HK1022141B

HK1022141B - Process for preparing substituted valine amide derivatives

Info

Publication number: HK1022141B
Application number: HK00101060.3A
Authority: HK
Inventors: E‧里瓦德内拉
Original assignee: 拜尔公司
Priority date: 1996-08-02
Filing date: 1997-07-21
Publication date: 2003-09-11

Description

Process for preparing substituted valinamide derivatives

The invention relates to a valinamide derivative and a preparation method thereof.

Valinamide derivatives are known and have excellent effects in pest control. In particular as fungicides, especially for crop protection (EP-472996).

It has been found that the known valinamide derivatives can be prepared very simply and in high yields and purity, in a manner which is substantially free of organic solvents.

The present application thus provides a process for the preparation of a compound of general formula (I):

in the formula R¹Is isopropyl, R²Is chlorine, methyl, ethyl or methoxy,

the method comprises the following steps:

a) reacting alkaline aqueous solution of L-valine with isopropyl chloride,

b) after neutralization, the reaction product obtained is reacted further with isopropyl chloride in the presence of catalytic amounts of tertiary amine and optionally in the presence of an organic solvent,

c) the reaction product obtained is then reacted with the corresponding substituted phenethylamine optionally dissolved in an organic solvent, with optional addition of an organic solvent, at least one organic solvent being used in step b) or c).

The valinamide derivatives obtained by this process can be easily processed and isolated and are easily prepared in compact form in high space-time yields.

The process of the invention or the individual process steps a) and b), respectively, are preferably carried out with water as the total solvent or diluent.

The products of process steps a) and b) can be isolated and used for further reactions. However, the process is preferably carried out in a one-pot process without intermediate separation, optionally with the mother liquor being returned to the next batch or optionally being subjected to continuous treatment.

For process steps a) and b), preferably isopropyl chloride is used. The ester is preferably added to the corresponding solution or reaction mixture, preferably in an over molar amount, based on the amount of valine or the reaction product of process step a), and in a total amount of 2 to 3 moles, based on 1 mole of valine.

Preferred addition or reaction temperatures are from-20 ℃ to 80 ℃, in particular from 10 to 50 ℃ for process step a) and from-20 ℃ to 40 ℃, in particular from 10 to 30 ℃ for process step b). The process steps a) and b) are preferably carried out at room temperature, optionally with cooling of the exothermic reaction.

Process step a) is carried out alkaline in an alkaline medium, i.e.preferably in the presence of inorganic bases such as KOH and, in particular, NaOH. The base is used in excess, in particular in an amount of 1 to 3 moles, based on 1 mole of valine.

The neutralization in process step a) is preferably carried out using mineral acids such as sulfuric acid and, in particular, hydrochloric acid, in particular to a pH of about 7.

Process step b) is preferably carried out in the presence of catalytic amounts of tertiary amines, preferably pyridine, picoline, dimethylaminopyridine, triethylamine and/or, in particular, dimethylbenzylamine (Desmorapid DB)^). In the present application, the catalytic amount preferably means 1/10,000-1/100 moles of catalyst per mole of valine.

For process step c) and the subsequent working up, it is particularly important to dissolve the phenethylamine in a small amount of organic solvent and to react it only with the product of process step b).

The solvents used are preferably acetates, methyl tert-butyl ether and especially tert-amyl methyl ether (TAME). The amount of the organic solvent is preferably 50 to 800 ml, in particular 100 to 500 ml, based on 0.3 mol of the corresponding phenethylamine. The phenethylamine pre-dissolved in this way is then preferably added to the reaction mixture of process step b), the amount of phenethylamine being equimolar or in slight excess relative to valine.

For better working up of the target compound prepared in process step c), the reaction mixture of process step c) is heated, optionally under pressure, to a temperature of from 40 ℃ to the corresponding boiling point of the organic solvent until optimum separation of the organic phase from the aqueous liquid phase is observed. The organic phase is then processed by conventional methods.

The products obtained by the process of the invention, which consist essentially of the defined isomeric mixtures of the desired valinamide derivatives, can be used without further purification, for example as fungicides for crop protection.

Therefore, in addition to the advantages described above, the method of the present invention has the following advantages: the process uses water as the total solvent and diluent, preferably 50-500 g, especially 100-300 g, of water, to produce the desired product in high yield and purity. The following examples illustrate the invention. The present invention is not limited to these examples.

Example 1

35.8 g (0.305 mol) of L-valine were added to a mixture consisting of 105 g of water and 63.6 g (0.716 mol) of 45% (w/v) sodium hydroxide solution. The mixture was stirred until a clear solution was formed.

45.4 g (0.366 mol) of isopropyl chloroformate are added dropwise at room temperature over 2 hours. The mixture was then stirred for 30 minutes. The pH was adjusted to 7 using 37% (w/v) hydrochloric acid.

To the reaction solution was added 0.4 g (0.003 mol) of Desmorapid DB^. The mixture was then stirred for 15 minutes and then 38.4 g (0.31 mol) of isopropyl chloroformate were added. The mixture was stirred for an additional 1 hour.

Then a solution of 44.6 g (0.31 mol) of p-methylphenethylamine in 200 ml of TAME (tert-amyl methyl ether) was added dropwise over 2 hours. While the mixture remained stirrable, a white solid precipitated immediately.

The mixture was heated to 70 ℃ at which temperature the phases were separated and the organic phase was washed with 100 ml of water. It was allowed to cool to 40 ℃ and filtered at this temperature. The suction cake was then washed with a small amount of TAME and subsequently dried.

