Patent GB-664695-A (GB)
Title: Improvements in and relating to the production of 1-phenyl-substituted 2-acyl amino-propane-1,3 diols
Filed: 1948-12-15
Abstract: An o -aminoacetophenone of formula <FORM:0664695/IV (b)/1> is condensed with formaldehyde in the presence of an alkaline condensation catalyst to give a compound of formula <FORM:0664695/IV (b)/2> the CO group of which may be reduced before or after the OH group is acylated.  In the above formul  R1 and R2 are the same or different and are hydrogen, halogen, lower alkyl or lower alkoxy radicles and the term "acyl" includes lower aliphatic acyl, halogen-substituted lower aliphatic acyl, benzoyl, substituted benzoyl and araliphatic acyl radicles.  Formaldehyde may be supplied as gas, as an aqueous or alcoholic solution or as paraformaldehyde or other formaldehyde yielding polymer. Preferably an excess of formaldehyde is used, e.g. up to 4 or 5 mols.  Solvents may be used and water, aqueous or anhydrous lower aliphatic alcohols, moist dialkyl ethers and dioxane-water mixtures are specified. Condensation catalysts may be organic bases, inorganic bases or inorganic salts of acidic or pseudo-acidic organic compounds and many are specified.  Weak alkaline catalysts are preferred, e.g. sodium and potassium bicarbonate, calcium hydroxide, pyridine, triethylamine, N-ethyl morpholine and N,N-dimethylaniline, since when strong alkalies are used the catalyst must be removed or deactivated immediately reaction ceases to prevent conversion of the product to the corresponding methylene bis compound.  In general, 0.05 mol. or less of catalyst is used.  Temperatures specified are from 0-75 DEG C., with reaction times of a few minutes to several hours. Reduction may be effected with hydrogen and a metal hydrogenation catalyst, by an oxidizable aluminium alkoxide or nascent hydrogen made by reacting a metal with an acid, lower aliphatic alcohol, water or mixtures thereof.  Catalytic hydrogenation is effected at about 25-4000, preferably 40-1000, p.s.i., and below 100 DEG , preferably about 20-40 DEG  C.  Conventional hydrogenation catalysts are listed and solvents which may be used.  Solvents, metals and alloys used for the reduction with nascent hydrogen are of conventional type and many are specified, those preferred being sodium, potassium or calcium and absolute ethanol or methanol, sodium or potassium amalgam in moist ether, ethanol or acetic acid and iron in dilute aqueous ethanol containing acetic acid.  With aluminium alkoxides a lower aliphatic alcohol, preferably corresponding to the alkoxide, is used at about 20-125 DEG  C. Alkoxides of secondary alcohols such as isopropanol and sec.-butanol are preferred.  When halogens are present in the phenyl ring it is preferred that the alkoxide method be used. Acylation is effected with an acyl halide or anhydride under substantially anhydrous conditions above or with a conventional acylation catalyst, many of which are specified.  Temperatures of about 10-140 DEG , preferably about 60-120 DEG  C., and inert solvents such as benzene, petroleum ether and toluene may be present. Products are used in the synthesis of antibiotics.  In examples: (1) o  - benzoylaminoacetophenone, paraformaldehyde, methanol and potassium carbonate yield a  - benzamido - b  - hydroxypropiophenone which is reduced with hydrogen in the presence of Raney nickel and ethanol to [dl]-4- and [dl] reg.-1-phenyl-2-benzamidopropane-1,3-diol, which are separated by fractional crystallization from ethanol; (2) o  - benzoylaminoacetophenone, paraformaldehyde and methanol are reacted in the presence of (a) sodium bicarbonate, (b) sodium, and (c) and (d) potassium carbonate to yield a -benzamido-b -hydroxypropiophenone which is reduced with hydrogen and palladium oxide in methanol to the corresponding diol as in (1) or alternatively acylated with acetic anhydride in the presence of sulphuric acid and the a -benzamido-b -acetoxypropiophenone thus made is reduced with hydrogen and Raney nickel in methanol to [dl] - 4 - and [dl] - reg. - 1 - phenyl - 2 - benzamido-3-acetoxy-propane-1-ol, which are separated by fractional crystallization; (3) o -acetylaminoacetophenone, paraformaldehyde, methanol and sodium bicarbonate yield a -acetamido-b -hydroxypropiophenone which is reduced with hydrogen and Raney nickel in ethanol to give [dl]-4- and [dl]-reg.-1-phenyl-2-acetamidopropane-1,3-diol which are separated by fractional crystallization from ethanol or aqueous ethanol or is alternatively acetylated with acetic anhydride and sulphuric acid or dry pyridine and the a -acetamido-b -acetoxypropiophenone thus made is reduced with hydrogen, Raney nickel and ethanol to the [dl]-4-isomer of the corresponding alcohol; (4) o  - benzoylamino - 2 - methylacetophenone, paraformaldehyde, ethanol and pyridine are warmed to yield a -benzamido - b  - hydroxy - 2 - methylpropiophenone, which is reduced with hydrogen, palladium oxide and ethanol to yield the [dl]-4- and [dl]-reg.-isomers of the corresponding diol separated by fractional crystallization from methanol or is alternatively benzoylated with benzoyl chloride and pyridine and the benzoyl derivative thus made is reduced with hydrogen, palladium oxide and ethanol to yield 1-(21-methyl - phenyl) - 2 - benzamido - 3 - benzoxypropane-1-ol; (5) o -(p-methylbenzoylamino)-3-methoxyacetophenone, paraformaldehyde, ethanol and calcium hydroxide are warmed to yield a  - (p - methylbenzamido) - b  - hydroxy - 3-methoxypropiophenone which is reduced with sodium and ethanol containing a small quantity of water to yield 1-(31-methoxyphenyl) - 2 - (p - methylbenzamido) propane-1,3-diol which is separable into structural isomers by fractional crystallization from methanol or p  aqueous ethanol; (6) o -propionylamino - 3,4 - dimethylacetophenone, paraformaldehyde, ethanol and sodium carbonate yield a -propionamido-$b-hydroxy-3,4-dimethylpropiophenone which is reduced with hydrogen, Raney nickel and ethanol to yield [dl]-4- and [dl] - reg. - 1 - (31,41 - dimethylphenyl) - 2 - propionamidopropane-1,3-diol or is alternatively benzoylated with benzoic anhydride in benzene and sulphuric acid and the benzoyl derivative thus made is reduced with hydrogen, Raney nickel and ethanol to yield 1-(31, 41-dimethylphenyl) - 2 - propionamido - 3 - benzoxypropane-1-ol; and in (7) o -phenylacetoamido-4-chloroacetophenone, paraformaldehyde, methanol and sodium bicarbonate are warmed to yield a -phenylacetamido - b  - hydroxy - 4 - chloropropiophenone which is reduced with aluminium isopropylate in isopropanol to yield 1-p-chlorophenyl - 2 - phenylacetamidopropane - 1,3 - diol or is alternatively acetylated with acetic anhydride.  The Specification as open to inspection under Sect. 91 refers to the use of o -carbalkoxyas well as o -acyl-aminoacetophenone starting materials and the acyl group of the above formul  is replaced by R, which may be hydrogen, carboalkoxy or acyl radicles.  In (f) of example (2) a  - benzamido - b  - hydroxypropiophenone is refluxed with 5 per cent HCl to yield a -amino-b -hydroxypropiophenone.  Specifications 652,273-652,280 inclusive are referred to.  This subject-matter does not appear in the Specification as accepted.