JPH05286902A - Method for producing α-chloro-β-keto ester derivative - Google Patents

Abstract

(57) [Summary] (Revised) [Purpose] α-chloro-, which is the starting material compound for drug production
Provided is an improved process for making β-keto ester derivatives. [Structure] In a methylene chloride solution of tert-butyl 4-phenyl-3-oxobutanoate and tert-butanol,
A methylene chloride solution of sulfuryl chloride was added dropwise and reacted to obtain tert-butyl 2-chloro-4-phenyl-3-oxobutanoate according to the following formula.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to an improved process for the preparation of .alpha.-chloro-.beta.-ketoester derivatives. More specifically, the present invention has the general formula [II]

[Chemical 3] [Wherein R ₁ is a lower alkyl group or a lower alkenyl group, R ₂ is a hydrogen atom or a lower alkyl group, and R ₃ is a phenyl group optionally substituted with a halogen atom, or a halogen atom substituted Optionally a naphthyl group,
Or the general formula A ₁ -D-A ₂ (wherein A ₁ is a phenyl group which may be substituted with a halogen atom, A ₂ is a phenylene group which may be substituted with a halogen atom, and D
Represents a carbonyl group or a group represented by a single bond). ] It is related with the manufacturing method of the (alpha)-chloro- (beta) -keto ester derivative shown by these.

Α-Chloro-represented by the above general formula [II]
The β-ketoester derivative can be hydrolyzed and decarboxylated by a conventional method to give an intermediate of general formula [III]

[Chemical 4] [In the formula, R ₂ and R ₃ have the same meaning as described above. ]
It is possible to easily lead to an α-chloroketone derivative represented by For example, JP-A-63-152368 (Example 1-6) describes that a thiazole derivative useful as a therapeutic agent for rheumatoid arthritis can be obtained from an α-chloroketone derivative.

[0003]

2. Description of the Related Art Conventionally, the following method has been known as a method for producing a corresponding α-chloro-β-ketoester derivative from a β-ketoester derivative. (A) Allihn et al., Chemiche Berichte, 11 567 (1878) (b) L. Garanti et al., Journal of Organic Chemistry, 42 1389 (1977) (c) HMWalborsky et al., Journal of the American Chemical Society, 80 187 (1958) (D) G. Buchi et al., Journal of Organic
Chemistry, 38 4348 (1973)

[0004]

Allihn et al. Obtained a corresponding α-chloro-β-ketoester derivative from a β-ketoester derivative with sulfuryl chloride in an inert solvent, but the yield was low and the reaction site was low. Since it has low selectivity, it contains a lot of impurities and cannot be said to be an industrially useful production method.
The method of L. Garanti et al. Is a similar method of Allihn et al., But has problems such as complicated operation and low yield.
Chlorine method such as HMWalborsky or G.Buch
The method using tert-butyl hypochlorite such as i is also complicated in operation, and it is difficult to say that the yield is high.
Further, there is a problem in handling the reagent. As described above, all of the conventional methods for producing an α-chloro-β-ketoester derivative have drawbacks and are not necessarily industrially useful methods.

[0005]

Means for Solving the Problems Under the circumstances, the present inventors have diligently studied a method for producing an α-chloro-β-ketoester derivative [II], and as a result, β represented by the following general formula [I] is obtained. It was found that the α-chloro-β-ketoester derivative [II] was obtained in high yield by reacting the ketoester derivative with sulfuryl chloride in the presence of alcohol in an inert solvent, and completed the present invention. It was

That is, the present invention has the general formula [I]

[Chemical 5] [Wherein R ₁ is a lower alkyl group or a lower alkenyl group, R ₂ is a hydrogen atom or a lower alkyl group, and R ₃ is a phenyl group optionally substituted with a halogen atom, or a halogen atom substituted Optionally a naphthyl group,
Or the general formula A ₁ -D-A ₂ (wherein A ₁ is a phenyl group optionally substituted with a halogen atom, A ₂ is a phenylene group optionally substituted with a halogen atom, and D is a carbonyl group). Group or a group represented by a single bond). ] The β-ketoester derivative represented by the above and α-chloro-β-represented by the above-mentioned general formula [II], which comprises reacting sulfuryl chloride in an inert solvent.
In the method for producing a ketoester derivative, the reaction is carried out by the general formula R ₁ OH [wherein R ₁ has the same meaning as described above. ]
Α-chloro-β-represented by the general formula [II], which is characterized in that it is carried out in the presence of an alcohol represented by
The present invention relates to a method for producing a ketoester derivative.

