JPH04210941A - Hydroxyiminoheptanoic esters and production thereof - Google Patents

Abstract

PURPOSE:To provide a novel hodroxyiminoheptanoic ester highly useful as an intermediate for cilastatin and a beta-oxoacid ester as a raw material for the production thereof. CONSTITUTION:The objective compound of formula I (R<1> is 1-6C alkyl; X is Cl or Br) (e.g. methyl 7-chloro-2-hydroxyiminoheptanoate) and the other objective compound of formula II [R<2> is 1-5C alkyl or OR<3>; R<3> is 1-6C alkyl) (e.g. a 7- halo-2-(1-oxoethyl)-heptanoic ester]. The former compound can be obtained by reaction at 0-50 deg.C for 10min to 24hr between (A) a compound of formula II and (B) a nitrosating agent of formula III (R<4> is H, alkyl, halogen or SO3H), while the compound of the formula III can be obtained by reaction in the presence of a base at 50-150 deg.C between (C) a halopentane derivative of formula IV (Y is halogen) and (D) a beta-oxoacid derivative of formula V.

Description

[Detailed description of the invention]

[0001]

[Industrial Field of Application] The present invention relates to hydroxyiminoheptanoic acid esters represented by the general formula [1] and a method for producing the same, a method for producing a haloketoacid derivative [3] using the same,
Furthermore, the present invention relates to β-oxoacid esters represented by the general formula [2] and a method for producing the same. [0002]

[1]

The hydroxyiminohebutanoic acid esters represented by the formula (wherein R1 and X have the same meanings as above) are not known. [0003] Further, as halogen-substituted β-oxo acid esters, β-oxo acid ester derivatives represented by the general formula [8] [8] (wherein R1 and X have the same meanings as above) are Although it is known,
General formula [2] [2] (In the formula, R1 and X have the same meanings as above. R2 represents an alkyl group having 1 to 5 carbon atoms or an OR3 group. Here, R3 The β-oxoacid esters represented by (representing an alkyl group) are not known. [0004] The present inventors synthesized various hydroxyimino acid esters and β-oxo acid esters, and as a result of studying these, the above-mentioned hydroxyiminohebutanoic acid esters [1] and β-oxo acid esters [ 2] is
Haloketo acid derivatives represented by the general formula [3] [3] (wherein, X has the same meaning as above, and R represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms), which is the raw material for Shirasufutin ( J.Med.Chem.1987,3
0.1074) was found to be an important intermediate, leading to the present invention. [0005]

[Means for Solving the Problems] That is, the present invention provides a hydroxyiminohebutanoic acid ester represented by the general formula [1], a method for producing the same, and a haloketo acid derivative using the same.
The present invention also provides a method for producing compound [3], as well as β-oxoacid esters represented by general formula [2], which are important raw materials for producing compound [1], and a method for producing the same. [00061 Hereinafter, the present invention will be described in detail. The β-oxoacid esters [2] of the present invention have the general formula [5] [5] (wherein, X represents the same meaning as above, and Y is a halogen atom (however, when X is a chlorine atom, Y is is not a fluorine atom, and when X is a bromine atom, Y is neither a fluorine atom nor a chlorine atom) or a methanesulfonyloxy group or p
-Represents a toluenesulfonyloxy group. ) and a β-oxoacid derivative represented by the general formula [6] [6] (wherein R1 and R2 have the same meanings as above) in the presence of a base. can do. [0007] In this reaction, the halopentane derivative [5] used is, for example, 1,5-dichloropentane, 1-bromo-5-chloropentane, 1-iodo-
Dihalopentane such as 5-chloropentane, 1,5-dibromopentane, 1-bromo-5-iodopentane, 5-halopentyl sulfonate such as 5-chloropentyl methanesulfonate, 5-chloropentyl p-toluenesulfonate, etc. Preferred examples include 1,5-dichloropentane, ■-bromo-5-chloropentane, ■-iodo-5-chloropentane, 5-chloropentyl methanesulfonate, and 5-chloropentyl p-toluenesulfonate. . [0008] Further, as the β-oxoacid derivative [6], for example, acetoacetate, 3-oxopentanoate, 3-oxohexanoate, 3-oxoheptanoate, 3-oxooctanoate, etc. Examples include 3-oxo acid esters and malonic acid diesters, and acetoacetic acid ester and malonic acid diester are preferably used. Here, the substituent R1 may be a linear or branched alkyl group such as a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, or a hexyl group. In addition, when the β-oxoacid derivative [6] is a malonic acid diester, that is, R2 is 10R3
In this case, R1 and R3 are preferably the same substituent. [0009] The molar ratio of the halopentane derivative [5] and the β-oxoacid derivative [6] is usually around an equimolar ratio, but either of the above compounds [5] or [6] may be charged in excess. .

