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Method and reagents for N-alkylating ureides

a technology of n-alkylated ureides and reagents, which is applied in the direction of biocide, drug compositions, muscular disorders, etc., can solve the problems of complex reaction, high toxic and regulated, salts, dimers, and other side products being formed

Inactive Publication Date: 2006-01-10
TARO PHARMA INDS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0005]The invention method avoids the use of volatile, carcinogenic chloromethyl methyl ether, replacing that reagent with a more reactive, less volatile alternative which may be generated in situ (without risk to the operator).
[0006]The invention solves a previously unrecognized problem limiting the applicability of methoxymethanesulfante alkylation to alcohols and amines. Ureides are much less basic than amines, so a different method for oxyalkylation is required. This invention differs from the method of Karger et al. by using a ureide, a non-aqueous basic catalyst, and an aprotic solvent, modifications which were not previously known or suggested. The inventive method allows use of a variety of sulfonates to prepare a broad variety of oxyalkylated ureides, some not previously known. The simplicity and convenience of the invention provide advantages that were not previously appreciated.

Problems solved by technology

However, it is highly toxic and regulated as a carcinogen.
With amines, the reaction was complex and led to salts, dimers, and other side products being formed.

Method used

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  • Method and reagents for N-alkylating ureides
  • Method and reagents for N-alkylating ureides
  • Method and reagents for N-alkylating ureides

Examples

Experimental program
Comparison scheme
Effect test

example 1

N,N′-bismethoxymethyl-5,5-diphenylbarbituric acid

A. Using a Hindered Tertiary Amine Catalyst

[0044]Dimethoxymethane (10.85 g) was added at 0° C. to 19.7 g of acetylmethanesulfonate. The reaction was stirred at 25° C. for 2 hours. The resultant solution was then added gradually over 45 minutes to a mixture of 10 g of 5,5-diphenylbarbituric acid and 13.85 g of N,N-diisopropyl ethyl amine in 60 ml of dry dimethylformamide. The resultant reaction mixture was stirred for about 15 minutes and then diluted with 180 ml of 2 N HCl, followed by 300 ml of ethyl acetate. The phases were separated and the ethyl acetate phase was washed first with 150 ml of saturated aqueous sodium chloride and then with 150 ml of 2N aqueous NaOH. The organic (ethyl acetate) phase was dried over anhydrous sodium sulfate, filtered and concentrated to dryness to give 12.2 g of N,N′-bismethoxymethyl-5,5-diphenylbarbituric acid. Crystalization from 48 ml of toluene afforded 10.5 g of pure product (79.6% yield).

B. Usin...

example 2

N,N′-Bisethoxymethyl-5,5-diphenylbarbituric acid

[0049]By the procedure of Example 1A, using diethoxymethane (15.42 g) in place of dimethoxymethane (10.85 g), there is obtained a 68% yield of pure N,N′-bismethoxymethyl-5,5-diphenylbarbituric acid.

example 3

3-Methoxymethylphenytoin

[0050]By the procedure of 1A, using phenytoin (18 g) in place of 5,5-diphenylbarbituric acid (10 g), there is obtained a 70% yield of 3-methoxymethylphenytoin.

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Abstract

A method of N-alkoxyalkylating ureides according to the invention comprises reacting a ureide of structure I with an alkylating agent of structure III in the presence of a basic catalyst in an aprotic reaction medium. The ureide may be a 5,5-disubstituted barbituric acid, or it may be phenytoin, glutethimide, and ethosuximide. The alkylating agent is an ester of a sulfonic acid. The base may be a hydride or amine. A preferred process comprises N-alkoxyalkylating 5,5-diphenyl-barbituric acid with methoxymethyl methanesulfonate in the presence of di-isopropyl ethyl amine and isolating the resultant N,N′-bismethoxymethyl-5,5-diphenyl-barbituric acid. The invention also contemplates the novel compounds N-methoxymethyl-5,5-diphenylbarbituric acid, N-methoxymethyl ethosuximide, and N-methoxymethyl glutethimide, and a method comprising administering them to a patient.

Description

BACKGROUND OF THE INVENTION[0001]The invention relates to a new means for N-alkylating ureides that is higher yielding, more convenient, and safer to use than techniques practiced heretofore. This approach is particularly suited to preparing N-(alkoxyalkylene) ureides, which include anti-convulsant drugs of the N-substituted barbituric acid class.[0002]The term ureide is used in e.g. Foye, Principles of Medicinal Chemistry, 3d ed. (1990), pp. 164, 179, which is incorporated herein by reference. Ureides are a class of imides of general structure I: Examples, include hypnotics, such as acecarbromal, apronalide, bromisolvalum, capuride, carbromal, and ectylurea; and anticonvulsant drugs such as hydantoins, glutarimides, oxazolidinediones, succinimides, and barbiturates such as barbituric acid (structure II). [0003]U.S. Pat. No. 4,628,056 teaches a method of making 1,3 bis(methoxymethyl)-5,5-diphenyl barbituric acid (also called (N,N′-bis(methoxymethyl)-5,5-diphenyl barbituric acid) by ...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): C07D239/62C07D233/74A61K31/515C07D263/44A61K31/496A61P25/00A61P25/08C07C231/08C07C233/90C07C273/18C07C275/48C07D207/40C07D207/408C07D211/88
CPCC07D207/40C07D207/408C07D263/44C07D233/74C07D239/62C07D211/88A61P21/02A61P25/00A61P25/08A61P25/22
Inventor GUTMAN, DANIELAHERZOG, HERSHEL
Owner TARO PHARMA INDS
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