DE1134078B - Process for the preparation of optically active phenthiazine derivatives substituted in the 3-position by sulfur-containing groups - Google Patents

Description

The invention relates to a process for the preparation of optically active phenthiazine derivatives of the general formula

Method of manufacture

of optically active, in 3-position

substituted by sulfur-containing groups

Phenthiazine derivatives

in which R _{1 represents} a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, an aryl or aralkyl group and R _{2 represents} a hydrogen atom or an alkyl group having 1 to 4 carbon atoms. The optical activity of the above compounds is based on the asymmetric carbon atom of the piperidine ring, labeled +.

The optically active basic compounds of the above formula I are prepared according to the invention, either by treating the racemic base mixture with an optically active acid in the mixture of diastereomeric salts is converted, from which the uniform ones by fractional crystallization Wins components and sets the optically active bases in freedom from the salts, or by one Phenthiazine derivative of the general formula

Applicant:
ίο Sandoz AG, Basel (Switzerland)

Representative: Dr. W. Schalk, Dipl.-Ing. P. Wirth,

Dipl.-Ing. G. E. M. Dannenberg

and Dr. V. Schmied-Kowarzik, patent attorneys,

Frankfurt / M., Große Eschenheimer Str. 39

Claimed priority:
Switzerland of July 31, 1957 (No. 49 028),
ao December 6, 1957 (No. 53 450) and May 9, 1958 (No. 59 343)

Dr. Jany Renz, Dr. Jean-Pierre Bourquin, Basel,

Dr. Guido Gamboni, Binningen,
and Gustav Schwarb, Basel (Switzerland),

have been named as inventors

SR ₁

wherein R _{1 has the} above meaning with an optically active piperidine derivative of the general formula

Hal-CH ₂ -CH ₂ -CH

III

where R _{2 has the} above meaning and Hal stands for a chlorine, bromine or iodine atom, condenses.

The patent application relates to the preparation of racemic phenthiazine derivatives of the formula I S 52942 IVd / 12p (German Auslegeschrift 1 128 856). It was found that one of the optical antipodes of phenthiazine derivatives of the general formula I can be obtained by a Phenthiazine derivative of the formula II with an optically active halogen-containing piperidine derivative of the formula III implemented by processes known per se or by one according to patent application S 52942 IVd / 12p (German Auslegeschrift 1 128 856) prepared racemic phenthiazine derivative of the formula I via the Salt with an optically active carboxylic acid splits into the optical antipodes.

The separation of the phenthiazine derivatives of the formula I in their optical antipodes has to be one therapeutically usable separation of the pharmacological properties. Both stereoisomers have the pharmacodynamic ones generally known for this group of basic phenthiazine derivatives Properties: Among other things, they develop pronounced spasmolytic, histaminolytic,

209 628/265

sympatholytic and adrenolytic effects as well as a pronounced sedative or calming effect. But the clockwise one stands out Isomers compared to the levorotatory and the racemate have a stronger mode of action, and especially with regard to the adrenaline inhibition and the narcosis-potentiating effect, where the activity is five to six times or one and a half to two times stronger in the clockwise than in the counterclockwise antipode. Unexpectedly, however, it has shown that the left-handed connections with regard to certain pharmacological properties act more specifically than the dextrorotatory compounds and that accordingly Certain indications respond better to treatment with the levorotatory derivatives.

The following comparative experiments show that, for example, (-) - 3-methylmercapto-10- {2HN-methylpiperidyl- (2'0] -ethyl- (1 ')} - phenthiazine (I) and the (+) - 3-methylmercapto-10- {2 '- [> T-methylpiperidyl- (2 ")] - ethyl- (1')} - phenthiazine (II) that known from the German Auslegeschrift 1 008 737 and produced by the same process 3 - chlorine -10 - {2 '- [N - methylpiperidyl - (2 ")] ethyl- (1')} - phenthiazine (III) are superior in terms of adrenolytic effect.

method
Adrenolytic effect

The inhibitory effect of the compounds on that induced by adrenaline was examined Contraction of the isolated seminal vesicle of the guinea pig. The effect was numerical Related to the action of dihydroergotamine (DHE), a compound whose strong adrenaline inhibition is known. This was chosen as a unit. (Literature on DHE and the method used: Rothlin et al., Helvetica Physiologica Acta, Vol. 3 [1945], p. C 43.)

