JPH03101637A - Novel ketoester and its production - Google Patents

Abstract

NEW MATERIAL:A ketoester expressed by formula I (R<1> and R<2> are alkyl, alkenyl, cycloalkyl or aralkyl or acetal type protecting groups capable of together forming alkylene; R<3> to R<5> are H, alkyl, alkenyl, aryl, cycloalkyl or aralkyl). EXAMPLE:Methyl 5-(dimethoxymethyl)-3-methoxycarbonyl-2-oxaheptanate. USE:An intermediate of 2-(2-imidazolin-2-yl)pyridines useful as herbicides, capable of readily producing them inexpensively and readily from an easily obtainable raw material in high yield. PREPARATION:A compound expressed by formula II is reacted with a compound expressed by formula III (R<6> is each group in R<5>) in the presence of a base to provide the compound expressed by formula I. The above-mentioned herbicides expressed by formula IV can be readily produced in high yield from the compound I through compounds expressed by formula V to formula VI.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a ketoester represented by the general formula (1) and a method for producing the same. The ketoester represented by the general formula (1) provided by the present invention is an intermediate of the herbicide, 2-(2-imidazolin-2-yl)pyridine, as described below.
V) (In the formula, R1 and Rz are the same or different and represent an alkyl group, an alkenyl group, a cycloalkyl group, or an aralkyl group, or together represent an acetal-type protecting group for an alkylene group, and R ', R' and Rs are the same or different and each represent a hydrogen atom, an alkyl group, an alkenyl group, an aryl group, a cycloalkyl group or an aralkyl group). Useful.

[Problems to be solved by conventional techniques and inventions] Conventionally,
It is known that the pyridine-2,3-dicarboxylic acid derivative represented by the general formula (IV) can be produced by the following method.

Jsu lower margin (in the formula, X represents a halogen atom such as chlorine, bromine, iodine, etc.) N-monosubstituted-l-azadiene and electrophilic olefin are reacted to form 5-monosubstituted pyridine-2,3-dicarboxylic acid. Method for producing derivatives (European Patent Application Publication No. 0161)
(See Specification No. 221 (1985)). (2) A method in which quinoline or its derivatives are oxidized with ozone or an oxidizing agent such as potassium permanganate to cleave the benzene ring and synthesize pyridine-2,3-dicarboxylic acid or its derivatives (Rec. Trav. Chim. 1 Sat,
24 1 (1955)). However, all of these methods require expensive raw materials and are difficult to assemble.
In addition, it is difficult to obtain the product because it is dangerous to handle, the yield of the final substance is low, and a large amount of by-products are produced, so it takes a lot of effort to obtain a product with high purity. There are many issues such as what is required.

