NO117887B - - Google Patents

Description

Process for the preparation of phenthiazine derivatives.

It has been shown that it is possible to

arrive at multi-double substituted

phenthiazine derivatives of the general formula I

in that a phenthiazine derivative with the general formula II

where R-, R2, R3 and R4 have the same meaning as above, is condensed with et

2-(piperidyl-2')-1-haloethane with it

general formula III

where R5 has the same meaning as above.

The method can, for example, be carried out in such a way that a phenthiazine derivative of formula II is dissolved in a suitable organic solvent, e.g. benzene, toluene, xylol, and reacted in the presence of a suitable condensing agent, e.g. alkali amide or alkali hydroxide with a piperidine derivative of formula III at room temperature or at elevated temperature.

After completion of the reaction, the reaction mixture is shaken out with water and freed from solvent at reduced pressure. The reaction product that remains is purified by distillation in high vacuum and can then be transferred to a suitable salt.

The basic compounds that are produced

according to the present method are oily or crystalline at room temperature and form permanent salts with acids. The phenthiazine derivatives produced according to the present method are sedative, but not narcotic. In experiments with animals, it was found that they reduce the animals' spontaneous activity and reduce the stimulating effect of various pharmaceuticals,

. like for example. methamphetamine and caffeine. They enhance the effect of analgesics and of barbiturates and other drugs, but themselves, even in large doses, cause neither narcosis nor coordination disorders. The test animals show in the electroencephalogram under the influence of phenthiazine derivatives produced according to the invention such changes as are typical for sedatives. The compounds inhibit the emetic effect of certain emetic agents. Larger doses lower the body temperature without affecting oxygen consumption. Furthermore, these compounds inhibit the effect of adrenaline on the single organ and on the whole animal, they reduce the effect of a sympathetic irritation (sympatholytic effect) and lower blood

the pressure, but only to a moderate extent. These phenthiazine derivatives have an acetylcholine-, histamine- and barium chloride-inhibiting effect (antihistamine effect and spasmolytic effect).

Corresponding to the pharmacodynamic properties that have just been described, the phenthiazine derivatives produced according to the invention can be used therapeutically as spasmolytics and neuroplegics, further for anesthetic preparation before operations and as sedatives. Deer's area of application is arousal and anxiety states due to the most diverse psychoses, habitual and compulsive notions of various kinds, e.g. also during weaning treatments, further states of tension and restlessness for various genesis, e.g. in arteriosclerosis, in menopause, as a result of vegetative disturbances or insomnia; vomiting, e.g. during pregnancy is quieted, and pain sensitivity is reduced. These compounds also provide good service in the fight against allergic disease cases.

The phenthiazine derivatives can be taken orally in daily doses of 100-1200 mg or intramuscularly in daily doses of 50-200 mg, as the dosage must be adapted in each individual case. The mode of action is characterized by a relaxation and sedation of the patient, without drowsiness or other side effects occurring. Even large doses, up to 1200 mg. per us, is well tolerated.

Examples:

1) 10-[2'-(N-methyl-piperidyl-2")-ethyl]-phenthiazine

199.15 g of phenthiazine is dissolved in approx.

five times the amount of abs xylol and, with stirring, heated to boiling under reflux with 46.8 g of sodium amide

(20% profit) for 2y2 hours. Without interrupting the heating, a solution of 177.6 g of 2-(N-methyl-piperidyl-2')-1-chloroethane [T. R. Norton, R.A. Seibert, A.A. Benson and F.W. Bergstrom, J. Am. Chem. Soc. 68, 1573

(1946)] (kp = 84°C/10 mm) (10% excess) in an equal amount of abs xylol. After 10 hours of boiling, cooling is carried out, and by adding 15 g of ammonium chloride, the excess of sodium amide is decomposed. The reaction solution is shaken out several times with a total of the same volume of water and evaporated in a vacuum at 70°. The residue is treated in the cold with three times the amount of petroleum ether (bp 40-60°), the petroleum ether is decanted from the unconsumed phenthiazine, and the solvent is driven off at normal pressure on a steam bath.

The remainder is distilled under high vacuum in a sausage flask, during which the fraction that passes over at a pressure of 0.05 mm Hg between 190 and 200° is collected. The analyte 10-[2'(N-methyl-piperidyl-2")-ethyl]-phenthiazine has a melting point of 95-97° and a boiling point of 194-196° at 0.05 mm Hg.