The results are summarized in the following table:

45

substance R. Adrenolytic effect
DHE = I. I! Optical J
II j antipodes \
III S - CH ₃
S-CH ₃
Cl 1.4
6.3
0.48

55

60

From these data, it can be seen that the two optically active methyl mercapto compounds No. I and II have a significantly stronger adrenolytic effect than the racemic 3-chlorophenthiazine derivative No. III. Substance I is about three times and substance II even thirteen times more adrenolytic effective as substance III.

The method is carried out, for example, in such a way that a in the 3-position is replaced by a sulfur-containing Group substituted phenthiazine derivative of the general formula II in a suitable organic Solvents, e.g. B-. Benzene, toluene, xylene, dichlorobenzene or nitrobenzene, dissolved and in the presence an alkaline condensing agent, e.g. B. Sodium or potassium hydroxide, sodium amide, sodium metal, Lithium hydride, sodium tert-butoxide, d. H. Alkali metals or compounds thereof, such as Hydroxides, amides, hydrides or alkanolates, with an optically active piperidine derivative of the general Formula III is implemented at room temperature or at elevated temperature.

The reaction can also be carried out without a solvent by melting the reactants together are, although with a reduction in the yield, also due to the presence of a condensing agent can be dispensed with.

After the reaction has ended, the reaction mixture is extracted by shaking with water, and so is the solvent evaporated under reduced pressure; however, the new substances can also be extracted from the reaction mixture extracted by dilute mineral or organic acids and extracted from the aqueous Phase can be eliminated by adding alkalis or ammonia. The optically active bases are taken up in benzene or another water-immiscible solvent and then freed from the solvent again by evaporation. The optically active bases can by Purified distillation in a high vacuum and converted into a suitable salt with organic or inorganic Acids are transferred.

The piperidine halide required for the production of optically active phenthiazine derivatives of the general Formula III can e.g. B. can be obtained as follows:

The salt of the corresponding piperidine alcohol is prepared with a suitable optically active acid and separates the two antipodes by fractional crystallization. By hydrolysis of the crystallization products the optically active carbinol bases are obtained with a suitable halogenating agent converted into the corresponding optically active piperidine halides of the general formula III can be.

The method can also be carried out in such a way that one according to the patent application S 52942 IVd / 12p (German Auslegeschrift 1 128 856) produced racemic 3-mercaptophenthiazine derivative of the general formula I in a suitable organic solvent, e.g. B. acetone, dissolves and with a corresponding solution of a suitable optical active organic acid such as di-p-toluyl-D-tartaric acid or di-benzoyl-D-tartaric acid, added and allowed to crystallize.

The salt formation can also take place by adding equimolar amounts of the racemate and the optical active acid can be dissolved directly in a suitable solvent by heating.

If acetone is used as the solvent, the levorotatory salt crystallizes after a short time the right-handed phenthiazine base. This optically active salt is sucked off and mixed with fresh Solvent boiled a few more times.

The levorotatory antipode found in the mother liquor can be crystallized by the Purify corresponding di-p-toluyl-L-tartrates.

The two optically active 3-mercaptophenthiazine derivatives are obtained by cleaving the optically active crystalline salts of formula I.

The optically active basic compounds prepared by the present process are at Room temperature oily or crystalline and form solid, stable salts with acids. You should be in the Therapy can be used.

