Patent GB-1116736-A (GB)
Title: Improvements in or relating to 3-morpholinone and morpholine-3-thione derivatives
IPC: C07C49/80
Filed: 1966-02-11
Abstract: Novel compounds of formula <FORM:1116736/C2/1> wherein X is O or S; R1 is H, -OH, C1- 7 alkyl, or Ar, provided that, when R1 is -OH, said X is O; R2 is H, C1- 7 alkyl, amino-alkyl (C1- 7), C1- 7 alkyl-amino-C1- 7 alkyl, or acyl, provided that, when R2 is acyl, said X is O and R1 is not -OH; R3 and R4 are H, C1- 7 alkyl or Ar; Ar is an aryl or heterocyclic group or an aryl group substituted with hydroxy-C1- 7 alkyl, halo-C1- 7 alkyl, C1- 7 alkoxy, aryl-C1- 7 alkoxy, halo, nitro, amino, C1- 7 alkylamino, or cyclic ether groups, and the dotted line between the 5- and 6-carbon atoms indicates the presence of an optional double with Ar the sole substituent in the 6-position provided that when said double bond is present R1 is other than hydroxy, are prepared when the 5,6-bond is single, X is oxygen, R1 is other than hydroxy and R2 is other than acyl by (i) reacting a compound of formula: <FORM:1116736/C2/2> with sodium hydride to produce the sodium derivative, reacting this with a haloalkylester of formula Hal-CH(R1)CO.O-alkyl to produce a compound <FORM:1116736/C2/3> which is the cyclized to produce a compound of formula I; or (ii) by reacting II with the halide or anhydride of an appropriately a -halo-substituted acid to give the corresponding amide of formula <FORM:1116736/C2/4> which is then cyclized to compound I.  When R1 is hydroxy compound I is prepared by reacting II with a dihaloacetyl halide to yield the corresponding a -dihaloacetamide derivative which is then either reacted with an organic amine base and the product hydrolysed, or reacted with an alkali metal base.  When X is oxygen, and R1 and R2 are other than hydroxy and acyl, and when a double bond exists in the 5,6-positions, compounds I are prepared by reacting a compound of formula <FORM:1116736/C2/5> with the halide or anhydride of an appropriately a -halo substituted acid to give a compound of formula <FORM:1116736/C2/6> which is then cyclized with a base.  Alkyl or substituted alkyl and acyl substituents may be introduced into the 4-position by reacting the corresponding 4-unsubstituted morpholinones with the appropriate alkylating or acylating agent. When X is sulphur compounds of formula I are prepared by reacting the corresponding morpholine-3-ones with phosphorus pentasulphide to produce morpholine-3-thiones.  Examples 28, 35 and 55 describe the preparation of 2-hydroxyimino-3(-4 and -2 respectively)-trifluoromethyl -propiophenones by reaction of the corresponding trifluoromethyl-propiophenones with butyl nitrite and hydrogen chloride.  Examples 29, 36/37, and 56/57 describe the preparation of a -(1-aminoethyl)-m(p and o)-trifluoromethyl benzylalcohols by reduction of the 2-hydroxyimino-derivatives above with hydrogen over a palladium/carbon catalyst.  Examples 36 and 56 describe the preparation of 2-amino-4(and 2-)trifluoromethyl propiophenones by reduction of the hydroxyimino-propiophenones above with hydrogen over a palladium/carbon catalyst.  o, m and p-Trifluoromethyl propiophenones are prepared by reaction of the corresponding benzonitriles with ethyl magnesium bromides.  a -Hydroxyimino-41-benzyloxypropiophenone is prepared by reacting 41-benzyloxypropiophenone with butylnitrite and hydrogen chloride.  a - (1 - Aminoethyl) - p - benzyloxybenzyl alcohol is prepared by reduction of the a -hydroxyimino derivative with hydrogen in the presence of a nickel catalyst.  This specification includes a disclaimer to the compounds claimed in Specification 1,016,828 and to their methods of preparation.