DE1095288B - Process for the preparation of 1-, 2-, 3- and 4-azaphenthiazines substituted in the 10-position - Google Patents

Description

Process for the preparation of 1-, 2-, 3- and 4-azaphenthiazines substituted in the 10-position The present invention relates to a process for the preparation of 1-, 2-, 3- and 4-azaphenthiazines of the general formula which are substituted in the 10-position where the benzene or pyridine nucleus can be substituted and Q is a basic radical - AZ or where Z represents a dimethyl or diethylamino, pyrrolidino, piperidino, piperazino, N-alkylpiperazino or morpholino radical, A a divalent, saturated aliphatic hydrocarbon radical with a straight or branched chain and 2 to 6 carbon atoms, of which two or three stand in a straight chain between the two nitrogen atoms, and A 'the remainder denotes, where n stands for 0, 1, 2 or 3, and of their salts.

The azaphenthiazine is used as a substituent in the benzene or pyridine nucleus for example a halogen atom in question.

The compounds mentioned are prepared by either a) an azaphenthiazine unsubstituted in the 10-position with a compound of the formula Hai - Q can react, the reaction of 4-azaphenthiazines with a compound Hal - AZ is excluded if Z is a dimethyl or diethylamino, pyrrolidino, Means piperidino, piperazino or morpholino radical, or b) one in the 10-position azaphenthiazine substituted by a radical - AX, in which X is a reactive esterified OH group, such as a halogen atom, or the remainder of a sulfuric acid or Sulfonic acid ester is reacted with an amine of the formula HZ.

The reaction is preferably carried out in a solvent with increased Boiling point, such as a hydrocarbon, e.g. xylene, at the boiling point of the solvent carried out. You can in the presence of a condensing agent from the group of alkali metals and their derivatives, for example an alkali carbonate, -hydrids, -amids- or -hydroxyds, work.

The 1-, 3- and 4-azaphenthiazines used as starting materials can be obtained by cyclization (elimination of hydrogen halide) of compounds of the general formula getting produced. In this formula, the schematic symbol means a pyridyl radical, where the nitrogen atom occupies one of the positions (a), (b) or (c) of the formula II; one of the radicals Y 'or Y denotes a halogen atom and the other denotes the radical N H2; the benzene ring can optionally be substituted, for example by a halogen atom.

The 2-azaphenthiazine required as a starting material can accordingly that of V. A. Petrow (Journ. Chem. Soc., 1945, p. 591) for the preparation of 4-nitro-2-azaphenthiazine described procedure are produced.

The compounds of the formula used as starting substances in procedure b) can be obtained by applying the method described by Gilman in Journ.

Amer. Chem. Soc., 66, p. 890 (1944) the azaphenthiazines or by the action of an α-chloro-w-bromoalkane on the sodium derivative of an azaphenthiazine.

The new azaphenthiazine derivatives have valuable pharmacodynamic properties Properties that enable their use in human and veterinary medicine. You can use antihistamines, anti-parkinsonism agents, ganglion blockers, antispasmodics, Antiemetics, local anesthetics, or anti-shock agents; they can also be used as effectiveness enhancers used by anesthetics and analgesics.

The compounds obtainable according to the invention are the known, superior to similarly constructed connections. For example, 10- (2'-dimethylaminopropyl) -2-azaphenthiazine, 10- (3'-dimethylamino-propyl) -3-azaphenthiazine, 10- (2'-dimethylamino-propyl) -3 -azaphenthiazine, 10- (3'-dimethylamino-2'-methyl-propyl) -3-azaphenthiazine, 10- (3'-pyrolidino-propyl) -3-azaphenthiazine, 10- (3 '- [4 "-methylpiperazino-propyl) -3-azaphenthiazine, 10- (2', 3'-bis- [dimethylamino] -propyl) -3-azaphenthiazine, 10- (2 ', 3' -bispiperidino-propyl) -3-azaphenthiazine, 10- (2 ', 3'-bis- [dimethylamino] propyl) -4-azaphenthiazine and 10- (2'-methyl-3'-dimethylamino-propyl) -1 -azaphenthiazine to the known 0- (3'-dimethylamino-propyl) -phenthiazine with regard to the antihistamine effectiveness, the spasmolytic effect, the antiemetic Effect or the anti-shock effect clearly superior.