The substitution sites in the phenothiazine structure are numbered according to Beilstein, 4th edition, vol. 27, p. 63:

The following examples are intended to explain the process according to the invention. The melting and boiling points are uncorrected.

example 1

(-> 3-Methylmercapto-10- {2 '- [N-methylpiperidyl- (2 ")] - ethyl- ( 1 ')} - phenthiazine

a) Di- (p-toluyl) -D-tartrate des (-) - 2- [N-methyl-

piperidyl- (2)] -ethane- (1) -ol

685 g of di (p-toluyl-D-tartaric acid by the decomposition point of 171. to 173 ⁰ C, [oc] l ° = -140 ° (c = 1% in ethanol) (Helvetica Chimica Acta, Vol. 26 [1943] , P. 922), dissolved in 2500 ecm of absolute ethanol, are added to 244 g of 2- [N-methylpiperidyl- (2 ')] -ethane- (1) -ol, dissolved in 500 ecm of absolute ethanol, crystallized after a few minutes After this has been recrystallized nine times from six to nine times the amount of 95% ethanol, the pure di- (p-toluyl) -D-tartrate des (-) - 2- [N-methylpiperidyl- (2 ')] - Ethane- (l) -ols with a constant melting point of 185 to 187 ° C, [«] *> = -113 ° (c = 1% in glacial acetic acid).

b) (-) - 2- [N-methylpiperidyl- (2 ')] -ethane- (1) -ol

166 g of di- (p-toluyl) -D-tartrate des (-) - 2- [N-methylpiperidyl- (2 ')] -ethane- (l) -ol are dissolved in 830 ecm of water and added in portions with good cooling 498 ecm of 30% sodium hydroxide solution were added. Then 206 g of solid potassium hydroxide are added with cooling; while the internal temperature must not exceed 2O ⁰ C. The mixture is extracted twice with 300 ecm each and once with 100 ecm chloroform.

The combined chloroform extracts are dried with 50 g of potash. After evaporation of the chloroform in vacuo at 40 ⁰ C obtained by the distillation of pure (-) - 2- [N-methylpiperidyl (2 ')] - ethane (l) -ol, bp _u = 105 to 107 ° C. , [a] f = -67.2 ° (undiluted).

c) (-) - 2- [N-methylpiperidyl- (2 ')] - 1-chloroethane
34.9 g of (-) - 2- [N-methylpiperidyl- (2 ')] -ethane- (1) -ol

are dissolved in 50 ecm chloroform in a sulphonation flask. At a maximum ^{internal temperature of 10 °} C., a rapid stream of hydrochloric acid gas is passed in with cooling until it is saturated. 58 g of thionyl chloride are then added dropwise at 10 ^{° C. over the course of 15 minutes.} The mixture is refluxed for 2 hours and then evaporated to dryness. The residue is dissolved at 0 ⁰ C in 65 cc of water and then 65 cc of 30% sodium hydroxide added. The oily layer that separates is shaken out three times with 300 ecm of chloroform each time and dried over 50 g of potash. After the chloroform has been evaporated off in vacuo at 40 ^° C., pure (-) - 2- [N-methylpiperidyl- (2 ')] -1-chloroethane of KP. _u = 80 to 83 ° C, [x] f = -70.5 ° (undiluted), ίο The hydrochloride of (· -) - 2- [N-methylpiperidyl- (2 ')] - l-chloroethane melts after three recrystallization Acetone constant at 160 to 161 ° C, [«] *> = -44.1 ° (c = 1% in water).

d) (-) - 3-Methylmercapto-10- {2 '- [N-methylpiperidyl- (2 ")] - ethyl- ( 1 ')} - phenthiazine

30.5 g of 3-Methylmercaptophenthiazin mp = 138 to 140 ° C, 5.8 g of finely powdered sodium amide and 170 cc of anhydrous xylene is heated under stirring for 3 hours at reflux at a bath temperature of 18O ⁰ C to boiling. Without interrupting the heating, is allowed within 1V ₂ hours, a solution of 20 g of the levorotatory 2 - [N - methylpiperidyl - (2 ')] - 1 - chloräthans, [ «] !?