Bases used in the reaction include sodium alkoxides such as sodium methoxide and sodium ethoxide, potassium methoxide, potassium ter
Examples include potassium alkoxides such as t,-butoxide, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, and alkali metal carbonates such as sodium carbonate and potassium carbonate. The amount used is 1 mole or more, usually 1 to 3 times the mole of the halopentane derivative.

[0011] Although the reaction can be carried out without a solvent, it is also possible to use a solvent. Examples of solvents include alcohols such as methanol, ethanol, and isopropyl alcohol, aromatic solvents such as toluene and xylene, halogenated aromatic solvents such as chlorobenzene and 0-dichlorobenzene, n-hexane, n-hebutane, and cyclohexane. Examples include aliphatic solvents such as , and ketone solvents such as methyl isobutyl ketone. [0012] The reaction temperature can be generally carried out in the range of 0 to 300°C, preferably in the range of 50 to 150°C. The reaction time is not particularly limited. [0013] Furthermore, when using an alkali metal hydroxide as a base, it may be better to carry out the reaction while removing generated water. [0014] After the reaction is completed, the produced salt is removed by filtration or dissolved in water, extracted, and the solvent is distilled off to obtain β-oxoacid esters represented by the general formula [2]. It can be purified by distillation if necessary, but it can also be used unpurified in the next step. [0015] The β-oxo acid esters [2] thus obtained are 7-halo 2-(1-oxoethyl)
hebutanoic acid ester, 7-halo 2-(1-oxopropyl)-hebutanoic acid ester, 7-halo 2-(1-oxobutyl)-heptane ester, 7-halo 2-(1
oxopentyl)-heptanoic acid ester, 7-baro2-
β- such as (1-oxohexyl)-hebutanoic acid ester
Keto acid esters, 7-vallocalpomethoxyhebutanoate, 7-vallocalpoethoxyhebutanoate, 7-vallocalpoproboxyhebutanoate, 7-vallocalpobutoxyhebutanoate, Examples include diesters such as 7-vallocalpopentoxyhebutanoate and 7-vallocalpohexoxyhebutanoate (halo means chloro or bromo). [0016] Furthermore, the hydroxyiminohebutanoic acid esters [1] of the present invention are combined with the β-oxoacid esters [2] and the general formula [4] 0NOR4 (4) (wherein, R4 is a hydrogen atom, an alkyl group, It is obtained by reacting with a nitrosating agent represented by (representing a halogen atom or a 5OsH group). [0017] As the β-oxoacid ester [2], the above-mentioned ones are used, but preferably 7-chloro-2
(1-oxoethyl)-heptanoic acid ester, 7-chloro-2-carbomethoxy-hebutanoic acid ester, 7-chloro-2-carboethoxy-hebutanoic acid ester are used. [0018] Examples of the nitrosating agent [4] include methyl nitrite, ethyl nitrite, propyl nitrite, butyl nitrite, pentyl nitrite, hexyl nitrite, heptyl nitrite, octyl nitrite, nonyl nitrite, and Nitrite alkyl esters such as decyl nitrate, nitrosyl halides such as nitrosyl chloride, nitrosyl sulfuric acid, or nitrous acid can be mentioned, and nitrite alkyl esters usually include methyl nitrite, ethyl nitrite, and propyl nitrite. , lower alkyl esters such as butyl nitrite are used. Furthermore, nitrite alkyl esters may be generated and used within the reaction system. An example of this method is to prepare nitrites such as sodium nitrite or potassium nitrite and alcohols such as methanol, ethanol, propatool, butanol, pentanol, hexanol, etc., and then add an acid to the mixture. I can give it to you. [0019] The amount of the nitrosating agent used is 1 mole or more relative to the β-oxoacid ester [2], and usually 1 mole or more.
~3 moles are used. [00201 reaction degree is usually -10 to 80°C,
Preferably it is 0 to 50°C. The reaction time is not particularly limited, but is usually 10 minutes to 24 hours. [0021] A solvent can also be used in the reaction. Any solvent can be used as long as it does not inhibit the reaction, such as n-hebutane, n-hexane,
Examples include hydrocarbons such as cyclohexane and halogenated hydrocarbons such as 1,2-dichloroethane. Furthermore, when a nitrite alkyl ester is used as the nitrosating agent [4], a corresponding alcohol, for example n-butanol for n-butyl nitrite, can also be used. [0022] Also, in the reaction, water, alcohol, etc. may be added as additives for the purpose of promoting the reaction. [0023] The reaction product thus obtained,
Hydroxyiminoheptanoic acid esters [1] can also be obtained by performing normal operations such as extraction and concentration, but the compound [1] can be used as a raw material for the next step without isolating it from the reaction solution. You can also do it. [0024] Hydroxyiminohebutanoic acid esters [1], which are compounds of the present invention, are thus obtained. If such hydroxyiminohebutanoic acid esters [1] are used, for example, haloketo acid derivatives (3) which are intermediates of cirasufuthin (J, Med, Chem, 1987.3)
0.1074) can be advantageously produced. [0025] Conventional methods for synthesizing the haloketo acid derivative [3] include a) a method in which 1-bromo-5-halopentane is reacted with magnesium in a THF solvent, and then reacted with diethyl oxalate (JP-A-6O-248612
Lb) A method of reacting an L3-dithiane derivative with 1,5-dibromopentane (J, Med, Chem. 1987.30, 1074) is known. [0026] However, in both of the above techniques, it is necessary to strictly control the water content in the reaction, and in a) it is difficult to recover the solvent with high purity, and in b), the 1,3-dithiane used Derivatives are expensive, etc.
It was not satisfactory for industrial production. [0027] On the other hand, in the method using hydroxyiminoheptanoic acid esters [1], for example, hydroxyiminoheptanoic acid esters [1] are reacted with aldehydes or ketones in the presence of an acid to form a haloketoacid derivative. [3] can be obtained. [0028] Examples of acids used here include commonly used inorganic or organic acids such as hydrochloric acid, sulfuric acid, nitric acid, and acetic acid. The amount used is not particularly limited, but it is usually at least 0.001 mole, preferably 0.0 mole, relative to the hydroxyiminohebutanoic acid ester [1].
It is 1 mole or more. [0029] Also, in the previous step, a nitrosating agent [4]
When nitrosyl sulfuric acid is used as the nitrosyl sulfuric acid and the reaction is carried out without isolating the hydroxyiminoheptanoic acid ester [1], it is not necessary to add an acid because the nitrosyl sulfuric acid becomes sulfuric acid after the nitrosation reaction.

Examples of the aldehydes used include formalin, glyoxylic acid, glyoxal, acetaldehyde, and propionaldehyde, and examples of the ketones include diacetyl. The amount used is 1 mole or more relative to the hydroxyiminohebutanoic acid ester [1], and usually 1 to 1 mole.
It is preferable to use 5 times the mole amount. [0031] The reaction time is not particularly limited, but is usually 1 to
It is 24 hours. The reaction temperature is usually 0 to 70°C, preferably 5 to 40°C. [0032] After completion of the reaction, the reaction product is subjected to conventional post-treatment operations such as extraction, liquid separation, neutralization, and solvent distillation to obtain a haloketoacid derivative represented by the general formula [3]. [0033]