In the above general formula [I] or [II],
Examples of the lower alkyl group include methyl, ethyl, n-
Propyl, isopropyl, n-butyl, tert-butyl,
carbon number 1-, such as n-pentyl or n-hexyl
6 include straight chain or branched alkyl groups.
Examples of the lower alkenyl group include a straight-chain or branched alkenyl group having 2 to 6 carbon atoms such as vinyl, allyl, or 3,3-dimethylanyl.

Examples of the halogen atom include fluorine, chlorine, bromine, and iodine atoms. Examples of the alcohol represented by the general formula R ₁ OH include saturated or unsaturated, for example, methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, n-
Pentanol, n-hexanol, vinyl alcohol,
Examples thereof include allyl alcohol and linear or branched alcohols having 1 to 6 carbon atoms such as 3,3-dimethylallyl alcohol. As the inert solvent used in the reaction of the present invention, aromatic hydrocarbons such as benzene, toluene, or xylene, halogenated hydrocarbons such as methylene chloride, chloroform, or 1,2-dichloroethane,
Ethers such as ethyl ether or isopropyl ether, or mixed solvents thereof, and the like,
Aromatic hydrocarbons and halogenated hydrocarbons are preferable, and halogenated hydrocarbons are more preferable.

[0009] As R ₁ in the alcohol represented by R ₁ OH used in the present invention may be different from R ₁ in that the starting material β- ketoester derivative [I], the alcohol having the same group Preference is given to using. The amount of alcohol used is β-keto ester derivative [I]
It is possible to use 0.5 to 5 moles, but it is preferable to use it in a range of 0.5 to 2 moles, and it is more preferable to use a slight excess with respect to the β-ketoester derivative [I]. It gives good results when used and equimolar with the sulfuryl chloride used in the reaction. The amount of sulfuryl chloride used can be 0.9 to 5 mol with respect to the β-ketoester derivative [I], but it is preferably used within a range of 1 to 2 mol, and more preferably β-.
It is preferable to use a slight excess with respect to the ketoester derivative [I].

The reaction is carried out by dissolving the β-ketoester derivative [I] and an alcohol in an inert solvent and adding sulfuryl chloride dropwise thereto. The sulfuryl chloride is dissolved in the inert solvent, and β-ketoester derivative A solution of ketoester derivative [I] and alcohol may be added dropwise. Dripping
It takes a few minutes to 10 hours, but 30 minutes to 5 hours
Good results are given during the time. The reaction temperature is -20 ° C to the boiling point of the solvent used, but -1
The temperature is preferably between 0 ° C and 30 ° C, more preferably between 0 ° C and 15 ° C. After completion of the dropping, the reaction is allowed to proceed for several minutes to 10 hours, but usually the reaction is completed within 10 minutes to 1 hour.

After completion of the reaction, the solvent is distilled off under reduced pressure, or the organic layer is washed with water and then the solvent is distilled off under reduced pressure, or the sulfuryl chloride used is , 0.5 to 10 mol of sodium bicarbonate, potassium bicarbonate and the like powders were added and filtered, and then the solvent was distilled off under reduced pressure to obtain the above-mentioned general formula [II].
The α-chloro-β-keto ester derivative represented by can be obtained. Α-chloro-β obtained by the present invention
The ketoester derivative can be converted to the α-chloroketone derivative represented by the above general formula [III] by performing hydrolysis and decarboxylation reaction in the presence of an acid. The hydrolysis and decarboxylation reaction can be carried out by a method well known to those skilled in the art, for example, the method described in Synthesis (1987), 188. The β-ketoester derivative represented by the general formula [I], which is the starting material of the present invention, can be prepared from the arylacetic acid derivative represented by the general formula [IV] by, for example, Osamu Yonemitsu et al.
It can be easily produced by the method of Organic Chemistry 43 2087 (1978)).