C20H24N2S calculated C = 74.03 H = 7.45 N == 8.63%

found 74.22 7.23 8.75%

To form the hydrochloride, it dissolves

free base in ten times the amount of abs alcohol and mixed with 25% alcoholic hydrochloric acid, until the solution reacts acidic

towards the Congo, after which the hydrochloride eventually separates out crystalline. The analyzed hydrochloride melts at 166—168°.

C..()H24N.,S . HC1 calculated C = 66.55 H = 7.14 N = 7.76%

found 66.41 6.95 7.94% 2) 3-chloro-10-[2'-(N-methyl-piperidyl-2")-ethyl]-phenthiazine.

232.5 g of 3-chloro-phenthiazine [P. Charpen-tier, P. Gailliot, R. Jacob, J. Gaudschon and P. Buisson, Cr: 235.60 (1952)] (m.p. 199— 201°) is dissolved in fourfold the amount of abs xylol and, with stirring, heated to boiling together with 46.8 g of sodium amide (20% excess) for 2 1/2 hours under reflux. Without interrupting the heating, a solution of 177.6 g of 2-(N-methyl-piperidyl-2')-1-chloro-ethane [T. R. Norton, R. A. Seibert, A. A. Benson, and F. W. Bergstrom, J. Am. Chem. Soc. 68 1573 (1946)]

(10 per cent excess) in an equal quantity of abs xylol dripped in during two hours. After stirring for 10 hours, cooling is carried out, and by adding 15 g of ammonium chloride,

the excess sodium amide cleaved. React. the ion solution is shaken several times with a total of an equal volume of water and evaporated in a vacuum at 70°. The residue is digested in the cold with three times the amount of petroleum ether (bp 40—60°), the petroleum ether is decanted from unused 3-chlorophenthiazine and the solvent driven off at normal pressure on a steam bath.

The remainder is distilled under high vacuum in a sausage flask, during which the fraction that passes over at a pressure of 0.05 mm Hg between 200 and 220° is collected. The analyte 3-chloro-10-[2'-(N-methyl-piperidyl-2")-ethyl]-phenthiazine has a boiling point of 206-211° C. at 0.05 mm Hg.

C2UH2BN2SC1 calculated C = 66.92 H = 6.46 percent.

found 66.97 6.45 per cent.

To form the hydrochloride, it becomes free

base dissolved in ten times the amount of abs alcohol and mixed with 25 per cent alcoholic hydrochloric acid, until the solution reacts acidic

towards the Congo, after which the hydrochloride eventually separates out crystalline. The analyzed hydrochloride melts at 213—215°.

C20H.,;,N2SC1. HC1 calculated C = 60.75 H = 6.12 N = 7.08 percent.

found 60.80 6.24 7.05 percent 3) 3-bromo-10-[2'-(N-methyl-pyridyl-2")-ethyl]-phenthiazine.

278.17 g of 3-bromo-phenthiazine (m.p. 199—

201 °C) is dissolved in the fourfold

amount of abs xylol and heated with stirring for 2½ hours under reflux together with 46.8 g of sodium amide (20 percent excess). Without interrupting the heating, a solution of 177.6 g of 2-(N-methyl-piperidyl-2')-1-chloro-ethane [T.R.Norton, R.

A. Seibert, A. A. Benson, and F. W. Bergstrøm, J. Am. Chem. Soc. 68 1573 1946)]

(10 percent excess) in the same amount of abs xylol dripped in during 2 hours. After 10 hours of boiling, cooling is carried out and by adding 15 g of ammonium chloride becomes

the excess sodium amide cleaved. Reac-

the ion solution is shaken out several times with a total of the same volume of water and evaporated in a vacuum at 70°. The residue is treated in the cold with three times the amount of petroleum ether (bp 40—60°), the petroleum ether decanted from unused 3-bromo-phenthiazine, and the solvent driven off at ordinary pressure on a steam bath.

The remainder is distilled under high vacuum in a sausage flask, during which the fraction that passes over at a pressure of 0.05 mm Hg between 210 and 230° is collected. The analyte 3-bromo-10-2'-(N-methyl-piperidyl-2")-ethyl-phenthiazine has a boiling point of 216-218° at 0.07 mm Hg.

<C>2()H23N2SBr calculated C = 59.55 H = 5.75 percent found 59.88 5.72 percent.

To form the hydrochloride dissolves

the free base in the tenfold amount of absolute alcohol and mixed with 25% alcoholic hydrochloric acid, until the solution reacts acidly

towards the Congo, after which the hydrochloride eventually separates out crystalline. The analyzing hydrochloride melts at 218-220° C.

C20H23N2SBr.. HC1 calculated C = 54.61 H = 5.50 percent.

found 54.96 5.60 percent 4) 1-chloro-10-[2'-(N-methyl-piperidyl-2")-ethyl]-phenthiazine.

