Patent GB-579169-A (GB)
Title: Manufacture of lactones
IPC: C07J17/00
Filed: 1943-03-16
Abstract: A process for the preparation of lactones comprises treating with a metal described in the literature for use in the Reformatzky reaction in the presence of an inert solvent a saturated or unsaturated compound of the formula <FORM:0579169/IV/1> where R1 and R2 each represent a hydrogen atom or cycloaliphatic or aromatic residues, and when both represent such residues the latter may be linked together by a bridge.  X represents a halogen atom.  Y1 to Y3 represent hydrogen atoms and/or alkyl residues and n is either zero or unity. The starting materials are ketols or oxyaldehydes esterified with a - or b -halogenated fatty acids such as chloro-, bromo-, or iodo-acetic acid, -propionic acid, -butyric acid or -valeric acid.  They are preferably prepared by the reaction of diazoketones with the said fatty acids, diazo ketones mentioned as suitable starting materials include diazoaceto benzene, diazo-aceto-cyclohexane, p - oxy - diazoacetobenzene or -cyclo - hexane, 31 - diazo - aceto - 4 - oxy - a  : b  - diethyl - stilbene, 41-diazo-aceto-4-oxy-a  : b -diethyl-stilbene, or -dihydrostilbene, diazo camphor, diazo-epicamphor, D 5 : 6- 3 - oxy - 21 - diazopregnene - 20 - one, diazoprogesterone, D 5 : 6-3-oxy-23-diazonorcholene - 22 - one, D 5 : 6 - 3 - oxy - 25 - diazo - 26 : 27-bisnor-cholestene-24-one, 21-diazo-pregnane-3-ol-20-one, D 5 : 6-3-oxy-21-methyl-21-diazano-pregnene-20-one, and the corresponding esters or ethers.  Compounds of the steroid structure which are hydroxylated in 7-, 12- or 14-positions may also be used.  The lactone products of the invention may contain either a 5- or a 6-membered ring which may be saturated and hydroxylated, or unsaturated.  The saturated compounds may be treated to split off water and give a b  : g -unsaturated lactone ring, or a ring in which the double bond is in either the g  : d - or a  : b -position.  The condensation is carried out using metals which are suitable for the reformatzky reaction in a solvent such as benzene, toluene, dioxane or ether.  The splitting off of water referred to above for the purpose of preparing an unsaturated lactone ring may be carried out by treatment with fatty acid anhydrides as well as by distillation or sublimation under reduced pressure, and, if desired, after admixture with surface active materials such as aluminium oxide, silica gel, activated carbon and fuller's earth.  In examples: (1) D 5 : 6-3-acetoxy-21-bromacetoxy-pregnene-20-one, prepared by treatment of D 5 : 6 - 3 - acetoxy - 21 - diazo - pregnene - 20 - one with bromacetic acid, is boiled with zinc spangles in benzene solution and the product worked up to give D 5-3-acetoxy-20 : 21-dioxynorcholenic acid lactone.  The corresponding unsaturated lactone is prepared by heating to 240 DEG  C. in vacuo, or by prolonged boiling with acetic anhydride.  It has the structure D 5 : 6; 20 : 22-3-acetoxy-21-oxy-norcholadienic acid lactone.  By acid saponification D 5 : 6; 20 : 22 - 3 : 21 - dioxy - norcholadienic acid lactone is formed; (2) D 5-3-acetoxy-21-bromacetoxy-pregnene-20-one is refluxed with zinc spangles in dioxane solution and the product worked up and separated into its constituents by chromatographic analysis to give D 5 : 6; 20 : 22-3 - acetoxy - 21 - oxy - norcholadienic acid and D 5 : 6-3-acetoxy-20 : 21-dioxy-norcholenic acid; (3) D 5 : 6 - 3 - acetoxy - 25 - bromacetoxy - 26 : 27 - bisnorcholestene-24-one prepared by treatment of D 5 : 6 - 3 - acetoxy - 25 - diazo - 26 : 27 - bisnor - cholestene-24-one with bromacetic acid is refluxed with zinc spangles in benzene solution to form on working up b -[D 5 : 6-3-oxy-norcholenyl - (23)] - b  : g  - dioxy - n - butyric acid g lactone or its 3-mono-acetate.  On treatment of this product with acetic anhydride for several hours, there is obtained D a  : b -b -[D 5 : 6-3-acetoxy - norcholenyl - (23)] - butenolid.  Acid saponification of this compound gives D a  : b -b -[D 5 : 6 - 3 - oxy - norcholenyl - (23)] - butenolid. If in the preparation of the starting material an a -bromopropionic ester is used in place of a bromacetic acid ester, there is obtained the corresponding butenolid methylated in the a -position.  If b -halogen fatty acids are used, pentenolids are obtained.  Analogous products having a methyl group in the g -position are obtained by employing D 5 : 6-3-acetoxy-25-bromacetixy - 27 - norcholestene - 24 - one. This compound is obtained by the reaction of D 5 : 6-3-acetoxy cholenic acid chloride with diazoethane, and subsequent boiling with bromacetic acid; (4) D 5 : 6 - 3 - acetoxy - 23 - bromacetoxy - norcholene-22-one prepared by treatment of D 5 : 6 - 3 - acetoxy - 23 - diazo - norcholene - 22 - one with bromacetic acid is refluxed in benzene solution with zinc spangles to form D a  : b -b -[D 5 : 6 - 3 - acetoxy - pregnenyl - (20)] - butenolid.  Saponification with dioxane-hydrochloric acid gives the corresponding 3-oxy-compound; (5) 3 - oxy - 21 - bromacetoxy - pregnane - 20 - one, obtained from 21-diazo-pregnane-3-ol-20-one by reaction with bromacetic acid is refluxed with zinc spangles in benzene solution to give D 20 : 22 - 3 - acetoxy - 21 - oxy - norcholenic acid lactone.  Acid saponification gives 14-desoxy-digitoxigenin which is also known as the lactone of D 20 : 22-3-21-dioxy-norcholenic acid.  The free acid is also obtained by chromatographic separation.  This acid when boiled with acetic anhydride for some hours splits off water to form the acetate of the lactone of D 20 : 22-3 : 21 - dioxy - norcholenic acid; (6) 31 - diazo - aceto - 4 - acetoxy -a  : b  - diethyl - dihydrostilbene is reacted with bromacetic ester to form the corresponding ketol ester which is then refluxed in benzene solution with zinc-copper to give on working up the 31 - D a  : b  - butenolid of 4-acetoxy -a  : b  - diethyl - dihydrostilbene.  There is also obtained at the same time the 31-b  : g -dioxy - n - butyric acid-g -lactone of 4 - acetoxy - a b -diethyl-dihydrostilbene.