CH294019A - Process for the preparation of threo-1-p-nitrophenyl-2-dichloroacetamido-3-chloro-propanol-1. - Google Patents

Description

Process for the preparation of threo-l-p-nitrophenyl-2-dichloroacetamido-3-chloro-propanol-1. The subject of the present invention is a process for the preparation of a new aromatic acylamido-alcohol, that is to say the threo geometric isomer of 1-p-nitrophenyl-2-dichloroacetamido-3-chloro- propanol-1 from @ormule

Due to the presence of two asymmetric carbon atoms in the a and ss positions of the phenyl ring, the above formula corresponds to two epimeric geometric forms depending on the relative position of the substituents carried by these two asymmetric carbon atoms. By analogy to the nomenclature adopted by Rebstock et al. (Am. soe. 71, p. 2158-2173 [1919]) with regard to the stereoisomers of 1-p-nitrophenyl-2-dichloracAtamido-propanediol-1 ,3 (chloramphenicol), these two geometric isomers are designated by the prefixes allo and threo . Each of the two geometric isomers allo and threo can exist in a racemic form (DL) and in two optically active forms (D and L) thus giving a total of nix different isomers: DL-threo, DL-allo, L-hello, D-hello, L-threo and D-threo. It should be noted that the designation of the isomers as D and L bears no relation to the actual sense of optical rotation, but relates only to the configuration ä, the carbon atom at position a of the phenyl ring. . The D-threo isomer has the same configuration with respect to this carbon atom at position a as the therapeutically active isomer of chloramphenicol which has been designated D-thr6o- 1- p - nitr opheny 1-2- dichloracetamido - propane-diol-1, 3.

The process according to the invention for the preparation of threo-1-p-nitrophenyl-2-dichloro-acetamido-3-chloro-propanol-1 is characterized in that it deals with allo-1-p-nitroph6nyl-2- dichloroacetamido-3-chloro-propanol-1 with strong sulfuric acid, in that the reaction mixture is diluted with water and then neutralized with a base. As Base, an aqueous ammonia is preferred. Usually, an heats the starting material (allo isomer) with strong sulfuric acid to a temperature of about 45°, an then dilutes with cold water and an neutralizes the reaction mixture with aqueous ammonia at a temperature close to 0° C. Preferably, the racemic form or the optical L-isomer of allo-1-p-nitrophenyl-2-dichloro-acetamido-3-chloro-propanol is used as starting body. -1. By the process according to the invention, an 6pimerization of the allo compound into the corresponding threo compound takes place. The DL-allo isomer gives rise to the formation of the DL-thrdo isomer, the D-allo isomer leads to the formation of Fisomere L-threo, and the starting Fisomere L-allo finally rings Fisomere D-thrdo.

The threo-1-nitrophenyl-2-dichloroacetamido-3-chloro-propanol-1 obtained by the process according to the invention is a new crystallized substance. All of its optical forms (DL, D and L) are important intermediates for the preparation of antibiotics. The radical form melts at 135-136 C, and the optically active isomers (D and L) melt at 130-131 C. The optical rotation [a] 21 is for the D-thrdo form = + 20 7 (c = 40/a in ethyl acetate) and for the L-thrdo form=-21% (c=4.6% in ethyl acetate).

The starting material for the process according to the invention can be prepared in the following way: 50 g of DL-α-dichloroacetamido-13-hydroxy-p-nitropropioph6none and 65 cm3 of thionyl chloride are heated under reflux for 2 hours. The mixture is allowed to crystallize in the cold, filtered, the residue is washed with anhydrous ether and the product obtained is dried in a vacuum over caustic potash. In this way, DL-a-dichloroacet-amido-ss-chloro-p-nitropropiophenone is obtained. 0n then heated 10.5 g of this compound with 16 g of aluminum isopropoxide in 250 cm3 of anhydrous isopropanol. Preferably, an performs this operation in a reduction apparatus as described in Organic Reactions, volume 11, page 197. During this reaction, 135 cm3 of a mixture of acetone and isopropyl alcohol separate by distillation. After cooling, the contents of the container are taken up in 90 cms of 2N sulfuric acid. Then an adds 400 cms of water, after which a precipitate forms. This is filtered, dried in air and extracted with ethyl acetate. By addition of petroleum ether, 5.6 g of a crude product precipitates, which, after recrystallization from aqueous ethyl alcohol, melts at 133-134 C. This product is 1e DL-allo- l-p-nitrophynyl-2-dichloroacgt-amido-3-chloro-propanol-1 which can serve as a starting body. The following examples show how the first process according to the invention can be implemented.