= -70.5 °, add dropwise in 20 ecm of anhydrous xylene. After heating for a further 3 hours, the reaction mixture is cooled and 130 ecm of anhydrous xylene is added. Now you shake out first twice with 150 ecm of water and then once with 305 ecm of 15% tartaric acid solution. The tartaric acid solution is extracted twice with 100 ecm of benzene each time. The aqueous solution is prepared with 120 cc of 30 ° / ₀ sodium hydroxide solution alkaline ago (phenolphthalein). The precipitated oily levorotatory base is shaken out once with 200 ecm and twice with 100 ecm of benzene each time and the benzene solution is washed out twice with 100 ecm of water each time. After drying over a little potash and distilling off the benzene, the left-turning crude base remains. After separating a first running from Kp. _OjO1 to 215 ⁰ C., the levorotatory base, bp-O obtained in the distillation ₁ Oi = 215-217 ⁰ C.

For cleaning purposes, this antipode, which rotates to the left, is dissolved in 110 ecm of isopropanol and allowed to ^{crystallize at 0} ° C. while stirring. It is washed on the suction filter with 30 ecm of ice-cold isopropanol.

After two recrystallizations from three times the amount of isopropanol, the analytically pure (-) - 3-methylmercapto-10- {2 '- [N-methylpiperidyl- (2 ")] - ethyl- (1')} - phenthiazine with the constant F is obtained . = 60 to 62 ⁰ C, [α]! ⁰ = -20.6 ° (c = 1% in ethanol).

Example 2

(+) - 3-Methylmercapto-10- {2 '- [N-methylpiperidyl- (2 ")] - ethyl- (1')} - phenthiazine

a) Di- (p-toluyl) -L-tartrate of (+) - 2- [N-methylpiperidyl- (2 ')] -ethane- (l) -ol

From the concentrated mother liquor residues (845 g) of the recrystallization described in Example 1 under a) to separate the left-turning antipode, 30% strength is added by hydrolysis at 0 ° C. with 2540 ecm Sodium hydroxide solution is an antipode mixture of 2- [N-methylpiperidyl- (2 ')] -ethane- (l) -ol with the rotation value [ä] d ° = + 42.9 ° obtained.

185 g of this antipode mixture, dissolved in 400 ecm of absolute ethanol, are added to 500 g of di- (p-toluyl) -

L-tartaric acid from the decomposition point 171 to 173 ⁰ C, and extracted twice with 100 ecm of benzene each time and [λ] !? = + 140 ° (c = l% i ⁿ ethanol) dissolved in 2500 cc of the benzene solution twice with 100 cc water ausÄthanol. A short time afterwards, the crude washed crystallized. After drying, salt out a little potash. After six times crystallization from and distilling off the benzene, the right nine times the amount of 95% ethanol remains, the 5 rotating crude base is obtained. After separating off a pure di- (p-toluyl) -L-tartrate of the (+) - 2- [N-methyl forerunner from bp _M1 to 214 ° C, the piperidyl- (2 ')] - ethane- (l) -ols of constant F. = distillation the clockwise rotating base of boiling point ₀₁ = 185 to 187 ° C, [«]? = + 113 ° (c = 1% in glacial acetic acid). 214 to 217 ⁰ C.

i. \ / - ^ ι πα Α * λ ι · -α ι «-Μ» * i. n \ ι ^For cleaning you loosen this clockwise

b) (+) - 2- [N-methylpiperidyl- (2)] -ethane- (l) -ol _{lo antipodes} J _{nm ccm} isopropanol and leaves at ⁰ ° C

