CS231132B1 - Process for preparing DL threo-1- (p-nitrophenyl) -2-amino-1,3-propanediol hydrochloride - Google Patents

Abstract

The essence of the invention lies in the fact that the nitration of 4-phenyl-5-acetylamino-1,3-dioxane is carried out in nitromethane, or nitromethane and phosphoric acid or nitromethane and anhydrous magnesium sulfate and alumina. The resulting product is hydrolyzed to DL-threo-1-(p-nitrophenyl)-2-amino-1,3-propanediol hydrochloride, which is an important intermediate in the synthesis of ochloramphenicol.

Description

The present invention relates to a process for the preparation of DL-threo-1- (p-nitrophenyl) -2-amino-1,3-propanediol hydrochloride (Formula III) by nitration of 4-phenyl-5-acetylamino-1,3-dioxane (I).

The D-antipode obtained by resolution of the racemic compound after dichloro acetylation affords the antibiotic chloramphenicol.

Dioxane nitration is one of the stages of the newly proposed synthesis of chloramphenicol. In the present synthesis of chloramphenicol, this nitration does not occur.

Nitration of 4-phenyl-5-acetylamino-1,3-dioxane, its deacetylation product 4-phenyl-5-amino-1,3-dioxane, as well as the product of ** hydrolytic ring opening of DL-threo-1-phenyl-2- The amino-1,3-propanediol nitration mixture provides a mixture of ortho and para nitrophenyl derivatives. The use of the nitration mixture in acetic anhydride affords little to the desired para-nitro derivative.

The present invention provides a process for the preparation of DL-threo-1- (p-nitrophenyl) -2-amino-1,3-propanediol hydrochloride (Formula III) by nitration of 4-phenyl-5-acetylamino-1,3-dioxane by nitration in nitromethane, yielding in good yield the desired para-nitro derivative (Formula II). The addition of phosphoric acid or anhydrous cupric sulphate and alumina increases the yield even further. Because of its disadvantageous weight, it is hydrolyzed immediately to DL-threo-1- (p-nitrophenyl) -2-amino-1,3-propanediol hydrochloride, which can easily be converted to the chloramphenicol antibiotic. Nitration according to the invention yields the desired p-nitroderivative almost free of orthotivatives.

231 132

An embodiment of the process according to the invention is illustrated in more detail by way of examples.

Example 1

Weight: 4 g

7.5 ml

7.5 ml 25 ml

4-phenyl-5-acetylamino-1,3-dioxane

HN (k / density = 1.52 kg / m 2)

H ₂ SO ₄ /96% / oh ₃ no ₂ nitration mixture

Method:

A three-necked flask equipped with a stirrer was charged with 10 mL of CH-NO 2 and nitration mixture. The contents were cooled to -20 ° C and a solution of 4-phenyl-5-acetylamino-1,3-dioxane in 15 mL of CH 2 NO 3 was added dropwise over 30 minutes with continued stirring for 1 hour. The reaction mixture was then poured into 100 mL of water and extracted with 3 x 40 mL of CHCl 3, then dried over MgSO 4. The desiccant was filtered off, the solvent was evaporated in vacuo and the honey-like product was subjected to hydrolysis without further isolation. Hydrolysis was performed in a two-neck flask equipped with a dropping funnel and a descending condenser. The nitration product was dissolved in 50 mL of 30% HCl and 160 mL of HCl was distilled dropwise. The contents were concentrated to 35 mL and cooled to 0 ° C. The precipitated crystals were aspirated, washed with 10 ml of isopropyl alcohol and dried. 2.28 g (50.8%) of DL-threo-1- (p-nitrophenyl) -2-amino-1,3-propanediol hydrochloride were obtained _from mp 172-176 ° C.

Example 2

Navážka:

g of 4-phenyl-5-acetylamino-1,3-dioxane

7.5 ml spreaders (density = 1.52 kg / m ³⁾ _{inside the sm8s} g

7.5 ml H ₂ SO ₊ (96 °) g H 2 PO 4 and kieselguhr ml CH ₃ NO ₂ x 40 ml CHCl ₃

Method:

The flask was charged with 10 mL of CH ₃ NO ₂ , nitration mixture and H ₃ PO ₄ on diatomaceous earth. The mixture was cooled to -20 ° C and a solution of 4-phenyl-5-acetylamino-1,3-dioxane in 15 mL of CH 2 NO 3 was added dropwise with stirring over 45 minutes. Stirring was continued for 45 minutes at the same temperature. The reaction mixture was then poured into 100 ml of water, extra

231132 was added with 3 x 40 mL CHCl 3 and dried over MgSO 4. After filtering off the desiccant and distilling off the solvent, the honey-like residue was hydrolyzed. The procedure was as in Example 1. Yield 2.35 g (52.4%) of DL "threo-l- / p-nitrophenyl / -2-amino-l, 3-propanediol _# mp 172-175 ° 0th

Example 3

Weight: 4 g. _with 4-phenyl-5-acetylamino-l, 3-dioxane.

7.5 ml HNO 4 (density = 1.52 kg / nPi)

7.5 ml H ₂ SO ₄ (96%) of CuSO g ^ (anhydrous) alumina (grinding) a mixed acid

S 25 ml

Method:

ch ₃ no ₂

The flask was charged with 10 mL of CH 2 NO 3, nitration mixture, CuSO 4 and alumina. The further procedure was identical to Example 2.

2.35 g (52.4%) of DL-threo-1- (p-nitrophenyl) -2-amino-1,3-propanediol hydrochloride were obtained, m.p. Mp 172-175 ° C.

Claims (3)

SUBJECT OF THE INVENTION 231 132 Process for the preparation of DL-threo-1- (p-nitrophenyl) -2-amino-1,3-propanediol hydrochloride by nitration of 4-phenyl-5-acetylamino-1,3-dioxane, characterized in that the nitration is carried out in nitromethane, followed by hydrolysis. 2. Process according to claim 1, characterized in that the nitration is carried out in nitromethane and phosphoric acid. 3. A process according to claim 1, wherein the nitration is carried out in nitromethane, anhydrous copper sulfate and alumina.