JPH09249631A - Production of n-((r)-1-(2,4-dichlorophenyl)ethyl)-(s)-2-cyano-3,3-dimethylbutanamide - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a process for producing N-[(R)-1-(2,4-dichlorophenyl) ethyl]-(S)-2-cyano-3,3-dimethylbutanamide in high efficiency. SOLUTION: This process for the production of N-[(R)-1-(2,4-dichlorophenyl) ethyl]-(S)-2-cyano-3,3-dimethylbutanamide comprises the crystallization of a mixture of N-[(R)-1-(2,4-dichlorophenyl)ethyl]-(R)-2-cyano-3,3-dimethylbutanamide and N-[(R)-1-(2,4-dichlorophenyl)ethyl]-(S)-2-cyano-3,3-dimethylbutanamide or N-[(R)-1-(2,4-dichlorophenyl)ethyl]-(R)-2-cyano-3,3-dimethylbutanamide under basic condition.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to N-[(R) -1-
(2,4-Dichlorophenyl) ethyl]-(S) -2-
It relates to a method for producing cyano-3,3-dimethylbutanamide.

2. Description of the Related Art N- [1- (2,4-dichlorophenyl)
It is described in JP-A-2-76846 that ethyl] -2-cyano-3,3-dimethylbutanamide (hereinafter referred to as compound 1) has an excellent plant disease control effect.

By the way, since compound 1 has one asymmetric carbon atom on the acid side and one asymmetric carbon atom on the amine side, a total of four optical isomers, namely (acid side, amine side) ) In that order, (R, R) [hereinafter referred to as X1. ], (S,
S) [Hereafter referred to as X2. ], (R, S) [hereinafter referred to as Y1. ] And (S, R) [hereinafter referred to as Y2. ], But as shown in Japanese Patent Application No. 7-289795 and Reference Example 6 described later, the present inventors have found that plant disease controlling activity is concentrated on Y2 and X1 and that Y2 is It was found that the plant disease controlling activity is far stronger than that of X1. From this, Y2 having a particularly excellent plant disease controlling activity, that is, N-[(R) -1- (2,4-dichlorophenyl) ethyl]-(S) -2-cyano-3,3-dimethylbutane It is desired to develop an industrially advantageous production method for amides.

[0002]

In view of the above situation, the inventors of the present invention have made earnest studies on a method for industrially producing Y2. As a result, a mixture of X1 and Y2 or X1 under basic conditions has been obtained. The present invention was completed by discovering that Y2 is crystallized while X1 is isomerized to Y2 and Y2 is efficiently obtained by subjecting it to crystallization. That is, the present invention uses X1 and Y
Provided is a method for producing Y2, which comprises crystallization of a mixture with 2 or X1 under basic conditions.

[0003]

BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, the crystallization operation is usually carried out by mixing a mixture of X1 and Y2 or X1 with an appropriate solvent, heating to 50 to 220 ° C. if necessary, and then adding a basic compound. And, in a state where a phase transfer catalyst is added, if necessary, usually within a temperature range of 0 to 100 ° C., usually 0.5 to 1
It is carried out by an operation such as cooling for 0 hours, partial removal of the solvent by distillation, and / or changing the polarity of the solvent (addition of another solvent having a different polarity). A small amount of Y2 seed crystal may be added to promote crystallization. In the present invention, as the raw material compound, a mixture of X1 and Y1 in any proportion or X1 is used.
Mixtures of approximately equal proportions with 1 are used. The solvent used is not particularly limited as long as it is non-reactive in the crystallization operation, for example, xylene, cumene,
Aromatic hydrocarbon solvent such as mesitylene, aliphatic hydrocarbon solvent such as hexane and octane, halogenated aromatic hydrocarbon solvent such as chlorobenzene and dichlorobenzene, ether solvent such as diglyme, triglyme and dioxane, alcohol such as ethanol and propanol Examples thereof include a solvent, water, a mixed solvent of water and the alcohol solvent, or a mixture thereof. The basic compound used is preferably a strong basic compound, for example, sodium hydroxide,
Alkali metal hydroxides such as potassium hydroxide; Alkaline earth metal hydroxides such as calcium hydroxide; Alkali metal carbonates such as potassium carbonate; Dimethylaminopyridine, 1,8-diazabicyclo [5.4. 0] Undes-
Organic strongly basic compounds such as 7-ene and 1,5-diazabicyclo [4.3.0] non-5-ene; alkoxides of alkali metals such as sodium methoxide (eg C1
-C5 alkoxide); an alkali metal such as sodium; an alkaline earth metal such as calcium; or a mixture thereof. The amount of such a basic compound to be used is a mixture of X1 and Y2 or 1 mol of X1. In general, the proportion is 0.0001 to 0.5 mol. Examples of the phase transfer catalyst used as necessary include, for example, quaternary ammonium salts such as tetrabutylammonium chloride, tetrabutylammonium bromide, and benzyltriethylammonium chloride, and the like. The amount is usually 0.0001 to 0.1 mol with respect to the mixture of X1 and Y2 or 1 mol of X1. In the present invention, a preferred solvent / basic compound / phase transfer catalyst embodiment is, for example, an aromatic hydrocarbon solvent and water or a halogenated aromatic hydrocarbon solvent and water / alkali metal hydroxide / quaternary ammonium salt. ;
Examples thereof include alkali metal carbonate / alcohol solvent and water; alkali metal alkoxide / alcohol solvent and the like. The mixed solution after crystallization is usually neutralized with dilute hydrochloric acid, etc., if necessary, and the precipitated crystals are collected by filtration, and if necessary, a suitable solvent (for example, a hydrocarbon solvent such as xylene, cumene or mesitylene, Hexane, aliphatic hydrocarbon solvent such as octane, chlorobenzene, halogenated aromatic hydrocarbon solvent such as dichlorobenzene, diglyme, triglyme, ether solvent such as dioxane, ethanol, alcohol solvent such as propanol, water and the alcohol solvent The desired Y2 can be isolated by washing with a mixed solvent or a mixture thereof and then drying. Further, in order to improve the crystal properties, Y2 crystals can be taken out by the following crystallization operation. That is, X1
And a mixture of Y2 and Y1 are dissolved in an organic solvent such as monochlorobenzene, dichlorobenzene, and toluene that is azeotropic with water, and then the solution is kept at about 70 to 100 ° C. On the other hand, water, an alkali metal hydroxide and a quaternary ammonium salt were charged into another container equipped with a thermometer, a cooling pipe for condensing distillate and a stirrer, and the temperature was raised to about 100 ° C. Then, a solution (incubated at about 70 to 100 ° C.) dissolved in the above organic solvent is slowly added thereto.
When the organic solvent is azeotropically distilled with water, the Y2 crystals are precipitated almost at the same time. The Y2 water slurry thus obtained is slowly cooled to about 20 to 40 ° C., neutralized with an acid such as dilute hydrochloric acid if necessary, and the crystals are collected by filtration, washed with water and dried. As a result, Y2 can be obtained as a crystalline powder having good filterability.

The mixture of X1 and Y2 or X1 which is the raw material compound used in the present invention can be efficiently produced, for example, by the following method. α-cyano-tert
- and C ₂ -C ₄ alkyl esters of butyl acetate (R) -
1- (2,4-dichlorophenyl) ethylamine and 1
A method of reacting at 30 to 250 ° C. The reaction is α-cyano-
C ₂ -C ₄ alkyl ester of tert-butylacetic acid (racemic form or optically active form) and (R) -1
-(2,4-Dichlorophenyl) ethylamine (optical purity does not need to be 100% ee (enantiomeric excess), and may be, for example, an optically active substance rich in (R) -form with an optical purity of 75% ee or more.) Can be carried out by reacting with and without solvent at a reaction temperature of 130 to 250 ° C., preferably 130 to 220 ° C., usually for 0.5 to 24 hours. The amount of reactants used for C ₂ -C ₄ alkyl 1 mole of α- cyano -tert- butyl acetate (R) -1- (2,4- dichlorophenyl) ethylamine is usually 0.9 to 1. It is a ratio of 2 mol. The solvent used as necessary is inert in the reaction and
There is no particular limitation as long as it has a boiling point of 30 to 250 ° C. or higher, and for example, xylene, cumene,
Examples thereof include hydrocarbon solvents such as mesitylene, halogenated aromatic hydrocarbon solvents such as chlorobenzene and dichlorobenzene, ether solvents such as diglyme and triglyme, or a mixture thereof. The reaction solution after the reaction is usually
The resulting crystals are collected by crystallization operation such as cooling to room temperature, washed with an appropriate solvent (organic solvent such as methanol, ethanol, isopropanol, hexane, monochlorobenzene, water or a mixed solvent thereof) and then dried. By doing so, the desired compound can be obtained.
The C ₂ -C ₄ alkyl ester of α-cyano-tert-butylacetic acid used as a starting compound in the production method is described in, for example, J. Am. Chem. Soc. 72 , 47
91 (1950) and the like. (R) -1- (2,4-dichlorophenyl) ethylamine is, for example, Organic Reaction Vol 5,301-3.
30 (1949) and JP-A-2-306942, and the like.

