DE1059460B - Process for the preparation of phenthiazine derivatives - Google Patents

Description

GERMAN

The invention relates to processes for the preparation of new phenthiazine derivatives of the general formula

-COOR

Method of manufacture
of phenthiazine derivatives

their salts and their quaternary ammonium derivatives.

In this formula, X is a sulfur atom or a - SO - or - SO ₂ - radical, T a mono- or dialkylamino radical in which the alkyl radicals have 1 to 5 carbon atoms, or the radical of a cyclic non-aromatic amine, such as the pyrrolidino, Piperidino, morpholino, piperazino or 4-alkylpiperazino radical, and B is an aliphatic divalent hydrocarbon radical with a straight or branched chain and 2 to 5 carbon atoms, which can optionally be substituted by a radical - B '- T', where B 'is a simple one Means bond or the methylene radical and T 'has the same meanings as T. R denotes a low molecular weight alkyl radical with a maximum of 4 carbon atoms.

These compounds can be obtained in the present invention by using any of the following methods will:

1. Exposure to an aminoalkyl halogen compound of the general formula Hai - B - T, wherein Hai is a Halogen atom and B and T have the above meaning or one of its salts on a suitable phenthiazine. The reaction can be carried out with or without a solvent in the presence or absence of a condensing agent are executed. It is advantageous to use an aromatic hydrocarbon as a solvent, for example Toluene or xylene, and in the presence of a condensing agent, preferably from the group of alkali metals and their derivatives, such as, for example, the hydrides, amides, hydroxides, alcoholates, metal alkyls or -aryls and especially metallic sodium, sodium amide, Sodium or potassium hydroxide in powder form, lithium hydride, sodium tert-butoxide, butullithium or Phenyllithium to condense, preferably at the boiling point of the solvent. It is beneficial the aminoalkyl halogen compound in the form of the free base in solution, for example in benzene, toluene or xylene, to be used, and the solution to the mixture of the other reaction components in which the selected Phenthiazine can already be present at least partially in the form of the alkali metal salt, to be added. The reaction can also be carried out with a salt of the aminoalkyl halogen compound, but in this case it is obvious required a larger amount of condensate notifier:

Societe des Usines Chimiques

Rhone-Poulenc,

Paris

Representative: Dr. F. Zumstein
and Dipl.-Chem. Dr. rer. nat. E. Assmann,
Patent Attorneys, Munich 2, Bräuhausstr. 4th

Claimed priority:
France from January 10th and November 24th 1956

Robert Michel Jacob, Ablon-sur-Seine,

and Jacques Georges Robert,

Gentilly, Seine (France),

have been named as inventors

Use agents to neutralize the acidity of the salt used.

In the case where the divalent aliphatic radical - B - in the above formula is a branched asymmetric one Chain, such as

-CH ₂ -CH-,

CH,

- C Ix - C Ix 2 - f

CH,

- C χ! -C XX2 -C / -H-2- y -O JnL) -C XX2

CH,

CH ₃

means, a rearrangement can occur in the course of the reaction, that of that which occurs in the case of preparation des 10- [2'-dimethylaminopropyl- (l ')] -phenthiazines by condensation of a dimethylaminohalopropane with the phenthiazine takes place, corresponds to (cf.Charpentier, Comptes Rendus hebdomadaires des seances de l'Academie des Sciences, Vol. 225 [1947],

P. 306). Here you get, if you get from 2-dimethylamino-1-chloropropane or l-dimethylamino-2-chloropropane goes out, always the same final mixture in which the 10- [2'-dimethylaminopropyl- (1 ')] -phenthiazine is present in predominant amount.

909 557/419

2. Heating an aminoalkyl ester of the phenthiazine-LO-carboxylic acid the general formula

-COOR

COO -B-T

in which the various symbols are as defined above, to a temperature above 100 ° C and preferably to a temperature between L50 and 220 ⁰ C.

3. If one wishes to obtain compounds for which the radical - SO - or - SO ₂ - denotes in the above formula IX, oxidation of the corresponding derivatives, for whose general formula X denotes a sulfur atom, according to processes known per se.