262 g of di- (p-toluyl) -L-tartrate des (+) - 2- [N-methyl- crystallize with stirring. One washes on the piperidyl- (2 ')] -ethane- (l) -ols are in 1310 ecm water suction filter with 30 ecm ice-cold isopropanol after, after two recrystallization from the three-787 ecm 30% sodium hydroxide solution added. Subsequently, times the amount of isopropanol is obtained 326 g of solid potassium hydroxide 15 of pure (+) - 3 - methyl mercapto -10 - {2 '- [N - methyl added; while the internal temperature 20 ° C must not piperidyl (2 ")] - ethyl (Γ)} - phenthiazine with the exceed. The mixture is extracted twice with a constant temperature of 60 to 62 ° C, [«] ?? = + 20.5 ° (c - 400 ecm each and once with 200 ecm chloroform. The 1% in ethanol).

combined chloroform extracts are dried with the corresponding racemate of 3-methylmercapto-

50 g potash. After evaporation of the chloro- 20 10- {2 '- [N-methylpiperidyl- (2 ")] - ethyl- (1')} - phenform in vacuo at 40 ° C., distillethiazine is obtained according to patent application S 52942 IVb / 12p tion of pure (+) - 2- (N-methylpiperidyl- (2 ')] -ethane- (l) -ol (German Auslegeschrift 1 128 856) shows the m.p. = from bp _u = 105 to 107 ° C , [<x] i ° = + 66.7 ° (un- 72 ° C (± 2 °). thinned). Example 3

c) (+) - 2- [N-methylpiperidyl- (2 ')] - 1-chloroethane ²⁵ ₍ _). 3. Ethyl mercapto - 10 - {2 '- [N - methylpiper-

59.5 g of (+) - 2- [N-methylpiperidyl- (2 ')] -ethane- (1) -olidyl- (2 ")] -ethyl- (1')} -phenthiazine

are dissolved in 90 ecm chloroform in a sulphonation flask. 45.4 g of 3-ethyl mercaptophenothiazine (F. = 95 to

At an internal temperature of at most 10 ° C, 8.2 g of finely powdered sodium amide are passed in under 97 ° C), and a rapid stream of hydrochloric acid gas is passed in for cooling until 30,260 ecm of anhydrous xylene are saturated with stirring. 99 g of thionyl chloride are then added dropwise over the course of 3 hours under reflux in a bath of 15 minutes at 10 ° C. temperature of 18O ⁰ C heated to boiling. Without interrupting the boiling, the mixture is boiled for 2 hours with heating, allowed to reflux and then evaporated to dryness. The I ¹ Za hours a solution of 28.3 g of 2- [N-methyl-residue is dissolved at ⁰ C in 110 cc water and 35 piperidyl (2 ')] - l-chloroethane ([ «] = !? -70.5 °, then add 110 cc of 30% sodium hydroxide solution. The oily layer, which has been prepared in accordance with Example 1) in 28 cc of anhydrous and separates off, is shaken and tri-xylene is added dropwise. After a further 3 hours of heating with 500 ecm of chloroform each time and drying over, the reaction mixture is cooled and 210 ecm of 50 g of potash are added. After the anhydrous xylene has evaporated. Now you first shake forms in a vacuum at 40 ° C is obtained by distillation 40 twice with 250 ecm of water and then once with ion pure (H -) - 2- [N-methylpiperidyl- (2 ')] - l-chloro 450 cc of aqueous 15% strength ^e of r tartaric acid solution. Ethane with a b.p. _u = 80 to 83 ° C, [«] ?? = + 69.9 ° (un- The tartaric acid solution is diluted twice with 130 ecm). Benzene shaken out. The aqueous solution makes

The hydrochloric of (+) - 2- [N-methylpiperidylman with 200 ecm aqueous 30% sodium hydroxide solution (2 ')] -1-chloroethane melts alkaline (phenolphthalein) after being converted three times. The precipitated oily crystallize from acetone constantly at 160 to 161 ⁰ C, base is extracted once with 250 ecm and twice with [(x] ² g = + 43.7 ° (c = 1% in water). 120 ecm benzene and the Benzene solution

,,,. ,,,. ,,, * m ro / TXT ..Ui- · Washed out twice with 120 ecm of water. To

d) (+) - 3-Methylrne _r capto-10- {2 - [N-methylprperi- _{dem drying over a little potash} and distilling off

dyl- (2)] - ethyl- (l)} - _{50 °} phenthiazm _{Benzok remains the crude base Zurüclc Man erha} j _t

