DE940897C - Process for preparing the threo forms of oxazolines - Google Patents

Description

Process for Making the Threo Forms of Oxazolines The invention relates to a process for the preparation of oxazolines and more particularly, but not exclusively, to the preparation of threo-2-dichloromethyl-4-oxymethyl-5- (p-nitrophenyl) -d.7 oxazoline , whose dl- and d (-) - forms have therapeutic effectiveness, which, however, primarily as intermediates for the preparation of the corresponding forms of threo-2-dichloroacetamino-i- (p-nitrophenyl) -propanediols- (i, 3) whose .d (-) form is known as the antibiotic chloramphenicol. According to the invention, the threo forms of oxazolines are of the general formula wherein R1 is an aliphatic group having not more than 3 carbon atoms, especially a dichloromethyl group, and R2 is a hydrogen atom or an acyl group, especially an acetyl, benzoyl or carbalkoxy group or an unchanged carboxyl group-containing succinyl radical, prepared by the erythro form a compound of the formula where R1 has the above meaning and R is an acyl group, especially one of the acyl groups which are listed above to explain R2, treated with an alkali, preferably sodium or potassium hydroxide.

It is known that the threo forms of 2-aminoi- (p-nitrophenyl) propanediols (i, 3) and the corresponding 2-acylamino compounds by hydrolysis of in the 2-position substituted threo-4-oxymethyl- (or -acyloxymethyl-) -5- (p-nitrophenyl) -d 2- oxazolines can be produced. Suitable starting materials for manufacture these oxazolines are the corresponding erythro forms (also called "allo" forms) of 2-acylamino-i- (p-nitrophenyl) -propanediols- (i, 3). The procedure then closes also at one stage or another the measure of epimerization.

In the course of experiments in connection with the above process it was found that the desired threo-oxazolines of the general formula can be obtained easily and without significant contamination with the erythro epimers if .die erythro-2-acylamino-z- (p-nitrophenyl) -propanediols- (1, 3) initially in. Derivate of the type being transformed. In the above formulas, R denotes an acyl or carbalkoxy group, CORl an aliphatic acyl group with not more than q. Carbon atoms, preferably acetyl or a halogen-substituted acetyl, and R denotes either hydrogen or the group R.

According to the invention, nitric acid esters are then of the general type Formula (II) with alkali (especially sodium hydroxide) preferably in the cold or at a moderate temperature (i.e. at a temperature not above about 40 °) and preferably in an organic solvent, e.g. B. aqueous ethyl alcohol, implemented.

If the radical R is an easily split off group, such as acetyl, Benzoyl, acidic succinyl or carbethoxy, it becomes under the conditions of the reaction the nitric acid ester of the formula (II) is split off with alkali, and the reaction product is a 4-oxymethyloxazoline. However, if a more consistent group R is used, so the reaction product is e.g. B. a 4-acyloxymethyl- or 4-casbalkoxymethyloxazoline, its acyl or carbalkoxy group either during the subsequent hydrolysis of the Oxazoline is removed in a known manner or later. Of course it's possible, to select the groups C O R., and R such that under the hydrolysis conditions the group CORl is split off. The end product is threo-2-amino-i- (p-nitrophenyl) -propanediol- (1, 3) instead of the 2-acylamino compound.

Since an important feature of the invention is that an oxazoline is produced which can be converted directly into chloramphenicol or the dl mixture, the d (-) - compound being chloramphenicol, by hydrolysis, it is advantageous that the. The radical R is dichloromethyl and R is easily cleavable. The implementation can then be shown schematically as follows Preferably, dl- or 1-erythro-2-dichloroaceta.mino-3-acetoxy-i- (p-nitrophenyl) -propanol- (i) is treated with concentrated nitric acid (d = 1.5o) and, according to the invention, an alcoholic solution or suspension of the resulting nitric acid ester treated with a slight excess of sodium or potassium hydroxide solution at room temperature or slightly elevated temperature (ie a temperature not exceeding about 40 °), so that dl- or d-threo-2-dichloromethyl-4-oxymethyl-5 - (p-nitrophenyl) -d 2 oxazoline is formed.