Therefore, the object of the present invention is to provide a new biridine-2,3-dicarboxylic acid derivative which can be easily produced in high yield from inexpensive and easily available industrial raw materials, and which can be easily derived in high yield and from pyridine-2,3-dicarboxylic acid derivatives. The objective is to provide a chemical compound that is Another object of the present invention is to provide a method for producing the novel compound. [Means for Solving the Problems] According to the present invention, the above object is achieved by the ketoester represented by the general formula (1), and also by the ketoester represented by the general formula (T
I) A compound represented by ρ3 (wherein Rl , R, , R' and R4 are as defined above) and general formula (III) (wherein RS is as defined above and R6 is Bs (which is the same as or different from and represents a hydrogen atom, an alkyl group, an alkenyl group, an aryl group, a cycloalkyl group, or an aralkyl group)) in the presence of a base. This is accomplished by the method for producing ketoesters shown in RI SRt of the above general formula
, R3, R4, RS and R" will be explained in detail.
Rl and Rt are the same or different and are, for example, an alkyl group, an alkenyl group, an aralkyl group or a cycloalkyl group having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms,
For example, alkyl groups such as methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, 3-methylbutyl group, pentyl group, octyl group; vinyl group, l-
Alkenyl groups such as bropenyl group, allyl group, isobropenyl group, 2-methylallyl group, 1-butenyl group, 2-butenyl group, brenyl group, 3-methyl-3-butenyl group, 2,3-dimethyl-2-butenyl group : cycloalkyl group such as cycloprobyl group, cyclopentyl group, cyclohexyl group; or benzyl group, ■-phenylethyl group,
It is an aralkyl group such as 2-phenylethyl group. Rl and R again! may be taken together to form a ring, such as ethylene group, propylene group, ethylethylene group, trimethylene group, or 1-methyltrimethylene group. R2, R4, RS and R6 are the same or different and are a hydrogen atom, an alkyl group, an alkenyl group, an aryl group, a cycloalkyl group, or an aralkyl group, such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, n-butyl group, isobutyl group, sec-
Alkyl groups such as butyl group, tert-butyl group, pentyl group, octyl group, 3,7-dimethyloctyl group;
Vinyl group, 1-bropenyl group, allyl group, isoprobenyl group, 2-methylallyl group, 1-butenyl group, 2-butenyl group, brenyl group, 3-methyl-3-butenyl group, 2
, 3-dimethyl-2-phtenyl group, 3-methyl-2-bentenyl group, 3-methyl-3-pentenyl group, 3.7
-dimethyl-2-octenyl group, 3,7-dimethyl-6
-Alkenyl groups such as octenyl groups; aryl groups such as phenyl, tolyl, xylyl, and naphthyl groups; cycloprobyl, cyclopentyl, cyclohexyl groups,
Cycloalkyl group such as menthyl group; benzyl group, 1-
Phenylethyl group, 2-phenylethyl group, 1-phenylbrobyl group, 3-phenylprobyl group, 2-methyl-
These are aralkyl groups such as 1-phenylprobyl group and 2-naphthylethyl group.

In the present invention, a base catalyst commonly used in Claisen reactions can be used as the catalyst.

Specific examples include metal hydrides such as sodium hydride and potassium hydride; sodium amide; lithium diisopropylamide; sodium methoxide, sodium ethoxide, sodium butoxide, potassium methoxide, potassium ethoxide, potassium butoxide. Examples include metal alkoxides such as side, and the use of metal alkoxides is particularly preferred. The amount of the base catalyst added is preferably 0.5 to 2 mol, preferably 0.8 to 1.5 mol, per 1 mol of compound (■).

This reaction is carried out in an organic solvent. Examples of organic solvents used include hydrocarbons such as benzene and toluene; halogenated hydrocarbons such as methylene chloride and 1,2-dichloroethane; and ethers such as diethyl ether and diisobrobyl ether. The amount of organic solvent to be used is such that the concentration of compound (II) is approximately 0. The amount is preferably 1 to 5 mol/l. The reaction temperature is about 20-180"C, preferably 50-1
It is preferable to carry out the process at a temperature of 50°C. The pressure may be normal pressure or reduced pressure.

The ketoester of general formula (1) obtained by the above reaction can be separated by a conventional method. For example, by neutralizing with water and acid, separating the aqueous layer, then washing the organic layer with water, distilling off low-boiling substances under reduced pressure, and subjecting the residue to silica gel column chromatography,
The ketoester of general 2N) can be isolated.

The compound represented by the general formula (n) used as a raw material can be synthesized according to the following route. R Cor CH. CHO α-substituted or unsubstituted acetaldehyde ↓ 2-position substituted or unsubstituted 1-(N-biberidinyl) monoethylene ↓ HOC CH CHz CL COOR'R3 4-position substituted or unsubstituted 4-formylbutyric acid ester ↓ R' 4-position Substituted or unsubstituted 4-dimethoxymethylbutyric acid ester In the above reaction, a known route (J. Org. C
hew. 198B, 'L, 3370). That is, in a secondary amine such as biperidine, in the presence of a dehydrating agent such as anhydrous potassium carbonate, molecular shubus, or anhydrous magnesium sulfate, the temperature is cooled to -5 to 10°C under a nitrogen atmosphere, and α-substituted or unsubstituted acetaldehyde is added dropwise. do. 1 more
The reaction is carried out for 5 hours at -5 to 10'C to synthesize 2-substituted or unsubstituted 1-(N-piveridinyl)-monoethylene.