232.5 g of 1-chloro-phenthiazine (P. Charpen-tier, P. Galliot, R. Jacob, Y. Gaudschon and P. Buisson C. r. 235, 60 (1952) (m.p. 116— 117°) is dissolved in 875 cm3 of abs xylol and, with stirring, heated to boiling for 2½ hours under reflux together with 46.8 g of sodium amide (20% excess). Without interrupting the heating, a solution of 177.6 g of 2-(N- methyl-piperidyl-2')-1-chloro-ethane (bp 84° at 10 mm Hg (10 per cent excess) in 175 cm' < abs xylol is added dropwise over the course of 2 hours. After stirring for 10 hours, cooling is carried out, and by adding 15 g of ammonium chloride, the excess of sodium amide is split. The reaction solution is shaken in vacuo at 70° bath temperature. The residue is stirred with about 2-2.5 l of petroleum ether to remove the 1-chloro-phenthiazine and filtered through a talc -

filter. The petroleum ether extract is evaporated under vacuum, and the residue distilled under high vacuum in a sausage flask, during which the fraction that passes over at a pressure of 0.05 mm Hg between 210 and 230° is collected.

The analyzed 1-chloro-10-[2'-(N-methyl-piperidyl-2")-ethyl]-phenthiazine has a boiling point of 227° at 0.07 mm Hg.

To form the hydrochloride, 188.5 g of the base is dissolved in 310 ems abs ethanol and mixed with 25% ethanolic hydrochloric acid until the solution reacts congo acid. After adding 600 ems of ether, the mixture is allowed to stand cold for 12 hours and then filtered off. The analyzed hydrochloride of 1-chloro-10-[2'-(N-methyl-piperidyl-2")-ethyl]-phenthiazine has a melting point of 195-197° and is identical to the substance obtained in Example 7 of the patent No. 89 921. 5) Di-chloro-10-[2'-(N-methyl-piperidyl-2")-ethyl]-phenthiazine.

A mixture of 16.0 g of di-(m-chloro-phenyl)-amine, prepared as indicated by L. A. Elson and C. S. Glbson, J. Chem, Soc. 1931, 301, and 4.35 g of sulfur and 0.2 g of iodine are heated for 40 min. in an oil bath at 260°. To the reaction mixture, 75 cm3 of chlorobenzene is added at once, the mixture is heated for 10 min. to boiling and filtered off while hot. The filtrate is allowed to stand at room temperature, during which substance A crystallizes out. Substance A, a dichlorophenthiazine is suctioned out, dried, sublimed in high vacuum at 0.05 mm Hg at 220° and recrystallized from 60 cm 3 of boiling benzol. Mp 258— 260° (Block) (small leaves).

8.35 g of this dichlorophenthiazine with m.p. 258-260° (Block) is dissolved in 40 ems abs xylol and heated to boiling for one hour with stirring and reflux cooling with 1.45 g of sodium amide (20 percent . profit). Without interrupting the heating, a solution of 5.55 g of 2-(N-methyl-

piperidyl-2')-1-chloroethane (10 per cent excess) in 6 cm3 of abs xylol was added dropwise over the course of one hour. After boiling for 15 hours, cooling is carried out, and by adding 0.5 g of ammonium chloride, the excess of sodium amide is decomposed. After adding 50 ems of benzol, the reaction solution is shaken out three times with water, each time with 30 ems. The xylene-benzene extract is evaporated in vacuum at 70° bath temperature, and the evaporation residue is stirred out with 75 cm3 of petroleum ether and finally filtered through a talc filter to remove unreacted dichlorophenthiazine. After evaporation of petroleum ether in a vacuum, the residue is distilled in high vacuum in a sausage flask, after which the fraction that passes over at 0.05 mm Hg at 225-235° is collected.

The analyte di-chloro-10-[2'-(N-methyl-piperidyl-2")-ethyl]-phenthiazine boils at 0.06 mm Hg at 232°.

C20H22N2SCI2 calculated C = 61.06 H=5.64 N = 7.12 percent.

(393.38) found 61.28 5.55 7.06 per cent.

To form the hydrochloride, 7.8 g of the base are dissolved in 150 ems of ether and mixed with ethereal hydrogen chloride to form Congo acid: reaction, after which the hydrochloride precipitates out. The hydrochloride is then dissolved in 35 cm3 abs ethanol, the solution mixed with 140 cm3 abs ether and left cold for 12 hours for crystallization. The analyzed hydrochloride of di-chloro-10-[2'-(N-methyl-piperidyl-2")-ethyl]-phenthiazine has a melting point of 202-204° after previous sintering. C-uH-Ni-SCli;. HC1 calculated C = 55.88 H = 5.39 N = 6.52% (429.84) found 55.81 5.34 6.32% 6) Di-chloro-10-|2'-(N-methyl -piperidyl-2")-ethyl]-phenthiazine.

