JPH0283360A - Production of glycol amide or its analogue - Google Patents

Abstract

PURPOSE:To easily obtain the subject compound useful as an acylamidase substrate, etc., at room temperature in a short time by reacting an alpha-halogen compound with an arylmethyl alcohol in the presence of a base and debenzylating the product. CONSTITUTION:The glycol amide of formula III and its analogue can be produced by reacting a compound of formula I (R1, R2 and X are H, lower alkyl, lower alkynyl, etc.; Y is halogen) with an arylmethyl alcohol in the presence of a base (e.g., sodium hydride metallic sodium or K2CO3) and subjecting the resultant compound of formula II (Ar is aryl) to debenzylation reaction. The objective compound is produced without using excess reaction reagent nor adding a quaternary ammonium salt to the reaction system.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a method for synthesizing glycolamide or its analogs. Glycolamide or its analog provided by the present invention is a substrate of acylamidase (Honma, "
"Pseudomonas aeruginosa and its infectious diseases" pages 43-46 (Bunkodo, 1
975)) or intermediates for the production of herbicides (US Pat. No. 3,399,988, DE-OS No. 22014)
No. 32 and DE-O3 No. 2647568).

[Conventional technology]

A method for synthesizing glycolamide analogs from α-halogeno acid amide is disclosed in Japanese Patent Publication No. 35162/1983.

[Problem to be solved by the invention]

In the above method, after converting the halogen atom at the α-position to acetoxy, Estes obtains a glycolamide analog by water decomposition. A heating operation is required to reach the above reaction temperature, and a long reaction time is also required.

Furthermore, an improved method of this method was published in Japanese Patent Application Laid-Open No. 55-105624.
Disclosed in the issue. Although this method no longer requires an excessive amount of acetate to produce acetoxy, it still requires heating operations to reach a reaction temperature of 100°C or higher, and the reaction time is 4 hours or more. It takes. In addition, a special quaternary ammonium salt must be added, which is very complicated. Therefore, an object of the present invention is to provide a method for producing glycolamide or its analogs, which allows easy setting of reaction conditions and shortens reaction time.

[Means to solve the problem]

The present invention achieves the above object by the following method.

That is, (1) general formula (wherein R,, R2, and X may be the same or different, each being hydrogen and lower alkyl;

It represents a lower alkenyl, alkynyl, aralkyl or aryl group, and R1 and R2 or R and X may be bonded to form a cyclic structure. Note that RI +R,,X may be a substituent containing nitrogen, oxygen, or sulfur. ) A method for producing glycolamide or its analogues represented by the general formula (wherein R+, Rz, and X are the same as in formula (1) above, and Y represents a halogen atom) as a starting compound. By reacting this with aryl methyl alcohol in the presence of a base, the general formula (wherein R,,R,,X are the same as in the above formula (1).A
r represents an aryl group. ) is debenzylated. As the aryl methyl alcohol, benzyl alcohol or 4-methoxyphenyl methyl alcohol is preferably used. In addition, sodium hydride and sodium metal are used as bases.

Preference is given to using potassium carbonate, triethylamine or pyridine.

The α-allylmethoxy compound represented by the formula (I[[) of the present invention is synthesized by reacting the α-halogen compound of the formula (II) with an aryl methyl alcohol under basic conditions. Suitable organic solvents to be used include tetrahydrofuran, diethyl ether, dioxane, dimethylformamide, dimethyl sulfoxide, benzene, and toluene. Further, as the aryl methyl alcohol, benzyl alcohol or 4-methoxyphenyl methyl alcohol is preferable because it facilitates the subsequent deallyl methylation. Further, as the base, sodium hydride, sodium metal, potassium carbonate, triethylamine or pyridine is preferable. If these alcohols or bases are used, heating operation becomes unnecessary. This reaction is an exothermic reaction and does not require a heating operation, but even if heated, a temperature of 50°C or less is sufficient. Moreover, this reaction is completed in a short time (within 1 hour). The desired product is recovered from the reaction mixture according to conventional methods.

For example, the desired product is obtained by adding water to the reaction mixture, extracting with a suitable organic solvent such as ethyl acetate, distilling off the solvent from the extract, and purifying the residue by recrystallization or column chromatography. be able to.

Further, in order to obtain glycolamide or its analogue (1) from the α-allylmethoxy compound (I[[), palladium carbon catalyst, palladium barium sulfate catalyst, platinum carbon catalyst, platinum oxide catalyst or copper chromite catalyst In the presence of
A hydrogenation reaction of α-allylmethoxy compound (I[[) may be performed. Ethanol, methanol, acetic acid, tetrahydrofuran, dimethylformamide, and benzene can be used as the solvent. As before, this reaction does not require any heating operation and is completed within 1 hour at room temperature. By removing the metal catalyst by filtration and concentrating the filtrate under reduced pressure, the desired glycolamide and its analogs (1) can be obtained.