Effects of the Invention The hydroxyiminoheptanoic acid esters [1], which are the compounds of the present invention, are extremely useful as intermediates for cirasufuthin. Furthermore, the method for producing haloketo acid derivatives via hydroxyiminohebutanoic acid esters [1] is industrially more advantageous than conventional methods. Furthermore, hydroxyiminoheptanoic acid esters [1] can be easily obtained from β-oxo acid esters [2], and the β-oxo acid esters [2] are also obtained from halopentane derivatives [5] and β-oxo acid derivatives. It can be easily produced from [6]. [0034]

[Examples] The present invention will be explained in more detail with reference to Examples below, but the present invention is not limited to the Examples. [0035] Example 1 Ethyl acetoacetate (6-1:) 2260.2 g (2,
0 mol), 300 g of methyl isobutyl ketone and 1
-Bromo-5-chloropentane [:5-1] 311.0
g (1.68 mol) was added and the temperature was 80-90°C. Add 300g of anhydrous potassium carbonate to it and leave for 12 hours.
The reaction was carried out at 80-90°C. Then add 34% potassium carbonate
1.4g was added and the reaction was further continued for 6 hours. After the reaction was completed, it was filtered, and the methyl isobutyl ketone layer was washed with water and then concentrated under reduced pressure. Concentrated residue 398.6g Ethyl 7-chloro-2-(1-oxoethyl)-heptanoate content 70.8% Yield 72.6% This was purified by column chromatography to obtain pure 7-chloro-2-(1-oxoethyl)-heptanoate.
Ethyl (oxoethyl)-hebutanoate [2-1] was obtained. [0036] Example 2 135 g of ethanol was added to 684 g (2,92 mol) of ethyl 7-chloro-2-(1-oxoethyl)-hebutanoate (2-1) and cooled to 5° C. While maintaining the temperature, 43゜5% nitrosyl sulfate [4-1]-
941 g (3.22 ml) of sulfuric acid solution was added dropwise over 1 hour. Thereafter, the mixture was stirred at 5°C for 1 hour at 20°C. 1000g toluene in another flask
and 487 g of 36% formalin aqueous solution (5,84 mo
l) was taken and heated to 2025°C. The above reaction solution was added dropwise into the solution over a period of 1 hour. After keeping the temperature for 2 hours, the mixture was separated and the toluene layer was separated. The toluene layer was neutralized with saturated sodium bicarbonate solution, and then the neutralized aqueous layer was separated. The toluene layer was washed with water and concentrated under reduced pressure to give ethyl 7chloro-2-oxoheptanoate (3-1) 501
g (2.42 mol) was obtained. Yield 83.0% [0037] Example 3 208 g (0,886 mol) of ethyl 7-chloro-2-(1-oxoethyl)-hebutanoate [2-1] was dissolved in 5
After cooling to ℃, 43.5% nitrosyl sulfate (4-1
) - 310.4 g (1,06 mol) of sulfuric acid solution and 31 mol of water
．． A mixed solution of 9 g was added dropwise over 1 hour while maintaining the temperature at 5°C. After stirring for 1 hour at 5℃,
℃. In another flask, add 200 ml of 1,2 dichloromethane.
g and 36% formalin aqueous solution 110°7g (1,3
3 mol) was taken and heated to 20-25°C. The above reaction solution was added dropwise into the solution over a period of 1 hour. After keeping the temperature for 2 hours, the mixture was separated, and the 2-dichloroethane layer was separated. (2) The 2-dichloroethane layer was neutralized with saturated sodium bicarbonate solution, and then the neutralized aqueous layer was separated. The 1,2-dichloroethane layer was washed with water and concentrated under reduced pressure to give ethyl 7-chloro-2-oxoheptanoate (
3-1) 149g (0,721mol) was obtained. Yield 81.4%