[0012]

[Chemical 6] [In the formula, R ₁ , R ₂ , and R ₃ have the same meanings as described above. ]

[0013]

INDUSTRIAL APPLICABILITY According to the method of the present invention, an α-chloro-β-ketoester derivative [II] which is useful as a starting material compound for an α-chloroketone derivative [III] which is an important intermediate for pharmaceuticals
However, it is now possible to obtain it easily and in high yield.

[0014]

EXAMPLES The present invention will be specifically described below with reference to Reference Examples, Examples, and Comparative Examples, but the present invention is not limited to these. Reference Example 1 Synthesis of tert-butyl 4-phenyl-3-oxobutanoate

[Chemical 7]

37.3 g of Meldrum's acid was added to dichloroethane 200
Dissolve it in ml and add 40.94 g of pyridine.
A solution of 20 g of phenylacetyl chloride in 30 ml of dichloroethane was added dropwise at 5 ° C over 40 minutes. After adding 20 ml of dichloroethane and reacting at -5 to 5 ° C for 1 hour, 28.77 g of tert-butanol was added over 0 to 0 to 0.
It was added dropwise at 10 ° C. After reacting at 0-10 ° C for 1 hour,
The reaction was carried out at 75-80 ° C for 2 hours. After cooling to room temperature, 5% hydrochloric acid 200 ml, water 200 ml, 5% sodium bicarbonate water 200 ml,
The mixture was washed with 200 ml of water in this order, activated carbon was added, and the mixture was filtered. The filtrate was concentrated under reduced pressure with an evaporator, and 33 g of the obtained oily substance was purified by column chromatography using 1320 g of silica gel and normal hexane containing 10% of ethyl acetate,
20.7 g of the title compound was obtained. NMR (CDCl ₃ , δppm): 1.46 (9H, s), 3.37 (2H, s), 3.82 (2H,
s), 7.19 ~ 7.37 (5H, m), 12.29 (S) IR (KBr) ν (cm ^-1 ): 1729,1716

Reference Example 2 Synthesis of tert-butyl 4- (1-naphthyl) -3-oxobutanoate

[Chemical 8]

20 g of 1-naphthyl acetic acid and 45 ml of toluene
14 g of thionyl chloride was added dropwise at 67 to 73 ° C. over 45 minutes to the solution containing a small amount of dimethylformamide. After reacting at this temperature for 3 hours, toluene was distilled off under reduced pressure by an evaporator. The obtained oily substance was dissolved in 40 ml of dichloroethane, and Meldrum's acid 3 was added.
1 g was added dropwise to a solution in which 75 ml of dichloroethane and 33.9 g of pyridine were dissolved at -10 to -4 ° C over 35 minutes. -1
The reaction was carried out at 1 to -6 ° C for 1 hour, and 23.8 g of tert-butanol was added dropwise at -6 to 0 ° C over 30 minutes. The temperature is gradually raised to room temperature, and the reaction is performed at 55 to 58 ° C for 1 hour, 66 to 68 ° C for 1 hour, and 77 to 78 ° C for 1 hour and 30 minutes, and then 2 to 8
5% Hydrochloric acid water was added at 0 ° C. and the layers were separated. An oily substance (33.7 g) obtained by washing 150 g of 5% aqueous potassium carbonate solution and 100 g of water in this order and concentrating dichloroethane under reduced pressure with an evaporator was subjected to column chromatography using 1300 g of silica gel and normal hexane containing 10% of ethyl acetate. Purified,
23.5 g of the title compound was obtained. NMR (CDCl ₃ , δppm): 1.43 (9H, s), 3.33 (2H, s), 4.26 (2H,
s), 7.38 to 7.58 (4H, m), 7.79 to 7.89 (3H, m) IR (KBr) ν (cm ^-1 ): 1736,1712

Reference Example 3 Synthesis of tert-butyl 4- (3-benzoylphenyl) -3-oxopentanoate