It is a particular advantage of the inventive method that the preferred oxazolines, namely the dl- and d (-) - threo-2-dichloromethyl-4-oxymethyl-5- (p-nitrophenyl) -d2 oxazoline, directly in the pure state and without contamination by the other isomers 2-dichloromethyl-4-p-nitrophenyl-oxymethyl-42 oxazoline obtained and this .immediate, z. B. by dissolving in dilute mineral acid and then Neutralization with a base, in dl- or d-threo-2-dichloroacetamino-i- (p-nitrophenyl) -propanediol- (1, 3) can be converted. The whole procedure can thus be used as one procedure the epimerization of erythro-2-dichloroacetamino-i- (p-nitrophenyl) -propanediol- (i, 3) be considered.

The production of the nitric acid esters as such is not an issue of the present application.

The following examples are intended to explain the invention in more detail.

Example i One gives i g of dl-erythro-2-dichloroacetamino-3-acetoxy-i- (p-nitrophenyl) -propanol- (i) with stirring to q. ccm nitric acid (d = 1.5o), which is cooled to -6o0. Man lets the light yellow nitric acid solution spontaneously dissolve within about 1 hour o ° heat. The solution is then poured into a mixture of 25 cc of water while stirring and poured 25g of ice and stirred the resulting suspension for a further 15 minutes. The separated white solid mass is filtered off, pulverized in a mortar and washed with water. The yield of crude nitric acid ester is almost quantitative. By recrystallizing the crude product from 15 cc of methanol, pure dl-erythro-2-dichloroacetamino-3-acetoxy-i- (p-nitrophenyl) propanol (i) nitric acid ester is obtained in light yellow cubes, F. = 126 to 127 °.

The dl-erythro-2-dichloroacetamino-3-acetoxyi- (p-nitrophenyl) -propanol- (i) was made by reacting dl-erythro-2-dichloroacetamino-i- (p-nitrophenyl) -propanediol- (1, .3) with a little more than the theoretical amount of acetyl chloride in the presence of pyridine obtain. The product melts at 116 to 117 °.

410 mg of the dl-erythro-2-dichloroacetamino-3-acetoxy-i- (p-nitrop4enyl) propanol (i) nitric acid ester prepared as above were suspended at 0 ° in 8 cc of methanol. To the 'stirred suspension became slowly added 1 cc of 2N sodium hydroxide solution. After 3 minutes it was light yellow Solution formed, and this was then gradually heated to 3o to q.0 °. After io Standing at this temperature for minutes, the reaction mixture was heated to 10 ° cooled and neutralized with 2N acetic acid solution. The product crystallized when distilled water is added in light yellow plates. The recrystallization from aqueous methanol gave pure dl-threo-2-dichloromethyl-q.-oxymethyl-5- (p-nitrophenyl) -d2 oxazoline, m.p. 128-129 °.

When crude dl-erythro-2-dichloroacetan-iino-3-acetoxy-i- (p-nitrophenyl) -propanol- (i) is converted directly into the oxazoline, the overall yield is 80% theoretical.

Example 2 1.35 g of 1-erythro-2-dichloroacetamino-3-acetoxyi- (p-nitrophenyl) -propano1- (i) were regularly added to stirred nitric acid cooled to about -30 ° (d = i, 50) admitted. The mixture was allowed to warm up spontaneously to 0 ° and the one thus obtained was poured clear colorless solution to 20 g of a stirred ice-water mixture. The white microcrystalline The suspension was stirred for 10 minutes before being filtered off, and then the crude 1-erythro-2-dichloroacetamino-3-acetoxy-i- (p-nitrophenyl) propanol (i) nitric acid esters washed with water. The yield was 1.35 g, 90% of theory; the melting point of the material after recrystallization from methanol was 139 to 1q.0 °.

2 g. crude 1-erythro-2-dichloroacetamino-3-acetoxy-i- (p-nitrophenyl) -propanol- (i) -nitric acid ester were suspended in 10 cc of methanol and then a slight excess of 2N sodium hydroxide admitted. A yellow solution was obtained at first, but later separated Crystals off. After standing for 3/4 hours at room temperature and for 10 minutes Standing at 35 °, the suspension was cooled to 5 ° before the pale yellow crystals filtered off. 1.15 g of d-threo-2-dichloromethyl-q. - oxymethyl - 5 - (p - Nitrophenyl) -d2 oxazoline obtained in 77.5 ° / ° iger yield, m.p. = 133 to 135 °.