Example 4 Methyl 7-chloro-2-(1-oxoethyl)-heptanoate (2-2) 6.5 g (0,0295 mol)
After adding 50 g of n-hebutane to and cooling to 5°C, 43.
A mixed solution of 5% nitrosylsulfuric acid aqueous solution and 0.531 g of water was added dropwise over 1 hour while maintaining the temperature at 5°C. Thereafter, the mixture was stirred at 5°C for 1 hour and then heated to 20°C. In another flask, 15 g of 36% formalin aqueous solution (0,1
80 mol) was taken and heated to 20-25°C. The above reaction solution was added dropwise into the solution over a period of 1 hour. After keeping the temperature for 1 hour, 100 g of n-hebutane was further added to separate the layers, and the n-hebutane layer was separated. The n-hebutane layer was neutralized with saturated sodium bicarbonate solution, and then the neutralized aqueous layer was separated. The n-hebutane layer was washed with water and concentrated under reduced pressure to obtain 3.4 g (0,0176 mol) of methyl 7-chloro-2-oxoheptanoate (3-2). Yield 60% [0039] Example 5 Ethyl acetoacetate [:6-1) 109.3g, n-
100 g of hebutane and 185.5 g of 1-bromo-5-chloropentane (5-1) were added and the temperature was raised to 90°C. 193.5 g of anhydrous potassium carbonate was added little by little to the mixture, and 100 g of 1-bromo-5-chloropentane (5-1) was added.
The mixture was heated and stirred at 0°C for 14 hours. After that, it was filtered using Nutsche, and the n-hebutane layer was combined with the previous n-hebutane layer.
347 g of a hebutane solution of crude ethyl 7-chloro-2-(1-oxoethyl)-hebutanoate (2-1) was obtained. 7-
Ethyl chloro-2-(1-oxoethyl)-hebutanoate content 44.3%

