JPS5862165A - Preparation of 5-amino-3,4-dihydro-2h-imidazole-2,4-diones - Google Patents

Abstract

PURPOSE:To obtain the titled substance useful as a drug, agricultural chemical, their intermediates, etc. in high yield, by reacting amidinecarboxylic acid amide with phosgene or chloroformic trichloromethyl ester in the presence of pyridine. CONSTITUTION:A compound shown by the formulaI[R<2> is 1-4C alkyl, 2-5C alkenyl, 5-7C cycloalkyl, or 7-10C aralkyl; R<1> is R<2> or a group shown by the formula II (R<3> is 1-4C alkyl, or halogen; n is 0, 1, 2, or 3)]is reacted with phosgene or chloroformic trichloromethyl ester in the presence of pyridine at -20-40 deg.C for 1-24hr to give a compound shown by the formula III. In the reaction, a solvent such as an aromatic hydrocarbon, halogenated hydrocarbon, etc. which is sufficiently anhydrous is preperably used. The amount of pyridine used is 2mol based on 1mol phosgene and 4mol based on 1mol chloroformic trichloromethyl ester.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing 5-amino-3,4-dihydro-2H-imidazole-2,4-diones.

Tetrahedron Letters, 2827 (1979
), by reacting ethyl 2-methylimino-2-chloroacetate and phenylurea in the presence of hydrogen chloride,
Methylamino-3-7enyl-3,4-dihydro-2H
A method for producing -imidazole-2,4-dione is disclosed. According to this method.

The desired product was obtained in a relatively good yield of 60%.
However, it is not disclosed what happens with other compounds.

The purpose of this invention is to provide 5-amino-3,4-dihydro-2
The object of the present invention is to provide a novel and generally practicable production method that can obtain H-imidazole-2,4-diones in relatively good yields.

This invention.

[In the formula, Hl is an alkyl group having 1 to 4 carbon atoms,
5 alkenyl group, cycloalkyl group having 5 to 7 carbon atoms,
an aralkyl group having 7 to 10 carbon atoms or -CyR3n(R
s represents an alkyl group having 1 to 4 carbon atoms or a halogen atom, and n is O, 1, 2 or 3. ), R2 is an alkyl group having 1 to 4 carbon atoms, and 2 to 4 carbon atoms.
5 alkenyl group.

Cycloalkyl group having 5 to 7 carbon atoms or 7 to 10 carbon atoms
represents an aralkyl group, and R1 and R2 may be the same or different. ], and phosgene or chloroformic acid trichloromethyl ester are reacted in the presence of pyridine (wherein R1 and R2 each have the same meaning as above). 5-amino' represented by
This is the productivity of 3,4-dihydro 2H-imidazole-2,4-diones.

5-amino-3,4-dihydro-2 obtained by this invention
H-imidazole-2,4-diones are used in pharmaceuticals, agricultural chemicals,
Furthermore, it is useful as an intermediate for these.

Specific examples of amidinecarboxylic acid amides represented by formula [1] include N-methylamidinecarboxylic acid methylamide, N-ethylamidinecarboxylic acid ethylamide, N-methylamidinecarboxylic acid ethylamide, and
-Propylamidinecarboxylic acid propyldemide, N-butylamidinecarboxylic acid butyramide, N-allylamidinecarboxylic acid allylamide, N-cyclohexylamidinecarboxylic acid cyclohexylamide, N-benzylamidinecarboxylic acid benzylamide, N-phenylamidinecarboxylic acid, acid cyclohexylamide , N-xylylamidinecarboxylic acid allylamide, N-xylylamidinecarboxylic acid butylamide, N-chlorotolylamidinecarboxylic acid butylamide, and the like.

In the method of the present invention, the reaction of the amidinecarboxylic acid amide represented by the formula [1] with phosgene or trichloromethyl chloroformate in the presence of pyridine is preferably carried out using a solvent. Any solvent may be used as long as it is inert to the reaction in the method of this invention. Aromatic hydrocarbons such as toluene, chlorobenzene, and dichlorobenzene.

Examples include halogenated hydrocarbons such as methylene chloride, carbon tetrachloride, and ethylene chloride. Note that it is desirable that the solvent be sufficiently dehydrated prior to the reaction.

There are no particular restrictions on the order in which the raw materials are added.

Conveniently, an organic solution of phosgene or chloroformic acid trichloromethyl ester is added to a solution or suspension in an organic solvent containing amidine carboxylic acid amides and pyridine.

The amount of amidinecarboxylic acid amide used is preferably 90.75 to 1 mol per mol of Phosdef and 0.35 to 0.5 mol per mol of trichloromethyl chloroformate.

The amount of pyridine used is preferably about 2 moles per mole and a half of phosgene, and about 4 moles per mole of trichloromethyl chloroformate.