Purification is achieved by filtering off the solid, washing with ether, distilling off the ether, and then distilling. This compound is then reacted with an acrylic ester by Michael addition reaction to form a 4-form-substituted or unsubstituted 4-form-butyric ester. At this time, the reaction conditions may be those commonly used for the Michael addition reaction between enamines and α,β unsaturated esters, such as 2-substituted or unsubstituted 1-(N-biperidinyl)monoethylene and an organic solvent such as acetonitrile. The mixed solution is cooled to below 0 to 10°C, and a mixed solution of acrylic ester and acetonitrile is added dropwise thereto. The reaction is further continued at room temperature for 1 to 20 hours and under reflux for 10 to 50 hours. Then, acetic acid and water are added and the mixture is refluxed for 1 to 20 hours. For purification, after the reaction is complete, cool to room temperature, saturate the aqueous layer with sodium chloride, and extract with ether. 5% hydrochloric acid for the ether layer,
Obtained by washing with 5% sodium hydrogen carbonate and saturated aqueous sodium chloride solution, drying over anhydrous magnesium sulfate, and distilling. Then, by acetalizing this compound with, for example, methyl orthoacetate, a 4-dimethoxymethylbutyric acid ester substituted or unsubstituted at the 4-position is synthesized. The reaction conditions were 4-substituted or unsubstituted 4-
A methanol solution of sulfuric acid was added to a mixed solution of formylbutyrate, methyl orthoacetate, and methanol at an internal temperature of 60'C.
Drip so as not to exceed. The reaction is carried out until the conversion rate of the 4-formylbutyric acid ester substituted or unsubstituted at the 4-position reaches 100%, and the 4-dimethoxymethylbutyric acid ester substituted or unsubstituted at the 4-position is combined. For purification, after the reaction is complete, neutralize with sodium methoxide and distill to obtain 4-dimethoxymethylbutyric acid ester substituted or unsubstituted at the 4-position. The ketoester represented by the general formula (1) can be easily converted into the pyridine-2,3-dicarboxylic acid derivative represented by the general formula (IV) in high yield by, for example, the following method. (1) (V) (Vl) (IV) (In the above formula, R1, R2, R3, R4 and RS are as defined above.) That is, the ketoester represented by the general formula (1) is dissolved in an acid aqueous solution. The deprotected compound (V) is obtained by the treatment. As the acid, for example, an inorganic acid such as hydrochloric acid, nitric acid, or sulfuric acid, or an organic acid such as acetic acid is used. The amount of acid used is preferably about 1 to 50 moles per mole of ketoester represented by general formula (I). This reaction is preferably carried out without a solvent or in an organic solvent. Hydrocarbons such as hexane, cyclohexane, benzene and toluene, or ethers such as diethyl ether and isobrobyl ether are used as the organic solvent. The amount of the molar solvent to be used is preferably such that the concentration of the ketoester represented by the general formula (1) is about 0.05 to 1 mol/l.
Preferably, the reaction is carried out within a temperature range of about 10-100°C. After the reaction is complete, separate the liquid and if necessary neutralize with sodium bicarbonate and wash with water. Thereafter, the solvent is distilled off, and the compound (Vl) is obtained by reacting with ammonia water or ammonia gas. The amount of ammonia used is approximately 0.0% per mole of the compound. An amount of 8 to 2 moles is preferred.
This reaction is preferably carried out in an organic solvent, and alcohols such as methanol and ethanol, or ethers such as isopropyl ether and 1,4-dioxane are used as the organic solvent. The amount of organic solvent used is such that the concentration of compound (V) is approximately 0. The amount is preferably 1 to 5 mol/l.

Preferably, the reaction is carried out within a temperature range of about 10-100°C. Furthermore, this reaction solution is treated with an oxidizing agent or a dehydrogenation catalyst. As the oxidizing agent, sodium nitrite and acetic acid or air are preferred, and as the dehydrogenation catalyst, para-toluenesulfonic acid is preferred. A pyridine-2,3-dicarboxylic acid derivative represented by general formula (IV) is obtained by subjecting the resulting reaction solution to a conventional purification method, such as distillation. The present invention will be explained in more detail with reference to Examples below, but the present invention is not limited to these Examples.

