 mg of the desired compound (29% yield). ) Got.

The analytical data of the target compound are shown below.

1H-NMR (CDC13) δ (ppm): 1.32 (t, J = 7.lHz, 3H), 4.39 (q, J = 7.1Hz, 2H),

7.48-7.73 (m, 2H), 8.02-8.12 (m, 2H).

19F-NMR (CDC13) δ (ppm): -108.15 (s, 2F).

IR (neat) cm-1: 1776,1716,1701,1316,1159.

Import

(Synthesis of 2,2-difluoro-3-oxo-5-phenylethyl valerate) Same as Example 1 except that dodecanoic acid chloride was used instead of hydrodecynamoyl oxalate. To give the desired compound [369 mg, 80% yield].

The analytical data of this target compound is shown below.

1H-NMR (CDC13) δ (ppm): 1.32 (t,

4.33 (q, J = 7.1Hz, 2H), 7.10-7.36 (m, 5H).

19F-NMR (CDC13) δ (ppm): -114.42 (s, 2F).

IR (neat) cm-1: 1779,1749,1315,1122.

Example 4

(Synthesis of 2,2-difluoro-3-oxo-14-ethyl monobutyrate)

Use of phenylacetyl-cuff instead of dodecanoic-cuff Except for above, the target compound was obtained in the same manner as in Example 1 [305 mg, 70% yield].

The analytical data of this target compound is shown below.

1H- 麵 R (CDC13) δ (ppm): 1.31 (t, J = 7.lHz, 3H), 4.05 (s, 2H),

4.31 (q, J = 7.1Hz, 2H), 7.17-7.42 (m, 5H).

19F-NMR (CDC13) δ (ppm): -133.80 (s, 2F).

IR (neat) cm-1: 1779, 1752, 1315, 1143.

卖 Example 5

(Synthesis of 2,2-difluoro-3-oxo-13-cyclohexyl hexylpropionate)

The desired compound was obtained in the same manner as in Example 1 except that cyclohexanecarbonyl chloride was used instead of dodecanoic acid chloride [341 mg, 81% yield].

The analytical data of this target compound is shown below.

1H-NMR (CDC13) δ (ppm): 1.10-2.00 (m, 10H), 1.35 (t, J-7.1Ηζ, 3H),

2.82-2.99 (m, lH), 4.87 (q, J = 7.1 Hz, 2H). 19F-NMR (CDC13) δ (ppm):-113.63 (s, 2F).

IR (neat) cm-1: 1781, 1738, 1315, 1144.

(Synthesis of 2,2-difluoro-3-oxobutyrate)

The desired compound was obtained in the same manner as in Example 1 except that acetyl chloride was used instead of dodecanoic acid chloride [161 mg, 54% yield]. The analytical data of this target compound is shown below.

1H-NMR (CDC13) δ (ppm): 1.36 (t, J = 7.2 Hz, 3H), 2.41 (t, J = 1.6 Hz, 3H),

4.38 (q, J = 7.2Hz, 2H). W 1/665 1/11 3

19F-NMR (CDC13) δ (ppm): -114.20 (s, ZF).

IR (neat) cm-1: 1779,1760,1315,1135.

mrn i

(Synthesis of 2,2-difluoro-3-oxo_4-ethylpentenoate) The target compound was obtained in the same manner as in Example 1 except that cinnamoyl oxalate was used in place of dodecanoic acid chloride. [334 mg, 73% yield].

The analytical data of this target compound is shown below.

1H-NMR (CDC13) d (ppm): 1.35 (t, J = 7.2 Hz, 3H), 4.39 (q, J = 7.2 Hz, 2H),

7.04-7.17 (m, lH), 7.38-7.69 (m, 5H), 7.88-7.99 (m, lH).

19F-NMR (CDC13) δ (ppm): -114.15 (s, 2F).

IR (neat) cm-1: 1776, 1706, 1609, 1305, 1127

Example 8

(Synthesis of 2,2-difluoro-5,5-dimethyl-1-oxohexanoate)

The desired compound was obtained in the same manner as in Example 1 except that tert-butylacetylacetyl chloride was used instead of dodecanoic acid octalide [272 mg, 68% yield].

An analysis of the target compound is shown below.

