Patent GB-857426-A (GB)
Title: Substituted pyrrolidines
Inventor: WRAGG WILLIAM ROBERT
IPC: C07D207/20
Filed: 1958-03-28
Abstract: The invention comprises compounds of the general formula: <FORM:0857426/IV(b)/1> where R1 represents a hydrogen atom or a C1-3 alkyl or alkenyl group, R2, R21, R5 and R51 represent methyl or ethyl groups, R3, R31 and R4 represent hydrogen atoms or C1-3 alkyl groups, the total number of carbon atoms in the groups R1, R2, R21, R3, R31, R4, R5 and R51 being at least 5; and acid addition salts thereof; and the preparation thereof, where R4 is hydrogen, by reducing a compound of the formula:  <FORM:0857426/IV(b)/2> and, where R1 is hydrogen, by reducing a compound of the formula:  <FORM:0857426/IV(b)/3> and, where R31 and R4 are both hydrogen atoms, by reducing a compound of the formula:  <FORM:0857426/IV(b)/4> and, where R21 and R51 are both methyl groups, by replacing the cyano groups in the compound of the formula:  <FORM:0857426/IV(b)/5> by methyl groups, and, where R1 is an alkyl or alkenyl group, by appropriate alkylations and alkenylations, and, if desired, converting the products of any of these processes into their acid addition salts; also pharmaceutical compositions containing the products (see Group VI).  The products, which are ganglion blocking agents, may also be prepared by reducing a compound of the formula:  <FORM:0857426/IV(b)/6> where X represents a halogen atom.  2, 2, 5, 5-Tetramethyl-pyrrolidine is prepared by treating 2, 2, 5, 5-tetramethyl-pyrrolid-3-one with hydrazine and potassium hydroxide.  4-Pyrrolidones of the formula II where R3 and/or R13 are alkyl groups are prepared by appropriate alkylation of the corresponding compounds where R3 and R13 are hydrogen atoms which in turn are prepared by treatment of compounds of the formula: <FORM:0857426/IV(b)/7> with a hypobromite in alkali: 4-Halogeno-pyrrolidineo of the formula III where X is a halogen atom are prepared from the corresponding 4-pyrrolidinols which are themselves prepared by reduction of the corresponding 4-pyrrolidones. 1-Hydroxy-pyrrolidines of the formula IV are prepared by reacting compounds of the formula:  <FORM:0857426/IV(b)/8> with an organo-metallic compound containing a labile R15 radical. \se3,4-Pyrrolines of the formula V are prepared by dehydrating corresponding 3-pyrrolidinols or by treating corresponding 3-amino-pyrrolidines with a nitrite in mineral acid.  2, 5-Dicyano-pyrrolidines of the formula VI are prepared by condensing the dicyanohydrins of g -diketones of the formula R2CO,CR3R13,CHR4-COR5 with R1NH2.  3-Carboxamido-D 3,4-pyrrolines of the formula VIII are prepared by brominating 4-piperidones of the formula:  <FORM:0857426/IV(b)/9> and treating the resultant 3, 5-dibromo-derivatives with ammonia in the presence of a strong base. Compounds of the formula IX are prepared by condensing compounds of the formulae:  <FORM:0857426/IV(b)/100> and reducing the product having the formula:  <FORM:0857426/IV(b)/111> In the first Provisional Specification there is described a further process for the preparation of a compound of the invention in which an appropriate 4-pyrrolidone is reacted with an appropriate Grignard reagent and the product is successively dehydrated and reduced.ALSO:Pharmaceutical compositions comprise compounds of the general formula:  <FORM:0857426/VI/1> where R1 represents a hydrogen atom or a C1-3 alkyl or alkenyl group, R2, R21, R5 and R51 represent methyl or ethyl groups, R3, R31 and R4 represent hydrogen atoms or C1-3 alkyl groups, the total number of carbon atoms in the groups R1, R2, R21, R3, R31, R4, R5 and R51 being at least 5, or acid addition salts thereof; with a suitable pharmaceutical diluent.  Oral preparations include tablets, pills, powders, granules, capsules, emulsions, solutions, suspensions, syrups and elixirs.  Preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions or emulsions.  Examples are given of a syrup, tablets and injectable solutions.  Specified salts are hydrohalides, phosphates, nitrates, sulphates, maleates, fumarates, citrates, tartrates, methanesulphonates and ethanedisulphonates.