You first proceed as indicated in

first paragraph of the previous example, then evaporates the chlorbesol mother liquor of the dichlorophenthiazine with m.p. 258-260°

(Block) in a vacuum at a bath temperature of 80—100° and distills the remainder in a sausage flask, during which the fraction that goes

above at a pressure of 0.06 mm Hg at 160— 210° is collected. The distillate, which contains the two isomers B and C, is dissolved in 12.5 ems of boiling benzol, and after the solution is filtered after standing at room temperature for two hours, it is mixed with 12.5 cm« of petroleum ether. After the solution has stood cold for 12 hours, substance B, also a dichlorophenthiazine, crystallizes out while the positional isomer C remains in solution.

The substance B is sucked out and recrystallized from benzene petroleum ether (1:1). This di-chloro-phenthiazine crystallizes in small needles with mp 142-144°.

5.0 g of dichlorophenthiazine with m.p. 142—

144° is dissolved in 25 om3 abs xylol and heated to boiling together with 0.88 g of sodium amide (20 per cent excess) in an oil-

bath temperature of 170 with stirring for one hour under reflux cooling. Without interrupting the heating, a solution of 3.6 g of 2-(N-methyl-piperidyl-2')-1-chloroethane (20% excess) in 5 ems abs xylol is added dropwise over the course of 1 hour. After 15 hours of heating, cooling is carried out, and by adding 0.5 g of ammonium chloride, the excess of sodium amide is decomposed. After adding 50 cm3 of benzol, the reaction solution is shaken out three times with water, each time with 40 cm3. The xyol-benzene extract is evaporated in vacuo at 70° bath temperature, and the evaporation residue is stirred at room temperature with 65 cm 3 of petroleum ether and filtered through a talc filter to remove unreacted di-chlorophenthiazine. After evaporation of the kerosene in a vacuum, the evaporation residue is distilled in a vacuum in a sausage flask, during which the fraction that passes at 0.08 mm Hg between 230 and 235° is captured.

The analyzed di-chloro-10-[2'-(N-methyl-piperidyl-2")-ethyl-phenthiazine has a boiling point of 232-233° at 0.08 mm Hg.

C20H22N2SCI2 calculated C = 61.06 H = 5.64 N = 7.12 percent.

(393.38) found 61.19 5.69 7.44 per cent.

To form the hydrochloride dissolves

4.89 g of the base in 100 cm/'> of abs ether and mixed with ethereal hydrogen chloride to a congo-acid reaction, after which the hydrochloride precipitates. The hydrochloride is dissolved in 52 cm3 of chloroform, mixed with 35 cm3 of benzol, added to 435 ems of ice-cold petroleum ether while shaking and

set aside cold for 2 hours. The hydrochloride is hygroscopic.

The analyzed hydrochloride of di-chloro-10-[2'-(N-methyl-piperldyl-2")-ethyl-phenthiazine has a melting point of 102—105° and contains y, moles of crystal water. C20H22N2SCI2'. HC1. y2 H2O (438 .85)

calculated C = 54.73 H = 5.52 N = 6.38 O = 1.82 Cl = 24.24 % found 54.71 5.57 6.00 1.85 24.01 %

7) Chloro-methoxy-10-|2'-(N-methyl-piperidyl-2")-ethyl]-phenthiazine. A mixture of 30.0 g of (m-chlorophenyl)-(m-methoxyphenyl)-amine (kp 142—143° at 0.02 mm Hg.), prepared by a corresponding modification of the method described by L. A. Elson and C. S. Gibson (J. Chem. Soc. 1931 301), 8.25 g of sulfur and 0.3 g . iodine is mixed in an oil bath at 170° in the course of 45 min. After brief cooling, 150 ems of chlorobenzene are added, the mixture is boiled for 5 min. and filtered while hot. After standing cold for 12 hours, a chlorine crystallizes methoxy-phenthiazine from file funnel, and after filtering off and drying at 0.08 mm Hg at 180° this is sublimed. Recrystallization from 25 cm3 of benzol gives the compound in flat prisms with m.p. 208 -210°.