78.4 g of product (content: 96.3%) are obtained. Corresponding to 77.3% of the theoretical yield.

The organic mother liquor gives, after distillation of the solvent, 35.1 g of residue, 43.7% of which is the desired product (yield: 15.7% of theory).

Comparative example 2

35.8 g (0.305 mol) of L-valine were added to a mixture consisting of 105 g of water and 63.6 g (0.716 mol) of 45% (w/v) sodium hydroxide solution at room temperature. The mixture was stirred until a clear solution was formed.

44.6 g (0.31 mol) of p-methylphenethylamine (3) were added over 2 hours. The mixture was then stirred for 1 hour. In the process, the suspension formed becomes very thick, although it remains just stirrable. The mixture was then filtered at room temperature by suction and the suction cake was then washed with 500 ml of water. Drying yielded 99.5 grams of a solid of which 65.1% was the desired product. Corresponding to a yield of 66.3% of theory.

Example 3

35.8 g (0.305 mol) of L-valine are dissolved at room temperature in a mixture of 105 g of water and 63.6 g (0.716 mol) of 45% (w/v) sodium hydroxide solution. The mixture was stirred until a clear solution was formed.

45.4 g (0.366 mol) isopropyl chloroformate (98.9% w/v) were added dropwise over 2 hours. The mixture was then stirred for 30 minutes and the pH adjusted to 7 by the addition of 2.9 g of 37% (w/v) hydrochloric acid.

650 ml of TAME and 0.4 g of Desmorapid DB are added to the reaction medium^. The mixture was then stirred for 15 minutes and then an additional 38.4 g (0.31 mole) of isopropyl chloroformate (98.9% w/v) was added over 1 hour.

The mixture was then stirred for 1 hour and a solution of 44.6 g (0.31 mol) of p-methylphenethylamine (93.9% w/v) in 130 ml of TAME was added over 2 hours. The mixture was then stirred for 1 hour and 100 ml of sodium hydroxide solution (1N) was added to the suspension. The phases were separated at 55 ℃. The organic phase is then extracted once with 50 ml of water at 55 ℃ and cooled to 0 ℃.

The mixture was then stirred for 30 minutes and the solid was filtered off with suction under reduced pressure. The filter cake was then washed with a small amount of TAME and dried in a vacuum oven. The filtrate was evaporated in a rotary evaporator.

75.1 g of suction cake are obtained, which contains 99.7% of active ingredient (76.6% of the theoretical yield).

The mother liquor residue after evaporation (17.2 g) contained 56.6% of active ingredient.

Example 4

45.4 g (0.366 mol) isopropyl chloroformate (98.9% w/v) were added dropwise over 2 hours. The mixture was then stirred for 30 minutes and the pH adjusted to 7 by the addition of 3 g of 37% (w/v) hydrochloric acid.

To the reaction medium were added 650 ml of TAME, 15.3 g of the mother liquor residue of example 3 and 0.4 g of Desmorapid DB^。

The mixture was stirred for 15 minutes and then an additional 38.4 g (0.31 mole) of isopropyl chloroformate (98.9% w/v) was added over 1 hour. The mixture was then stirred for 1 hour and a solution of 44.6 g (0.31 mol) of p-methylphenethylamine (93.9% w/v) in 130 ml of TAME was added over 2 hours. The mixture was then stirred for a further 1 hour and 100 ml of sodium hydroxide solution (1N) were added to the suspension. The phases were separated at 55 ℃. The organic phase is then extracted once with 100 ml of water at 55 ℃ and subsequently cooled to 0 ℃. The mixture was then stirred for 30 minutes and the solid was filtered off with suction under reduced pressure. The filter cake was then washed with a small amount of TAME and dried in a vacuum oven. The filtrate was evaporated in a rotary evaporator.

92.8 g of suction cake are obtained, which contains 97.4% of active ingredient (92.5% of theory).

Claims

1. A process for the preparation of a compound of general formula (I):

in the formula R¹Is isopropyl, and R²Is chlorine, methyl, ethyl or methoxy,

the method is characterized by comprising the following steps:

a) reacting alkaline aqueous solution of L-valine with isopropyl chloride,

c) the reaction product obtained is then optionally mixed with an organic solvent and reacted with the correspondingly substituted phenethylamine, optionally dissolved in an organic solvent, at least one organic solvent being used in step b) or c).

2. The process according to claim 1, characterized in that the addition or reaction temperature of process step a) is from-20 ℃ to 80 ℃, the addition or reaction temperature of process step b) is from-20 ℃ to 40 ℃, and the addition or reaction temperature of process step c) is from 0 ℃ to 30 ℃.

3. The process according to claim 1, wherein the catalytically active tertiary amine in process step b) is pyridine, picoline, dimethylaminopyridine, triethylamine and/or dimethylbenzylamine.

4. The process of claim 1, characterized in that the organic solvent is an acetate, methyl tert-butyl ether or tert-amyl methyl ether.

5. The process of claim 1, characterized in that the amount of the organic solvent is 50 to 800 ml based on 0.3 mol of the corresponding phenethylamine.

6. The process of claim 1, wherein in process step c), after the addition of phenylethylamine, the reaction mixture is heated to a temperature of from 40 ℃ to the boiling point of the corresponding organic solvent.

7. The process of claim 1, wherein p-methylphenylethylamine is used in process step c).