The following examples illustrate the invention without restricting it.

Example 1 1.35 g of sodium amide (content 92%) to a partial solution of 6 g of l-azaphenthiazine in 140 ccm of xylene and then add a solution dropwise to this mixture over a period of about 1 hour of 4.8 g of diethylaminochloroethane in 20 cc of xylene. The mixture is 1 hour heated to reflux. After cooling, 150 ccm of water are added and the mixture is acidified concentrated hydrochloric acid (until it turns Congo red), the xylene layer decanted off, then extract the aqueous phase with 100 cc of benzene, then make the aqueous phase Phase alkaline with sodium hydroxide solution (36 ° Be) and extract the released base with it Ether. After distilling off the ether, the residue is distilled, and you receives 4.8 g of 10- [2'-diethylamino-ethyl- (l ') l-l-azaphenthiazine in the form of a viscous, straw yellow oil; Bp 0.3hj, 0.4 196 to 197 "C.

This base gives an acid oxalate, F. 154 "C, and a picrate, F. 124 to 125 ° C.

The l-azaphenthiazine required as starting material, mp 248 ° C, can be prepared according to the following reaction scheme: Example 2 By the same procedure as described in Example 1, except that the diethylaminochloroethane is replaced by 4 g of 1-dimethylamino-3-chloropropane and the reaction mixture is heated for 4 hours after the addition of the 1-dimethylamino-3-chloropropane is complete, 4 is obtained , 13 g of 10- [3'-dimethylamino-propyl- (l ')] l-azaphenthiazine in the form of an amber-colored, very viscous oil, which mostly distills between 210 and 2120 ° C. at a pressure of 0.5 mm Hg column.

This base produces an oxalate that melts at 2120 ° C.

Example 3 A mixture of 3.7 g of 2-azaphenthiazine is heated, 1 g of sodium amide and 370 cc of anhydrous xylene under reflux for 1112 hours. In the boiling xylene suspension of the sodium derivative of 2-azaphenthiazine thus obtained 17 cc of a 180/0 xylene solution of 1-dimethylamino-2-chloropropane are left within 112 hours pour in and then continue refluxing for 5 hours. After cooling down the xylene solution is washed with water and then with 300 ccm, then with Extracted 200 cc of 0.1 N hydrochloric acid.

The combined hydrochloric acid extracts are mixed with 10 cc sodium hydroxide solution (i.e. = 1.33) made alkaline. The separating oil is twice with 250 ccm Ether extracted. The ether extracts are dried over sodium sulfate distilled on a water bath and the oily residue rectified in vacuo. Man thus receives 3.5 g of 10- [2'-dimethylamino-propyl- (1 ')] - 2-azaphenthiazine, which in a Pressure of 0.5 mm Hg column boils between 185 and 195 ° C. That in ethanol by adding Hydrochloric acid produced from alcoholic hydrochloric acid melts at 222 to 2230 C.

The 2-azaphenthiazine used as the starting substance can be prepared according to the following reaction scheme: Example 4 The procedure described in Example 1 is repeated, except that 7.1 g of 3-azaphenthiazine, 1.6 g of sodium amide, 5.7 g of 1-diethylamino-2-chloroethane and 120 cc of xylene are used. Rectification gives 7.8 g of 10- (2'-diethylaminoethyl) -3-azaphenthiazine in the form of a viscous, straw-yellow oil; Kp. 0.2 to 0.4 197 to 1990C. This base provides a monohydrochloride which crystallizes in prisms, mp 195 to 196 "C, and a dipicrate, mp 200 ° C.

The 3-azaphenthiazine, F. 165 "C, is like the t-azaphenthiazine under Using 3-nitro-4-chloropyridine instead of 2-chloro-3-nitropyridine.

