JPH09309872A - N-benzoylhydantoic acid and production thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new compound useful a therapeutic agent as a complication of diabetes mellitus. SOLUTION: This N-benzoylhydantoic acid is a compound of formula I [X is a halogen; Y is a halogen, a 1-6C alkyl, nitro, cyano, a sulfonic acid ester or a carboxylic acid ester; (n) is 1-4; in the case of (n)>=2, plural Y's may be different from one another; R is H or a 1-6C alkyl], e.g. 1-N-(2,4-dichlorobenzoyl) hydantoic acid ethyl ester. The compound of the formula I is obtained by reacting a benzoic acid derivative of formula II (Z is hydroxyl, a halogen or a 1-5C alkoxy) with a hydantoic acid of formula III in an inert solvent (e.g.; toluene or pyridine) at (-)10-200 deg.C. The compound of the formula I is useful as a synthetic raw material for an N-derivative of quinazolinediones such as 7-chloro-1-ethoxycarbonylmethyl-2,4(2H,3H)-quinazolinedione.

Description

Detailed Description of the Invention

[0001]

The present invention relates to a novel compound, N
-Benzoylhydantoic acids and methods for their synthesis. This compound is useful as a raw material for manufacturing a therapeutic drug for diabetic complications.

[0002]

2. Description of the Prior Art A compound having an alkyl substituent at the 1-position and 3-position of 2,4 (1H, 3H) -quinazolinedione is
FK-366 (Zenarest, which is a compound of interest in terms of physiological activity, for example, a therapeutic drug for diabetic complications)
at: Fujisawa Pharmaceutical Co., Ltd.) is being developed. As a method for synthesizing this, N-alkylation of 7-chloro-1-ethoxycarbonylmethyl-2,4 (1H, 3H) -quinazolinedione and ester hydrolysis are known as shown below. . (ChemistryExpr
ess, Vol. 8, No. 9,761-764 (19
93))

[0003]

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7-chloro-1-ethoxycarbonylmethyl-2,4 (1H, 3) which is an intermediate raw material of FK-366.
As a synthetic method of (H) -quinazolinedione, selective alkylation of 7-chloro-2,4 (1H, 3H) -quinazolinedione as shown in the following reaction formula is recommended.
(Chemistry Express, Vol. 8,
No. 9,761-764 (1993))

[0005]

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[0006]

However, this method cannot be said to be an advantageous production method because HMDS and ethyl bromoacetate as raw materials are expensive. Therefore, 7-chloro-1-ethoxycarbonylmethyl-2,4 (1H, 3
An inexpensive method for producing (H) -quinazolinedione is desired. The present invention uses a route different from the above to obtain 7-chloro-1-ethoxycarbonylmethyl-2,4 (1H, 3
It is intended to provide a novel compound as a raw material for producing (H) -quinazolinedione and a method for producing the same.

[0007]

We have found that compounds of general formula (1) are quinazolines such as 7-chloro-1-ethoxycarbonylmethyl-2,4 (1H, 3H) -quinazolinedione. It has been found that it is useful as a raw material for synthesizing N-derivatives of diones.

[0008]

[Chemical 6]

(Wherein X represents a halogen atom, Y represents a halogen atom, an alkyl group having 1 to 6 carbon atoms, a nitro group, a cyano group, a sulfonic acid ester group or a carboxylic acid ester group, and n is 1 to 1). It represents an integer of 4. When n is an integer of 2 or more, a plurality of Ys may be different from each other.
R represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. ) When this compound is ring-closed, N- of quinazolinediones is
A derivative is produced.

[0010]

[Chemical 7]

The compound of the general formula (1) according to the present invention will be described in more detail. Examples of the halogen atom represented by X include a chlorine atom and a fluorine atom. Y
When represents a halogen atom, Y represents a chlorine atom, a fluorine atom or the like. When Y represents an alkyl group, Y represents a chain or cyclic alkyl group having 1 to 6 carbon atoms such as methyl group, ethyl group, t-butyl group, cyclohexyl group. When Y represents a sulfonate group, Y represents a methoxysulfonyl group, an ethoxysulfonyl group, an i-propoxysulfonyl group, a butoxysulfonyl group, a p-methylphenoxysulfonyl group, or the like.
When Y represents a carboxylic acid ester group, Y represents a methoxycarbonyl group, an ethoxycarbonyl group, a butoxycarbonyl group, a phenoxycarbonyl group or the like. R
Is an alkyl group, R is a methyl group, an ethyl group, a t-butyl group, a cyclohexyl group or the like having 1 to 1 carbon atoms.
6 represents a chain or cyclic alkyl group. General formula (1)
Examples of the compound represented by are as follows.

