United States Patent Office Patented Sept.2,763,643 18, 1956 1. 2 will take place within the range of about 25 to 120° C. 2,763,643 Examples of preferred solvents are the nitro and nitrile compounds such as nitrobenzene, nitromethane, nitro AZACYCLOHEPTANE COMPOUNDS AND ethane, 1-nitropropane, and . METHODS FOR PREPARING THEM If the precipitate that forms from the aforesaid reaction Richard F. Tislow, Richard de Vere Huber, and Julius is large, the reaction mixture is chilled with ice- and Diamond, Philadelphia, Pa., assignors to American then treated with a large volume of relatively low boiling Home Products Corporation, New York, N. Y., a cor ketone, Such as or methyl-ethylketone. If little poration of Delaware or no precipitate forms, the reaction mixture is treated No Drawing. Application September 3, 1954, lo with a relatively non-polar solvent such as diethylether, Serial No. 454,195 heptane or . Surprisingly, an excellent granular product is obtained by adding the reaction mixture gradu 9 Claims. (CI. 260-239) ally to the non-polar solvent, rather than using the re This invention relates to azacycloheptane compounds lis verse procedure. and more particularly to bis-quaternary salts comprising The desired product obtained as a precipitate is sepa said heterocyclic rings. rated from the reaction mixture, washed with non-polar The compounds of the invention fall within the follow Solvent and dried. If further precipitation is sought, the ing general formula: product may be recrystallized from a mixture of a low 20 boiling alcohol of 1 to 5 carbon atoms and low boiling -- - - ketone having 3 to 6 carbon atoms, ether, or hydrocarbon Solvent being used additionally if the crystallization takes & N-alk-ST:i. A place too slowly. !---4, S--- The azacycloheptane reactant may be prepared as dis wherein closed in Diamond and Bruce Patent No. 2,666,050, dated XY.sm 25 Jan. 12, 1954, and in their applications Ser. Nos. 400,136. :---1 and 403,448 filed respectively on Dec. 23, 1953 and represents an azacycloheptane ring, R1 represents a lower jan. 11, 1954. Application Ser. No. 400,136 teaches the alkyl, preferably methyl, "alk' indicates a divalent alkyl method for making 4-arylazacycloheptanes having also ene of 4 to 12 carbon atoms and A stands for 30 in the 4-position either , -CONH2, -COOH, a pharmacologically non-toxic anion. Suitable salts of or -COO alkali metal. the free bases may comprise the bromides, iodides, nitrates, To make the 4-arylazacycloheptanes of application Ser. sulphates or salts of the lower aliphatic carboxylic acids. No. 400,136 one utilizes the corresponding 4-aryl-4-cyano Actually any acid may be used which is known to be azacycloheptane whose general formula is shown in the pharmacologically safe. above mentioned patent and which is made as shown by 3. 5 reactions 1, 2 and 3 therein. The cyano substituent is With regard to the azacycloheptanering represented hydrolyzed by, known procedures to form the amide or above, it may be more specifically illustrated by the -CONH2 radical. Alternatively, the amide may be structure -' , formed by reacting the 4-cyano compound with a higher alcohol and a base, as for example heptanol and potas R R. R. 40 sium hydroxide at a temperature of about 160 C. C.H.--CH-) To obtain the carboxylic acid radical, -COOH in place : /.N of the cyano group, the reaction with alcohol and base CH-CH-cfi, as above described is carried out at a higher temperature, wherein R2 and R3 stand for hydrogen or a lower alkyl, 45 in the neighborhood of 200°C. If the 4-amide compound while R4 represents either hydrogen, cyano, -COO. lower is reacted with an alkali metal hydroxide alone, the alkali alkyl, -COO. alkali metal, -CO lower alkyl, -CONH2, metal carboxylic acid salt will form. Should one merely -COOH or -O-CO"lower alkyl. wish to remove the cyano substituent, the 4-cyano com The compounds of the invention are pharmacologically pound may be heated at about 250° C. in the presence of useful in the veterinary or human field in that they have 50 alkali metal hydroxide and water. By another procedure, been found to possess curare-like, musicle-relaxing