1H- 丽 R (CDC13) δ (ppm): 1.08 (s, 9H), 1.37 (t, J = 7.2Hz, 3H),

2.61-2.66 (m, 2H), 4.38 (q, J = 7.2Hz, 2H).

19F-NMR (CDC13) δ (ppm): -114.10 (s, 2F).

IR (neat) cm-1: 1781,1760,1314,1122.

mrn 8 (Synthesis of 2,2-difluoro-1- (2-furyl) -13-oxopropionate)

The desired compound was obtained in the same manner as in Example 1 except that 2-furoyl chloride was used instead of dodecanoic acid chloride [23 mg, 59% yield].

The analytical data of this target compound is shown below.

1H-band R (CDC13) δ (ppm): 1.32 (t, J = 7.2Hz, 3H), 4.38 (q, J = 7.2Hz, 2H),

6.62-6.68 (m, lH), 7.52-7.58 (m, lH), 7.52-7.58 (m, lH), 7.76-7.80 (m, lH).

19F-NMR (CDC13) δ (ppm): -111.00 (s, 2F).

IR (neat) cm-1: 1778, 1690, 1462, 1159, 1032.

Presidency 1 0

(Synthesis of 2,2-difluoro-4-benzyloxy-3-oxobutyrate)

The desired compound was obtained in the same manner as in Example 1 except that benzyloxyacetyl chloride was used instead of dodecanoic acid cuprate [3 13 mg, 64% yield].

The analytical data of this target compound is shown below.

1H-丽 R (CDC13) δ (ppm): 1.31 (t, J = 7.lHz, 3H), 4.32 (q, J = 7.2Hz, 2H),

4.50 (s, 2H), 4.62 (s, ZH), 7.29-7.42 (m, 5H) .19F-NMR (CDC13) δ (ppm): -115.52 (s, 2F).

IR (neat) cm-1: 1782, 1765, 1315, 1147, 1124.

M 1 1

2,78 mg of ethyl 2,2 difluoro-3-oxododecanoate obtained in Example 1, (1 mmol), RuBr2 [(R) -BI NAP] l 0 mg (0. 1 mmo 1) and degassed ethanol (3 ml) were added, hydrogen was introduced (100 atm), and the mixture was stirred at 100 ° C for 24 hours. After cooling the reaction vessel, hydrogen was released and the reaction solution was taken out. After evaporating the solvent, the residue was isolated and purified by silica gel chromatography (ethyl acetate: hexane = 1: 7) to obtain the corresponding hydroxy ester (280 mg, yield 100%). The optical purity was measured using a Daicel 0D-H column (ethanol: hexane = 1: 1100), and it was 78% ee.

The analytical data for this product is shown below.

1H-NMR (CDC13) ^ (ppm): 0.81-0.94 (m, 3H), 1.12-2.04 (m, 17H),

1.37 (t, J = 7.1Hz, 3H), 3.90-4.12 (m, lH), 4.36 (q, J = 7.1Hz, 2H).

19F-NMR (CDC13) 5 (ppm): -115.45 (dd, J = 264.1,7.5Hz, IF),

-123.01 (dd, J = 264.1, 15.0Hz, IF).

IR (neat) cm-1: 3466,2926, 1760, 1316, 1094.

Claims

The scope of the claims

1. An acid halide represented by the following general formula [1] and a difluoroketene silyl acetal represented by the following general formula [2] are reacted under non-catalytic conditions or in the presence of a metal-based catalyst, A method for producing poly (5-difluoro-5-ketoester), characterized by obtaining poly (difluoro-/?-Ketoester) represented by the following general formula (3).

General formula [1]:

0

-General

General formula (3 J

(However, in the general formulas (1), (2) and (3), R ¹ represents an alkyl group, an aryl group, an aralkyl group, an alkenyl group, an alkynyl group, an alkyloxy group, an aryloxy group, an alkenyloxy group, R ² represents an alkyl group, an aralkyl group, an aralkyl group, an alkenyl group or an alkynyl group, and R ^{: i} , R ⁴ and R ⁵ are the same or different groups. An alkyl group, an aryl group, an aralkyl group, and an alkenyl group which may form a cyclic group together with each other. A alkynyl group, an alkoxy group, an aryloxy group, an alkenyloxy group, an alkynyloxy group or an aralkyloxy group, and X ¹ represents a halogen atom. )

2. The method for producing a mono-difluoro-ketoester according to claim 1, wherein a transition metal-based catalyst is used as the metal-based catalyst.

