Patent GB-773011-A (GB)
Title: Improvements relating to new compounds comprising dihydro-1, 3-oxazine-2,4(3h)-diones and salts thereof
IPC: C07D265/06
Filed: 1955-06-15
Abstract: The invention comprises dihydro-1,3-oxazine-2,4-(3H)-diones of general formula <FORM:0773011/IV(b)/1> wherein R1, R2, R3, R4 are hydrogen or alkyl, mononuclear aryl, substituted mononuclear aryl, aralkyl, alkaryl, alkenyl, cycloalkyl, cycloalkenyl, heterocyclic, or either pair thereof may jointly represent an alkylene radical, at least one of R1-R4 not being hydrogen; R5 is hydrogen or an alkyl radical having from one to four carbon atoms; X is oxygen or sulphur; and when R5 is hydrogen the invention also comprises salts thereof. The compounds are prepared by reacting an alkyl ester of a substituted b -hydroxypropionic acid of formula R3R4C-(OH).C(R1)(R2).CO2Alk, wherein Alk is a lower alkyl radical having one to four carbon atoms, with phosgene or thiophosgene and reacting the resulting chloroformyloxy or chlorothioformyloxy derivative R3R4C(OCXCl).C(R1) (R2).CO2-Alk, with ammonia or a primary amine NH2R5 to yield the corresponding carbamyloxy or thiocarbamyloxy derivative R3R4C(OCXNHR5).C-(R1)(R2) .CO2Alk, which is then ring-closed in the presence of a strong base, preferably an alkali metal alkoxide in the presence of a lower alkanol.  The initial chloroformylation is preferably effected at between -20 DEG  C. and 30 DEG  C. in an inert solvent, e.g. chloroform, benzene, ether, dioxane or toluene, using an acid acceptor, e.g. 1 - phenyl - 2,3 - dimethyl - 5 - pyrazolone, dimethylaniline, pyridine or quinoline. Dihydro-oxazine-diones unsubstituted on the N atom form water-soluble salts with metals, e.g. potassium, sodium, and calcium.  In an example phosgene in toluene is treated with ethyl 2,2 - dimethyl - 3 - phenylhydracrylate and 1 - phenyl - 2,3 - dimethyl - 5 - pyrazolone in chloroform, the mixture concentrated and extracted with ether yielding (2-carbethoxy-2-methyl-1-phenyl) propyl chloroformate, which is dissolved in chloroform and treated with ammonia giving (2 - carbethoxy - 2 - methyl - 1 - phenyl) propyl carbamate, which on cyclization with methanolic sodium methoxide yields 5,5-dimethyldihydro - 6 - phenyl - 1,3 - oxazine - 2,4 - (3H) - dione.  Other examples describe the preparation of the following dihydro-1,3-oxazine - 2,4 - (3H) - diones:-6 - phenyl -, 5-methyl-6 - phenyl-, 5 - ethyl - 6 - phenyl-, 5 - propyl - 6 - phenyl-, 5 - isopropyl - 6 - phenyl-, 5,5 - diethyl-6 - phenyl-, 5 - methyl - 5 - ethyl - 6 - phenyl-, 5,5,3 - trimethyl - 6 - phenyl-, 5,5 - diethyl - 3 - methyl - 6 - phenyl-, 5,5 - dimethyl - 6 - phenyl-2 - thio-, 5 - ethyl - 6 - butyl-, 5,5 - dimethyl - 6 - butyl-, 5 - ethyl - 6 - isobutyl-, 5,5,6 - triethyl-, 5,5 - dimethyl - 6 - (1 - methylbutyl)-, 5 - (1-methylpropyl) - 6 - ethyl-, 5,5 - dimethyl - 6,6 - dipropyl-, 5 - ethyl - 6 - hexyl-, 5 - ethyl - 6 - cyclohexyl-, 5,5 - dimethyl - 6 - vinyl-, 5-ethyl-6 - benzyl-, 5 - ethyl - 6 - propenyl-, 5 - ethyl - 6-(4 - chlorophenyl), 5 - (1 - methylpropyl) - 6 - (3 - chlorophenyl)-, 5,5 - dimethyl - 6 - isoamyl-, 5 - methyl - 6 - (4 - isopropylphenyl)-, 5 - methyl-6 - phenylethyl-, 5,5 - dimethyl - 6 - (4 - tolyl)-, 5,5 - dimethyl - 6,6 - pentamethylene -, 5 - methyl - 6 - (2 - thienyl)-, 5,5 - dimethyl - 6 - (2 - pyridyl)-, 5 - ethyl - 3 - (cyclohexen - 1 - yl)-.  Details for the preparation of the corresponding intermediate chloroformyloxy (or chlorothioformyloxy) and carbamyloxy (or thiocarbamyloxy) compounds are also given.  In several examples (Nos. 5, 6, 7, 9 and 13) a mixture of two racemic pairs of isomers of the oxazine derivative is obtained, and the pairs then separated by fractional crystallization from methanol and ethanol.  The following substituted b -hydroxypropionic acid ethyl esters, required as starting materials, are prepared via the Reformatsky reaction:-2 - ethyl - 2 - methyl - 3 - phenyl - hydracrylate, 3 - phenyl - 2 - propyl - hydracrylate, 2 - ethyl - 3 - hydroxyheptanoate, 2,2,6 - trimethyl - 3 - hydroxyheptanoate, 2,2-dimethyl-3-hydroxy-heptanoate, 2,2-diethyl - 3 - hydroxyvalerate, 2 - ethyl - 3 - hydroxy - 5 - methylhexanoate, 2 - ethyl - 3 - (4 - chlorophenyl) - hydracrylate, [3 - (3 - chlorophenyl) - 2 - (1 - methylpropyl)] - hydracrylate, a  - ethyl - b  - hydroxy - g  - phenyl-butyrate, 3 - hydroxy - 2 - methyl - 5 - phenyl-valerate, a  - ethyl - b  - hydroxycyclohexane-propionate, b - hydroxy - a  - methyl - 2 - thiophenepropionate, a ,a  - dimethyl - b  - hydroxy-2 - pyridinepropionate, 3 - hydroxy - 2,2,4 - trimethylheptanoate, [3 - hydroxy - 2 - (1 - methyl-propyl)] - valerate and a  - ethyl - b  - hydroxy - 3-cyclohexene-1-propionate.