action one may decyanate, the azacycloheptane by reacting the among other pharmacological actions. Thus, in com corresponding 4-cyano compound with an alkali-metal pounds where R4 represents hydrogen, a ganglionic stimul amide in the presence of an inert organic solvent of the lating action has also been noted. Compounds showing hydrocarbon type such as hexane or benzene, or their the strongest curare-like action are those where R2 and 55 higher homologues. R3 stand for hydrogen with R4 representing an ester of The 4-acyloxy azacycloalkanes of application Ser. No. the -COO-lower alkyl type, and with the alkylene chain 403448 may be prepared from the corresponding 4-cyano having from 4 to 10 carbon atoms. - compounds of Patent No. 2,666,050 described previously. The compounds may be prepared by heating the aza Thus, the cyano compound is subjected to decyanation as cycloheptane with an alkylene dihalide preferably using 60 above described and the decyanated product is then reacted a molar ratio of at least 2:1 azacycloalkane to halide. with a tetra lead salt of a lower aliphatic carboxylic acid, It has been found that substantial yields may be with the reaction being carried out in the presence of the achieved if the reaction takes place in a solvent and if corresponding aliphatic acid. As an example, the reaction. the solvent medium is highly polar, having a high dielec to replace the cyano radical with the acyloxy radical tric constant or moment under standard conditions. 65 -O-CO-CH3 is carried out using lead tetra-acetate (20° C.) of about 2.5 Debye units or greater. The dielec in the presence of as a solvent, the temperature tric constant should be about 10 (epsilon) or greater and of reaction being in the neighborhood of about 80 to preferably from about 15 to 40 when measured under 85 C. standard conditions. Additionally the highly polar sol The following examples disclose the invention in vent should have a boiling point above about 70° C. since 70 specific detail. It should be clearly understood that the the reaction goes best and with the greatest yield within. examples are merely for illustration and are not to be. the range of about 70 to 100° C. although the reaction construed as limitative of the invention. 2,768,643 3 4. EXAMPLE 1. EXAMPLE 4. 1,4-bis-(4-cyano-1-methyl-4-phenyl-azacycloheptane 1,5-bis-(1-methyl-4-phenyl-azacycloheptane-onium)- onium)-tetramethylene dibromide pentamethylene dibromide - 5 1-methyl-4-phenyl-azacycloheptane 2.0 g. (0.011 4-cyano-1-methyl-4-phenyl - azacycloheptane, 2.6 g. mole) and 1,5-dibromopentane, 1.2 g. (0.0050 mole) in (0.012 mole), 1,4-dibromobutane, 1.1 g. (0.0050 mole), 8 m. of benzonitrile were heated at 100° C. for about and nitromethane, 8 ml, were mixed and heated at 100 3 hours. White crystals appeared after first 5 minutes. C. for 6 hours. The product was precipitated by the After cooling to room temperature, it was treated addition of dry ether. After trituration with ether, it 0 with acetone with stirring, filtered, and washed on the was crystallized by dissolving in a hot mixture of acetone filter with acetone and ether. This gave a white solid and (minimum), evaporating and cooling. product that was recrystallized from a mixture of acetone The desired product melted at 226-28° C. (decomposi- and methanol (minimum) and melted at 238-239 C. tion). Analysis.-C31H48N2Br2: Analysis.-C32H44N4Br2: 5 - - -- ,percent Bromine,percent Nitrogen, Bromine, -a-worm------percent percent Caled------4.61 26.3 Found------4.85 - 26.6 Caled------8.68 24.8 20 Found------3.96 24, 8 EXAMPLE 5 1,6-bis-(1-methyl-4-phenyl-azacycloheptane-onium)- EXAMPLE 2 hexamethylene dibromide and dinitrate 1,5-bis-(4-cyano-1-methyl-4-phenyl-azacycloheptane- 25 methyl-4-phenylazacycloheptane, 1.9 g (0.019 (Englicientiocher mole), 1,6-dibromohexane, 1.2 g (0.0050 mole), and nitrobenzene 3.0 ml, were mixed and heated at 100° C. 4-cyano-1-methyl-4-phenyl - azacycloheptane, 2.6 g. for 1.5 hours. After cooling, the thick mass was mixed (0.012 mole), 1,5-dibromopentane, 1.2 g (0.0050 mole), well with acetone to disperse the crystals and filtered, and nitrobenzene, 8 ml, were mixed and heated at 100° 30 The solid was washed and dried under ether for 4 days. C. for 6 hours. After cooling in an ice-bath, acetone, The desired product melted at 200-202°C. 15 ml, was added with stirring. The solid, after filter- Analysis.