GB2196005A - Preparation of 3-amino-5-methylisoxazole - Google Patents

Description

GB2196005A 1

SPECIFICATION

Process for the manufacture of 3-amino-5-methyllsoxazole The present invention relates to a process for the manufacture of 3-amino- isoxazoles. More 5 particularly, the invention relates to an improved process for the manufacture of 3-amino-5 methylisoxazole (hereafter referred to as 3-AMI) at high yields.

BACKGROUND TO THE INVENTION

The compound 3-AMI is known as an important raw material for the preparation of sulfonam- 10 ide derivatives which are widely used as antibacterical agents. Thus for example, by condensa tion of 3-AMI with N-protected p-aminobenzenesulfonyl chloride, sulfamethoxazole is obtained which is one of the most effective sulfa drugs. 3-AMI is mentioned as a new compound in the U.K. Patent No. 814,276 as a starting material for the manuacture of sulfa drugs. According to the patent, 3-AMI is obtained by the hydrolysis of ethyl-5- methylisoxazole-3-carbamate. 15 The literature is quite abundant with methods dealing with the manufacture of derivatives of 3- amino-isoxazoles having the formula:

rl--, -NH2 20 N R14 0 1-11 wherein: R represents: hydrogen, an alkyl group containing 1-5 carbon atoms and aryl groups.

The general scheme of these methods involves the reaction between a hydroxylamine, or 25 derivatives thereof, with suitable nitrile compounds and the cyclization of the resulting intermedi ate product using alkali hydroxide solutions. One of the main disadvantages of the known methods is the relatively poor yields which are in the range of 50-76% only. Attempts to improve the yields of the methods, based on the above scheme, were unsuccessful and accord ingly other routes, which are more complicated or are requiring more expensive starting materials 30 were suggested. Thus for instance according to C.A. 98, 126062, it is suggested to carry out this synthesis by starting with 3-carbamoyl-5-methylisoxazole and a mixture of sodium hydroxide and sodium hypochlorite.

It is -an object of the present invention to provide an improved process for the manufacture of 3-amino-5-methylisoxazole. It is another object of the present invention to provide an improved 35 process for the manufacture of 3-amino-'5-methylisoxazole at high yields. It is yet another object of the present invention to provide an improved process for the manufacture of 3-amino-5 methylisoxazole (3-AMI) which is of a high purity.

SUMMARY OF THE INVENTION 40

The invention consists of an improved process for the manufacture of 3AMI, by reacting a nitrile compound selected from the group consisting of 2,3- dibromobutyronitrile (DBBN), 2 bromo-3-methoxybutyronitrile (BMBN), 2-bromocrotononitrile (2-13CN), tetrolonitrile (TN) and mix tures thereof with hydroxyurea in an alkali metal hydroxide medium, the pH during the reaction being maintained in the range of 10.1-13. It was unexpectedly found that by carrying out the 45 reaction of the nitrile-hydroxyurea compound under a controlled pH range, the most preferred being between 10.5-12.5, the yields obtained are considerably improved being above 90%.

Moreover, the 3-AMI product is substantially free of the 5-amino-3methylisoxazole (5-AMI) which is one of the main impurities present in the prior art methods.

Another advantage of the process according to the present invention, is the relatively short 50 reaction time required in the cyclization step producing the 3-AMI. Whereas the prior art methods are mentioning long periods up to 24 hours, according to the present invention even less than 4 hours were found to be sufficient to obtain the high yields of 3-AMI. This enables to carry out the process even in a continuous manner.

According to a preferred embodiment, the reaction in the alkali metal hydroxide medium, is 55 carried out in the presence of an inert organic solvent for example primary alcohols, dioxane, tetrahydrofuran and the like or any mixture thereof. Specific examples of alcohols are methanol, ethanol etc.

Suitable alkali metal hydroxides to be employed during the cyclization step are sodium, potas- sium and lithium hydroxide, the first one being most preferable being also the less expensive. 60 The alkali metal hydroxide is added generally in the form of an aqueous solution, the preferred concentration range being between 30% to 50% by wt. The reaction temperature is not critical, generally being from about room temperature to the reflux temperature of the solvents utilized.