Reference example 1 (raw material synthesis) 27 with stirrer! 1-(N-
150 g (1.06 mol) of (piperidinyl)-1-butene
and 750 cc of a7tonitrile, and after cooling to 5'C, add 116 g (1.35 g) of methyl acrylate.
mol) and 300 cc of acetonitrile were fed in 30 minutes using a pump. Then stirred at room temperature for 8 hours,
The mixture was further refluxed for 4 hours. After that, 400cc of water and 64ml of acetic acid
．． 3 g (1.07 mol) was added and refluxed for 4 hours. After cooling to room temperature, saturate the aqueous layer with sodium chloride, then extract the aqueous layer with ether and combine with the organic layer. 5% organic layer
The mixture was washed with HCf, 5% NaHCO, and saturated brine, dried over magnesium sulfate, and purified by distillation to obtain 141.7 g of methyl 4-formylhexanoate. (Yield 84.
5%, purity 99.6%, bp 61-62°C/0.
3 ++uwHg reduced pressure) Reference Example 2 (Raw material synthesis) Reference Example 1 was placed in a 500cc glass flask equipped with a stirrer.
Methyl 4-formylhexanoate 1 obtained in 29.4
g (0.8 2 mol) and 108 g of methyl orthoacetate
(0.90 mol) and 45 g of methanol, and added sulfuric acid 0.
．． 1 2 g (0.0012 mol) and methanol 2
5 g of the mixed solution was added dropwise over 1 hour, and the reaction was continued for an additional 2 hours. After the reaction is completed, it is neutralized with sodium methoxide and purified by distillation to obtain 160% of methyl dimethyl 4-formylhexanoate. Obtained 2 g. (Yield 96.0
%, purity 99.7%, bp82-83℃/1 mm+
Hg vacuum) Reference Example 3 (raw materials combined) 100 ml of methyl 4-formylhexanoate obtained in Reference Example 1 was placed in a 300 cc glass flask equipped with a stirrer.
g (0.63 mol), ethylene glycol 40.8 g (
0.66 mol), balatoluenesulfonic acid 0. 2 4
g (0.0013 mol) and cyclohexane 100
cc was added, methanol was distilled off while azeotropically with cyclohexane, and the reaction was allowed to proceed for 2 hours. After the reaction is complete,
Neutralize with sodium methoxide and purify by distillation to obtain 4-
115.2 g of methyl ethylene glycol acetal formylhexanoate was obtained. (Yield 92.2%, purity 99.
2%, bp86-88°C/0. 4 ms+Hg
Reduced pressure) Example 1 56.7 g (0.89 mol) of sodium methoxide and 300 cc of isopropyl ether were placed in a 2-liter glass flask equipped with a stirrer, and Reference Example 2 was added to the dropping funnel.
Add 151.6 g (0.74 moles) of methyl dimethyl acecolyte 4-formylhexanoate obtained above, 131.6 g (1.12 moles) of dimethyl oxalate, and 400 cc of isopropyl ether, dissolve with heat, and reflux. It was dropped within 2 hours. The reaction was continued for a further 7 hours, and the remaining methanol was azeotropically distilled off with isopropyl ether. After the reaction was completed, 11 g of water and 53.5 g (0.89 mol) of acetic acid were added to neutralize the mixture, followed by liquid separation.

After washing the organic layer with water, it was determined by gas chromatography (internal standard method), and 171.3 g (0.5 9 mol, yield 79.5%). Furthermore, the residue obtained by distilling off isoprobyl ether was purified by column chromatography using silica gel, and the following instrumental analysis data confirmed that it was methyl 5-(dimethoxymethyl)-3-methoxycarbonyl-2-oxaheptanate. It was confirmed.