-C32H5ON2Br2: ing, was triturated well with dry ether and dried at 50 C. The desired product melted at 205-210° C. It may Nitrogen, Bromine, be recrystallized from acetone and methanol (minimum). 35 percent percent Analysis.-C33H46N4Br2: Calcd--...-- 4.52 25.8 Found------4.64 23.9 Nitrogen, Bromine, percent percent 40 Silver nitrate, 0.55 g. (0.0032 mole), in 10 ml. of distilled water was added dropwise with stirring to 1.0 g. (0.0016 Sisir:::::::::::::::::::::::::::: S- 33 mole) of 1,6-bis-(4-phenyl-1-methylazacycloheptane: - - - - onium)-hexamethylene dibromide in 25 mi. of distilled water at room temperature. After stirring 15 minutes EXAMPLE 3 more, the mixture was filtered. The water of the clear 4 filtrate was removed under a pressure of 10 mm. and 1,4-bis-(1-methyl-4-phenyl-azacycloheptane-onium)- heated with a hot water bath. The residue was made tetramethylene dibromide granular by trituration with anhydrous ether, filtered, and - dried over P2O5 at 25 C. (5 mm.). The water soluble A mixture of 0.05 mole (10.7 g.) 4-cyano-1-methyl-4- product started to melt at 750° C. phenylazacycloheptane and 0.11 mole (4.3 g) sodamide 60 Analysis for C32H5ON4O6: in 100 ml. of toluene was refluxed while stirring for 6 hours. The cooled mixture was washed with water, then Carbon Hydrogen Nitrogen the toluene layer extracted with acid, the acid extract ------washed with ether, treated with and Caled------65.6 8.53 9.56 the reaction product extracted with ether. The ether ex- 55 Found 60.7 8.5 9,35 tract was dried, filtered, and distilled. The product, 1 methyl-4-phenyl-azacyclophetane was collected at 88- EXAMPLE 6 90°Anal C. (0.25 Caled mm.); forcision: in 29 1.5288. C, 82.47; H, 10.12; N, Irbising:it::philohep-hic-?a- es - 7.40. Found: C, 82.20; H, 10.41; N, 7.51. " 4-carbethoxy-1-methyl-4-phenvi loheptane, 2.6 1-methyl-4-phenyl-azacycloheptane, 2.0 g. (0.011 O 6i e y a". y- eny Eye E. 5 9. mole)ml. of andacetonitrile 1,4-dibromobitani were heated at 82°(0.60so C. for inole), about 38 and(090 nitrobenzene, mile), “bronobutan, 8 ml, were mixed 0.6 and g heated(0.000 at in 100 hours. White crystals appeared. The mixture was C. for 18 hours. Many crystals. At room temperature cooled, filtered and washed with acetone-ether on the 65 it was mixed well with 100 ml. acetone, then filtered. filter. It was dried overnight. This gave a white solid The solid was washed with acetone and then washed that melted at 223-25 C. and dried under ether. This gave the desired product Analysis.--CaoH46N2Br2: that melted at 207-210° C. with decomposition. O o Analysis.-C36H54N2O4Br2:

Nitrogen, Bromine, 70 Nitrogen, Bromine, percent percent percent percent

Caled------4.71 26.9 Caled------3.79 21.7 Found------4.39 27.5 Found------4.32 21.8 75 2,768,648 5 6 EXAMPLE7 Analysis-C40H2N2O4Br2: 1,5-bis-(4-carbethoxy-4-phenyl-1-methyl-azacyclohep tane-onium)-pentamethylene dibromide Nitrogen, Bromine, percent percent

4-carbethoxy-4-phenyl-1-methyl-azacycloheptane, 1.3 g. 5 a--w (0.0050 mole), 1,5-dibromopentane, 0.57 g. (0.0025 Caled------3.52 20. mole), and nitrobenzene, 2 ml, were mixed and heated Found------3.50. 18.3 at 80-100° C. for 17 hours. After cooling, the mixture was diluted with 10 ml. of acetone, filtered, and added EXAMPLE 11 dropwise with stirring to 200 ml...of dry ether. The granular precipitate was washed by trituration with dry 10 1,10-bis-(4-carbethoxy - 1 - methyl - 4 - azacycloheptane ether, filtered quickly, and dried at 25° C. (5 mm.) over otium)-decamethylene diiodide P2O5. It amounted to 1.6 g. (85%) and started to melt 4-carbethoxy-1-methyl-4-phenyl-azacycloheptane, 2.9 g. at 85° C. (0.011 mole), 1,10-diiododecane, 2.0 g (0.0050 mole), Analysis-For C3H56N2O4Br2: and nitrobenzene, 5 ml., were mixed together and heated 5 15 hours at 100° C. After cooling down to 5 °C, and Nitrogen, Brontine, mixing well with