11.0 chloro-methoxy-phenthiazine with m.p. 208-210° is dissolved in 55 cm3 of abs xylol and heated together with 1.95 g of sodium amide (20 per cent excess) at a bath temperature of 170° under stirring for one hour with reflux cooling. Without interrupting the heating, a solution of 8.1 g

2-(N-methyl-piperidyl-2')-1-chloroethane (20

percent excess) in 10 cm« of xylol dripped in during one hour. After 15 hours of heating, cooling is carried out, and by adding 0.5 g of ammonium chloride, the excess of sodium amide is decomposed. After adding 50 ems

benzol, the reaction solution is shaken out three times with water, each time with 20 cm» The xyol-benzene extract is evaporated in vacuo at 70° bath temperature, and the evaporation residue digested with 200

cm3 petroleum ether and filtered while hot through a talc filter to remove unreacted chloro-imethoxy-phenthiazln. After evaporation of the petroleum ether in vacuum, the evaporation residue is distilled under high vacuum in a sausage flask, during which the fraction that passes below 0.005 mm Hg between 220 and 230° is collected. The analyte chloro-methoxy-10-[2'-(N-methyl-piperidyl-2"-ethyl]-phenthiazine has bp 225° at 0.02 mm Hg).

C^H^NoSOCl calculated C = 64.84 H = 6.48 N = 7.20 0 = 4.11 percent.

(388.96) found 65.16 6.76 7.45 4.28 per cent.

To form the hydrochloride dissolves

10.07 g of the base in 250 cm3 of ether and mixed with 1 ethereal hydrogen chloride for a Congolese reaction, during which the hydrochloride precipitates. The hydrochloride is then dissolved in 30 ems chloroform, mixed with 75 ems benzol and, with shaking, held out for 750 cm' >

cold petroleum ether and set aside cold. The hydrochloride is hygroscopic.

The analyzed hydrochloride of chloro-methoxy-10-[2'-(N-methyl-piperidyl-2")-ethyl] phenthiazine has an indistinct melting point. The substance sinters from about 80° and foams at about 110°.

C21H25N2SOCl. HC1. y2 H2O (434.43)

calculated C = 58.06 H = 6.26 N = 6.45 O = 5.52 percent found 58.25 6.06 6.00 5.11 percent

8) 3-Chloro-10-[2'-(N-ethyl-pipe).

55.4 g of 3-chloro-phenthiazine (P. Charpen-tier, P. Galliot, R. Jacob, J. Gaudschon and P. Buisson C. r. 235, 60 (1952) (m.p. 199— 201° C), 14.2 g sodium hydroxide, fine

powdered, and 140 cm3 of xylol is heated to boiling with stirring for three hours with reflux cooling (with water separator). The oil bath temperature is 180° C.

Without interrupting the heating, one becomes

solution of 50.0 g of 2-(N-ethyl-piperidyl-2')-1-chloroethane (Beilstein, 4th edition 20, 105) (bp = 99-103° at 10 mm Hg) in 50

ems xyol dripped in over two and a half hours. After a further three hours of heating, cooling is carried out. After the addition of 100 ems xylol, the reaction solution

:ridyl-2")-ethyl-1']-phenthiazine.

The mixture was shaken out with water three times, each time with 250 cm3. The xylene solution is evaporated in vacuum at 70°. The residue is digested at room temperature with a total of 350 ems of petroleum ether (bp 40-60°) and filtered through a talc filter. Some 3-chloro-phenthiazine remains. After evaporation of the petroleum ether solution, the residue is distilled under high vacuum. After separation of a run to 200° at 0.02 mm Hg, the main fraction distills between 205 and 225° at 0.02 mm Hg.

The analyte 3-chloro-10-[2'-(N-ethyl-piperidyl-2")-ethyl-1']-phenthiazine has bp 218° at 0.015 mm Hg.

C21H2KN2SC1 calculated C == 67.62 H = 6.76 N = 7.51 Cl = 9.51 percent.

(372.96) found 67.60 6.63 7.39 9.53 per cent.

To form the hydrochloride dissolves

660 g of the free base in 400 ems abs ethanol and mix with so much 25% ethanolic hydrogen chloride that the solution reacts

res congo acid, after which the hydrochloride eventually separates out crystalline. The analyzed hydrochloride melts at 215— 217°.

C2tH25N2SCl. HC1 calculated C = 61.60 H = 6.40 N = 6.84 Cl = 17.32 percent.

(409.42) found 61.48 6.42 Cl =6.98 N= 17.14 % 9) 3-bromo-10-[2'-(N-ethyl-piperidyl-2")-ethyl-1 ']-phenthiazine.