Example <I>1:</I> 0n introduced in small portions and while cooling 5 g of DL-allo-1-p-nitropheny 1 2-dichloroacetamido-3-chloro-propanol-1 in 20 cm3 of sulfuric acid at 66 Be . The solution is heated for 20 minutes at a temperature of 45° C. After cooling, it is poured onto 80 g of crushed ice. Then, an adds 65 cm3 of methyl alcohol to dissolve the thick precipitate which has formed. 0n added, while cooling vigorously, 88 cm3 of aqueous ammonia at 22 Be. It is allowed to crystallize, RTI ID="0002.0271" WI="7" HE="4" LX="1324" LY="902"> then the precipitate is filtered, washed with distilled water and dried in 1st vacuum Over sulfuric acid. In this way, 4.3 g of DL-thr6o-1-p-nitropheny 1-2-dichloroacetamido-3-chloro-propanol-1 with a melting point of 135-136 C are obtained.

Example <I>2:</I> 0.70 g of L-allo-l-p-nitrophenyl-2-dichlor-acetamido-3-chloro-propanol-1 (m.p. =114 to 116 C and [a] D =- 12 36 [c=4% in methanol]) is dissolved at about 0° C. in 2.8 cm3 of sulfuric acid at 66 BA. The solution obtained is heated for 25 minutes at 45° C., then poured onto 20 g of crushed ice. 10 cm3 of methanol are added to facilitate the dissolution of the acid sulphate of 1-p-nitrophenyl-1-dichloroacetoxy-2-amino-3-chloropropane which precipitates. The resulting solution is made alkaline with 22 Be aqueous ammonia. The crystallized product is then filtered, washed with water and dried in a desiccator over sulfuric acid. 0n thus obtains 0.55 g of D-threo-1-p-nitroph6nyl-2-di-chloroacetamido-3-chloro-propanol-1 of melting point 126-127 C; [a1'6=+1865 (c=4% in ethyl acetate); after purification, this substance has the following characteristics: p. f. =130-131°C; [a] D = + 20 7 (c = 4% in ethyl acetate).

Example <I>3:</I> 0.19 g of D-allo-l-p-nitrophenyl-2-dichlor-acetamido-3-chloro-propanol-1 Crude with melting point 79 C and [a] D = + 10 40 (c = 40/0 in methanol) is treated as in example `?. We obtain. 0.12 g of L-threo-1-p-nitrophenyl-2-dichloroacetamido-3-chloro-propanol-1 from p. f. =125-128 C and [a] D = −18 8 e = 9% in ethyl acetate); this substance has, after purification, the following characteristics: p. f. = 130-131 C, [a] D = -21 8 (c = 4.6% in ethyl acetate).

Claims (2)

CLAIM- Process for the preparation of threo-1-p-nitro-phenyl-2-diehloracetamido-3-chloro-propanol-l, characterized in that allo-1-p-nit'ropheny l- 2-diehloracetamido-3-chloro-propanol-1 with strong sulfuric acid, in that the reaction mixture is diluted with water and then neutralized with a base. Threo-1-p-nitrophenyl-2-dichloroacet-amido-3-chloro-propanol-1 is a crystallized substance. Its racemic form melts at 135-136 C, while its optically active forms (D and L) melt at 130-13l C. The optical rotation [a] D = + `?0 7 for the D-threo form (c = 4% in ethyl acetate), and [a] D = - 2l. 8 for the L-threo form (e = 4.6 0/(1 in ethyl acetate). SUB-CLAIMS 1. Process according to claim, characterized in that the alto isomer is heated with strong sulfuric acid, in that the reaction mixture is diluted with cold water and in that the neutralization with said base is carried out at a temperature close to 0 C. 2. Method according to claim, characterized in that the reaction mixture is neutralized using ammonia.