If the reaction temperature is too high, the yield of the desired product will decrease, so it is generally preferable to employ a temperature in the range of -20 to 40°C. The reaction time is usually 1 to 24 hours.

The desired product, 5-amino-3,4-dihydro-2H
-Imidazole-2,4-diones can be isolated, for example, by the following method.

After washing the reaction product mixture with water to remove by-produced pyridinium chloride as an aqueous solution, the organic solvent is distilled off to obtain a mixture containing the desired product, and then, by a conventional purification method such as a recrystallization method, A purified product of the desired product is isolated.

5-amino- represented by the formula [machi] obtained by this invention
Specific examples of 3,4-dihydro-2H-imidazole-2A-diones include 3-methyl-5-methylamino-
3,4-dihydro-2H-imidazole-2,4-dione, 3-ethyl-5-ethylamino''-3,4-dihydro-2H-imidazole-2A-dione, 3-propyl-5-propylamino-dione , 4-diLir0-2H-imi, C, 2,4-dione, 3-butyl-5-butylamino-3,4-dihydro-2H-imidazole-2,4
-dione, 3-allyl-5-allylamino-3,4-dihydro-2H-imidazole2,4-dione, 3-cyclohexyl-5-cyclohexylamino-3,4-dihydro-2H-imidazole-2,4-dione , 3-benzyl-5-benzylamino-3,4-dihydro-2H-
Imidazole-2,4-dione, 5-anilino-3-cyclohexyl-3,4-dihydro-2H-(midazole-2J4-dione, 3-allyl-5-xylidino-3,
4-dihydro-2H-imidazole-2,4-dione,
3-Butyl-5-xylidino-3A-dihydro 2H-
Imidazole-2,4-dione.

Examples include 3-butyl-5-chlorotoluidino-3,4-dihydro-2H-imidazole-2,4-dione.

Next, examples will be shown. In an example, 5-amino-3
,4-dihydro-2H-imidazole-2,4-dione is the yield based on the amidinecarboxylic acid amide used.

Example 1 Ethylene chloride 10 containing chloroformic acid trichloromethyl ester 0.62 was added to ethylene chloride 30 containing 0.8'6F of N-ingrobilamidinecarboxylic acid ingropyramide and 0.96F pyridine under water cooling. After the addition, the mixture was allowed to react for 2 hours while stirring at room temperature.

After the reaction, 30% of water was added to the obtained reaction product mixture at room temperature, and the mixture was separated into an aqueous layer and an organic layer. After drying the organic layer over anhydrous sodium sulfate, it was concentrated under reduced pressure to give 3-isopropyl-5-improvylamino-3,4-dihydro-
2H-imidazole-2,4-dione crystal o, 55y
(Yield: 86 cm) was obtained. Recrystallize this with inglobil ether.

Colorless prismatic crystals with a melting point of 14'7.5 to 148.5°C were obtained. The elemental analysis values are shown below.

CHN Analysis value 54.79 7.49 21.34 Calculated $ 54.81 7.67, 21.30 (C
Q HIlI N, o2) Example 2 Ethylene chloride 20Il+/ containing N-(n-butyl)amidinecarboxylic acid (--butyl)amide 1.99F and pyridine 1.97F was cooled with a cryogen (ice-salt). After dropping 15% of ethylene chloride containing 1.28 V of chloroformic acid trichloromethyl ester, the mixture was reacted for 4 hours with stirring at room temperature.

After the reaction, 25 m7 of water was added to the reaction product mixture obtained. was added, and the layers were separated into an aqueous layer and an organic layer. The organic layer was dried over anhydrous sodium chloride and concentrated under reduced pressure. The residual sticky substance 2.5'7F was treated with silica gel (Wakogel C-zoo
, 5oy) and eluted with a mixed solvent of benzene and ethyl acetate in a volume ratio of 4:1. After elution with solvent 300rn, solvent 200rn
1. The solution obtained by elution with

Concentrate under reduced pressure to give 3(n,-butyl)-5-(n
-butylamino)-3,4-dihydro-2H-imidazole-2,4-dione crystals i, 61y (yield near 2%)
) was obtained. This was recrystallized with inglobil ether,
Colorless crystals with a melting point of 94.5-95.5°C were obtained. The elemental analysis values are shown below.

CHN analysis value 58.44 8.29. 18.84 Calculated value 58.64 8.50 18.65 (CI
(as IHIQN302) Example 3 N-allylamidinecarboxylic acid allylamide 0.84F
and pyridine 1.02f to ethylene chloride 30-, under water cooling, chloroformic acid trichloromethyl ester o, 64y
After adding dropwise 10- of ethylene chloride, the mixture was reacted for 2 hours with stirring at room temperature.