55.0 g 3-bromo-phenthiazine (m.p. 199—

201°), 11.9 g of finely powdered sodium hydroxide and 140 ems of xylol are heated with stirring for three hours with reflux (with water separator) to boiling. The oil bath temperature is 180°.

Without interrupting the heating becomes one

solution of 417 g of 2-(N-ethyl-piperidyl-2')-1-chloro-ethane (Beilstein 4. oppi., 20, 105)

(bp 99—103° at 10 mm Hg) in 40 ems xylol dropped in during three hours. After a further three hours of heating, cooling is carried out. After the addition of 100 cm" of xylol, the reaction solution is shaken out three times with water each time with

250 ems. The xylene solution is evaporated in vacuum at 70°. The residue is digested at room temperature with 300 ems petroleum ether (40-60°) and filtered through a talc filter to separate out any undissolved 3-bromo-phenthiazine. After evaporation of the clear petroleum ether solution, the residue is distilled under high vacuum. After separating a run up to 218° at 0.015 mm Hg, the main fraction distills between 218 and 230° at 0.015 mm Hg.

The analyte 3-bromo-10-[2'-(N-ethyl-piperidyl-2")-ethyl-1']-phenthiazine has bp 222° at 0.015 mm Hg.

C.MH95N2SBr calculated C = 60.42 H = 6.04 N= 6.71 percent.

(417.42) found C= 60.57 H = 5.99 N = 6.71 percent.

To form the hydrochloride, dissolve 40

g of the free base 240 cm3 abs ethanol and mix with so much 25% ethanolic hydrogen chloride that the solution reacts

Congo acid, after which the hydrochloride eventually separates out crystalline. The analyzed hydrochloride melts at 222— 224°.

C2, H25N.,SBr . HC1 calculated C = 55;57 H = 5.77 N = 6.17 S = 7.06 percent.

(453.89) found 55.68 5.53 6.34 7.07 % 10) 3-chloro-10-[2'-(piperidyl-2")-ethyl-1']-phenthiazine.

80.0 g 3-chloro-phenthiazine (m.p. 199—

201°), 14.7 g of finely powdered sodium amide and 450 cm 3 of xylol are heated together with stirring for two hours at an oil bath temperature of 180° to boiling with reflux cooling.

Without interrupting the heating, one becomes

solution of 60.6 g of 2-(piperidyl-2')-1-chloroethane (Beilstein 4. oppi., 20, 105) (bp 84° at 12 mm Hg) in 60 cm" of xylol into two hours. After a further two hours of heating, cooling is carried out, and after the addition of 10 g of ammonium chloride, in order to decompose the excess of sodium amide, a further 100 cm" of xylol is added. The reaction solution is shaken out with water three times each time with 500 cm 3 . The xylene solution is evaporated in vacuo at

70°, the residue digested at room temperature with 500 cm3 of petroleum ether (40-60°) and filtered through a talc filter. Some 3-chloro-phenthiazine remains. After evaporation

ing of the petroleum ether solution, the remainder is distilled in high vacuum. The main fraction, which distills between 220 and 240° at 0.01 mm Hg is collected.

18.0 g of the collected main fraction is dissolved in 210 µl of petroleum ether (40-60°) and introduced into a column of 600 g of aluminum oxide (Merck). The chromatogram is developed, each time being eluted fifteen times in succession with 1.5 l of benzol. Fractions 2-9 are combined and, after evaporation of the benzene, converted to the corresponding hydrochloride.

7.8 g of oily, pale yellow base which has been purified in the aluminum column is dissolved in a warm state in 25 cm3 abs ethanol mixed with 25 percent ethanolic hydrogen chloride until congo acid reaction and left in the cold. The hydrochloride eventually crystallizes out. The analyte hydrochloride of 3-chloro-10-f2'-(piperidyl-2")-ethyl-1']-phenthiazine melts at 190-192°.

CI(1H21N2CIS . HC1 calculated C = 59.84 H = 5.81 N = 7.34 Cl = 18.60 per cent.

(381.34) found 59.50 5.87 N=7.68 Cl = 18.28% 11) 3-bromo-10-r2'-(piperidyl-2")-ethyl-1']-phenthiazine.

70.0 g 3-bromo-phenthiazine (m.p. 199—

201°), 10.8 g finely powdered sodium amide

and 450 cm3 of xylol are heated together while stirring to boiling under reflux

run cooling at a bath temperature of 180°.

