Patent GB-704946-A (GB)
Title: Process for obtaining aminodiol derivatives
Filed: 1950-05-03
Abstract: The Specification comprises D 2 - oxazoline compounds of the formula <FORM:0704946/IV(b)/1> where R1 and R2 are alike or different and represent hydrogen, halogen lower alkyl or alkoxy radicals R3 is a lower alkyl, halogenated lower alkyl, phenyl, substituted phenyl or phenalkyl radical; R111 is an esterified carboxyl group, a hydroxymethyl group or an acyloxymethyl group and Y is hydrogen or a nitro group.  Such compounds are formed as intermediates in a process for the production of amino diol derivatives of the formula <FORM:0704946/IV(b)/2> where R is hydrogen or an acyl radical which comprises reacting an amino hydroxy compound of the formula <FORM:0704946/IV(b)/3> where R1 is a hydroxymethyl group or an esterified carboxyl group with an imino ether compound of formula <FORM:0704946/IV(b)/4> where R11 may be one of the radicals represented by R3, or a salt thereof, to obtain a D 2-oxazoline compound of formula <FORM:0704946/IV(b)/5> and where R1 is an esterified carboxyl group reducing it to a hydroxymethyl group, acylating the hydroxyl group of the 4-hydroxymethyl-D 2-oxazoline compound to give the 4-acyloxymethyl D 2-oxazoline compound, nitrating the phenyl ring of the latter to give the compound of formula <FORM:0704946/IV(b)/6> which is hydrolyzed directly or stepwise to the amino-diol derivative of the above formula.  As products of the stepwise hydrolysis are formed compounds of the first general formula above where R111 is -CH2OH (e.g. by reaction with alkali below 35 DEG C.) and of the second general formula where R is H or acyl (e.g. by treatment with dilute mineral acid or heating with water).  The 1-nitrophenyl-1-acyloxy-2-aminopropane-3-ol formed as the hydrolytic product spontaneously rearranges to the acylamido diol.  The general formulae represent the (l)-q , (d)-q , (l)-reg or (d)-reg. isomers in separated form, or the (dl) q  or (dl) reg. optical racemates or the total unresolved mixture of structural and optical isomers.  The reduction of the esterified carboxyl group may be effected with lithium aluminium hydride or catalytically. Nitration may be carried out with 100 per cent. nitric acid or fuming nitric acid at below 25 DEG C. preferably between -10 DEG  and +10 DEG C.  The reaction with the imino ether is effected at below 50 DEG C., preferably 20 DEG  to 35 DEG C.  In examples (1) (dl)-q -2-methyl-5-phenyl-4-hydroxymethyl -D 2-oxazoline is prepared by either reacting (dl)-q -1-phenyl-2-aminopropane -1, 3-diol and acetimino ethyl ether hydrochloride or by reacting (dl)-q -phenyl serinate with acetimino ethyl ether hydrochloride and reducing the (dl)-q -2-methyl-5-phenyl-4-carbethoxy-D 2-oxazoline thus obtained with lithium aluminium hydride.  The product is acetylated and then nitrated to give (dl)-q -2-methyl-5-p - nitrophenyl-4-acetoxymethyl-D 2-oxazoline, which on hydrolysis with alcoholic ammonia or dilute sodium hydroxide gives (dl)-q -2-methyl - 5 - p - nitrophenyl - 4 - hydroxy - methyl D 2-oxazoline.  