The first step of the process consists of the reaction between a nitrile, and hydroxyurea. This reaction is carried out under vigorous stirring. The nitrile is selected from D1313N, BMBN, 2-13CN 65 2 GB2196005A 2 and TN or any mixture thereof, prepared according to the methods known in the art. The BIVIBN - seems to be a new compound which is not described in the literature. It is obtained by the bromination of crotononitrile (CN) in methanol.

The hydroxyurea can be added either in its pure form or produced in-situ without any isolation or purification. Thus for instance, hydroxyurea can be prepared by mixing alkyl carbarnates and 5 hydroxylamine salts in basic aqueous medium. The hydroxylamine may be in the form of a free base or an acid addition salt such as hydrochloride, hydrosulfate and the like. In the latter case, the hydroxylamine will be formed in-situ, by reacting the acid salt with sodium hydroxide in the presence of alkyl carbarnates as known in the art, The main feature of the present invention, is the production of the 3-AMI by the reaction of 10 the suitable nitriles and hydroxyurea in the presence of alkali metal hydroxide in a critical narrow PH range. It was found that the high yields are achieved only when the reaction is produced under a PH ranging from 10.1 to 13 and most preferable at a PH range of between 10.5 to 12.5. When the PH is below 10. 1 or above 13, a sharp decrease occurs in the yield being -accompanied by an increase of 5-AIVII known as the main impurity. This will clearly appear from 15 the Examples presented below. The inventors are not yet in a position to give a definite explanation of this phenomena.

The control of the PH in the above narrow range can be obtained by adding continuously small portions of alkaline metal hydroxide, using a conventional PH electrode as monitoring device. Of course a person skilled in the art may utilize any other expedients for monitoring the 20 PH at the above range.

The invention will be hereafter illustrated by the following Examples without being limited thereto. A person skilled in the art after reading the specification, will be in a position to appreciate the gist of the invention and many variations might be conceived and incorporated therein. 25 EXAMPLES I to 5.

A solution containing 53.6 gr (0.8 moles) of crotononitrile and 42.5 ml of absolute methanol was mixed vigorously in a three-necked flask. 128 gr (0.8 moles) of bromine were introduced dropwise into the solution. After the addition was completed the solution was left for 24 hours 30 aging and was found to consist of about 79% DBBN.

To an amount of 130 mls of cold solution from the above resulted DBBN solution, it was added under vigorous stirring a solution consisting of 20 g sodium hydroxide dissolved in 75 ml water.

The solution was stirred for five minutes after the addition was completed, the organic layer 35 was separated and dried over anhydrous MgSO,. 69.66 gr of a pale yellow mixture was obtained. According to NIVIR spectrum, using tetrachloroethane as internal standard, the solution contained 85% of 2-BCN, 10.5% of BIVIBN and 1.1% of tetrolonitrile (TN).

Aqueous hydroxyurea (HXU) solution was prepared from 95 gr hydroxylammoniurn hydrochlo- ride and 129 gr of ethyl carbarnate in a basic medium 1 130 gr of the mixture prepared above 40 was introduced dropwise to the cold vigorously stirred HXU solution, while the PH was kept between certain limits by occasional addition of 50% NaOH solution. After the addition was completed, the reaction mixture was mixed for 1 hr at room temperature and then refluxed for about 3 hours.

The solution was cooled, filtered and extracted with 3x250 ml of ethyl acetate. The com- 45 bined organic layer was dried over anhydrous MgSO, and evaporated. The resulting oil was analyzed by HPLC using a Bio-R ad, Aminex HPX-72-0, 300 mmx7 mm column; 0. 01 N NaOH was used as eluant.

The experiment was repeated under the same conditions, the difference being the PH range maintained during the NaOH addition. The results are summarized in the following Table 1. 50 TABLE 1. Yields of 3-AMI produced at various pli ranges using crude 2-BCN as a nitrile source. 55 Ex.1 Ex.2 Ex.3 EX.4 EX.5 pH limits 9-10 10-11 11-12 12-13 13-14 60 3-AMI yield 70.9 85.6 83.0 79.5 52.1 5-AMI yield 3.4.2.1 1.5 1.1 2.0 65 3 GB2196005A 3 From the above Table 1, it appears clearly the improved results of the 3- AMI obtained according to the present invention. When the pH is kept in the range of 10.1-13, the yields are in the range of 79.5% to 85.6% compared with 70.9% and 52.1% when the pH ranges are between 9-10 and 13-14, i.e. below or above the optimal range discovered according to the present invention. Also, the 3-AMI product is purer than that obtained in the pH ranges outside the 5 range of the present invention, containing less 5-AMI, which is the main impurity co-produced in the process.