1-N- (2,4-dichlorobenzoyl)
-Ethyl hydantoinate, 1-N- (2-chloro-4-
Methylbenzoyl) -hydantoic acid, 1-N- (2-
Chloro-4-nitrobenzoyl) -hydantoic acid, 1
-N- (2-chloro-1-cyanobenzoyl) -hydantoic acid, 1-N- (2-chloro-4-methylsulfonyl) hydantoic acid, 1-N- (2-chloro-4-methoxycarbonyl) hydantoic acid . The compound of the general formula (1) can be easily synthesized from the corresponding benzoic acid or its reactive derivative and the corresponding hydantoin acid ester.

[0013]

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In the above formula, Z is a hydroxyl group; a halogen atom such as a chlorine atom or a fluorine atom; or a methoxy group,
It represents a chain-like alkoxy group having 1 to 5 carbon atoms such as an ethoxy group and a t-butoxy group. Z is preferably a halogen atom from the viewpoint that the reaction proceeds promptly. This reaction is carried out in an inert solvent at -10 to 200 ° C, preferably 10
Performed at ~ 150 ° C. Examples of the inert solvent include saturated hydrocarbons such as hexane and heptane; aromatic hydrocarbons such as benzene and toluene; ethers such as tetrahydrofuran and diethyl ether; aromatic amines such as pyridine; and tertiary amines such as triethylamine. Kinds and the like are used. The time required for the reaction depends on the raw materials and solvents used,
Although it varies depending on the reaction temperature and the like, it is usually 10 minutes to 10 hours. The hydantoinic acid ester, which is the starting material for the above reaction, can be easily synthesized from the corresponding glycine ester salt and cyanate by the following formula.

[0015]

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Next, the present invention will be described more specifically by way of examples, but the present invention is not limited to the following examples.

[0017]

Example: To 20 ml of dehydrated pyridine was added 730 mg (5 mmol) of ethyl hydantoinate, and the mixture was stirred for 2,4-
838 mg of dichlorobenzoyl chloride (4 mmo
20 ml of the pyridine solution of l) was added dropwise at 25 ° C. 25
After stirring at ℃ for 1 hour, add toluene and water to the reaction mixture,
The product was extracted into toluene. After thoroughly washing the toluene layer with water, toluene was distilled off under reduced pressure to obtain a pale yellow solid. The obtained solid was recrystallized from ethanol to give ethyl 1-N- (2,4-dichlorobenzoyl) -hydantoinate as white fine needle crystals (1.00 g, yield 79%).
I got

Melting point 178.0 to 178.5 ° C. (decomposition) Mass analysis value 318 ¹ H-NMR (DMSO-d6, δ): 1.20 (3
H, t, J = 7 Hz), 4.00 (2H, d, J = 6H)
z), 4.12 (2H, q, J = 7Hz), 7.52
(1H, dd, J = 8Hz, 2Hz), 7.59 (1
H, d, J = 8 Hz), 7.73 (1H, d, J = 2H)
z), 8.61 (1H, broad), 11.04 (1
H, broad) ¹³ C-NMR (DMSO-d6, δ): 14.05, 4
1.38, 60.56, 127.39, 129.24,
130.33, 131.05, 133.71, 135.
58, 152.94, 167.16, 169.63

Claims (2)

[Claims] 1. An N-benzoylhydantoic acid represented by the general formula (1): (In the formula, X represents a halogen atom, Y represents a halogen atom,
N represents an alkyl group having 1 to 6 carbon atoms, a nitro group, a cyano group, a sulfonic acid ester group or a carboxylic acid ester group, n
Represents an integer of 1 to 4. In addition, when n is an integer greater than or equal to 2, some Y may mutually differ. R represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. ) 2. A process for producing N-benzoylhydantoic acid according to claim 1, wherein the benzoic acid derivative represented by the general formula (2) is reacted with the hydantoic acid represented by the general formula (3). . Embedded image (In the formula, X, Y and n are as defined in the general formula (1). Z is a hydroxyl group, a halogen atom or a carbon number of 1 to 1.
5 represents an alkoxy group. ) (In the formula, R is the same as the definition in the general formula (1))