Certain of the phenthiazine derivatives according to the invention can be in racemic or optically active form. The optically active derivatives can according to certain of the processes described above can be obtained by starting materials that are themselves are optically active, goes out. You can also choose from the corresponding racemates of the general formula I. can be produced by optical splitting.

The products according to the invention have valuable pharmacodynamic properties, the one, and in particular the substances, for which the remainder in the above general formula

- B - CH ₂ - CH - N (CH ₃ ) ₂
CH _a

- CH ₂ -CH - CH ₂ -N (CH _{3) 2}

CH,

means effective antihistamines, and the others, especially those who have the chains

is for example 3-carbomethoxy-10- (3'-dimethylaminopropyl) which is available according to the invention -phenthiazine to the analogous 3-chloro-10- (3'-dimethylaminopropyl) -phenthiazine known from Swiss patent 298 685 superior in terms of narcosis-potentiating, anti-emetic and anti-shock effects; the said This is because the substance obtainable according to the invention shows a significantly better anesthesia-potentiating effect and in particular a much better anti-shock effect.

Test report
Comparative experiments

The product 3-carbomethoxy-10- (3'-dimethylaminopropyl) obtainable according to Example 1 - phenthiazine (product A) was derived from the Swiss patent 298685 known compound 3-chloro-10- (3'-dimethylaminopropyl) -phenthiazine (product B) compared. The comparison has been assessed for anesthesia potentiating, anti-emetic and anti-shock effects in the following manner carried out.

a) Potentiation of the ether anesthesia

The product to be examined is administered to the test animal (mouse) subcutaneously in doses of 5, 10 and 20 mg / kg. 30 minutes later, the mice treated in this way are placed in a bell jar in which a certain Amount of ether has evaporated. After anesthesia has occurred, the mice are taken out of the bell and put in place Duration of anesthesia in minutes in the open air.

In the case of the comparison substance (product B), an anesthetic duration of 27 minutes is observed in a dose of 20 mg / kg. This duration of anesthesia is taken as the basis, and the other results that are associated with both the substance obtainable according to the invention as well as with the lower doses were obtained with product B, are expressed as a percentage with respect to product B at 20 mg / kg subcutaneously in the table below.

b) Antiemetic effect

- (CH ₂ ) ₃ N (CH ₃ ) ₂

- CH ₂ - CH - CH ₂ N (CH ₃ ) ₂
CH,

for potentiating anesthesia and for use in deconnecting the vegetative nervous system active and superior to the compounds of the same type known up to now. The products that this like chains, and the corresponding pyrrolidine derivatives are also notable hypotensors. Others are also antiemetics or spasmolytics. The substances for which in the general formula of Residual B is substituted by an amine radical - B '- T', are particularly useful as antispasmodics and local anesthetics useful.

As already mentioned above, the phenthiazine derivatives obtainable according to the invention have very favorable therapeutic properties in various respects, whereby they are superior to the known, analogous compounds. As can be seen from the following comparative experiments (method according to G. Chen and Ch. E ns or,
Journal of Pharmacology, Vol. 98 [1950] p. 245)

The product to be investigated is administered subcutaneously to the test animal (dog) in various doses 30 minutes before the subcutaneous injection of 0.1 mg / kg apomorphine. The mean number of vomiting occurring during 30 minutes after administration of the apomorphine is recorded. Is determined for each dose, the percent reduction in vomiting, relative to the control animals, and calculates the dose which causes a 5O ° / _O strength reduction of vomitus (DA _50).

The results are given in the table below.

c) anti-shock effect

(Technique according to Noble and Collip, Quarterly journal of experimental Physiology and cognate Medical Sciences, Vol. 31, [1942] p. 187)

Rats are shocked by placing them in metal drums that rotate on their axis at a speed of 40 revolutions per minute. Before the experiment, the rats receive the product to be examined subcutaneously in various doses. The mortality is determined after 720 revolutions of the drums and the dose of product is determined which 50% of the animals against this mortality (DA ₅₀ in mg / kg)

protects. The results are given in the table below.