After cooling 347 g of the hebutane solution of crude ethyl 7-chloro-2-(1oxoethyl)-heptanoate [2-1] obtained here to 5° C., a 43.5% nitrosyl sulfuric acid-sulfuric acid solution was added. A mixed solution of 227 g and 12.7 g of water was added dropwise over 1 hour while maintaining the temperature at 5°C. Then, take 200g of 36% formalin aqueous solution and
The temperature was 25°C. The above reaction solution was added dropwise into the solution over a period of 1 hour. After keeping the temperature for 2 hours, 400 ml of water was added to separate the heptane layer. This heptane layer was neutralized with saturated sodium bicarbonate solution, and then the neutralized aqueous layer was separated. The heptane layer was washed with water and then concentrated under reduced pressure to obtain 145.2 g (content: 82.0%) of ethyl 7-chloro-2-oxoheptanoate (3-1). Yield 68.9% (based on ethyl acetoacetate) [0041
1 Example 6 Methyl acetoacetate [6-2] 127.7g (1,1
mol) and 200 g of methanol were taken and heated to 30°C. 28.1% sodium methoxide/methanol solution 1
92 g (1.0 mol) was added dropwise and stirred for 1 hour. Then 1-bromo-5-chloropentane [5-1) 1
Add 55.5g (0,838mol) and heat at 70°C.
Time reacted. After the reaction is complete, the reaction solution is concentrated under reduced pressure.
500 g of toluene was added thereto, and the precipitated salt was filtered. The toluene layer was washed with water and then concentrated under reduced pressure to obtain 189.9 g of methyl 7-chloro-2-(1-oxoethyl)-hebutanoate [2-2]. Content 88.7%
Yield 91.2% b, p, 118-120℃ 10.6
-0.7mmHgN, M, R, (60MHz, C
DC13) δ (ppm) 1.0-2.1 (m,
8) 2.2(s, 3) 3.3-3.7(m
, 3) 3.8 (s, 3) [0042] 443.3 g of methyl 7-chloro-2-(1-oxoethyl)-heptanoate (2-2:) obtained above (content 88.7%,
0.174 mol) were added with 36.0 g of sodium nitrite and 130 g of methanol, and the mixture was cooled to 0°C. 51.2 g (0,522 mol) of concentrated sulfuric acid was added dropwise thereto over 3 hours. Thereafter, the mixture was stirred at 0° C. for 48 hours. Thereafter, the reaction solution was concentrated under reduced pressure. Furthermore, 200 g of toluene and 200 g of water were added thereto, and after stirring, the mixture was separated to obtain a toluene layer. The toluene layer was dried over magnesium sulfate and concentrated. The concentrated reaction solution was purified by column chromatography to obtain 25.8 g of methyl 7-chloro-2-hydroxyiminohebutanoate (1-2). Yield 71.5% N, M, R, ( 60MHz, CDC13)
δ(1)1)m) 1.3-2.2(m, 7)2.
5-2゜9 (m, 2) 3.5 (t, 2.J=5
．． 4Hz) 4.9 (s, 3) [0043] Example 7 Ethyl acetoacetate (6-1) 260.2g (2,0m
ol), 300 g of methyl isobutyl ketone and 311.0 g of 1-bromo-5-chloropentane [5-1] (
1.68 mol) was added thereto, and the temperature was set at 80-90°C. Add 300g of anhydrous potassium carbonate to it and leave it for 12 hours at 80-
The reaction was carried out at 90°C. Then add potassium carbonate to 341.4
g was added, and the reaction was further continued for 6 hours. After the reaction was completed, it was filtered, and the methyl isobutyl ketone layer was washed with water and then concentrated under reduced pressure to obtain crude ethyl 7-chloro-2-(1-oxoethyl)-hebutanoate [2-1:]. Concentrated residue 398.6
g Content 70.8% Yield 72.6% N, M, R, (60MHz, CDC13) δ
(ppm) 1.0-2.1 (m, 13) 2.2
(s, 3) 3.2-4.7 (m, 3)4.
2 (q, 2. J = 7.6 Hz) [0044] Example 8 Ethyl acetoacetate [6-1:] 2260.6 g (2,
0 mol) ,) 300 g of toluene and 1-bromo-5-
Chloropentane [5-1] 311.0g (1,68m
ol) was added and the temperature was 80-90°C. 300 g of anhydrous potassium carbonate was added thereto, and the mixture was heated to 100°C and reacted at the same temperature for 18 hours. After the reaction was completed, it was filtered, and the toluene layer was washed with water and then concentrated under reduced pressure to obtain crude ethyl 7-chloro-2-(1-oxoethyl)-hebutanoate [2-1]. Concentrated residue 403.8g Content 68.8% Yield 69.1% [0045] Example 9 Ethyl acetoacetate [6-1] 218.6g, n-hebutane 200g and 1-bromo-5-chloropentane (