33.5 g of 3-methylmercaptophenthiazine from F. = in the distillation the base of bp. _OjO1 - 240 bis

138 to 140 ° C, 6.4 g of finely powdered sodium amide 243 ° C.

and 170 ecm of anhydrous xylene are added with stirring. For cleaning, the base is dissolved in 165 ecm

for 3 hours under reflux with a bath petroleum ether and allowed to crystallize at 20 ° C with stirring

heated to boiling temperature of 180 ° C. Without that. After cooling to O ⁰ C is filtered and the

To interrupt heating, one can wash within the filter residue with 40 ecm petroleum ether.

IV2 hours a solution of 22 g of the dextrorotatory After recrystallizing twice from the three

- [N - methylpiperidyl - (2 ')] -1 - chloroethane, [cc \ ² g = times the amount of petroleum ether to obtain the analytical

+ 69.9 °, add dropwise in 25 ecm anhydrous xylene. pure (-) - 3 - ethyl mercapto - 10 - {2 '- [N - methyl-

After a further 3 hours of heating, the reaction is 60 piperidyl- (2 ")] - ethyl- (1 ')} - phenthiazine with the con-

mixture cooled and fixed with 130 ecm anhydrous xylene F. = 56 to 58 ° C, [oc] ² _D ° = -17.1 ° (c = 1%

offset. Now you shake first twice with each in ethanol). 150 cc of water and then once with 335 cc of 15 ° _o sodium example 4 /

Tartaric acid solution. The tartaric acid solution is. "..,,,". ",",,,.

shaken twice with 100 ecm benzene. The 6 ₅ (+) ^"3" ^ fc ^ Pf Γ / ° "^ ■ - P * - methylpiperwässerige solution is prepared with 120 cc of 30% ^ ^<2)] - ethyl- (l)} - phenth _ia zin

Caustic soda alkaline (phenolphthalein). The excellent 31 g of 3-ethyl mercaptophenthiazine, 5.6 g of fine powder

The dextrorotatory base that has fallen is mixed once with 200 ecm sodium amide and 175 ecm anhydrous xylene

9 10

are cooled with stirring for 3 hours, with 450 cc of 30% sodium hydroxide alkaline reflux at a bath temperature of 18O ⁰ C to made, and the precipitated oily base once heated boiling. Without interrupting the heating, with 1500 ecm and twice with 500 ecm benzene, a solution of shaken _{is released within 1V 2 hours.} The benzene solution is washed out with 1000 ecm 19.3 g of 2 - [N - methylpiperidyl - (2 ')] - 1 - chloroethane 5 water and over magnesium sulfate ([α] ο ⁰ = + 69.9 °, prepared according to Example 2) dried in 20 ecm. After the benzene has been distilled off in the anhydrous xylene, add dropwise. After a further 3 hours of vacuum, 159 g of the oily base remain. 2 g of heating, the reaction mixture is cooled. This base is mixed with crystalline 5 ecm of isopropanol and 140 ecm of anhydrous xylene. Well sated; F. = 60 to 62 ° C, [x] l ° = +20.5 ± 2 ° (c = 1% is first shaken twice with 170 ecm of water io in ethanol).

and then once with 310 ecm aqueous 15%. The fumarate is prepared by adding 131g

Tartaric acid solution. The tartaric acid solution is dissolved in the oily base in 400 ecm of absolute ethanol

shaken twice with 90 ecm benzene. The aqueous and a solution of 43 g of fumaric acid dissolved in

The solution is made with 140 ecm of aqueous 600 ecm of absolute ethanol. That immediately

30% strength sodium hydroxide solution, ^it alkaline (phenolphthalein). 15 crystallizing fumarate is made from 1000 ecm abso-

The precipitated oily base is recrystallized once with 170 ecm of ethanol. That's how you get it

and washed out twice with 80 ecm of water. analytically pure fumarate des (+ J-3-methyl mercapto-

After drying over a little potash and waste 10 - {2 '- [N - methylpiperidyl- (2 ")] - ethyl- (1')} - phen-

distilling the benzene leaves the crude base. thiazins from m.p. = 143 to 145 ° C. [χ] 1 ° = + 16.0 ± 2 °

The distillation gives the base of 20 (c = 1% in pyridine).
Kp 0.01 = 240 to 243 ⁰ C.