[Chemical 9]

From 20 g of 2- (3-benzoylphenyl) -propionic acid, 22.4 g of the title compound was obtained in the same manner as in Reference Example 2. NMR (CDCl ₃ , δppm): 1.42 (9H, s), 1.47 (3H, d, J = 6.93Hz),
3.31 (3H, dd), 4.0 (1H, q, J = 6.93Hz), 7.43〜7.82 (9H, m), 1
2.31 (S) IR (neat) ν (cm ^-1 ): 1734,1716

Reference Example 4 Synthesis of tert-butyl 4- (2-fluoro-4-biphenylyl) -3-oxopentanoate

[Chemical 10]

A dichloroethane solution obtained from 20 g of 2- (2-fluoro-4-biphenylyl) -propionic acid in the same manner as in Reference Example 2 was distilled off under reduced pressure with an evaporator to obtain 29.76 g of an oily product. Was given. This oily substance was dissolved in 40 g of methanol, and water 1
When 6 g was added and the precipitated crystals were filtered, 23.92 g of the title compound was obtained. NMR (CDCl ₃ , δppm): 1.43 (3H, dJ = 6.93Hz), 1.44 (9H, s),
3.35 (2H, dd), 3.95 (1H, q, J = 6.93Hz), 7.01 ~ 7.54 (8H, m) IR (KBr) ν (cm ^-1 ): 1724,1710

The compounds in Table 1 were synthesized in the same manner as in Reference Example 2.

[Table 1]

Example 1 tert-butyl 2-chloro-4
-Phenyl-3-oxobutanoate synthesis

[Chemical 11]

2.34 g of tert-butyl 4-phenyl-3-oxobutanoate obtained in Reference Example 1 and 0.81 g of tert-butanol were dissolved in 7 ml of methylene chloride, and 0-10
A solution of 1.48 g of sulfuryl chloride in 1.5 ml of methylene chloride was added dropwise at 50 ° C. over 50 minutes. 50 at 0-10 ° C
After reacting for minutes, 500 mg of sodium bicarbonate was added, and the mixture was kept at 0 to 10 ° C for 1 hour and then filtered. After washing with methylene chloride, the solvent was distilled off with an evaporator to obtain 2.72 g of a slightly yellow oily substance. This oily matter was purified by column chromatography using 150 g of silica gel and n-hexane containing 5% of ethyl acetate to obtain 2.03 g of the title compound.
Yield 75.6%. NMR (CDCl ₃ , δppm): 1.48 (9H, s), 4.01 (2H, dd), 4.79 (1H,
s), 7.20 ~ 7.38 (5H, m), 12.51 (S) IR (neat) ν (cm ^-1 ): 1750,1734

Example 2 tert-butyl 2-chloro-4
Synthesis of-(1-naphthyl) -3-oxobuta

[Chemical 12]

Tert-Butyl 4-obtained in Reference Example 2
(1-naphthyl) -3-oxobutanoate 2.84 g and te
Dissolve 0.81 g of rt-butanol in 7 ml of methylene chloride,
At 0-10 ° C, 1.48 g of sulfuryl chloride was added to methylene chloride.
The solution dissolved in 1.5 ml was added dropwise over 55 minutes. 0-1
The reaction was carried out at 0 ° C. for 1 hour, 10 ml of water was added, and the layers were separated. The mixture was extracted with 5 ml of methylene chloride, the organic layers were combined, dried over magnesium sulfate, and the solvent was distilled off with an evaporator to obtain 3.476 g of a slightly yellow oily substance. 2.5 g of this oily substance was purified by column chromatography using 150 g of silica gel and n-hexane containing 5% of ethyl acetate to obtain 1.686 g of the title compound. Yield 7
3.5%. NMR (CDCl ₃ , δppm): 1.44 (9H, s), 4.46 (2H, dd), 4.81 (1H,
s), 7.38 ~ 7.56 (4H, m) 7.82 ~ 7.90 (3H, m) IR (KBr) ν (cm ^-1 ): 1760,1730