[0005]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples. The isomer ratio of the obtained product (X1 / X2 / Y1
/ Y2) is high performance liquid chromatography (H
PLC): Device: Hitachi L-6200 Column: SUMIPAX YMC-GEL SIL + SUMICHIRAL OA-4700 (5 μm, diameter 4 mm × length 25 cm) (5 μm, diameter 4.6 mm × length 25 cm) Phase: n-hexane / ethanol = 100: 2 Detection: UV 256 nm] The yield of the obtained product was determined from the weight of the product. Example 1 20.0 g of a mixture of X1 and Y2 (isomer ratio X1 / X
2 / Y1 / Y2 = 47/2/2/50), 1,8-diazabicyclo [5.4.0] undes-7-ene 0.97
g and 60.0 g of monochlorobenzene in a mixture of 85
After raising the temperature to 0 ° C. to dissolve the mixture of X1 and Y2,
The mixture was gradually cooled to 55 ° C over 4 hours. Seed crystals were added to this, and the mixture was gradually cooled to room temperature, and the formed crystals were collected by filtration, washed with hexane three times, and then dried under reduced pressure to obtain Y2 (isomer ratio X1 / X2 / Y1 / Y2 = 9/7/0/84) was obtained. (Yield 79%) Example 2 20.0 g of a mixture of X1 and Y2 (isomer ratio X1 / X
(2 / Y1 / Y2 = 47/2/2/50), a mixture of 0.78 g of dimethylaminopyridine and 40.0 g of dioxane was heated to 90 ° C. to dissolve the mixture of X1 and Y2, and then it took 1 hour. And gradually cooled to 58 ° C. Seed crystals were added to this, and the mixture was gradually cooled to room temperature, and the formed crystals were collected by filtration, washed with hexane three times, and then dried under reduced pressure to obtain Y2 (isomer ratio X1 / X2 / Y1 / Y2 = 8/4 /
0/87) was obtained. (Yield 71%) Example 3 20.0 g of a mixture of X1 and Y2 (isomer ratio X1 / X
2 / Y1 / Y2 = 47/2/2/50), 90% of a mixture of 60.0 g of monochlorobenzene and 100.0 g of water.
After raising the temperature to 0 ° C. to dissolve the mixture of X1 and Y2,
To this, 3.6 g of a 10% aqueous potassium hydroxide solution and 0.02 g of tetrabutylammonium bromide were added. Four
Monochlorobenzene was distilled off over a period of time to precipitate crystals. After neutralizing with 10% hydrochloric acid water, the resulting crystals were collected by filtration, washed with water, and dried under reduced pressure to yield Y2 (isomer ratio X1 / X2 / Y1 / Y2 = 0/4/0 / 90) 1
9.5 g was obtained. (Yield 98%) Example 4 20.0 g of a mixture of X1 and Y2 (isomer ratio X1 / X
2 / Y1 / Y2 = 47/2/2/50), 78 of a mixture of 0.88 g of potassium carbonate and 40.0 g of ethanol.
After raising the temperature to 0 ° C. to dissolve the mixture of X1 and Y2,
200.0 g of water was added dropwise over 4 hours to precipitate crystals. The resulting crystals were collected by filtration, washed with water, and dried under reduced pressure to yield Y2 (isomer ratio X1 / X2 / Y1 / Y2 = 5 /
3/0/92) was obtained. (Yield 98%) Example 5 Water 266.7 g, 5% aqueous potassium hydroxide solution 5.2 g and benzyltriethylammonium chloride 0.15
After the temperature of the mixture of g was raised to 98 ° C., 20.0 g of a mixture of X1 and Y2 (isomer ratio X1 /
X2 / Y1 / Y2 = 47/2/2/50) was added dropwise to a solution of 50.0 g of monochlorobenzene at 80 ° C., and monochlorobenzene was azeotropically distilled with water to distill off crystals. . After neutralizing with 10% hydrochloric acid water, the resulting crystals were collected by filtration, washed with water, and dried under reduced pressure to yield Y2 (isomer ratio X1 / X2 / Y1 / Y2 = 7/3 /
0/90) was obtained. (99% yield)

Next, reference is made to Reference Examples 1 to 5 for producing a mixture of X1 and Y2, which are raw material compounds used in the present invention.
As shown. (Method A) Biguryuu type rectification column, C ₂ -C ₄ alkyl esters of a thermometer and a four-necked flask equipped with a mechanical stirrer (RS)-.alpha.-cyano -tert- butyl acetate and (R)-1- A predetermined amount of (2,4-dichlorophenyl) ethylamine was charged. After heating to 180 ° C, 1
The reaction was carried out at 80 to 190 ° C. for 5 to 10 hours while distilling the produced alcohol. After completion of the reaction, the reaction mixture was cooled to room temperature, the generated crystals were collected by filtration, and washed twice with hexane.
The obtained crystal was dried under reduced pressure to obtain a desired mixture of X1 and Y2. (Method B) helicoil packed with the seminal Tome搭(20 cm), a four-necked flask equipped with a thermometer and a mechanical stirrer (RS)-.alpha.-cyano -tert- butyl acetate C ₂ -C ₄
Predetermined amounts of alkyl ester and (R) -1- (2,4-dichlorophenyl) ethylamine were charged, and 50 ml of a prescribed solvent was added. This solution is heated and the alcohol produced is distilled off together with the solvent (about 30 ml) for 8-20
Refluxed for hours. After completion of the reaction, the mixture was cooled to room temperature, 50 ml of hexane was added, and the formed crystals were collected by filtration and washed twice with hexane. The obtained crystal was dried under reduced pressure to obtain a desired mixture of X1 and Y2. Table 1 shows the results.