Product ^
^ Test A. B. 1. Ethereal anesthesia: % Effect
at 20 mg / kg subcutaneously
at 10 mg / kg subcutaneously
at 5 mg / kg subcutaneously 110
90
73 100
63
32 2. Antiemetic effect:
DA ₅₀ in mg / kg subcutaneously 0.5 0.5 3. Anti-shock effect:
DA ₆₀ in mg / kg subcutaneously 0.05 0.3

The following examples illustrate the invention.

example 1

A boiling solution of 12.85 g of 3-carbomethoxyphenthiazine (R. Baltzly, M. Harfenist, FJ Webb, Journal of the American Chemical Society, vol. 68 [1946], p. 2673) in 200 ecm of anhydrous xylene is mixed with 2 , 25 g of 95 ° / ₀ sodium sodium amide and heated for 1 hour under reflux. 186 ecm of a xylene solution containing 6.68 g of 3-dimethylamino-1-chloropropane is then poured in over the course of 20 minutes and the mixture is refluxed for a further 16 hours. After cooling, it is stirred with 200 ecm of a 2N hydrochloric acid solution and 100 ecm of ether. The ether layer is separated off and the aqueous layer is extracted successively with 200, 100 and again with 100 ecm of ether. The aqueous layer is treated with 120 ecm 4 N sodium hydroxide solution and extracted successively with 200, 100 and again with 100 ecm ether. After drying the combined ether extracts over potassium carbonate and evaporation of the ether on the water bath, 13 g of a brown oil remain, which, after dissolving in 650 ecm of a mixture of equal parts of benzene and cyclohexane, is purified by chromatography on 200 g of aluminum oxide. It is eluted with the following solvents: 500 ecm of a mixture of 1 part of benzene and 1 part of cyclohexane, then 500 ecm of a mixture of 3 parts of benzene] and 1 part of cyclohexane and finally 500 ecm of pure benzene.

After combining the solutions, the solvents are evaporated on the water bath. 4.68 g remain Substance which is treated with maleic acid in ethyl acetate. 4.94 g of the maleate of 3-carbomethoxy-10- (3'-dimethylaminopropyl) -phenthiazine are obtained in this way with a melting point of 145 ° C after recrystallization from ethyl acetate.

Example 2

3.06 g of 95% sodium amide are added to a boiling solution of 20 g of 3-carbomethoxyphenthiazine in 250 ecm of anhydrous xylene and the mixture is refluxed for 1 hour. A solution of 10.2 g of 1-chloro-2-methyl-3-dimethylaminopropane in 30 ml of anhydrous xylene is then allowed to flow in over 15 minutes and the mixture is refluxed for 20 hours. After cooling, the mixture is stirred with 100 ecm water and 40 ecm 4 η-hydrochloric acid. The xylene phase is decanted off, the aqueous phase from which the hydrochloride has crystallized out is diluted with 1 liter of water and made alkaline with 60 ecm 4 η sodium hydroxide solution when heated. After the precipitated base has been extracted with ether, the combined ether extracts are dried over anhydrous potassium carbonate. After evaporation of the Athens on the water bath, 20 g of a brown oil remain which, after dissolving in 11% of a mixture of benzene and cyclohexane 3: 7, is purified by chromatography on 400 g of aluminum oxide. After elution, as described in Example 1, and evaporation of the solvent, 6.1 g of substance are obtained, which are dissolved in ethyl acetate and treated with a solution of hydrogen chloride in ether. In this way, 5.3 g of 3-carbomethoxy-10- (2'-methyl-3'-dimethylaminopropyl) -phenthiazin hydrochloride mp 198 ⁰ C after recrystallization from a mixture of chloroform and ethyl acetate.

Example 3

A solution was heated from 15 g of 3-Carbomethoxyphenthiazin in 200 cc of anhydrous xylene at 115 ° C, mixed with 2.45 g of 95 ° / ₀ sodium sodium amide and heated for 10 minutes under reflux. A solution of 9.3 g of 1-chloro-3-pyrrolidinopropane in 75 ecm of anhydrous xylene is then added and the mixture is refluxed again for 5 hours. After cooling, the reaction liquid is washed twice with a total of 300 ecm of water and the xylene phase is separated off, which is dried over anhydrous potassium carbonate and concentrated to dryness under a pressure of 20 mm of mercury and up to 100.degree.