3. The method for producing mono-, he-fluoro-1 /?-Ketoesters according to claim 1, wherein the metal-based catalyst is used in an amount of 0.001 to 100 equivalents to the acid halide.

4. The difluoroketene silyl acetate is manufactured using difluorochloroacetic acid ester represented by the following general formula [4], zinc and trialkylhalosilane, and the difluoroketene silyl acetate is converted to the acid The method for producing a difluoro-ketoester according to claim 1, which is reacted with a halide.

General formula [4]: X ² CF ₂ C0 ₂ R ²

(However, in the general formula [4], R ² is the same as described above, and X ² represents a chlorine atom, a bromine atom or an iodine atom.)

5. The use of difluoroacetate represented by the following general formula [4], zinc and trialkylhalosilane to produce difluoroketene silyl acetal represented by the following general formula [2]. A method for producing difluoroketene silyl acetal.

General formula [2]:

General formula [4]: X ² CF ₂ C0 ₂ R ^: (However, in the general formulas (2) and (4), R ² represents an alkyl group, an aryl group, an aralkyl group, an alkenyl group or an alkynyl group, and R ³ , R ⁴ and R ⁵ are the same as each other. Or an alkyl group, aryl group, aralkyl group, alkenyl group, alkynyl group, alkoxy group, aryloxy group, alkenyloxy group, alkynyloxy group or Represents an aralkyloxy group, and X ² represents a chlorine atom, a bromine atom or an iodine atom.)

6. Acid halide represented by the following general formula [1] and the following general formula

The difluoroketene silyl acetate represented by [2] is reacted under non-catalytic conditions or in the presence of a metal-based catalyst to give a difluoroketensilyl acetate represented by the following general formula [3]. /?-Ketoester is obtained, and furthermore, this difluoro-ketofluoro-5-ketoester is subjected to an asymmetric hydrogenation reaction using a hydrogenation catalyst to obtain an optically active fly, difluoro-? —Optically active hydroxyl, difluoro /? — Leading to hydroxyesters.

General formula (1) c-X C o = =

General formula (2)

F

General formula (3)

0

II

CF, OR 'General formula [5]:

0H 0

K one CH-CF ₂ - _c -OR ²

(However, in the general formulas (1), (2), (3) and (5), R ¹ represents an alkenyl group, an aryl group, an aralkyl group, an alkenyl group, an alkynyl group, an alkyloxy group, an aryloxy group, an alkenyl group. R ² represents an alkyl group, an aralkyl group, an aralkyl group, an alkenyl group or an alkynyl group; R ³ , R ⁴ and R ⁵ are the same or different from each other An alkyl group, an aryl group, an aralkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an aryloxy group, an alkenyloxy group, an alkynyloxy group, which may be combined with each other to form a cyclic group. X 'represents a halogen atom, and' C represents a chiral carbon atom.)

7. The optically active catalyst according to claim 7, wherein the hydrogenation catalyst is used in an amount of 0.001 to 10 mol% based on the phosphoric acid-difluoro-5-ketoester. —Difluoro-hydroxy ester production method.

8. A metal complex represented by the following general formula [6] is used as the hydrogenation catalyst, wherein the optically active iron, heijifluore /?-Hydroxylester according to claim 6 is used. Production method.

General formula [6]:

M (L)

9. The metal atom is Ru, Rh, Pd, Ir or Ni, and the ligand is (R) or (S) _BINAP, (R) or (S)-. T o 1—BI NAP, (R) or (S) —Xyl—BI NAP, (R, R) or (S, S) —Me—D uphos, (R, R) or (S, S ) —Me—BPE, (R, R) or (S, S) —DiPAMP, (R, R) or (S, S) —CHI RAP H〇S, (R,) or (S , S) — BP PM, (R, R) or (S, S) _N0R PH0 S, or (R, R) or (S, S) one DIOP, as claimed in claim 8 Method for producing optically active difluoro /?-Hydroxy esters.