'H-NMR (δin CDCIs): 0
．． 915 (t.3H), 1.20-1.82 (Iya.
3H). 1.82-2. lO(s.2H), 3
．． 24 (s. 311), 3.27 (s. 3H). 3
．． 83 (s.3H). 3.88 (s.3H).
4.07 (d, LH). 4.40 (dd, IN) I R (neat + νcm-') 2970 (
-CI. −). 1750 (C・0) Example 2 3.7 g of sodium ethoxide and 20 cc of isobrobyl ether were placed in a 200 cc glass flask equipped with a stirrer, and 4-obtained in the same manner as in Reference Example 2.
10g of ethyldimethylacecool formylhexanoate,
Diethyl oxalate log and isopropyl ether 3
0 cc of the solution was dissolved by heating and added dropwise from the dropping funnel over 1 hour under reflux. The reaction continued for a further 7 hours, and the residual ethanol was azeotropically distilled off with isobutyl ether. After the reaction is complete,
After neutralization, 70 cc of water and 3.3 g of acetic acid were added and the mixture was separated. After washing the organic layer with water, it was determined by gas chromatography (
As a result, 11.4 g of ethyl 5-(dimethoxymethyl)-3-ethoxycarbonyl-2-oxaheptanate was produced. Furthermore, the residue obtained by distilling off isobrobyl ether was purified by column chromatography using silica gel, and the following instrumental analysis data confirmed that it was ethyl 5-(dimethoxymethyl)-3-ethoxycarbonyl-2-oxaheptanate. It was confirmed.

'H-NMR (δ in CDCIs):
0.91 (t.3H), 1.10~2.10 (monk,
5H). 1.31 (t.3H) . 3.24 (s
．． 3H), 3.24(s, 3H). 3.30 (s
, 3H), 4.08(d.IH), 4.32(
q. 2H). 4.20 (@.IH) I R (neat * ycm-'): 2920
(-cut-), 1740 ((,.0) Example 3 5.8 g of sodium benzyl oxide and 20 cc of isopropyl ether were placed in a 200 cc glass flask equipped with a stirrer, and treated in the same manner as in Reference Example 2. 10 g of the obtained pendyl dimethyl 4-phorhexanoate, 15.1 g of dibenzyl oxalate, and 30 cc of isobrobyl ether were heated and dissolved, and the solution was added dropwise from the dropping funnel over 1 hour under reflux, and the reaction was continued for a further 7 hours. After completion, 70 cc of water and 2.7 g of acetic acid were added to neutralize and separate the layers.After washing the organic layer with water, it was quantified by gas chromatography (internal standard method), and it was found that benzyl 5-(dimethoxymethyl) = 3-pene. 12.3g of dylcarbonyl-2-oxaheptanate was produced.Furthermore, the residue obtained by distilling off the low boiling point was purified by column chromatography using silica gel, and the following instrumental analysis data revealed that benzyl 5-(dimethoxy It was confirmed that it was methyl)-3-penzylcarbonyl-2-oxaheptanate.'H-NMR (δin CDCj!3):
0.92 (t.3H). 1.02 ~ 1.86 (m
, 3H) , 1.86-2.06 (m, 3}!) .
3.43 (s, 3H). 3.50 (s, 3H),
4.20 (m.LH). 4.81 (dd, 18)
．． 5.20 (s, 4H). 7.25 (s, 108
) I R (neat, νcm-'): 2970
(-CH!-), 1740 (C=0) Example 4 In a 200 cc glass flask equipped with a stirrer, 20.1 g (0 .1 mole), 6.75 g (0.12 mole) of sodium methoxide, 17.5 g (0.15 mole) of dimethyl oxalate, and 100 cc of toluene were added, and methanol, which was produced under reflux, was distilled by azeotropic distillation with toluene. I left. After the reaction, acetic acid 7.1
g (0.12 mol) and water ioocc were added to neutralize the mixture, and then the liquid was separated. After washing the organic layer with water, it was determined by gas chromatography (internal standard method) to find that 22.8 g (0.0
79 mol, yield 79.9%) was viable. moreover,
The residue obtained by distilling toluene off was purified by column chromatography using silica gel, and the following instrumental analysis data revealed that methyl 5-(ethylene glycol acetal)
It was confirmed that it was -3-methoxycarbonyl-2-oxaheptanate.