Dissolve the oil residue in 500 ecm boiling n-heptane, the solution cools to about 10 ° C and separates it from the precipitated resin.

The heptane solution is passed through a column containing 200 g of aluminum oxide for chromatography and eluted with it ten fractions of 250 ecm n-heptane each. After union the solvent is evaporated from the elution filtrates.

The purified base (6.4 g) is dissolved in acetone in the acidic Oxalate transferred. After recrystallization from methanol, 5 g of acidic oxalate of 3-carbomethoxy-10- (3'-pyrrolidinopropyl) -phenthiazine are obtained in the form of a crystalline pale yellow powder with a melting point of 176 ° C.

Example 4

The procedure is as described in Example 3, but the 1-chloro-3-pyrrolidinopropane is replaced by 10.2 g 1-chloro-1-methyl-S-pyrrolidinopropane.

After evaporation of the xylene, the residue of 20 g of oil is dissolved in 500 ecm of a boiling mixture Equal parts of cyclohexane and petroleum ether (boiling point 35 to 50 ° C). The solution is cooled to about 5 ° C. and separated the precipitated solid resins by filtering.

The clear solution thus obtained is passed through a column containing 250 g of aluminum oxide for chromatography. It is eluted with 16 portions of 250 ecm each of a mixture from equal parts of cyclohexane and petroleum ether. After the eluate filtrates have been combined and the The purified base is recrystallized from n-heptane using a solvent. This gives 5 g of 3-carbomethoxy-10- (2'-methyl-3'-pyrrolidinopropyl) -phenthiazine in the form of a crystalline yellow powder with a temperature of 95 ° C.

Example 5

A solution is heated from 13.6 g of 3-Carbäthoxyphenthiazin in 200 cc of anhydrous xylene at 100 ° C, mixed with 2.25 g of 95 ° / ₀ sodium sodium amide and heated for 5 minutes under reflux. A solution of 6.7 g of 1-chloro-3-dimethylaminopropane in 180 ecm of anhydrous xylene is then poured in over a period of 15 minutes and the mixture is refluxed for another 2 hours. After cooling, the reaction medium is diluted with 100 ecm of ether and stirred with 125 ecm of about 0.8 η hydrochloric acid. The aqueous acidic phase is separated off, washed three times with 400 ecm of ether each time, made alkaline with 30 ecm of 4 η sodium hydroxide solution and the liberated base is extracted with 400 ecm of ether.

7 8

After the ether phase has been dried over anhydrous potassium, the organic phase is then stirred at 130 ecm

carbonate, if the solvent is evaporated in the usual 1.5 η hydrochloric acid, the aqueous acidic phase is washed three times

a lot of pressure and then at a pressure of a total of 200 ecm of ether, makes 30 ecm of soda

20 mm mercury column becomes alkaline by heating on the water lye (d = 1.33) and extracts the precipitated

bath. 5 base with 500 ecm ether. After drying the ethereal solution

The oil residue of 8.5 g is dissolved in 425 ecm of a mixture of cyclohexane-benzene (3: 7), evaporated over anhydrous potassium carbonate. Remove the solvents on the water bath.
For chromatography, the solution is passed through a column of crude S-carbomethoxy-phenthiazine-10-carbon with 160 g of aluminum oxide. Then the fixed acid 2'-diethylaminoethyl ester existing brown oil product is successively with 1400 ecm benzene and 900 ecm io residue is dissolved in 220 ecm o-dichlorobenzene, and that of a mixture of benzene-ethyl acetate (9: 1) solution is of 140 heated to 170 ⁰ C until the coal elutes. The filtrates from the elution are combined. After the evolution of dioxide has ended, for which about 1 ¹ ₂ hours of evaporation of the solvent leads to the results obtained. After cooling, the mass is taken up in purified base in ethyl acetate in the acidic maleate 530 ecm of ether and passed over three times in succession. After recrystallization from ethanol, 1.2 g of 15, stirred with a total of 450 ecm of about 0.35 η-hydrochloric acid, are obtained, acidic maleate of 3-carbethoxy-10- (3'-dimethylamino- After the aqueous acidic phases are combined, propyl) -phenthiazine washes in the form of a yellow crystalline, the mixture is made with 200 ecm of ether, made alkaline with 45 ecm of powder with a temperature of 48 ° C. 4 η sodium hydroxide solution and extracted in freedom

The 3-carbethoxy-set base used as starting substance four times with a total of 400 ecm of ether. Man

phenthiazine with a temperature of 152 ° C is made by esterification of the 20 dries the ether phase over anhydrous potassium

Phenthiazine-3-carboxylic acid with ethanol in the presence of carbonate and the solvent evaporated on the

Sulfuric acid produced. Water bath.