This compound on treatment with dilute hydrochloric acid at room temperature yields the hydrochloride of (dl)-q -1-p-nitrophenyl-1-acetoxy-2-amino - propane - 3 - ol from which on neutralization with ammonia, (dl) - q  - 1 - p - nitrophenyl - 2 - acetamidopropane - 1, 3 - diol is obtained. This same compound may be obtained by boiling (dl) -q -2-methyl-5-p-nitrophenyl-4-hydroxymethyl-D 2-oxazoline with water, or by acid hydrolysis of (dl) -q -2-methyl-5-p-nitrophenyl-4-acetoxy-methyl-D 2-oxazoline. The free base (dl) - q  - 1 - p - nitrophenyl - 2 - aminopropane - 1, 3-diol is prepared by treating (dl)-q -2-methyl-4-hydroxy or acetoxy-methyl-5-p-nitrophenyl - D 2 - oxazoline, or (dl) - q  - 1 - p - nitrophenyl - 2 - acetamido - propane - 1, 3 - diol with 5N hydrochloric acid on a steam bath; (2) (l)-q -2-Dichloromethyl-5-phenyl-4-hydroxymethyl - D 2 - oxazoline is prepared by reacting (l) q  - 1 - phenyl - 2 - aminopropane 1, 3-diol with dichlorocetimino ethyl ether hydrochloride or by reacting ethyl-(l)-q -phenyl serinate with dichloracetimino ethyl ether hydrochloride and reducing the resultant (l) - q  - 2 - dichloromethyl - 5 - phenyl - 4 - carbethoxy - D 2 - oxazoline with lithium aluminium hydride.  The product is acetylated and nitrated to give (l)-q -2-dichloromethyl-5-p-nitrophenyl - 4 - acetoxymethyl - D 2 - oxazoline which is hydrolyzed at room temperature with alcoholic ammonia or dilute sodium hydroxide to give (l)-q -2-dichloromethyl-5-p-nitrophenyl - 4 - hydroxymethyl - D 2 - oxazoline.  This compound on boiling with water or treatment with dilute hydrochloric acid at room temperature to give (l)-1-p-nitrophenyl-1-dichloracetoxy - 2 - aminopropane - 3 - ol followed by neutralization yields (l)-q -1-p-nitrophenyl-2-dichloracetamido-propane-1, 3-diol.  The same compound on heating with 5N hydrochloric acid yields (l)-q -1-p-nitrophenyl - 2 - aminopropane - 1, 3 - diol; (3) (dl) - q  - 2, 5 - Diphenyl - 4 - hydroxy - methyl - D 2 - oxazoline is produced by reaction of (dl) - q  - 1 - phenyl - 2 - aminopropane - 1, 3 - diol with benzimino ethyl ether hydrochloride or by reacting ethyl (dl)-q -phenyl serinate hydrochloride with benzimino ethyl ether hydrochloride and reducing the resultant (dl) - q  - 2, 5 - diphenyl - 4 - carbethoxy - D 2-oxazoline with lithium aluminium hydride. Acetylation and nitration of the product yield (dl) - q  - 2 - m - nitrophenyl - 4 - acetoxy - methyl - 5 - p - nitrophenyl - D 2 - oxazoline which on hydrolysis at room temperature with 0.2N sodium hydroxide gives on neutralization (dl) - q  - 2 - m - nitrophenyl - 4 - hydroxy - methyl - 5 - p - nitrophenyl - D 2 - oxazoline. Treatment of this product with hydrochloric acid at room temperature gives (dl) - q  - 1 - p - nitrophenyl - 2 - m - nitrobenzamido - propane - 1, 3-diol. Treatment at reflux temperature followed by neutralization gives (dl)-q -1-p-nitrophenyl - 2 - aminopropane - 1, 3 - diol; (4) ethyl (l)-q -phenyl serinate and acetimino ethyl ether hydrochloride are reacted to give (l) - q  - 2 - methyl - 5 - phenyl - 4 - carbethoxy - D 2 - oxazoline, which is reduced with lithium aluminium hydride to (l)-q -2-methyl-5-phenyl-4-hydroxymethyl-D 2-oxazoline.  The product is acetylated and then nitrated to give (l)-q  - 2 - methyl - 5 - p - nitrophenyl - 4 - acetoxy - methyl - D 2 - oxazoline, which on treatment in the cold with sodium hydroxide followed by neutralization gives (l) - q  - 2 - methyl - 5 - p - nitrophenyl - 4 - hydroxymethyl - D 2 - oxazoline. Treatment of this compound with 2 per cent. hydrochloric acid in the cold gives (l) - q - 1 - p - nitrophenyl - 2 - acetamido - propane - 1, 3 - diol, or refluxing with 5N hydrochloric acid gives (l) - q  - 1 - p - nitro - phenyl - 2 - aminopropane - 1, 3 - diol.  Reference has been directed by the Comptroller to Specifications 673,864 and 681,130.