Chloropropylate

A variation on the tryptamine synthesis is to use diethyl (3-chloropropyl)-malonate as the substrate for a one-pot Japp-Klingemann/Fischer procedure. The chloropropyl group alkylates the ct-nitrogen, forming the tryptamine side-chain. The precise stage at which the alkylation occurs is unclear[4]. 

Table 2 gives physical property data for propylene chlorohydrins. 2-Chloro-l-propanol [78-89-7] HOCH2CHCICH2, is also named 2-propylene chlorohydrin, 2-chloropropyl alcohol, or 2-chloro-l-hydroxypropane. l-Chloro-2-propanol [127-00-4] CICH2CHOHCH2, also known as j -propjlene chlorohydrin, 1-chloroisopropyl alcohol, and l-chloro-2-hydroxypropane, is a colorless Hquid, miscible in water, ethanol, and ethyl ether. 

Chloropropyl bromide (l-bromo-3-chloropropane) [109-70-6] M 157.5, b 142-145 , n 1.4732. Washed with cone H2SO4, water, 10% Na2C03 soln, water again and then dried with CaCl2 and fractionally distd just before use [Akagi, Oae and Murakami J Am Chem Soc 78 4034 1956]. 

As shovm above, the attachment of the aromatic ring to the carbon chain bearing the basic nitrogen may be accomplished through an ester or an amide configured in either direction. A simple ether linkage fulfills this function in yet another compound that exhibits local anesthetic activity. Thus, alkylation of the mono potassium salt of hydroquinone with butyl bromide affords the ether (77) alkylation of this with w-C3-chloropropyl)morpholine affords pramoxine (78)... 

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. ... 

Chlorpromazine (33) can probably be considered the prototype of the phenothiazine major tranquilizers. The antipsychotic potential of the phenothiazines was in fact discovered in the course of research with this agent. It is of note that, despite the great number of alternate analogs now available to clinicians, the original agent still finds considerable use. The first recorded preparation of this compound relies on the sulfuration reaction. Thus, heating 3-chlorodiphenylamine (30) with sulfur and iodine affords the desired phenothiazine (31) as well as a lesser amount of the isomeric product (32) produced by reaction at the 2 position. The predominance of reaction at 6 is perhaps due to the sterically hindered nature of the 2 position. Alkylation with w-C3-chloropropyl)dimethylamine by means of sodium amide affords chlorpromazine (33). ... 

The most complex side chain of the piperazine phenothiazines is to be found on chlorimpiphenine (86). The side chain is prepared by first alkylating monocarbethoxypiperazine with the chlorobenzimidazole 83 [itself attainable by alkylation of methylbenzimidazole with a dihalide). Removal of the carbethoxy group affords the substituted piperazine, 85. Alkylation of this base with the chloropropyl phenothiazine, 58, affords finally the desired compound (86). ... 

Replacement of the terminal nitrogen of the piperazine by carbon is said to enhance the antiemetic activity of the phenothiazines at the expense of the other pharmacologic effects. The simplest compound in this series, pipamazine (88), is prepared by alkylation of nipecotamide (87) with the chloropropyl phenothiazine (58). Preparation of the analogous sulfoxide begins with acetylation of the thiomethyl compound, 89 [prepared by a route... 

The requisite intermediate. 10-(3-chloropropyl)-2-acety(phenothiazine is prepared as follows To a suspension of sodamide (from 3 grams of sodium) in 300 ml of liquid ammonia is added 30 grams of 2-acetylphenothiazine. After stirring for one hour, there is added 19 grams of 1-bromo-3-chloropropane. The ammonia is allowed to evaporate and the residue is diluted with 200 ml of water. The mixture is extracted with ether and the ether solution is dried over anhydrous sodium sulfate, filtered and concentrated. 

The residue consists of crude 10-(3-chloropropyl)-2-acetylphenothiazine as a viscous oil and is used in the next step without further purification. The crude base obtained from the reaction of 10-(3-chloropropyl)-2-acetylphenothiazine with 1-(2-hydroxyethyl)piperazine is purified by conversion to its dimaleate salt, MP 167°-168.5° from ethanol. 

A mixture of 5.0 g of 3-chloro-5-(3-chloropropyl)-10,11 -dihydro-5H-dibenz(b,f)azepine, 5.0 g of 4-carbamoyl-4-piperidinopiperidine and 50 mi of dimethylformamide is heated at 100°C for 10 hours. The solvent is distilled off. After the addition of a 2% sodium carbonate solution to the flask, the content is scratched to yield a semisolid, which is dissolved in 50 ml of isopropanol. A solution of 5 g of maleic acid in 50 ml of isopropanol is added, and the precipitate is collected by filtration and recrystallized from isopropanol to give 5.6 g of crystalline 3-chloro-5-[3-(4-carbamoyl-4-piperidino-piperidino)propy I] -10,1 l-dihydro-SH-dibenz-Ib.fjazepine dilhydrogen maleate) with 1/2 molecule of water of crystallization melting at 181°C to 183°C. 

Chloropropyl)-1 -dihydro-2H-benzimidazol-2-one 5-Chloro-1 -dihydro-1 -(4-piperidinyl)-2H-benzimidazol-2-one... 

Thionyl chloride (67 grams) is added over 15 minutes to a mixture of 39.5 grams of the above prepared dihydrochloride salt and 400 ml of chloroform. Refluxing for 4 hours, cooling and filtering yields the dihydrochloride salt of 1-benzyloxyethyl-4-(3-chloropropyl)-piperazine, (VIP 201° to 202°C. The salt in aqueous solution is basified. Extraction with ether and evaporation of the solvent yields the free base. 

IVIagnesium (1.3 grams) in B ml of refluxing tetrahydrofuran is treated with 1 ml of ethyl bromide. A solution of 22.7 grams of 1-benzyloxyethyl-4-(3-chloropropyl)-piperazine in 50 ml of tetrahydrofuran is added slowly and the mixture Is refluxed for 1 hour. 

A solution of 54.1 grams of 1-formyl-4-(3 -chloropropyl)-piperazine, [prepared by formylat-ing 1-(3 -hydroxypropyl)-piperazine by refluxing in an excess of methyl formate, purifying the 1-formyl-4-(3 -hydroxypropyl)-piperazine by vacuum distillation, reacting this compound with an excess of thionyl chloride at reflux and isolating the desired 1-formyl-4-(3 -chloropropyl)-piperazine by neutralization with sodium carbonate solution followed by distillation] in 200 ml of toluene is added. The reflux period Is continued for 4 hours. 

Chemical Name N-(3-Chloropropyl)-Q -methylphenylethylamine hydrochloride Common Name —... 

The sodium derivative of the 2-trifluoromethylphenothiazine was prepared from 26.7 g (0.1 mol) of 2-trifluoromethylphenothiazine and 2.3 g (0.1 g atom) of sodium in 500 ml of liquid ammonia. After the reaction was completed, the ammonia was driven off and 500 ml of dry toluene were added. A solution of 25 g (0.09 mol) of N-(3-chloropropyl)-N -[2-(1,3-dioxanyl)-ethyl] -piperazine In 200 ml of toluene was added drop by drop to this solution which was then refluxed with stirring for 1B hours. After cooling, the precipitate which had formed was filtered and the filtrate was washed with water, dried and concentrated in vacuo. 33 g of brown oil, the N-3-(2-trifluoromethyl-10-phenothiazinyl)-propyl-N -2-[2-(1,3-dioxanyl)] -ethyl-piperazine, were obtained. 

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