. . The oil residue, weighing 22 g, is poured into 250 ecm petroleum

Example 6 _ether ( _Kp _ _{35 to SQQ} q _{gdöstj the solution for} chromatographic

A solution was heated from 12 g of 3-Carbobutoxy- 25 chromatography through a column of 250 g alumina phenthiazine in 200 cc of anhydrous xylene at 100 ⁰ C, and passed the fixed product successively with petroleum Puts with 1.78 g of 95 ° / ₀ sodium sodium amide and heated ether, eluted cyclohexane and benzene. After refluxing for 1 hour. The elution filtrate is then allowed to flow in 15 minutes and the solution is concentrated to dryness. A solution of 5.34 g of 1-chloro-3-dimethylaminopropane (15.7 g) in acetone, which has been purified in this way, is added by adding xylene anhydrous in 50 ecm and heated Another solution of hydrogen chloride in ether in the hydrochloride

3 hours under reflux. After cooling, it is diluted and transferred. After recrystallization from ethanol, the reaction medium is obtained with 200 ecm of ether and 14.8 g of 3-carbomethoxy-10- (2'-diethylaminoethyl) with 170 ecm of about 0.4 n-methanesulfonic acid are stirred. One separates phenthiazine hydrochloride in the form of a crystallized from the aqueous acid phase, it makes with 30 cc of a cream-colored powder melting at 200-201 ⁰ C.

4 η-sodium hydroxide solution is alkaline and extracts the free 35 The 3-carbomethoxy law used as the starting substance Base with 200 ecm ether. After the phenthiazine-10-carboxylic acid chloride has been dried, it has a melting point of 145 to 147 ° C Ether phase is evaporated over anhydrous potassium carbonate by the action of phosgene on 3-carbomethoxymane the solvent under ordinary pressure and phenthiazine in toluene in the presence of pyridine last produced under a pressure of 20 mm of mercury at ordinary temperature.

at 8O ⁰ C. 40. .

The oil residue, which weighs 12 g, is in 600 ecm of an .Example 0

Mixture of equal parts of cyclohexane and benzene A solution of 32 g of 3-carbomethoxy-

dissolved, the solution for chromatography passed through a phenthiazine-10-carboxylic acid chloride in 150 ecm water column with 240 g of aluminum oxide and the free toluene at 90 ° C, leaves in 35 minutes 26.2 g of 1-difixed product successively with 1000 ecm benzene , 45 äthylaminopropanol- (2) flow in and heated thereupon 1500 ecm benzene with a content of 2 ° / ₀ acetic acid- 5 hours under reflux. One works as in Example 7 ethyl ester, with 750 ecm benzene with a content of further described and isolates 31.3 g of one from crude 5 ° / ₀ acetic acid ethyl ester and with 500 ecm benzene with S-carbomethoxyphenthiazine-10-carboxylic acid-fS'-diethyleinem Eluted content of 10% ethyl acetate. After aminopropyl (2 ')] - ester existing brown oil, its combination of the elution filtrates and concentration to dryness 50 in acetone by adding a solution of hydrogen chloride, the thus obtained purified base (3.8 g) in acetone is converted into hydrochloride produced in ether at 187 to 190 ⁰ C converted the acidic oxalate. Melts after recrystallization.