5-1: ] 371. Add Og (2.0 mol) and
The temperature was 0°C. In it, 387g of anhydrous potassium carbonate (2
, 8 mol) was added thereto, and the mixture was heated and stirred at 100° C. for 12 hours. Thereafter, it was filtered using Nutsche to obtain an n-hebutane layer. The solid material on top of the Nutsche also contains 300g of n-hebutane.
The n-hebutane layer was combined with the previous n-hebutane layer and concentrated under reduced pressure to obtain 449.2 g of crude ethyl 7-chloro-2-(1-oxoethyl)-hebutanoate (2-1). Obtained. Ethyl 7-chloro-2-(1-oxoethyl)-hebutanoate content 74.1% 1-bromo-5-chloropentane content 22.1% Yield (based on ethyl acetoacetate) 84.4% recovery rate (1 -Bromo-5-chloropentane basis) 97°7% [0046] Ethyl 7-chloro-2-(1-oxoethyl)-hebutanoate [2-1:] obtained above 1198
．． 9 g (content 74.1%, 0.63 mol) was cooled to 5°C. 220 g (0.75 mol) of a 43.5% nitrosyl sulfuric acid-sulfuric acid solution was added dropwise thereto over 1 hour. Thereafter, the mixture was stirred at 5°C for 1 hour at 20°C. 500 g of toluene, 200 g of water, and 10 g of sulfamic acid were placed in another flask and heated to 10°C. The above reaction solution was added dropwise into the solution. After stirring for 1 hour, the liquid was separated and the toluene layer was separated. The toluene layer was neutralized with saturated sodium bicarbonate solution, and then the neutralized aqueous layer was separated. The toluene layer was washed with water and concentrated under reduced pressure.
-Ethyl chloro-2-hydroxyiminoheptanoate (1
-1) 124.3g was obtained. Yield 89.3% Melting point 36-38°C N, M, R, (60 MHz, CDC13) δ(I
)I)m) 1.1-2.1(m, 10) 2.3
-3゜9(m, 2) 3.5(t, 2.J=6.0) 4.3(q, 2
．． J = 7.0 Hz) [0047] Example 10 The toluene solution of ethyl 7-chloro-2-hydroxyiminoheptanoate (1-1) obtained in Example 9 was further reduced to 36% without performing vacuum concentration. Ethyl 7-chloro-2-oxohbutanoate [3-1] is obtained by dropping it into an aqueous formalin solution, then adding sulfuric acid, keeping it warm, adding water, separating, neutralizing, washing with water, and concentrating under reduced pressure. [0048] Example 11 28% Sodium Methylate/Methanol Solution 19.3
g and 50 g of methanol were placed in a flask, cooled to 0°C, 13.2 g of dimethyl malonate (6-3:) was added, and the mixture was stirred at 50°C for 1 hour.Thereafter, 1-bromo-5chloropentane [ 5-11] 18.6 g was added and stirred for 14 hours under reflux conditions.The reaction solution was concentrated under reduced pressure, and then 200 g of toluene and 100 g of water were added.
It was further stirred. Thereafter, the organic layer was separated, 10 g of magnesium sulfate was added to the organic layer, and the mixture was filtered, and the organic layer was further concentrated. 35.3 g of 43.5% nitrosyl sulfuric acid-sulfuric acid solution was placed in another flask and cooled to 0°C. The previously concentrated organic layer was added dropwise into the solution over a period of 1 hour. 1 at 0℃
After stirring for an hour, the mixture was heated to 20° C. and further stirred for 1 hour. 100 g of toluene and 100 g of a 10% formalin aqueous solution were placed in another flask and cooled to 5°C. The above reaction solution was added dropwise into the solution over 1 hour. Thereafter, the mixture was kept at 5°C for 1 hour and then stirred at 20°C for 12 hours. The organic layer was separated, washed with water, added with 5 g of magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 24 g of crude methyl 7-chloro-2-oxoheptanoate. This coarse 7-
By distilling methyl chloro-2-oxoheptanoate under reduced pressure, 14.3 g of methyl 7-chloro-2-oxoheptanoate [32] was obtained.

