Patent GB-795926-A (GB)
Title: New piperazine derivatives and processes for their preparation
Inventor: HORCLOIS RAYMOND JACQUES
IPC: C07D417/06
Filed: 1954-10-23
Abstract: The invention comprises compounds of the general formula <FORM:0795926/IV (b)/1> and their acid-addition and quaternary ammonium salts (including 8-chlorotheophylline salts), wherein X is hydrogen or halogen or an alkyl or alkoxy group of 1 to 4 carbon atoms, A and A1 are straight or branched alkylene groups of 2 to 4 carbon atoms, and R and R1 are each alkyl groups of 1 to 4 carbon atoms, or one of them is hydrogen and the other is alkyl of 1 to 4 carbon atoms or cycloalkyl, or -NRR1 represents a saturated heterocyclic group; and their preparation by the following methods:-(a) reacting an N-substituted phenthiazine C12H7(X)SN-A2-Y, wherein Y is a halogen atom or a sulphuric or sulphonic ester radical, with a compound <FORM:0795926/IV (b)/2> (b) reacting a phenthiazine C12H7(X)SNH with a compound <FORM:0795926/IV (b)/3> wherein Hal is a halogen atom; and (c) reacting a compound <FORM:0795926/IV (b)/4> with an amine T-NRR1, wherein one of T and Z is the group -A3-Y and the other is hydrogen; A2 and A3 being as A and A1 or being divalent groups containing a carbonyl group adjacent to the piperazine nucleus or to -NRR1 and convertible to A and A1 by reduction. These processes may be conducted in a solvent and in the presence of a condensing agent such as an alkali metal or a hydroxide, hydride, amide, alcoholate or organometallic derivative thereof. It is stated that when Z or T is branched isomerization can occur at one stage or other of the process with the production of 2 isomers which can be separated, for example, by conversion of the bases into hydrochlorides and fractional crystallization of these, with subsequent liberation of the individual free bases if desired. In examples: (1) 10-(2-11-piperazinylethyl)-phenthiazine and b -diethylaminochlorethane are condensed with sodamide in xylene to give 1-(2-101-phenthiazinylethyl)-4-(2-diethylaminoethyl) -piperazine, isolated as its trimaleate; (2) 1-(2-101-phenthiazinylethyl)-4-(2-dimethylaminoethyl) -piperazine trimaleate is similarly prepared; (3) from the appropriate phenthiazine and 1-dimethylamino-2-chloropropane, 1 - (2 - 101-phenthiazinylethyl)-4-(2-dimethylaminopropyl and 3-dimethylamino-2-propyl)-piperazines are obtained in admixture as hydrochlorides and then tri-picrates; (4) a mixture of 1-(2-101-phenthiazinylethyl)-4-(2-dimethylaminopropyl and 3-diethylamino-2-propyl)-piperazine hydrochlorides and tripicrates is similarly obtained; (5) 10-(2-chlorethyl)-phenthiazine and 1 - (3 - diethylaminopropyl)-piperazine at 200 DEG  C. give 1-(2-101-phenthiazinylethyl) - 4 - (3 - diethylaminopropyl) - piperazine, isolated as the trihydrochloride; (6) 3-chlorophenthiazine and 1-(3-chloropropyl)-4-(3 - diethylaminopropyl) - piperazine with sodamide in xylene give 1-(3-31-chloro-101-phenthiazinylpropyl) - 4 - (3 - diethylaminopropyl)-piperazine, isolated as the trihydrochloride and trimaleate; (7) 1-(2-101-phenthiazinylethyl)-4-(2-piperidinoethyl) -piperazine trimaleate is prepared as in (1) and the free base is converted to its trimethiodide; (8) 1-(2-31-chloro-101-phenthiazinylethyl) - 4 - (2 - morpholinoethyl)-piperazine trimaleate is similarly prepared and the free base is converted to its tri-theophyllineacetate; (9) 1-(1-101-phenthiazinyl-2-propyl)-4-(2-dimethylaminoethyl) -piperazine trimaleate is prepared by the method of (5); (10) 1-(3-31-methoxy - 101 - phenthiazinylpropyl) - 4 - (2 - dimethylaminoethyl)-piperazine trimaleate and the corresponding 31-methyl compound are prepared by the method of (6); (11) 1-(3-31-chloro-101 - phenthiazinylpropyl) - 4 - (3 - 11 - pyrrolidinylpropyl) -piperazine trimaleate is prepared as in (7); (12) 1-(2-101-phenthiazinylethyl)-4-(3-chloropropyl) - piperazine dihydrochloride is heated with piperidine to give 1 - (2-101 - phenthiazinylethyl) - 4 - (3 - piperidinopropyl) - piperazine, isolated as the trimaleate; (13) 1-(2-101-phenthiazinylethyl - 4 - (3 - cyclohexylaminopropyl)-piperazine trihydrochloride is prepared as in (12); (14) 1-(2-31-chloro-101-phenthiazinylethyl) - 4 - piperidinoacetyl - piperazine is reduced with lithium aluminium hydride in tetrahydrofuran to 1 - (2 - 31 - chloro - 101 - phenthiazinylethyl) - 4 - (2 - piperidinoethyl) - piperazine, isolated as the trimaleate; (15) 1-(2-31-chloro - 101 - phenthiazinylethyl) - 4 - (2 - cyclohexylaminoethyl) - piperazine trimaleate is similarly prepared.  In the Provisional Specification the processes of the invention are defined in somewhat broader terms. Starting materials. 1-(3-Chloropropyl)-4-(3-diethylaminopropyl)-piperazine is prepared from 1 - chloro - 3 - bromopropane and 1 - (3 - diethylaminopropyl) - piperazine; 1 - (2 - dimethylaminoethyl - 4 - (3 - chloropropyl) - piperazine trihydrochloride is prepared from thionyl chloride and 1 - (2 - dimethylaminoethyl) - 4 - (3 - hydroxypropyl - piperazine hydrochloride, itself prepared as a base from 3-chloro-1-propanol and 1-(2-dimethylaminoethyl)-piperazine; 1-(2-101-phenthiazinylethyl) - 4 - (3 - chloropropyl) - piperazine, isolated as the dihydrochloride, is prepared from thionyl chloride and 1-(2-101-phenthiazinylethyl) - 4 - (3 - hydroxypropyl) - piperazine, the latter being prepared from 3-chloro-1-propanol and 10 - (2 - 11 - piperazinylethyl) - phenthiazine; 1 - (2 - 31 - chloro - 101 - phenthiazinylethyl) - 4 - piperidinoacetyl - piperazine (dipicrate described) is prepared from piperidine and 1-(2-31 - chloro - 101 - phenthiazinylethyl) - 4 - chloroacetylpiperazine, itself prepared from chloroacetyl chloride and 3-chloro-10-(2-11-piperazinylethyl) - phenthiazine; 1 - (2 - 31 - chloro-101 - phenthiazinylethyl) - 4 - 11 - cyclohexyl - aminoacetyl - piperazine dimaleate is also described.