Without interrupting the heating becomes one

resolution of. 44.5 and 2-(piperidyl-2')-1-chloroethane (Beilstein 4. oppi., 20, 105) (bp. 84° at 12 mm Hg) in 45 ems xylol added dropwise over the course of two hours . After a further two hours of heating, cooling is carried out, and after the addition of 10 g of ammonium chloride, in order to decompose excess sodium amide, a further 100 cm" of xylol is added. The reaction solution is shaken out three times with water, each time with 250 ems. The xylolop solution is evaporated in vacuo at 70°, and the residue is digested in a warm state with 400 cm 3 of petroleum ether (40-60°) and filtered through a talc filter. Some 3-bromo-phenthiazine remains. When approx. half of the petroleum ether has evaporated, it is decanted from a small, oily layer and then completely evaporated. The remainder is distilled in high vacuum. The main faction,

which distils between 210 and 240° at 0.i mm Hg. is intercepted.

5.1 g of the collected main fraction is dissolved in 90 cm 3 of petroleum ether (40-60 g) and chromatographed on 180 g of aluminum oxide (Merck). The chromatogram is developed, each time being eluted twice with 600 ems benzol. Fractions 2-9 are combined, and after evaporation of the benzol, the base is converted into the corresponding chloral hydrate.

3.0 g of the pale yellow, oily base that has been purified on aluminum oxide is dissolved hot in 12 cm3 of alcohol and carefully mixed with 25% alcoholic hydrochloric acid

Until congo acid reaction and set aside cold.

The hydrochloride eventually crystallizes out. The analyte hydrochloride of 3-bromo-10-[2'-(piperidyl-2")-ethyl-1']-phenthiazine melts at 206-208°.

C,(,H.MN9SBr .HC1 calculated C = 53.59 H = 5.21 N = 6.58

S = 7.53%

(425.83) found 53.73 5.28 N=6.39

S = 7.60% 12) 3-chloro-10-[2'-(N-n-propyl-piperidyl-2")-ethyl-1']-phenthiazine.

36.0 g 3-chloro-phenthiazine (loc.cit.), 9.25 g

finely powdered sodium hydroxide and 95 ems xylol are heated to boiling with reflux (with water separator) while stirring for three hours. The oil bath temperature is 180°.

Without interrupting the heating becomes one

solution of 35.0 g of 2-(N-n-propyl-piperidyl-2')-1-chloroethane (bp 106-113° at 11 mm Hg) which is prepared in a similar manner as indicated by Beilstein, 4. oppi. , 20, 105 for the corresponding N-ethyl derivative in 35 ems xylol dropped in during two and a half hours. After a further two hours of heating, cooling is carried out. After adding 100 cm 3 of xylol, the reaction solution is shaken out three times with water, each time with 100 cm 3 . The xylene solution is evaporated in a vacuum at 70°. The residue is digested at 40° with a total of 300 ems petroleum ether (40-60°), and filtered

through a talc filter. Some 3-chloro-phenthiazine remains. After evaporation of the petroleum ether solution, the residue is distilled under high vacuum. After separation of a process up to 210° at 0.01 mm Hg, the main fraction is distilled between 210 and 225° at 0.01 mm Hg.

38.0 g of the main fraction is dissolved in 280 ems of petroleum ether (40-60°) and chromatographed on 1.2 kg of aluminum oxide (Merck). The chromatogram is developed, each time being eluted four times with 4 liters of petroleum ether-benzene (9:1).

Fractions 1-3 are combined and, after evaporation of the solvent, the base is distilled once again in high vacuum.

The analyte 3-chloro-10-[2'-(N-n-propyl-piperidyl-2")-ethyl-1']-phenthiazine has a boiling point of 220° at 0.01 mm Hg.

C22H27N2SC1 calculated C = 68.28 H = 7.03 N = 7.24%

(386.99) found 68.47 6.97 7.17%

To form the tartrate, dissolve 8.6 g of

the pure base in 75 cm3 of vinegar. The filtered solution is poured into an ice-cold, filtered solution of 3.33 g of tartaric acid in 500

ems vinegar, during which the tartrate is precipitated. The analyzed tartrate contains 1 mol of crystal water and has a decomposition temperature of 95° (foam). Sinters from 65°.

C22H27N2SC1..C4He06 . H20 (555.09)

Calculated C = 56.25 H = 6.36 N = 5.05 0 = 20.18% found 56.05 6.38 4.61 20.03% 13) 3-chior-10-[2'- (N -iso-propyl-piperidyl-2")-ethyl-1']-phenthiazine.

27.8 g 3-chloro-phenthiazine (loc.cit.), 7, 13

g of finely powdered sodium hydroxide and 70 cm3 of xylol are heated to boiling for three hours with reflux (with water separator) while stirring. The oil bath temperature is 180°.