Claims (5)

[Claims] Claim 1: General formula [1] [1] (wherein R1 represents an alkyl group having 1 to 6 carbon atoms, and
represents a chlorine atom or a bromine atom. ) Hydroxyiminoheptanoic acid esters. [Claim 2] General formula [2] (2) (wherein R1 and represents an alkyl group having 1 to 6 carbon atoms) and the general formula [4]0NO
R4 (4) (wherein R4 represents a hydrogen atom, an alkyl group, a halogen atom or a 5O3H group) A hydroxyimino compound represented by the general formula [1] characterized in that it is reacted with a nitrosating agent represented by the following formula: A method for producing heptanoic acid esters. 3. The β-oxoacid esters represented by the general formula [2] have the general formula [5] [5] (wherein, X represents the same meaning as above, and Y represents a halogen atom (provided that X When is a chlorine atom, Y is not a fluorine atom, and when X is a bromine atom, Y is neither a fluorine atom nor a chlorine atom. and a β-oxoacid derivative represented by the general formula [6] [6] (wherein R1 and R2 have the same meanings as above) in the presence of a base. 3. The method of claim 2, characterized in that: [Claim 4] General formula [2] (2) (In the formula, R1, R2 and X have the same meanings as above. ) β-oxoacid esters represented by Claim 5: Hydroxyiminohebutanoic acid esters [
General formula [3] [3] characterized by reacting [1] with aldehydes or ketones in the presence of an acid [3] (wherein, (representing an alkyl group).