EXAMPLES 6 to 8.

An amount of 214 mls of a methanolic solution of D13BN, obtained as in Examples 1-5, was 10 added dropwise under vigorous stirring to an ice cooled solution of aqueous HXU (prepared as in Example 1-5) present in a 3 1 three-necked flask. To the mixture, a solution of NaOH (50% concentration by wt.) was added, maintaining strictly the pH range. When the addition was completed the crude mixture was worked up as described in Examples 1-5. Three experiments were repeated under the same conditions, the difference being the pH ranges kept during the 15 sodium hydroxide addition. The results are summarized in the following Table 2.

TABLE 2. Yields of 3-AMI produced at various PH ranges using crude DBBN as a nitrile source. 20 Ex. 6 Ex. 7 Ex.8 pH range 9-10 12-12.5 13.5-14 25 3-AM1 yield 65.01 82.3% 21% 5-AMI yield 4.10 >0.1% not mewwed 30 From the above Table 2, it again appears the improved results concerning yield and purity of the 3-AMI produced according to the present invention.

35 EXAMPLE 9

2-Bromocrotonitrile (2-13CN) was obtained by dehydrobromination of the D13BN obtained as in Examples 1-5, using a solution of NaOH. The 2-BCN was distilled under vacuum (50 degrees C/8 mm Hg). The procedure for obtaining the 3-AMI was the same as in Examples 1-5, using an amount of 147 9 of the distilled 2-BCN. The pH during the reaction, was maintained by the 40 addition of NaOH (50% concentration by wt.) in the range of 11-12. An amount of 88.15 g of 3-AMI was produced (Yield=90%) the 5-AMI impurity being less than 0.7%, as determined by the HPLC analysis (as mentioned in Examples 1-5).

It should'be pointed out that Examples 1, 5, 6, 8 do not illustrate the present invention and are presented for comparison purposes only. 45

Claims (13)

1, A process for the manufacture of 3-amino5-methylisoxazole, by reacting a nitrile corn- pound selected from the group consisting of 2,3-dibromobutyronitrile, 2- bromo-3-methyoxybuty ronitrile, 2-bromocrotononitrile and tetrolonitrile, or a mixture thereof with hydroxyurea in an - 50 alkali metal hydroxide medium, the pH during the reaction being maintained in the range of 10.1 to 13.

2. A process according to Claim 1, wherein the pH is maintained in the range of between 10.5 to 12.5.

3. A process according to Claims 1 or 2, wherein an inert organic solvent is present during 55 the reaction.

4. A process according to Claim 3, wherein said solvent is selected from the group consist- ing of primary alcohols, dioxane, tetrahydrofuran or mixtures thereof.

5. A process according to Claim 4, wherein said primary alcohol is methanol.

6. A process according to Claims 1 to 5, wherein the alkali metal hydroxide is selected from 60 sodium, potassium and lithium hydroxide.

7. A process according to Claim 6, wherein the alkali metal hydroxide is added as an aqueous solution having a concentration in the range.of 30% to 50% by weight.

8. A process according to Claims 1 to 7, wherein the hydroxyurea is produced in-situ during the process. 65 4 GB 2 196 005A 4

9. A process according to Claim 8, wherein the hydroxyurea is prepared from alkyl carbam- ate and hydroxylamine in an aqueous alkali medium.

10. A process according to Claims 1 to 9, wherein said pH range is monitored out by a pH electrode.

11. A process according to Claims 1 to 10, wherein the process is carried out in a continu- 5 ous manner.

12. A process for the manufacture of 3-amino-5-methylisoxazole substantially as described in the specification and claimed in any one of Claims 1 to 11.

13. 3-amino-5-methylisoxazole whenever prepared by the process claimed in Claim 12.

Published 1988 at The Patent Office, State House, 66/71 High Holborn, London WC 1 R 4TP. Further copies may be obtained from The Patent Office, Sales Branch, St Mary Cray, Orpington, Kent BR5. 3RD. Printed by Burgess & Son (Abingdon) Ltd, Con. 1/87.