For cleaning, the base is dissolved in 100 ecm petrol example 6

ether and can ^{crystallize at 20 0} C with stirring. (-) - 3 - methyl mercapto - 10 - {2 '- [N - methylpiper-

After cooling to 0 ⁰ C is filtered and the filter idyl- (2 ')] - ethyl (l')} - phenthiazine

The residue was washed off with 30 ecm petroleum ether. 25th

After recrystallizing twice from the three ^a ) C-) " ³ " methyl mercapto - 10 - {2 '- [N - methyl times the amount of petroleum ether one obtains the analytical pipendyl - (2)] - ethyl - (1)} - phenthiazm - direine (+) - 3 - ethyl mercapto - 10 - {T - [N - methyl- (p-toluyl) -L-tartrate
piperidyl- (2 ")] - ethyl- (1 ')} - phenthiazine with the con - From the mother liquors of the F. = 56 to 58 ⁰ C, [<x] ² S = + 17.3 ° (c = 1% crystallization to separate off the left in ethanol). The rotating salt is obtained by evaporation and subsequent liberation of the base, as in Example 5

described under b), an antipode mixture of

(+) - 3 - methyl mercapto - 10 - {2'- [N - methylpiper- 3 - methyl mercapto - 10 - {2 '- [N - methylpiper-

idyl- (2 ")] - äthyl- (l ')} - phenthiazine 35 idyl- (2")] - ethyl- (l')} - phenthiazins with the rotation value

. ,, "..,,,. ,., _r . _T ,, [ixYd ⁰ = -15.0 ± 2 ° (c = 1% in ethanol).

*} ⁽⁺ .] - ³ \ ^ ^yl ™ Tf ^Pt % l ^{ 1 ~ Ψ- ~ ^h f ⁵ Og of this antipode mixture and 54.6g di-

pipendyl - (2)] - diethyl - (1)} - phenthiazm - di- _(p _toluyl) -L-tartaric acid monohydrate at 40 ⁰ C

(p-toluyl) -D-tartrate dissolved _{in 500 cc of acetone. After} inoculation left

400 g of racemic 3-methylmercapto-10- {2 '- [N-me- 40 man with stirring first at room temperature

thylpiperidyl- (2 ")] - ethyl- (l ')} - phenthiazine (F. = 72 for 20 hours and then at 0 ⁰ C during

up to 74 ° C) and 436 g of di- (p-toluyl) -D-tartaric acid-mono- 3 hours crystallize and filtered off. On the

hydrate are dissolved in 4000 cc of acetone at 4O ⁰ C. The filter is washed with 100 ecm acetone. That

After inoculation, first moist crystals are left with stirring three times with a 7-fold increase

at room temperature for 20 hours and 45 amount of acetone for 5 hours each

then crystallize at O ⁰ C for 3 hours and boiled stirring. The analytically pure di- (p-toluyl) -

filtered off. Wash on the filter with 500 ecm L-tartrate des (-) - 3 - methylmercapto-10- {2 '- [N-me-

Acetone after. The moist product is treated three times with thylpiperidyl - (2 ")] - ethyl - (Γ)} - phenthiazines