[0007]

[Table 1] * 1. Alkyl of (RS) -α-cyano-tert-butylacetate alkyl (Et represents ethyl, Bu represents n-butyl, respectively). * 2. (RS) -α-cyano-tert-butyl acetate alkyl. * 3. Optically active 1- (2,4-dichlorophenyl) ethylamine rich in (R) -form. * 4. Obtained by analysis by the above high performance liquid chromatography. However, the mobile phase was n-hexane / ethanol / trifluoroacetic acid = 240: 10: 1, and the detection was UV254 nm. * 5. (R) -1- (2, with optical purity of 99.8% ee or higher
4-dichlorophenyl) ethylamine was used. * 6. (R) -1- (2,4-dichlorophenyl) ethylamine having an optical purity of 84% ee was used. * 7. (R) -1- (2,4-dichlorophenyl) ethylamine having an optical purity of 76% ee was used. * 8. X2 / Y1 = <0.1 / <0.1 * 9. X2 / Y1 = <0.1 / <0.1 * 10. X2 / Y1 = <0.1 / <0.1 * 11 . X2 / Y1 = 4/4 * 12. X2 / Y1 = 6/6

Reference Example 6 Each optical isomer of racemic compound 1 (X1, X2, Y1 and Y
2) High Performance Liquid Chromatography (HPL)
Table 2 summarizes the results of sorting and purification by C) and examining the plant disease (rice blast) control activity thereof. (1) HPLC preparative HPLC preparative conditions are as follows; Device: Hitachi L-6200 Column: SUMIPAX YMC-GEL SIL + SUMICHIRAL OA-4700 (5 μm, diameter 4 mm × length 25 cm) (5 μm, diameter Mobile phase: n-hexane / ethanol / trifluoroacetic acid = 240: 10: 1 detection: UV 254 nm] X1, X2, Y1, and Y2 were eluted in this order. The absolute structure (R / S) of each was determined by the X-ray structural analysis of each of X1 and Y (Y1 + Y2). (2) Test example A plastic pot was filled with sandy loam soil, and rice (Kinki 33
No.) was sowed and grown in a greenhouse for 20 days. Then, the reagent solution prepared in a wettable powder (obtained by thoroughly pulverizing and mixing 50 parts of compound 1, 3 parts of calcium ligninsulfonate, 2 parts of sodium lauryl sulfate and 45 parts of synthetic hydrous silicon oxide) with water was used as a reagent. It was diluted to a predetermined concentration and foliage sprayed so that it adhered sufficiently to the rice leaf surface. After spraying, the plants were air-dried, and a spore suspension of blast fungus was sprayed and inoculated. After the inoculation, the plants were left at 28 ° C. in the dark and humid for 4 days, and then the control efficacy was investigated. In addition, the control efficacy is "5", 10% if the disease state of the test plant at the time of the survey, that is, the microflora of leaves, stems, etc. “4” if the degree is recognized, “3” if about 30% is recognized, “2”, 7 if about 50% is recognized.
If about 0% is found, it is evaluated as “1”, and if there is no difference with the disease state when the compound is not tested, it is evaluated as “0” and evaluated in 6 levels, 5, 4, 3, respectively.
Shown as 2,1,0.

[0009]

[Table 2] *. Display the absolute structure of each asymmetric carbon in the order of (acid side, amine side).

Claims (2)

[Claims] 1. N-[(R) -1- (2,4-dichlorophenyl) ethyl]-(R) -2-cyano-3,3-dimethylbutanamide and N-[(R) -1- ( 2,4-dichlorophenyl) ethyl]-(S) -2-cyano-3,3-dimethylbutanamide or N-[(R) -1
-(2,4-Dichlorophenyl) ethyl]-(R) -2-
N-[(R) -1- (2,4, characterized in that cyano-3,3-dimethylbutanamide is crystallized under basic conditions.
-Dichlorophenyl) ethyl]-(S) -2-cyano-
A method for producing 3,3-dimethylbutanamide. 2. The method according to claim 1, wherein the crystallization is performed in the presence of a strongly basic compound.