3.3 g of acidic oxalate of the 3-carbohydrate are obtained from ethanol. A solution of 26.5 g of the above is heated

butoxy-10- (3'-dimethylaminopropyl) -phenthiazines in the oil described in 140 ecm o-dichlorobenzene to 165 to form a crystalline pale yellow powder with a ^{temperature of 138 55 180 0} C, until the evolution of carbon dioxide has ended, including up to 140 ° C. about 1 ¹ J ₂ hours are required. By applying the

The 3-carbobutoxy method used as the starting substance in Example 7 gives 21.4 g of phenthiazine with a mp of 149 ° C. by esterification of the crude base which is mixed with 250 ecm of petroleum ether (b.p. 35 to phenthiazine-3-carboxylic acid n-butanol in the presence of 5O ⁰ C) dissolves. The solution is passed to the chromatography prepared by sulfuric acid. 60 through a column with 250 g of aluminum oxide and eluted

the fixed product by successive Example 7 turning of petroleum ether-cyclohexane and mixtures

of cyclohexane and benzene. The 14.6 g weight

A solution was heated from 32 g of 3-carbomethoxy dampfungsrückstand the Elutionsfiltrate is ECM via the phenothiazine-10-carboxylic acid chloride in 150 water 65 in acetone by addition of a solution of hydrogen chloride anhydrous toluene at 9O ⁰ C and in 20 minutes in ether produced hydrochloride purified. From this 23.4 g of diethylaminoethanol. Then heated for 5 hours hydrochloride melting at about 200 ° to 210 ⁰ C is obtained under reflux. After cooling, the base is diluted back by known methods, which are easily post-solidified with 150 ecm of ether and stirred in the reaction medium and recrystallized from n-heptane. You sinander with 150, 100 and again with 100 ecm of water. 70 thus receives 2.2 g of 3-carbomethoxy-10- (2'-diethylamino-

propyl) -phenthiazin in the form of a yellow crystalline powder melting at 90 to 92 ⁰ C.

Example 9

A solution was heated from 15 g of 3-Carbomethoxyphenthiazin-lO-carboxylic acid chloride in 150 cc of anhydrous toluene at 90 ⁰ C, can in 15 minutes a solution of 14.1 g of 3- (4'-methylpiperazinyl) propanol in 50 cc of anhydrous toluene flow in and then heated under reflux for 4 hours. Using the procedure described in Example 7, 20 g of a brown oil consisting of crude 3-carbomethoxyphenthiazine-10-carboxylic acid 3 '- (4 "-methylpiperazinyl) propyl ester is isolated, the brown oil of which is prepared in ethanol by adding a solution of hydrogen chloride in ether Dihydrochloride melts at about 235 to 240 ° C.

The mixture is heated 14 g of the oil described in the foregoing 170 to 21O ⁰ C, until the evolution of carbon dioxide stopped, to which about 45 minutes are required. After cooling, the procedure described in Example 7 is worked up to give 7 g of a thick oil which is dissolved in 350 ecm of a mixture of cyclohexane and benzene (7: 3). The solution is passed through a column containing 140 g of aluminum oxide for chromatography and the fixed product is eluted successively with 10 parts of 250 ecm of benzene and 2 parts of a mixture of benzene and ethyl acetate (9: 1). After the elution fluids have been combined and evaporated to dryness, the purified base obtained in this way (1.3 g) in methanol is converted into the dihydrochloride by adding a solution of hydrogen chloride in ether. After recrystallization from methanol, 0.8 g of 3-carbomethoxy-10- [3 '- (4 "-methylpiperazinyl) propyl] -phenthiazine dihydrochloride is obtained in the form of a yellow crystalline powder with a melting point of about 215 ° C.

35 Example 10

A solution was heated from 32 g of 3-Carbomethoxyphenthiazin-10-carboxylic acid chloride in 50 cc of anhydrous toluene at 90 ⁰ C, can in 15 minutes 14.6 gl, 3-bis (dimethylamino) -propanol- (2) incorporate and then heated 4 hours under reflux. The procedure described in Example 7 continues and 27.6 g of a brown oil consisting of crude S-carbomethoxyphenthiazine-10-carboxylic acid, 3'-bis- ^ dimethylamine) propyl (2 ') ester are isolated. After purification on the produced ethanol in ditartrate is obtained 21.7 g of purified base, which slowly crystallizes and melts at 102 to 106 ⁰ C.

