Patent GB-692265-A (GB)
Title: Improvements in or relating to dichloracetamides
Inventor: HEYWOOD BASIL JASON
IPC: C07C233/16
Filed: 1950-05-19
Abstract: Stereoisomeric compounds, or mixtures thereof, of the general formula <FORM:0692265/IV (b)/1> (wherein R1 and R2 each represent hydrogen or jointly represent a group -CHR4- in which R4 represents hydrogen, an alkyl group of not more than 4 carbon atoms or an aryl group, and R3 represents hydrogen or a nitro group) are manufactured by reacting the corresponding compounds containing a free amino group with choral cyanhydrin, or a precursor therefor, in the presence of an acid-binding agent.  Convenient precursors for chloral cyanhydrin are chloral or chloral hydrate together with an alkali metal cyanide catalyst (preferably in a quantity less than one molecular equivalent of the reacting amine).  When chloral cyanhydrin itself is used it may first be reacted with an acid-binding agent and the amine treated with the product obtained (which probably contains dichloropyruvonitrile, since this compound has been shown to be capable of effecting the dichloracetylation, though with inferior yield).  The reaction may be effected in aqueous or non-aqueous media, advantageously at 0-25 DEG  C. with chloral cyanhydrin itself or at 60-100 DEG  C. with a precursor.  Suitable acid-binding agents are inorganic bases, tertiary organic bases, excess of the reacting amine, or excess of the alkali metal cyanide when used.  The process is applicable particularly to the preparation of chloramphenicol from D-threo-2-amino-1-p-nitrophenylpropane-1 : 3-diol, and the preparation of L- and DL-erythro-2-dichloracetamido-1-p-nitrophenylpropane-1 : 3-diol which are useful as intermediates for chloramphenicol and its racemate.  In examples: (1) DL-erythro-5-amino-4-phenyl-2-methyl-1 : 3-dioxane is heated with chloral hydrate in aqueous solution in the presence of calcium carbonate and sodium cyanide; (2) the calcium carbonate in (1) is replaced by sodium acetate and part of the water by dioxane; (3) DL-erythro-2-amino-1-p-nitrophenylpropan-1 : 3-diol is treated as in (1); (4) and (9) the calcium carbonate in (3) is replaced by magnesium oxide, and (5) by sodium carbonate; (6) the sodium cyanide in (5) is replaced by potassium cyanide; (7) the starting material of (5) is replaced by the L-isomer; (8) the sodium carbonate in (5) is replaced by excess of potassium cyanide; (10) p  DL-threo-2-amino - 1 - p - nitrophenylpropan - 1 : 3 - diol is heated with chloral hydrate, pyridine (or dioxane) and sodium cyanide; (11) DL-erythro-2 - amino - 1 - p - nitrophenylpropan - 1 : 3 - diol hydrochloride is agitated with chloral hydrate, sodium cyanide and pyridine in dioxane; (12) DL - erythro - 5 - amino - 4 - phenyl - 2 - methyl-1 : 3-dioxane is allowed to stand with chloral cyanhydrin, triethylamine and dioxane; (13) the DL-threo isomer is similarly treated; (14) DL - erythro - 5 - amino - 4 - phenyl - 2 - methyl-1 : 3-dioxane is dissolved in dilute hydrochloric acid, chloral cyanhydrin is added followed by caustic soda, and the suspension is allowed to stand; (15) DL-threo-2-amino-1-p-nitrophenylpropan-1 : 3-diol is allowed to stand with chloral cyanhydrin, triethylamine and dioxane; (16) the triethylamine in (15) is replaced by sodium carbonate; (17) chloral cyanhydrin is added to pyridine, and then DL-threo-2-amino-1-p-nitrophenylpropan-1 : 3-diol is added and the mixture heated; (18) DL - threo - 2 - amino - 1 - p - nitrophenylpropan-1 : 3-diol hydrochloride is dissolved in water, and chloral cyanhydrin is added followed by triethylamine; (19) L-erythro - 2 - amino - 1 - p - nitrophenylpropan - 1 : 3-diol hydrochloride is allowed to stand with chloral cyanhydrin, triethylamine and dioxane; (20) the DL-isomer (free base) is similarly reacted, but with a different order of mixing the reactants; (21) the hydrochloride of the DL-isomer is treated as in (19); (22) DL-erythro-2-amino - 1 - p - nitrophenylpropan - 1 : 3 - diol is allowed to stand with chloral cyanhydrin, sodium carbonate and pyridine; (23) and (24) DL-erythro-2-amino-1-phenylpropan-1 : 3-diol is allowed to stand with chloral cyanhydrin, triethylamine and dioxane; (24) chloral cyanhydrin is reacted with triethylamine in dioxane and the product is allowed to stand with DL-erythro - 2 - amino - 1 - p - nitrophenylpropan-1 : 3-diol.  According to the Provisional Specifications, R1 and R2 in the general formula above may also represent acyl, lower alkyl or aralkyl groups or jointly a bivalent atom or group such as -CO-, -SO2- or -CR6R7-(where R6 and R7 represent hydrogen atoms or lower alkyl, cycloalkyl, aryl or aralkyl groups), whilst the benzene ring may be additionally substituted by halogen atoms or lower alkyl or alkoxy radicals.  DL - Threo - and DL - erythro - 5 - amino - 4-phenyl - 2 - methyl - 1 : 3 - dioxane are obtainable by condensing bengaldehyde with 2-nitro-ethanol in the presence of sodium methoxide in methanol, liberating 2-nitro-1-phenylpropan-1 : 3-diol from its sodium salt so obtained, by the action of acetic acid in the presence of ether, separating the threo and erythro isomers by crystallization, condensing each with acetaldehyde in ether in the presence of an acid catalyst such as p-toluenesulphonic acid, and finally reducing the nitro group.