2- Chloro -10- phenothiazines

A mixture of 50 parts of the distillate, 25.6 parts of 3-bromoethyl acetate, 10.7 parts of potassium carbonate and 400 parts of toluene is stirred at reflux temperature for 16 hours. The mixture is heated with water. The organic layer is separated, washed with water and extracted with dilute hydrochloric acid. The resulting extract is washed with benzene, rendered alkaline and extracted with benzene. The resulting benzene solution is dried over anhydrous potassium carbonate, filtered and concentrated. The residue is dissolved in 300 parts of ethanol and treated with 2.2 equivalents of a 25% solution of anhydrous hydrochloric acid in 2-pro-pa nol. The resulting crystals are recrystallized from 400 parts of ethanol and 10 parts of water. The dihydrochloride of N-( 3-acetoxyethyl)-N -[7-(2 -chloro-10 -phenothiazine)propyl] piperazine melts unsharply at about 200°C to 230°C. 

Piperazineethanol, 4-[3(2-chloro-10-phenothiazine-10 yl) propyl]- BP (1973) USP Trilafon (Schering-Plough) ... 

To a stirred and refluxing suspension of 4.95 parts of 4-piperidinecarboxamide, 1 part of sodium iodide and 8.4 parts of potassium carbonate in 40 parts of butanone there are added In the course of 30 minutes9.3 parts of 2-chloro-10-(7-chloropropyl)phenothiazine in 40 parts of butanone. Stirring and refluxing are continued for 12 hours after which the mixture Is cooled and filtered. The filtrate is concentrated under vacuum to give a residue which is recrystallized from a mixture of 2-propanol and petroleum ether. The 1-[7-(2 -chloro-10 -phenothiazine)propyl] piperidine-4-carboxamide thus obtained melts at approximately 139°C. 

Thiosemicarbazone, in C-00120 5-Chloro-2-hydroxybenzaldehyde phenylthiosemicarbazone, C-00123 2-Chloro-10// phenothiazine, C-00198 5-[(4-Chlorophenyl)azo]-6-hydroxy-2-naphthalenesulfonic acid, C-00204... 

The 2-chloro-10-( y-chloropropyl)phenothiazine starting material is produced from 2-chloro-phenothiazine and 1 -bromo-3-chloropropane. 

Chlorpromazine is manufactured by heating 2-chloro-phenothiazine and 3-chloropropyl dime-thylamine in the presence of sodomide, followed by reaction with hydrogen chloride. 

A new route to 2-chloro-phenothiazines that contain C atoms has been described in which 2-amino-4-chlorobenzenethiol is condensed with [2- C]cyclohexanone to give the spiro-2,3-dihydrobenzothiazole (91) acylation of (91) followed by treatment with sulphuryl chloride gives a mixture of (92) and (93)." ... 

Chloro-5-nitrobenzaldehyde, -acetophenone, or -benzophenone derivatives treated with 2-aminothiophenol under alkaline conditions provided good yields of the corresponding dibenzo[(3,/][l,4]thiepins. Similar treatment of 2-chloro-3,5-dinitrobenzophenone (318) provided 58% of dibenzo[(3,/][l,4]thiepin 321 and 20% of phenothiazine 323. Its formation can be easily explain by the Smiles rearrangement of the initially formed intermediate 320 into diphenylamine derivative 322, followed by denitrocyclization reaction leading to the corresponding product of denitrocyclization 323 (Scheme 49). When the reaction was done in pyridine, only this product was isolated in 50% yield (57JCS3818). 

To anticipate briefly, shortening the length of the side chain in the phenothiazines from three to two carbon atoms changes I he activity of the products from neuroleptics to antihistaminic iigents. A rather similar effect is seen in the tricyclic antidepressants. Reaction of ketone, 27, with the Grignard reagent I rom 4-chloro-l-methylpipyridine (35) affords the tertiary alco-liol, 36. Dehydration gives the antihistamine, cyproheptadine (37). ... 

The parent drug of this series, promazine (24), was prepared originally as an antihistamine. Following the identification of the more potent chloro analog as an antipsychotic, it too came into use for that indication. The drug is prepared by straightforward alkylation of phenothiazine with w-C3-chloropropyl)di-methylamine by means of sodium hydride in xylene. ... 