Example 3 tert-butyl 2-chloro-4
Synthesis of-(3-benzoylphenyl) -3-oxopentanoate

[Chemical 13]

Tert-Butyl 4-obtained in Reference Example 3
The reaction was carried out in the same manner as in Example 2 from 3.52 g of (3-benzoylphenyl) -3-oxopentanoate to give 3.999.
g of a pale yellow oil was obtained. 3 g of this oily substance was purified by column chromatography using 150 g of silica gel and n-hexane containing 5% of ethyl acetate to obtain 2.387 g of the title compound. Yield 82.2%. NMR (CDCl ₃ , δppm): 1.42 (9H, d), 1.50 (3H, d, J = 6.93), 4.
29〜4.51 (1H, m), 4.78 (1H, d), 7.43〜7.83 (9H, m), 12.79
(S) IR (neat) ν (cm ^-1 ): 1756,1728

Example 4 tert-butyl 2-chloro-4
-(2-Fluoro-4-biphenylyl) -3-oxopentanoate

[Chemical 14]

Tert-Butyl 4-obtained in Reference Example 4
From 3.42 g of (2-fluoro-4-biphenylyl) -3-oxopentanoate, the reaction was carried out in the same manner as in Example 1 to obtain 3.851 g of a slightly yellow oily substance. The oily matter was purified by column chromatography using 200 g of silica gel and n-hexane containing 5% of ethyl acetate to obtain 3.320 g of the title compound. Yield 88.1%. NMR (CDCl ₃ , δppm): 1.43 (9H, d), 1.49 (3H, d, J = 6.93Hz),
4.22-4.37 (1H, m), 4.81 (1H, d), 7.04-7.55 (8H, m) IR (neat) ν (cm ^-1 ): 1761,1733

Example 5 Methyl 2-chloro-4- (2
-Fluoro-4-biphenylyl) -3-oxopentanoate

[Chemical 15]

2.6 g of methyl 4- (2-fluoro-4-biphenylyl) -3-oxopentanoate obtained in Reference Example 5 was dissolved in 8 ml of methylene chloride, and methanol 2
77 mg was added, and a solution prepared by dissolving 1.40 g of sulfuryl chloride in 2.6 ml of methylene chloride was added thereto at room temperature. 30 at room temperature
Minute reaction, distilling off the solvent under reduced pressure with an evaporator,
3.24 g of a pale yellow oil was obtained. This oily substance was converted to silica gel.
Using n-hexane containing 200 g and 10% of ethyl acetate,
Purification by column chromatography gave 2.756 g of the title compound. Yield 95.1%. NMR (CDCl ₃ , δppm): 1.51 (3H, t, J = 6.93Hz), 3.70 to 3.85
(3H, m), 4.24 ~ 4.42 (1H, m), 4.91 (1H, d), 7.04 ~ 7.55 (8H,
m)

Example 6 Ethyl 2-chloro-4- (2
-Fluoro-4-biphenylyl) -3-oxopentanoate

[Chemical 16]

4 g of ethyl 4- (2-fluoro-4-biphenylyl) -3-oxopentanoate obtained in Reference Example 6 was dissolved in 12 ml of methylene chloride, and methanol 4
08 mg was added. Sulfuryl chloride 1.
A solution of 80 g dissolved in 4 ml methylene chloride was added over about 30 minutes. The reaction was carried out at 0 to 5 ° C for 3 hours, and the solvent was distilled off under reduced pressure with an evaporator to obtain 4.86 g of a slightly yellow oily substance.
The oily matter was purified by column chromatography using 340 g of silica gel and n-hexane containing 10% of ethyl acetate to obtain 3.911 g of the title compound. Yield 90.1%. NMR (CDCl ₃ , δppm): 1.20 to 1.38 (3H, m), 1.51 (3H, t, J =
6.93Hz), 4.04 ~ 4.27 (2H, m), 4.08 ~ 4.38 (1H, m), 4.89
(1H, d), 7.04 ~ 7.55 (8H, m), 12.68 (S) IR (neat) ν (cm ^-1 ): 1762,1740

Example 7 Isopropyl 2-chloro-4
-(2-Fluoro-4-biphenylyl) -3-oxopentanoate

[Chemical 17]