After the reaction, 30 ml of water was added to the resulting reaction product mixture at room temperature to separate it into an aqueous layer and an organic layer. The organic layer was dried over anhydrous sulfuric acid and concentrated under reduced pressure. 0 sticky residue. B11 was converted into silica gel (Wako gel a-2
The mixture was passed through a column (diameter 25 nm) packed with 00,70f') and eluted with a mixed solvent of benzene and ethyl acetate in a volume ratio of 4:1. After elution with solvent 700-, solvent 550-
The solution obtained by elution with
%) was obtained. This was recrystallized with inglobil ether to obtain yellow prismatic crystals with a melting point of 94-95°C. The elemental analysis values are shown below.

OH'N Analysis value 55.84 5.76 22.00 Calculated value 55.95 5.74 21.75 (09H
(as IIN302) Example 4 N-cyclohexylamidinecarboxylic acid To ethylene chloride (30) containing cyclohexylamide (2.51P) and pyridine (1,972P) was added phosgene (1.5%) under cooling with a cryogen (ice-salt).
After dropping 20 ml of ethylene chloride containing 214, the mixture was reacted for 20 hours with stirring at room temperature.

After the reaction, 30 ml of water was added to the resulting reaction product mixture and filtered. The P solution was separated into an aqueous layer and an organic layer. After drying the organic layer with anhydrous sulfuric acid (IJum).

Concentration under reduced pressure gave 2.59y (yield: 94%) of crystals of 3-cyclohexyl-5-cyclohexylamino-3,4-dihydro-2H-(midazole-2j4-dione). Recrystallize it.

One point of colorless crystals having a temperature of 238 to 240°C was obtained. The elemental analysis values are shown below.

CHN Analysis value 65.20 8.36 15.28 Calculated value 64.96 8.63 15.15 (015
As H23N302] Example 5 N-benzylamidinecarboxylic acid benzylamide 1.9
To ethylene chloride 30- containing F and pyridine 1.41F,
After cooling with a cryogen (ice-salt), ethylene chloride Long containing 0.88 F of phosgene was added dropwise.

The mixture was allowed to react for 20 hours with stirring at room temperature.

After the reaction, 30 g of water was added to the resulting reaction product mixture at room temperature to separate it into an aqueous layer and an organic layer. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residual crystal ayo 9y was recrystallized from ethanol 40- to give 3-benzyl-5-benzylamino-3,4-dihydro-2H.
- Pale yellow fine needle crystals of imidazole-2,4-dione o
, 65r (yield: 31cm, melting point 168-168.5°C)
t- got it. The elemental analysis values are shown below.

OHN analysis value 69.93 '5.31 14.11
Calculated value 69.61 5.15 14.33 (C
'l? Example 6 Trichloromethyl chloroformate was added to 20 m of ethylene chloride containing N-(4-chloro-0-tolylfamidinecarboxylic acid inbutyramide 1.34F and pyridine oB81) under cooling with a cryogen (water-salt). After dropping ethylene chloride 2o containing varnish-til 0.58F.

The mixture was left stirring at room temperature for 15 hours.

After the reaction, 40% of water was added to the obtained reaction product mixture at room temperature, and the mixture was separated into an aqueous layer and an organic layer. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. Residue 1.4
7F, silica gel (Wakogel C-200, 100g
) and eluted with a mixed solvent of benzene and ethyl acetate in a volume ratio of 9:1. After eluting with 120 yd of solvent, the solution obtained by eluting with 165 yd of solvent was concentrated under reduced pressure to obtain 5-(4-chloro-
〇-Toluidino)-3-ynbutyl-3,4-dihydro-2H-imidazole-2,4-dione crystal 0.73
r (yield: 5o%) was obtained. This was recrystallized from cyclohexane to obtain yellow crystals with a melting point of 164-165°C. The elemental analysis values are shown below.

OHN 04 Analysis value 57.34 5.5'i' 14.06
11. '72 calculated value 5'7.24 5.49 14
．． 30 12.07 (as 0,, H, 602N, 02) Patent applicant Ube Industries, Ltd.

Claims (1)

[Scope of Claims] H [wherein R1 is an alkyl group having 1 to 4 carbon atoms, 2 to 4 carbon atoms]
5 alkenyl group, cycloalkyl group having 5 to 7 carbon atoms,
represents an aralkyl group having 7 to 10 carbon atoms or a group represented by 3n-()' (R3 represents an alkyl group having 1 to 4 carbon atoms or a halogen atom, and n is 0, 1.2 or 3); R2 is an alkyl group having 1' to 4 carbon atoms or an alknyl group having 2 to 5 carbon atoms. Cycloalkyl group having 5 to 7 carbon atoms or lip prime number 7 to 10
7ralkyl group, and R1 and R2 may be the same or different. ] R'NH-C-(, -Q ++ 1 8 (in the formula Bl and R2 each have the same meaning as above.) 5-amino-3,4-dihydro-2H-imidazole-2,4-diones.