Alkylation of phenothiazine with l-chloro-2-methyl-3-bromopropane affords the methylated analog (80) of the intermediate above. Use of this halide to alkylate the piperazine... 

Chemical Name 2-chloro-N,N-dimethyl-10H-phenothiazine-10-propanamine hydrochloride Common Name N-(3-dimethylaminopropyl)-3-chlorophenothiazine... 

To a suspension of sodamide in liquid ammonia and made from sodium in liquid ammonia, there is added fractionally and with stirring phenothiazine. After an hour there is added thereto, while maintaining the stirring, 1-chloro-2-methyl-3-bromopropane, then 700 cc of toluene. The ammonia is then driven off and heating under reflux is carried out for one hour. 

After cooling, water is added and the solution then decanted. The toluene phase is then evaporated in vacuo to constant weight. The residue is constituted of 10-(2-methyl-3-chloro-propyl)-phenothiazine containing a certain quantity of phenothiazine which has not reacted. As this product is not readily soluble in petroleum ether, it is possible to eliminate it by extraction by means of this solvent. 

By operating in this manner 10-(2-methyl-3-chloro-propyl)phenothiazine is obtained. A mixture of 10-(2-methyl-3-chloro-propyl)phenothiazine and 1-[2-(2-hydroxyethoxy)ethyl] piperazine is then heated at 110 -120°C for 20 hours. After cooling, the reaction product is dissolved in 200 cc of benzene and the solution washed several times with water. 

A stirred mixture of 5 parts of 2-chloro-10-[ r-(N Pipera2ino)propyl] phenothiazine, 1.92 parts of 2-bromoethanol, 2.11 parts of potassium carbonate and 35 parts of toluene is refluxed for 5 hours. The mixture is treated with water and benzene and the organic layer is separated, washed with water, dried over anhydrous potassium carbonate, filtered and evaporated. The residue is distilled at about 240°244°C and 0.15 mm pressure to yield 2-chloro-10-[-y-(N -/3-hydroxyethyl-N-pipera2ino)-propyl] phenothiazine according to U.S. Patent 2,838,507. 

Chemical Name 1-[3-(2-Chloro-10H-phenothiazin-10-yl)propyl] -4-pyridinecarboxamide... 

Chamical Nama 2-Chloro-10-[3-(4-methyl-1-piperazinyDpropyl] -lOH-phenothiazine Common Nama Chlormeprazine... 

Chloro-lO-13-(di-N-2-chloroethvl)aminopropvl)lphenthiazine hydrochloride (1.8 g) is heated in a sealed tube for 4 hours at 140°C with a 290 g/l aqueous solution (9 cc) of monomethylpiperazine. The contents of the tube are treated with chloroform (40 cc). The aqueous layer is decanted and the chloroform layer is shaken with N hydrochloric acid (15 cc followed by 2 cc). The aqueous solution is treated with sodium hydroxide (d = 1.33, 10 cc) and chloroform (20 cc). After evaporation of the solvent, the base (1.5 g) is obtained. A solution of maleic acid (1 g) in ethanol (5 cc) is added and after recrystallization from water, 3-chloro-10-13-(4 -methyl-1 -piperazinvDpropyll phenothiazine dimaleate is obtained, melting point 228°C (inst.). 

A mixture of 155 parts of 2-chloro-10-(7-chloropropyl)phenothiazine, 75 parts of sodium... 

CN 4-[3-(2-chloro-IO -phenothiazin-IO-yl)propyl]-l-piperazineethanol acetate (ester) dihydrochloride... 

Analogously prepared are the diesters of TV-methyl-phenothiazine diacetic acid and mono-/7-toluenesulfonyl-, chloro- or iodooligoethylene glycols.[144]... 

Serious side-effects have been associated with the important psychotherapeutic agent, chlorpromazine (358), almost since its introduction. High sensitivity to sunburn, pigmentation of the skin and ocular opacity are common phototoxic effects [ 196]. In a series of phenothiazines, the chloro-substituted compounds, particularly chlorpromazine, prochlorperazine and perphenazine, showed by far the greatest phototoxic activity [197, 198]. 

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