7 times the amount of acetone for 5 hours each time the decomposition point is 152 to 154 ° C. [«] O ° = + 69.9 ± 2 °

boiled with stirring. The analytically pure Di- 50 (c = 0.25% in ethanol),

(p - toluyl) - D - tartrate des (+) - 3 - methyl mercapto-,. ,. ",,,,,. ... ",

10 - {2 '- [N - methylpiperidyl - (2 ")] - ethyl- (l')} - phen- ^b ) <"). " ³ Γ ^ ÄT ^ Ü ΐ" ^{ l ' ' ^Y

thiazins has a decomposition point of 152 to 154 ° C. pipendyl- (2)] - ethyl- (1)} - phenthiazm

[ «]" = -70.0 ± 2 ° (c = 0.27 "Α, in ethanol) 63 g. (-) - 3 - methylmercapto - 10 - {2 '- [N-methyl -, -,, , - _{,, Λ} », n,, 'in fi / rvr μ, 55 piperidyl - (2")] - ethyl - (Γ)} - phenthiazine - dib) (+) - 3 - methylmercapto - 10 - {2 - [N - methyl (. _{p t} oluyl) -L-tartrate, 54 cc of concentrated hydrochloric acid, pipendyl- (2)] - ethyl- (l)} - phenthiazine diluted with 270 cc water and 270 g ecm ether 350 ( +) - 3 - Methylmercapto -10 - {2 '- [N-methyl- are piperidyl - (2 ")] - ethyl - (Γ)} - phenthiazm-di- (p-tolu- The ether solution is separated in the separating funnel abyl) -D-tartrate, 300 ecm concentrated hydrochloric acid, and the aqueous layer is extracted three times more thinly with 1500 ecm water and 1500 ecm ether with 50 ecm ether each time The solution is dried over magnesium sulphate in a flask until the solution is clear and the digester is stirred d recovered the aqueous layer three more times. The aqueous layer is extracted with ice with 300 ecm of ether each time. The ether solution 65 cooled, diluted with 80 cc of 30% ^he sodium hydroxide solution alkaline is made dried over magnesium sulfate and the di- and the precipitated oily base once (p-toluyl) -D-tartaric acid by evaporation of the ether with 300 cc and twice with 100 ecm benzene recovered. The aqueous layer is shaken with ice. The benzene solution is with 200 ecm

Washed out water and dried over magnesium sulfate. After the benzene has been distilled off in vacuo, 30 g of the oily base remain. 2 g of this base are crystallized from 6 ecm isopropanol; F. = 60 to 62 ° C, [txYo ⁰ = -20.6 ± 2 ° (c = 1% in ethanol).

The fumarate is produced by dissolving 28 g of the oily base in 85 ecm of absolute ethanol and adding it to a solution of 9.2 g of fumaric acid dissolved in 130 ecm of absolute ethanol. The fumarate which crystallizes out immediately is recrystallized from 210 ecm absolute ethanol. This gives the analytically pure fumarate of the (-) - 3 - methylmercapto-10 - {2 '- [N - methylpiperidyl - (2')] - ethyl (l ')} - phenthiazins mp = 143 to 145 ⁰ C. , [«] !? = -16.3 ± 2 ° (c = 1% for pyridine).

Claims (1)

PATENT CLAIM: Process for the preparation of optically active, in the 3-position by sulfur-containing groups ao substituted phenthiazine derivatives of the general formula SR ₁ R ₂ in which R _{1 represents} a hydrogen atom, an alkyl group with 1 to 5 carbon atoms, an aryl or aralkyl group and R _{2 stands} for a hydrogen atom or an alkyl group with 1 to 4 carbon atoms, characterized in that either the racemic base mixture is converted into the mixture of diastereomeric salts by treatment with an optically active acid , the uniform components are obtained therefrom by fractional crystallization and the optically active bases are set free from the salts, or a phenthiazine derivative of the general formula is used SR ₁ wherein R _{1 has the} above meaning with an optically active piperidine derivative of the general formula Hal-CH ₂ -CH ₂ -CH III where R _{2 has the} above meaning and Hal stands for a chlorine, bromine or iodine atom, condenses. Considered publications:
German interpretative document No. 1 008 737. © 209 628/265 7.62