Example 5 If you work as described in Example 4, but the diethylaminochloroethane replaced by 4.5 g of l-dimethylamino-3-chloropropane is obtained one 7.3 g of 10- [3'-dimethylamino-propyl- (1 ')] - 3-azaphenthiazine in the form of a viscous, straw yellow oil; Kp.o, s 193 to 1950C. This base gives an oxalate in white crystals, F. 158 to 1590 C, a monopicrate in orange crystals, F. 1660 C, and a dipicrate in yellow crystals, F. 238 to 2390 C.

Example 6 The procedure is as described in Example 5, but replaces the t-dimethylamino-3-chloropropane with the same amount of 1-dimethylamino-2-chloropropane and thus receives 6.05 g of 10- [2'-dimethylamino-propyl- (1) -3-azaphenethiazine in the form a viscous, light yellow oil; Bp 0.5 192 to 193 "C.

This base gives a monohydrochloride in light yellow crystals from F. 178 to 181 "C, a monopicrate in yellow crystals, F. 1750 C, and a dipicrate in light yellow crystals, F. 224 to 2260 C.

Example 7 1.4 g of sodium amide are added to a portion with stirring Solution of 6 g of 3-azaphenthiazine in 100 cc of xylene, then a solution is added dropwise of 5.3 g of 1,3-bis (dimethylamino) -2-chloropropane in 98 ccm of xylene and heated the mixture refluxed for 1 1/2 hours.

By treating the reaction mixture as described in Example 1, 6 g of 10- [2 ', 3'-bis- (dimethylamino) propyl (1 ')] -3-azaphenthiazine in the form of a very viscous oil, which for the most part was released at a pressure of 0.5 mm Hg column between 204 and 207 ° C distilled.

Example 8 12 g of 3-azaphenthiazine are heated with stirring for 3 hours with 3 g of sodium amide in 100 cc of xylene in a stream of nitrogen under reflux. then add a solution of 16 g of 1,3-bispiperidino-2-chloropropane in 20 minutes 40 cc of xylene are added, the mixture is heated under reflux for 8 hours and treated with 50 cc of water and 50 cc of ether. The aqueous layer is decanted and the organic layer is stirred Layer with 150 ccm 40 /, of hydrochloric acid. After decanting, the aqueous, acidic layer with 50ccm sodium hydroxide solution (d = 1.33), the base extracted with 100ccm Ether, the ethereal solution dries over potassium carbonate and concentrates. The raw product is recrystallized from 35 cc of acetone with treatment with activated charcoal. You get so 13.3 g of 10 - [2 ', 3' - bispiperidino - propyl - (1 ') 1-3-azaphenthiazine; 116 ° C.

Example 9 The procedure is as in Example 4, but the 3-azaphenthiazine is replaced by 6-chloro-3-azaphenthiazine and thus receives 1 0- [2'-diethvlaminoethyl- (1)] 6-chloro-3-aza phenthiazine; F. 1250 C. The latter gives an oxalate, which after recrystallization from ethanol melts at 1940 C.

Example 10 A mixture of 10 g of 3-azaphenthiazine, 2.3 g of 950/0 sodium amine and 120 cc of anhydrous xylene under nitrogen 1/2 Hour with stirring under reflux. In the boiling suspension of the so obtained Sodium derivative of 3-azaphenthiazine is left in a 75 cc in half an hour Pour 0.75 normal solution of 3-dimethylamino-2-methyl-1-chloropropane in xylene. Heating under reflux under nitrogen is continued for 2 hours and left over Stand overnight under nitrogen at ordinary temperature. The next day continues 50 cc of water are added to the reaction mixture, the xylene layer is decanted off and washed it with 50 cc of water and pulls it twice with 50 cc each and then twice with each 25 cc of n-hydrochloric acid. The hydrochloric acid layer is washed with 50 cc of ether and then made alkaline with 16 cc of 10 N sodium hydroxide solution.