The overall yield was 70% of theory. Example 3 o, 96 g of dl-erythro-2-dichloroacetamino-3-benzoyloxyi- (p-nitrophenyl) propanol- (i) became regularly stirred nitric acid (d = 1.5o) at about -30 ° in the course of 5 minutes added. The light yellow solution was allowed to settle over the course of 1 hour warm up spontaneously to o °. The reading was on a stirred mixture of 25 cc Poured water and 25g of ice. After stirring for 15 minutes, the suspension became white filtered and the solid substance washed well with water and placed in a vacuum desiccator dried. The yield (1.10 g) was 950/0 because dinitration took place had and the reaction product therefore the dl-erythro-2-dichloroacetamino-3- m'- nitrobenzoyloxy- i- (p-nitrophenyl) -propanol- (i) -i-nitric acid ester. Of the The melting point of the product after recrystallization from methanol was 138.8 up to 1q.1.5 °.

0.6 g of the dl-erythro-2-dichloroacetamino-3-m'-nitrobenzoyloxy-i- (p-nitrophenyl) -propanol- (i) -i-nitric acid ester were suspended in 12 cc of methanol with stirring at 0 ° and 1 , 5 cc of 2N sodium hydroxide was added, so that a light yellow solution was formed. The reaction mixture was then heated to 30 ° to 0 ° C. and kept at this temperature for 10 minutes. The solution was cooled to 10 ° before the oxazoline was precipitated by the addition of distilled water. The yield of crystals was 0.23 g = 6q.0/0 of theory. The crude dl-threo-2-dichloromethyl-4-oxymethyl-5- (p-nitrophenyl) -42 oxazoline had a melting point of 127 to 128.5 °.

Example q.

1.98 g of dl-erythro-2-dichloroacetano-3- (carbethoxy-oxy) -i- (p-nitrophenyl) -propanol- (i) were converted into the i-nitric acid ester in a manner similar to that described in the previous examples converted. The yield of dl-erythro-2-dichloroacetamino-3 - (carbethoxy - oxy) - i - (p - nitrophenyl) - propanol (i) - i-nitric acid ester was 2.05 g = q. [0/0 of theory and the melting point 120 to 123.5 °. The crude nitric acid ester obtained above was dissolved at 0 ° in 20 cc of methanol and 5 cc of 2-n sodium hydroxide were added. The solution was kept at 30 to 40 ° for 10 minutes and then cooled to 10 °. The product crystallized out by adding distilled water. The yield of crude dl-threo-2-dichloromethyl-4-oxymethyl-5- (p-nitrophenyl) -d2-oxazoline was 60% of theory. The product melted at 123.5 to Z28 °.

Example 5 2 g of dl-erythro-2-dichloroacetamino-3-succinoxyi- (p-nitrophenyl) -propanol- (i) were in a manner similar to that described in the previous examples in converted the i-nitric acid ester. The crude nitric acid ester, which one isn't in crystalline form was obtained by treating a methanolic Solution with 2-n-sodium hydroxide at 30 to 40 ° converted directly into the oxazoline. The 2N sodium hydroxide solution was thereby added dropwise and at such a rate added that the reaction medium is always just against colored clay yellow Reagent paper reacted alkaline. The reaction mixture was after the last Addition of sodium hydroxide kept at 30 to 40 ° for 10 minutes and then kept at 10 ° cooled down. The oxazoline was prepared in the same manner as in those previously described Examples isolated.

Example 6 410 mg of dl-erythro-2-dichloroacetamino-3-acetoxyi- (p-nitrophenyl) -propanol- (i) -nitric acid ester (prepared as in Example i) were suspended in 8 cc of methanol at 0 ° and 1.5 cc of 2-n potassium hydroxide were gradually added. The mixture was left for 1 hour stand at 0 ° and then heated to 30 to 40 ° for 10 minutes. The product was isolated by first cooling the reaction mixture to 10 ° and then distilling it Added water. 2io mg of dl-threo-2-dichloromethyl-4-oxymethyl-5- (p-nitrophenyl) -d, - oxazoline in 76% yield, mp = 127 to 128 °.

Claims (2)

PATENT CLAIMS: r. Process for the preparation of the threo forms of oxazolines of the general formula where R1 is an aliphatic group with not more than 3 carbon atoms, especially a dichloromethyl group, and R2 is a hydrogen atom or an acyl group, especially an acetyl, benzoyl or carbalkoxy group or a succinyl radical containing an unchanged carboxyl group, characterized in that the erythro form of a compound of the formula where R1 has the above meaning and R is an acyl group, especially one of the acyl groups which are listed above to explain R2, treated with an alkali, preferably sodium or potassium hydroxide. 2. The method according to claim i, characterized in that that the treatment with sodium or potassium hydroxide in an aqueous alcoholic medium is carried out at a temperature not exceeding about 40 °.