The deallyl methylation reaction can also be carried out using the metal catalyst for hydrogenation and cyclohexene or cyclohexadiene.

In addition, the deallyl methylation reaction can be carried out using sodium or lithium metal (the solvent is ammonia, ethanol, etc.).
Also boron trifluoride and boron tribromide.

Glycolamide or its analog (1) can also be obtained from the α-allylmethoxy compound (II[) by performing an allylmethylation reaction that can also be performed using a Lewis acid such as trifluoroacetic acid.

Next, the present invention will be explained in more detail with reference to Examples.

[Example 1] Under nitrogen atmosphere, 2.70 g of sodium hydride (11
3 mmol) of dry tetrahydrofuran in 75 ml, add benzyl alcohol 6.0 M (57,98 relative), and further add 2-chloroacetamide 5.00 g (53,5 m
mol) was added to room temperature, and then reacted at 40°C for 1 hour. The reaction solution was heated to 20°C, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and concentrated under reduced pressure to obtain a residue. By recrystallizing this with ethanol, 8.66 g (52.4 mmol) of 2-berzyloxyacetamide was obtained.

8.66 g (52.4 mmol) of the amide and 43.31 d of ethanol.

0.043 d of 36% hydrochloric acid was added, and further 866 mg of 10χ palladium carbon catalyst was added, followed by reaction for 30 minutes under a hydrogen atmosphere. 21.6 ml of methanol was added to the reaction solution, and insoluble materials were removed by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was recrystallized from ethanol to give 3.89 g (51.8 mmo) of glycolamide as white needle-like crystals.
l) was obtained.

NMR (δppm, CD30D) 3.97 (s, 2H), 4.77 (s, 3H) IR (cm-', KBr) 3360.3200.1680 [Example 2] Sodium hydride 175 under nitrogen atmosphere ■(7,29m
4-methoxybenzyl alcohol 0.82rd (6.58mm
ol) Additionally 1.25 g of 2-bromoacetic acid piperidide
(6.07 mmol) was added and reacted at room temperature for 1 hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and concentrated under reduced pressure to obtain a residue. This was subjected to silica gel column chromatography (eluent: dichloromethane).
The mixture was separated and purified to obtain 1.29 (5.53 mmol) of 2-(4-αmethoxyhensyloxy)acetic piperidide.

To 1.29 g (5.53 mmol) of the amide was added 6 ml of ethanol, 45 ml.

36% hydrochloric acid o and oiInl were added, and 129 cm of 10% palladium on carbon catalyst was added, followed by reaction for 30 minutes under a hydrogen atmosphere. 3.22 mf of methanol was added to the reaction solution, insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain 785 μm of 2-hydroxyacetic acid piperidide (
5.48 mmol) was obtained.

NMR (δppm, CDCI!t) 4.12 (s,
2B), 3.77-3.03 (m, 5H).

1.80-1.37 (+++, 6H) rR (CicII-', CIICL) 3420, 1640 Compounds according to the present invention not shown in the above examples could also be obtained by similar operations. The reaction time, which conventionally took more than 4 hours, was significantly shortened to less than 2 hours as seen in Example 1.2.

〔Effect of the invention〕

According to the present invention, a novel method for producing glycolamide or an analog thereof is provided.

Further, according to the present invention, there is no need to use an excessive amount of reaction reagents, and there is no need to add a special quaternary ammonium salt, and reaction conditions can be easily set.

Furthermore, there is no need to set the reaction at a high temperature such as reflux conditions, and the reaction can proceed sufficiently at room temperature, and the reaction time can also be shortened.

Claims (3)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) (In the formula, R_1, R_2, and X may be the same or different, and each is hydrogen, lower alkyl, lower alkenyl, alkynyl, It represents an aralkyl or aryl group, and R_1 and R_2 or R_1 and X may be combined to form a cyclic structure. R_1, R_2, and X may be a substituent containing nitrogen, oxygen, or sulfur.) A method for producing glycolamide or its analogs represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (II) (In the formula, R_1, R_2, and X are the same as the above formula (I), (Y represents a halogen atom) is used as a starting compound, and by reacting it with aryl methyl alcohol in the presence of a base, the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (III) (In the formula, R_1, R_2 , X is the same as the formula (I) above; Ar represents an aryl group) and debenzylation. (2) The manufacturing method according to claim 1, wherein benzyl alcohol or 4-methoxyphenylmethyl alcohol is used as the aryl methyl alcohol. (3) Sodium hydride, sodium metal as a base,
The manufacturing method according to claim 1 or 2, wherein potassium carbonate, triethylamine or pyridine is used.