The oily base which separates out is used twice with 100 ccm each time and then extracted twice with 50 cc ether each time. The combined essential extracts are washed with 50 cc water. It is dried over sodium sulphate and the ether is distilled on the water bath and rectify the residue in vacuo. This gives 11.5 g of 10- [3'-dimethylamino-2'-methylpropyl- (1 ')] - 3-azaphenthiazine, which at one pressure boils from 0.5 mm Hg column at 176 to 1830 C and after recrystallization Hexane melts at 92 to 93 ° C.

Example 11 A mixture of 8 g of 3-azaphenthiazine, 1.8 g of 950% sodium amide and 120 ccm of anhydrous xylene for 1 1/2 hours under nitrogen under reflux. In the boiling suspension of the sodium derivative obtained in this way A solution of 6.65 g of 1-pyrrolidino-3-chloropropane is left in 3-azaphenthiazine in 45 minutes pour into 50 cc anhydrous xylene.

The refluxing is continued for 3 hours under nitrogen and left to stand overnight under nitrogen at ordinary temperature. The next On the 2nd day, 30 ccm of water are added to the reaction mixture and the mixture is decanted the Remove the xylene layer, pull it off with 40 cc and then three times with 20 cc of n-hydrochloric acid each time the end. The hydrochloric acid layer is washed with 30 cc of ether and then with 12 cc of 10 Made n-caustic soda alkaline. The separating oily base is three times with 50 cc ether extracted each time. The ether extracts are washed with 30 cc of water and dried them over sodium sulfate, the ether is distilled off on a water bath and rectified the residue in vacuo. This gives 10 g of 10- [3'-pyrrolidino-propyl- (l) j-3-azaphenthiazine; Ko, 65 205 to 210 "C.

This is done by adding alcoholic hydrochloric acid to a solution of the Dihydrochloride obtained base in acetone melts at 207 to 208 "C.

Example 12 A mixture of 8 g of 3-azaphenthiazine, 120 cc of anhydrous xylene and 1.8 g of sodium amide for 1 hour under nitrogen Reflux.

In the xylene suspension of the sodium derivative of 3-azaphenthiazine thus obtained allowed dropwise in 1 hour with constant boiling of the xylene 73 com one Pour in 0.62 normal solution of 1- (4'-methylpiperazino) -3-chloropropane xylene. Heating is continued for 3 hours, cooled to ordinary temperature, and added add the reaction mixture dropwise with 30 cc of water. The xylene layer is decanted and extracts them one after the other with 80 cc, 40 cc and 20 cc of n-hydrochloric acid. the Hydrochloric acid solution is washed with 30 cc of ether and then with 16 cc of sodium hydroxide solution (d = 1.33) made alkaline. The striking oily base becomes 50 cc and then extracted twice with 20 cc benzene each time. The combined benzene extracts are with Washed 30 cc of water and then dried over sodium sulfate. One distills the benzene at a pressure of 20 mm Hg column and rectified the residue (16 g) in vacuo. In this way, 11.2 g of 10 - [3 '- (4 "- methylpiperazino) - propyl - (1) J -3-azaphenthiazine; Bp 0.15 205 to 2120C.

This is done by adding ethanolic hydrochloric acid to an ethanolic Solution of the base produced trihydrochloride melts at 260 to 2620 C (chromium block according to Maquenne).

Example 13 One works under the same conditions as in the example 7, but replaces the 3-azaphenthiazine with the same amount of 4-azaphenthiazine.

7.15 g of 10- [2 ', 3'-bis (dimethylamino) propyl- (t) J4-azaphenthiazine are obtained in this way as a yellowish, very viscous oil, mostly at a pressure of 0.5 mm Hg column Distilled between 196 and 199 "C.

Example 14 8 g of 10- (3'-chloropropyl-l ') 3-azaphenthiazine and then 30 cc of a 336/0 benzene solution of dimethylamine. The tube is closed and heated to 1000 ° C. for 7 hours.