18.4 g of the above-described crystallized base in solution in 120 ecm of o-dichlorobenzene are heated to 160 to 180 ° C. until the evolution of carbon dioxide has ceased, which takes about ¹ _1/2 hours. The procedure described in Example 7 is continued and 16.3 g of a brown, thick oil are obtained, which are dissolved in 320 ecm of cyclohexane. The solution is passed through a column with 160 g of aluminum oxide for chromatography and the fixed product is eluted with 1800 ecm of cyclohexane, 1800 ecm of a mixture of cyclohexane and benzene (2: 1) and 900 ecm of benzene. After the elution fluids have been combined and evaporated to dryness, the purified base obtained in this way (12.5 g) is converted into its monomaleate in ethyl acetate. After recrystallization from ethanol to obtain 11.4g of the monomaleate 3-carbomethoxy-10- [2 ', 3'-bis (dimethylamino) -propyl] -phenthia- interest in the form of a cream-colored crystalline powder melting at 180-181 ⁰ C. .

Example 11

In a solution of 5.13 g of 3-carbomethoxy-10- (3'-dimethylaminopropyl) -phenthiazin in 25 cc of glacial acetic acid is allowed to a solution of 2.1 g of pure sulfuric acid in 25 cc of acetic acid at 30 ⁰ C within a quarter of an hour and then a solution of 3.95 cc of 32.6 ° / ₀ sodium hydrogen peroxide in acetic acid 6 ecm flow; finally heated for 15 hours 6O ⁰ C. After cooling, pouring the reaction liquid into 300 cc of ice water and 115 cc of sodium hydroxide makes with [d = 1.33) alkaline; the precipitated base is extracted three times with 100 ecm ethyl acetate each time and the combined organic extracts are dried over anhydrous potassium carbonate and evaporated to dryness on a water bath. The crystallized crude base obtained is finally recrystallized from 30 ecm isopropanol. 2.6 g of 3-carbomethoxy-10- (3'-dimethylaminopropyl) -phenthiazine-9,9-dioxide are obtained in this way in cream-colored crystals with a melting point of 116 ° to 118 ° C. (Kofier).

Example 12

If one proceeds as in the previous example, but starting from 4.98 g of 3-carbomethoxy-10- (2'-methyl-3'-dimethylaminopropyl) -phenthiazine, 4.3 g of crude oily base are obtained. This base is dissolved in 35 ecm of ethanol and 2.2 ecm of a solution of 5 η of dry hydrochloric acid in ether is added; is obtained as 3.9 g of 3-carbomethoxy-10- (2'-methyl-3 ^/ dimethylaminopropyl) -phenthiazin-9,9-dioxide hydrochloride as a white crystalline product melting at about 150 ⁰ C (decomposition, Kofler) .

Claims (1)

PATENT CLAIM: Process for the preparation of phenthiazine derivatives of the general formula J-COOR Β —Τ in which X is a sulfur atom or a - SO - or - SO ₂ radical, T is a mono- or dialkylamino radical in which the alkyl radicals have 1 to 5 carbon atoms, or the radical of a cyclic, non-aromatic amine and B is a divalent aliphatic hydrocarbon radical with a straight or branched chain and 2 to 5 carbon atoms, where the radical B is optionally replaced by a radical - B '- T' can be substituted in which B 'is a Single bond or the methylene radical and T 'has the same meanings as T and R denotes a low molecular weight alkyl radical with a maximum of 4 carbon atoms, as well as their Salts and quaternary ammonium derivatives, characterized in that one a) an aminoalkyl halogen compound of the general formula Hai - B - T, in which Hai is a halogen atom means and B and T have the meanings given above, with a phenthiazine derivative the general formula I — COOR wherein X and R have the above meanings, converts or 909 557/419 b) a compound of the general formula L COOR or SO ₂ denotes the corresponding compounds, for which in the general formula XS denotes, oxidized by processes known per se and, if appropriate, the bases obtained are converted into their salts or quaternary ammonium compounds in a manner known per se. COO-B —T - in dei each icon, the above mentioned ^Contemplated publications: Have meaning, to over 10O ⁰ C, preferably 10 German Patent Nos. 910 301, 928 345; heated to 150 to 220 ° C or patent application B 28060 IVb / 12p (published c) for the establishment of connections for which in the 25.8.1955); General formula I X given above, SO Swiss patent specification No. 298 685.