Patent GB-728452-A (GB)
Title: The preparation of 22-tertiary amino steroids containing 20:22 double bond and 20 keto steroids
IPC: C07D295/10
Filed: 1952-03-12
Abstract: The invention comprises a 22-tertiaryaminobisnor-20 : 22-cholene which may contain a keto, acyloxy or hydroxy substituent in the 3-position, and a process for the preparation of a steroid having a double bond in the 20 : 22 position and a tertiary amino group in the 22-position by heating a steroid containing a 22-aldehyde group with a secondary amine at a temperature between approximately 25 DEG  and approximately 125 DEG  C. with or without continuously removing the water formed during the course of the reaction.  The process may be modified by oxonizing the 20 : 22 double bond at a temperature below approximately 30 DEG  C., and decomposing the 20 : 22-ozonide thus formed to give a 20-ketosteroid.  The 22-tertiaryamino compound may be formed at a temperature between 40 and 110 DEG  C. for a period between about 15 minutes and 40 hours, and the ozonide may be formed at a temperature between plus 30 DEG  and minus 30 DEG  C. Preferably from 1 to 1.5 moles., e.g. 1.1 to 1.3 moles., of ozone per mole. of the 22-tertiaryamino compound are used to form the ozonide. Suitable methods for decomposing the ozonide to form the 20-ketosteroid are steam distillation, addition to boiling acetic or propionic anhydride, and addition to liquid ammonia, concentrated aqueous potassium bisulphite, dilute solution of sodium bisulphite, a mixture of powdered zinc and water, and a mixture of powdered zinc and glacial acetic acid.  Secondary amines referred to are dialkylamines such as diethyl-, dibutyl-, dioctyl- and didodecylamine, cycloalkylamines such as dicyclohexylamine, cyclic saturated heterocyclic amines such as piperidine, 2- and 3-methylpiperidine, pyrrolidine, 2-methylpyrollidine, tetrahydroquinoline, oxazolidine and morpholine, aralkylalkylamines such as N-methylbenzylamine and dibenzylamine, substituted dialkylamines including hydroxy substituted dialkylamines such as diethanolamine, arylalkylamines such as N-methyl substituted aniline, toluidine and anisidine.  The Specification refers to a large number of steroid reactants containing a 22-aldehyde group which are of the following types: cholan-22-al and its 3-acyloxy, 3-alkoxy and 3 - keto derivatives, 3 - acyloxybisnor - 5 - cholan-22-al and the corresponding 3-hydroxy compound and the i ethers thereof, and the maleic anhydride, maleimide and maleic ester adducts of 5,7-choladien-22-al and the corresponding 3-hydroxy, 3-keto, 3- and 12-acyloxy and 3-alkoxy compounds, bisnor-5,7,9(11)-cholatrien-22-al and the corresponding 3-keto, 3-hydroxy-3-alkoxy and 3-acyloxy compounds, and 3-acyloxy-9,11 - oxidobisnor-5,7-choladien - 22-al and the corresponding 3-hydroxy and 3-keto compounds.  In the examples, the following compounds are prepared: 22-piperidino-4, 20 : 22-choladiene-3-one and the corresponding 22 - morpholino- and 22 - dibenzylamino - compounds, 3 - hydroxy - and 3 - acetoxy - 22 - piperidino-5, 20 : 22-choladiene, progesterone and pregnenolone.  A number of additional 20-ketosteroids and 22-tertiaryamino-steroids are referred to and are derived from 22-aldehydesteroids of the types referred to above.  Specification 680,778 is referred to.