Patent GB-778693-A (GB)
Title: Improvements in or relating to the production of spiro[cycloalkane-1,6-(m-thiazane-4-ones)]
IPC: C07D279/04
Filed: 1955-02-11
Abstract: The invention comprises spiro [cycloalkane-1,61-(m-thiazane-41-ones)] of the general formula <FORM:0778693/IV(b)/1> wherein Z is a polymethylene radical which may be substituted by one or more alkyl radicals containing 1 to 5 carbon atoms or by an alicyclic radical, the said polymethylene radical containing 4 to 6 carbon atoms, R1, R2 and X represent hydrogen or lower alkyl radicals containing 1 to 5 carbon atoms, Y represents an imino radical or a lower alkylimino radical containing not more than 2 carbon atoms, or X and Y together with the carbon and nitrogen atoms in the 2-and 3-positions respectively represent a dihydroimidazo ring to form a compound of the formula <FORM:0778693/IV(b)/2> wherein R1, R2 and Z have the above significance and the acid addition salts thereof, and the preparation thereof by reacting in the presence of an aliphatic carboxylic acid anhydride and a non-aqueous solvent, a thiourea having in one tautomeric form the general formula <FORM:0778693/IV(b)/3> wherein X and Y have the above significance, with an a -(1-halocycloalkane) alkanoic acid of the general formula <FORM:0778693/IV(b)/4> wherein R1, R2 and Z have the above significance and Hal represents chlorine, bromine or iodine, and if desired converting the product into an acid addition salt.  Acetic anhydride is the preferred carboxylic acid anhydride and glacial acetic acid is the preferred solvent.  A suitable reaction temperature is from 60 DEG  to 100 DEG  C.  The thiourea reactant may be thiourea, N,N1 - dimethylthiourea, N,N1 - diethylthiourea and ethylenethiourea.  Specified a -(1-halocycloalkane) alkanoic acids are a -(1-bromo-cyclopentane (and cycloheptane) acetic acid, a -(1-bromo-cyclohexane) acetic acid, and the corresponding 2-, 3- and 4-methyl-, 4-isopropyl-, 4-sec.- and tert.-butyl-, 4-tert.-amyl-, 4-cyclohexyl- and 3,3,5-trimethyl-cyclohexane substituted compounds, a -(1-bromo-cyclohexane) propionic acid, a  - (1 - bromo - cyclopentane) butyric acid, a -(1-bromo-cyclohexane) butyric acid and the corresponding 3- and 4-methyl and 3,3,5 - trimethyl - cyclohexane substituted compounds, a  - (1 - bromo - cyclohexane) isobutyric acid, a  - (1 - bromo - cyclohexane) valeric, isovaleric, heptanoic and caproic acids.  In the examples, the following compounds are prepared: spiro [cyclopentane-1,61-(21-imino-m-thiazane-41-one] and the corresponding 1,61-(51-ethyl - 21 - imino - m - thiazane - 41 - one), 1,61-(21 - methylimino - 31 - methyl - m - thiazane-41-one), and 1,71 - (21,31 - dihydro - 51 - H - imidazo - [21.11-b] - m - triazane - 51 - one compounds, spiro [3 - methyl - cyclohexane - 11,61 - (21 - imino - m - thiazane - 41 - one)] and the corresponding 21 - methyl - cyclohexane, 4 - methyl - cyclohexane, 4 - isopropyl - cyclohexane, 4-sec.-butyl - cyclohexane, and 3,3,5 - trimethyl - cyclohexane compounds, spiro [cyclohexane-1,61 - (51 - ethyl - 21 - imino - m - thiazane - 41 - one)] and the corresponding 51-methyl compound, spiro [4 - methyl - cyclohexane - 1,61 - (51 - ethyl - 21 - imino - m - thiazane - 41 - one)], spiro [4 - isopropyl - cyclohexane - 1,61 - (21 methylimino - 31 - methyl - m - thiazane - 41 - one)] and the corresponding 4-tert.-butyl-cyclohexane compound, spiro [cyclohexane - 1,61-(21 - methylimino - 31 - methyl - m - thiazane - 41 - one)] and the corresponding 21-ethylimino-31 - ethyl - m - thiazane - 41 - one, spiro [4-methyl - cyclohexane - 1,61 - (21 - methylimino - 31 - methyl - m - thiazane - 41 - one)], spiro [3-methyl - cyclohexane - 1,61 - (21 - ethylimino-31-ethyl - m - thiazane - 41 - one)], spiro [3 - methyl-cyclohexane - 1,71 - (21,31 - dihydro - 51 H - imidazo - [21.11bb] - m - thiazane - 51 - on and spiro [cycloheptane-1,61-(21-imino-m-thiazane-41-one) ].  Starting materials. a  - (1 - Bromocycloalkane) alkanoic acids of the above general formula are prepared by the action of fuming hydrobromic acid on the corresponding a -(1-hydroxycycloalkane) alkanoic acid or upon the unsaturated carboxylic acid obtained by removing water from the hydroxy-acid.  A number of the acids are specified and are referred to above.  a -(1-Hydroxycycloalkane alkanoic acids referred to above are prepared by means of a Reformatsky reaction between the required cycloalkanone and a -bromoalkanoate ester to give a -(1-hydroxycycloalkane) alkanoate ester which is then saponified. Unsaturated carboxylic acids referred to above are prepared by dehydrating and then saponifying the above a -(1-hydroxycycloalkane) alkanoate esters, or by condensing the required cycloalkanone with cyanoacetic acid in the presence of a base such as piperidine to give an unsaturated nitrile which is then subjected to an acid or alkaline hydrolysis.  Specification 778,694 is referred to.