Isopropyl 4 (2 obtained in Reference Example 7
3.28 g of -Fluoro-4-biphenylyl) -3-oxopentanoate was dissolved in 7 ml of methylene chloride and 660 mg of 2-propanol was added. A solution prepared by dissolving 1.48 g of sulfuryl chloride in 1.5 ml of methylene chloride at 0 to 5 ° C. was added thereto over about 1 hour. The reaction was carried out at 0 to 5 ° C for 1 hour, and the solvent was distilled off under reduced pressure with an evaporator to obtain 3.95 g of a slightly yellow oily substance. 2.5 g of this oily substance was purified by column chromatography using 200 g of silica gel and n-hexane containing 5% of ethyl acetate to obtain 1.88 g of the title compound.
Yield 82.1%. NMR (CDCl ₃ , δppm): 1.13 to 1.36 (6H, m), 1.48 to 1.53 (3
H, d), 4.23 ~ 4.51 (1H, m), 4.86 (1H, d), 4.93 ~ 5.15 (1H,
m), 7.05 ~ 7.55 (8H, m), 12.76 (S) IR (neat) ν (cm ^-1 ): 1761,1734

Reference Example 8 1-Chloro-3-phenyl-2
-Synthesis of propanone

[Chemical 18]

2 g of tert-butyl 2-chloro-4-phenyl-3-oxobutanoate obtained in Example 1 was dissolved in 12 ml of toluene, 36 mg of methanesulfonic acid was added, and the mixture was heated at 70-80 ° C. for 2 hours. Reacted for 30 minutes. The mixture was cooled to room temperature, 10 ml of water was added, the layers were separated, and further washed with 10 ml of water three times. After drying with magnesium sulfate,
When toluene was distilled off with an evaporator, 1.305 g of a slightly yellow oily substance was obtained. This oily substance was purified by column chromatography using 80 g of silica gel and n-hexane containing 10% of ethyl acetate to give the title compound 1.1.
91 g were obtained. Yield 95.4%. _{NMR (CDCl 3, δppm):} 3.89 (2H, s), 4.12 (2H, s), 7.21 ~7.
40 (5H, m)

Reference Example 9 Synthesis of 1-chloro-3- (1-naphthyl) -2-propanone

[Chemical 19]

Tert-Butyl 2-chloro-3- (1-naphthyl) -3-oxobutanoate obtained in Example 2
1.673 g was reacted according to the method of Example 8 and further purified by silica gel chromatography to obtain 1.145 g of the title compound. Yield 99.4%. _{NMR (CDCl 3, δppm):} 4.09 (2H, s), 4.33 (2H, s), 7.41 ~7.
91 (7H, m)

Reference Example 10 Synthesis of 1-chloro-3- (benzoylphenyl) -2-butanone

[Chemical 20]

2.026 g of tert-butyl 2-chloro-4- (3-benzoylphenyl) -3-oxopentanoate obtained in Example 3 was reacted according to the method of Example 8,
Further, it was purified by silica gel column chromatography to obtain 1.441 g of the title compound. Yield 96.0%. NMR (CDCl ₃ , δppm): 1.49 (3H, d, J = 6.93Hz), 4.09 (2H, d),
4.16 (1H, q, J = 6093Hz), 7.44〜7.82 (9H, m)

Reference Example 11 1-chloro-3- (2-fluoro-4-biphenylyl) -2-butanone

[Chemical 21]

Tert-Butyl 2-chloro-4- (2-fluoro-4-biphenylyl) -3 obtained in Example 4
3.051 g of -oxopentanoate was reacted according to the method of Example 8 and further purified by silica gel column chromatography to obtain 2.041 g of the title compound. Yield 91.1
%. NMR (CDCl ₃ , δppm): 1.48 (3H, d, J = 6.93Hz), 4.07 (1H, q, J
= 6.93Hz), 4.10 (2H, d), 7.03 ~ 7.55 (8H, m)