After cooling, you open the tube, chased away by heating the water bath, the solvent and the excess amine, dissolves the residue Add 20 cc of 100% hydrochloric acid and 30 cc of water and then extract twice each with 25 ccm of ether. The aqueous portion is then treated with activated charcoal and with 10 cc sodium hydroxide solution (36 "Be) are added. The organic base that is released is then added extracted four times with 25 cc ether each time. The ether solution is twice with 20 ccm Water washed and over anhydrous Dried sodium sulfate. Then you chase away the solvent and receives 4.6 g of 820/0ges 10- [3'-dimethylamino-propyl- (1 ')] -3-azaphenthiazine. This base gives a monopicrate, F. 1680C, a dipicrate, F. 2360C, and an oxalate, F. 160 to 162 "C. The mixed melting point with the salts according to Example 5 is none Melting point depression.

The 10- (3'-chloropropyl-1 ') 3-azaphenthiazine used as the starting material is the action of 9 g of 3-chloro-1-bromopropane on the sodium derivative of 8.7 g of 3-azaphenthiazine, prepared using sodium amide, were obtained. That way it gets 10.5 g of 10- (3'-chloropropyl) -3-azaphenthiazine in the form of an amber-colored, viscous oil.

Example 15 150 cc of toluene and 8 g of 1-azaphenthiazine are placed in a flask and sodium amide, made from 1.1 g of sodium and 200 cc of anhydrous ammoiac and refluxed until the evolution of ammonia ceased. then 6.5 g of 1-chloro-2-methyl-3-dimethylamino-propane are added continuously over a period of 30 minutes with stirring and reflux in the form of a 2.1 normal toluene solution. It is kept boiling for another hour to reflux and after cooling are successively and in portions 200 ccm of distilled Water and 25 cc of 200/0 hydrochloric acid. It is filtered through kieselguhr that previously treated with common salt and repeatedly calcined, the toluene phase separates and treats the aqueous phase with 200 cc of ether. The aqueous phase is then washed with sodium hydroxide solution made alkaline and then the released phenthiazine derivative once with 200 cc and extracted four times with 150 cc of ether each time. The ether extracts are with Treated activated charcoal, dried over anhydrous sodium sulfate and then distilled. This gives 8 g of a residue which, after rectification, 5.4 g of 10- [2'-methyl-3'-dimethylamino-propyl- (l ') Gives 1-1 -azaphenthiazine, bp 0.2 183 to 187 "C.

This base is then made by adding 2.3 g of finely ground oxalic acid to their hot, ethanolic solution (5.4 g base in 200 ml alcohol) in the oxalate convicted. It is cooled, left to stand in the refrigerator for 48 hours, and the formed ones are filtered off Crystals off, wash with 15 cc alcohol and dry. 4.5 g of oxalate are obtained in this way; F. 2040 C.

Claims (1)

PATENT CLAIM: Process for the preparation of 1-, 2-, 3- and 4-azaphenthiazines of the general formula which are substituted in the 10-position where the benzene or pyridine nucleus can be substituted and Q is a basic radical - AZ or where Z represents a dimethyl or diethylamino, pyrrolidino, piperidino, piperazino, N-alkylpiperazino or morpholino radical, A a divalent, saturated, aliphatic hydrocarbon radical with a straight or branched chain and 2 to 6 carbon atoms, of which two or three are in a straight chain between the two nitrogen atoms, and A 'the remainder denotes, where dz stands for 0, 1, 2 or 3, and of their salts, characterized in that either a) an azaphenthiazine unsubstituted in the 10-position is allowed to react with a compound of the formula HalQ, the reaction of 4-azaphenthiazines with a compound Hal - AZ is excluded if Z is a dimethyl or diethylamino, pyrrolidino, piperidino, piperazino or morpholino radical, or b) an azaphenthiazine substituted in the 10-position by a radical - AX, in which X is a reactive represents esterified OH group, reacts with an amine of the formula HZ. Older patents considered: German Patent No. 1 001 684.