Without interrupting the heating becomes one

solution of 27 g of 2-(N-iso-propyl-piperidyl-2')-1-chloroethane (bp 89-96° at 11 mm Hg), which is prepared in a similar manner as described by Beilstein, 4 oppi., 20, 105 for the corresponding N-ethyl derivative, in 30 cm3 of xylol dropped in during two and a half hours. After a further two hours of heating, the reaction solution is cooled and shaken out three times with water, each time with 75 ems. The xylene solution is evaporated in vacuum at 70°. The rest is digested at room temperature with a total of 250 ems petroleum ether (40-60°) and

filtered through a talcum filter. Some 3-chloro-phenthiazine remains. After in-

evaporation of the petroleum ether solution, the residue is distilled in high vacuum. After separation of a course up to 210° at 0.01 mm Hg. distills the main fraction between 210 and 222° at 0.01 mm Hg.

3.0 g of the main fraction is dissolved in 15 cm3 of petroleum ether (40-60°) and chromatographed on 90 g of aluminum oxide. The chromatogram is developed, as each time

be eluted three times with 300 cm» of petroleum ether. Fractions 1-3 are combined, and after evaporation of the solvent, the base is converted into the tartrate.

To form the tartrate, 1.73 g of the pure base is dissolved in 15 cm3 of acetic acid. The filtered solution is poured into an ice-cold, filtered solution of 0.67 g tartaric acid in 100 ems vinegar, during which the tartrate precipitates. The analyzed bartrate contains iy2 mol of crystal water and has a splitting point of 100° (foam). Sinters from 70°.

C22<H>27N2SC1. C4H(iO(i . iy2H20 (564.10)

calculated C = 55.35 H = 6.43 N = 4.97 0 = 21.27% found 55.36 6.04 4.67 21.33% 14) 3-chloro-10-[2'-(N-n -butyl-piperidyl-2")-ethyl-1']-phenthiazine.

26.7 g 3-chloro-phenthiazine (loc.cit.), 6.86 g

finely powdered sodium hydroxide and 65 cm3 of xylol are heated to boiling with reflux (with water separator) while stirring. The oil bath temperature is 180°.

Without interrupting the heating, a solution of 27.9 g of 2-(N-n-butyl-piperidyl-2')-1-chloro'-ethane (bp 62-68° at 0.5 mm Hg) which has been prepared in a similar manner as described by Beilstein, 4th oppi., 20, 105 for the corresponding N-ethyl derivative, in 30 cm3 of xylol dripped in during two and a half hours. After a further two hours, cooling is carried out. After the addition of 100 ems xylol, the reaction solution is shaken out with water three times each time with 100 ems. The xylene solution is now extracted with a total of 300 cm3 of 1.5 N acetic acid. The acetic acid extract is made phenolphthaleinalkaline with 100 ems of sodium hydroxide solution, and the separated base is extracted with a total of 250 cm3 of ether. The ether extract is dried over sodium sulphate, filtered and evaporated. The remainder is distilled in high vacuum. First, a stream is separated up to bp 215° at 0.01 mm Hg, and the main fraction, which distills between 215 and 235° at 0.01 mm Hg, is collected.

8.43 g of the main fraction is dissolved in 40 cm 3 of petroleum ether (40-60°) and chromatographed on 300 g of aluminum oxide (Merck). The chromatogram is developed, each time being eluted four times with 1.0 petroleum ether. Fractions 1-4 are combined, and after evaporation of the solvent, the base is distilled once more under high vacuum. The analyte 3-chloro-10-[2'-(N-n-butyl-piperidyl-2")-ethyl-1']-phenthiazine has a boiling point of 225° at 0.01 mm Hg.

C23H2(,N2SC1 calculated C = 68.88 H = 7.29 N = 6.99 Cl = 8.84 %

(401.01) found 68.72 7.35 6.67 8.43%

To form the tartrate, 6.8 g of the pure base is dissolved in 50 ems of acetic acid.

This filtered solution is kept cold, |

filtered solution of 2.54 g of tartaric acid in 380

cm3 of vinegar, during which the tartrate is precipitated.

The analyzed tartrate contains 2 mol of crystal water and has a cleavage point of 85° (foam). Sinters from 60°. C23H2gN2SCl. C4H606. 2H2O (587.13) calculated N = 4.77 O = 21.80% found 4.89 21.97%

characterized in that a phenthiazine derivative of the general formula II, where R1, R2, R3 and R4 have the same meaning as above

is condensed with a 2-(piperidyl-2')-1-haloethane with the general form

Claims (1)

Process for the preparation of multiply substituted phenthiazine derivatives of the general formula I. mel III, where RF, has the same meaning as above