'H-NMR (δin CDCl.x):
0.91 (t, 3H), 1.18~2.30 (+s
, 38). 2.24 (ddd, IH). 2.5
5(ddd.1}1). 3.38 (m, LH),
? ．． 60 (s.3H). 3.72 (s, 3H)
, 3.60-3.72 (m, IH) ,
4.32 (d.111), 4.50-4.81
(m, IH)I R (neat, νC
``1) 2950 (-CI+■-). 1740 (C・0)
Reference Example 4 Methyl 5-(dimethoxymethyl)-3 obtained in Example 1 was placed in a 300 cc glass flask equipped with a stirrer.
-methoxycarbonyl-2-oxaheptonate 18
4.4 g (purity 92.9%, 0.59 mol) and 50 cc of IN sulfuric acid were added and stirred at room temperature for 5 hours.

After the reaction was completed, 100 cc of isopropyl ether was added and the aqueous layer was removed by liquid separation. The obtained organic layer was neutralized with an aqueous sodium bicarbonate solution, further washed with 30 cc of water, and then quantified by gas chromatography (internal standard method). 5,6-dihydro-4H-pyran is 1
5 5. 1 g (0.527 mol, purity 82.9%
) obtained. Next, after distilling off isopropyl ether, the 5-ethyl-6-hydroxy-2 obtained in the above reaction
,3-dimethoxycarbonyl-5,6-dihydro-4H
-pyran 9.76 g (0.033 mol LL,
Put 20 cc of 4-dioxane into a 100 cc glass flask equipped with a stirrer, and add 25 cc of 4-dioxane from the dropping funnel at 30°C.
% aqueous ammonia (0.04 mol) was added dropwise over 30 minutes. After reacting for an additional 30 minutes, the temperature was raised to 50°C and air was blown in for 3 hours. When the reaction solution was quantitatively determined by gas chromatography (internal standard method), 5-ethyl.
Rubiridine-2,3-dimethoxycarbonyl is 7.0
4 g (0.03 1 mol, yield 94%) was obtained. The residue obtained by distilling off 1,4-dioxane was purified by column chromatography using silica gel, and it was confirmed to be 5-ethylpyridine-2,3-dimethoxycarbonyl based on the following instrumental analysis data.

'H-NMR (δ in CDCf3):
1.32 (t.3B), 2.75 (q, 2H),
3.92 (s, 311). 3.98 (S, 3B)
, 8.00 (d, IH). 8.62 (d, LH)
I R (neat, νc'Il-1) 2970
(-CHt-). 1740 (C=O) [Effects of the Invention] As is clear from the above examples, according to the method of the present invention, the general formula (1) can be easily obtained in high yield from inexpensive and easily available industrial raw materials. The ketoesters shown can be prepared. Further, as is clear from the above-mentioned Reference Examples, the ketoester represented by the general formula (1) of the present invention can be easily derived into a pyridine-2,3-dicarboxylic acid derivative in a high yield.

Claims (2)

[Claims] (1) General formula (I) ▲Mathematical formula, chemical formula, table, etc.▼(I) (In the formula, R^1 and R^2 are the same or different and are an alkyl group, an alkenyl group, a cycloalkyl group, or an aralkyl group. or represents an acetal-type protecting group which together form an alkylene group, and R^3, R^4 and R^5 are the same or different and represent a hydrogen atom, an alkyl group,
(representing an alkenyl group, an aryl group, a cycloalkyl group or an aralkyl group); (2) General formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) (In the formula, R^1 and R^2 are the same or different and are an alkyl group, an alkenyl group, a cycloalkyl group, or an aralkyl group. or represents an acetal-type protecting group which together form an alkylene group, R^3 and R^
4 is the same or different and represents a hydrogen atom, an alkyl group, an alkenyl group, an aryl group, a cycloalkyl group, or an aralkyl group) and general formula (III) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (III ) (wherein R^5 and R^6 are the same or different and represent a hydrogen atom, an alkyl group, an alkenyl group, an aryl group, a cycloalkyl group, or an aralkyl group) in the presence of a base. General formula (I) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I) (In the formula, R^1, R^2, R^3, R^4 and R^5 is as defined above).