Comparative Example 1 tert-butyl 2-chloro-4
Synthesis of -phenyl-3-oxobutanoate tert-butyl 4-phenyl-3-obtained in Reference Example 1
A solution of 2.34 g of oxobutanoate dissolved in 7 ml of methylene chloride and 1.48 g of sulfuryl chloride in 1.5 ml of methylene chloride was added at 0-5 ° C over 1 hour. 0-5 ° C
After reacting for 4 hours, 500 mg of sodium bicarbonate was added, and the mixture was reacted for 1 hour and filtered. The solvent was distilled off under reduced pressure with an evaporator to obtain 2.538 g of a slightly yellow oily substance. The oily matter was purified by column chromatography using 150 g of silica gel and n-hexane containing 5% of ethyl acetate to obtain 1.902 g of the title compound. Yield 70.8%.

Comparative Example 2 tert-butyl 2-chloro-4
Synthesis of-(1-naphthyl) -3-oxobutanoate (without addition of alcohol) 2.84 g of tert-butyl 4- (1-naphthyl) -3-oxobutanoate obtained in Reference Example 2 was salified. A solution prepared by dissolving 1.48 g of sulfuryl chloride in 1.5 ml of methylene chloride was added at 0-5 ° C. over 1 hour. 0 to
After reacting at 5 ° C for 7 hours, 10 ml of water was added to separate the layers. After drying with magnesium sulfate, the solvent was distilled off under reduced pressure with an evaporator to obtain 3.254 g of a slightly yellow oily substance. 2.5 g of this oily substance was purified by column chromatography using 150 g of silica gel and n-hexane containing 5% of ethyl acetate to obtain 1.515 g of the title compound. Yield 61.9%.

Comparative Example 3 tert-butyl 2-chloro-4
Synthesis of-(3-benzoylphenyl) -3-oxopentanoate (when no alcohol is added) 3.52 g of tert-butyl 4- (3-benzoylphenyl) -3-oxopentanoate obtained in Reference Example 3 Was reacted in the same manner as in Comparative Example 2 to obtain 4.024 g of a slightly yellow oily substance. The oil (3.0 g) was purified by column chromatography using 200 g of silica gel and n-hexane containing 5% of ethyl acetate to give the title compound (1.953 g). Yield 67.7%.

Comparative Example 4 tert-butyl 2-chloro-4
Synthesis of-(2-fluoro-4-biphenylyl) -3-oxopentanoate (when alcohol is not added) tert-butyl 4- (2-fluoro-4-biphenylyl) -obtained in Reference Example 4 3-oxopentanoate 1
From 0 g, the reaction was carried out in the same manner as in Comparative Example 2 to obtain 11.17 g of a slightly yellow oily substance. 10.17 g of this oily substance was added to silica gel.
Purification by column chromatography using 500 g and n-hexane containing 5.5% ethyl acetate gave 5.30 g of the title compound. Yield 48.1%. Table 2 shows yields of Examples according to the present invention and Comparative Examples in which alcohol is not added. The results show that the present invention in the presence of alcohol is excellent.

[0049]

[Table 2]

Claims (1)

[Claims] 1. A compound represented by the general formula [I]: [Wherein R ₁ is a lower alkyl group or a lower alkenyl group, R ₂ is a hydrogen atom or a lower alkyl group, and R ₃ is a phenyl group optionally substituted with a halogen atom, or a halogen atom substituted Optionally a naphthyl group,
Or the general formula A ₁ -D-A ₂ (wherein A ₁ is a phenyl group optionally substituted with a halogen atom, A ₂ is a phenylene group optionally substituted with a halogen atom, and D is a carbonyl group). Group or a group represented by a single bond). ] The β-ketoester derivative represented by the formula and sulfuryl chloride are reacted in an inert solvent in the general formula [II] [In the formula, R ₁ , R ₂ and R ₃ have the same meanings as described above. ] In the method for producing an α-chloro-β-ketoester derivative represented by the formula, the reaction is carried out by the general formula R ₁ OH [wherein
R ₁ has the same meaning as described above. ] The method for producing an α-chloro-β-ketoester derivative represented by the above general formula [II], which is carried out in the presence of an alcohol represented by the formula [II].