acetone some crystallization began. But percent percent after cooling down with a Dry-Ice and acetone bath and adding dry ether gradually, the main body of the product Calcd------3.72 21.3 20 came out of solution at a faster rate. It was filtered off, Found------4.08 20.0 washed with ether, and then reprecipitated by adding its EXAMPLE 8 solution in acetone-methanol (minimum) dropwise to 1,6-bis-(4-carbethoxy-1-methyl-4-phenyl-azacyloheptane stirred ether. The product melted at 190-195 C. onium)-hexamethylene dibromide 25, 4-carbethoxy-1-methyl-4-phenyl-azacycloheptane, 2.6 g. Nitrogen, Iodine, (0.010 mole), 1,6-dibromohexane, 1.2 g. (0.0050 mole) percent percent and nitrobenzene, 5 ml., were mixed and heated for 5 Calcd------3.06. 27.7 hou's at 100° C. The resultant solution was treated with Found.------2.84 26.5 ether (after cooling) in order to precipitate the product 30 - which was then triturated well and dried under ether. EXAMPLE 12 This gave the desired product that began to melt at 65° C. 1,4-bis-(4-cyano-1,2-dimethyl-4-phenyl-azacycloheptane onium)-tetramethylene dibromide Nitrogen, i3rottline, 85 To a solution of 1.43 moles (167.6 g.) of phenylacetoni percent percent trile in 250 ml. of toluene was added 1.29 mole (50.3 g.) of sodamide at Such a rate as to maintain the temperature 20.9 at 35-40°. The addition was effected under a nitrogen 20.6 atmosphere with stirring. After an additional 2 hours 40 at 35-40°, the mixture was cooled to 5. A dry toluene EXAMPLE 9 solution of 1-dimethylamino-2-chloropropane, prepared 1,7-bis-(4-carbethoxy-1-methyl-4-phenyl-azacycloheptane the same day from 1.23 moles (193 g.) of the hydro onium)-heptamethylene dibronide chloride and 1.37 moles (54.6 g.) of sodium hydroxide in 500 ml. of water and 250 ml. of toluene, was then 4-carbeth.cxy-1-methyl-4-phenyl-azacycloheptane, 2.6 g. added dropwise at 5-10. This temperature was main (0.010 mole), 1,7-dibromoheptane, 1.3 g. (0.0050 mole), $ tained an additional hour, then it was allowed to rise to and nitrobenzene, 4 ml., were mixed and heated 18 hours room temperature and stand overnight. The mixture was at 100° C. After cooling in an ice-bath, the reaction washed with water, extracted with 6.N-hydrochloric acid, Imixture was diluted with 30 ml. of acetone and added the acid extract washed with ether, basified, and extracted dropwise to ether with continuous stirring. The precipi with ether. The ether extract was dried, filtered, and tate was washed and dried under ether for 5 days. This distilled. A mixture of the isomers of the butyronitriles gave the product that began to melt at 85 C. boiled at 95-8 (0.2 min.), n28 1.5028. Analysis.-C39HeoN2O4Br2: To a stirred solution of 0.85 mole (172.8 g.) of a mix ture containing 4-dimethylamino-3- and 4-methyl-2-phen Nitrogen, Hroline, yl-n- in 1.2 . of toluene under a nitrogen at percent percent mosphere, was added portionwise 1.09 mole (42.6 g.), of sodamide. The rate of addition was controlled so as to Caled.-- 8 to 20.5 maintain the temperature at 35-40. This temperature Found------3.35 19.3 was kept an additional 2 hours. The red solution was cooled to -30 in a Dry Ice-acetone bath, and 0.898 mole EXAMPLE 10 fiC) (141.3 g.) of trimethylene chlorobromide in 250 ml. of 1,8-bis-(4-carhethoxy-1-methyl-4-phenyl-azacycloheptane toluene was added at such a rate as to maintain the tem oniini)-octamethylene dibromide perature between -25 and -15°. This temperature was 4-carbethoxy-1-methyl-4-phenyl-azacycloheptane, 2.6 g. maintained an additional 4 hour, then the stirred mixture was allowed to warm to room temperature and stand over (0.010 mole), 1,8-dibromo-octane, 1.3 g. (0.0050 mole). 35 night. The mixture was filtered and the toluene distilled and nitrobenzene, 4 m., were mixed and heated 18 hours from the filtrate at 30-35 (35 mm.). The liquid residue at 10 C. After cooling in an ice-bath, the reaction mix contained a mixture of the 1- and 2-methyl chlorhexanes. ture was diluted with 30 ml. of acetone. On standing Liquid residue from the proceding step was diluted to 30 minutes, crystallization began. By further dilution. 850 ml. with nitrobenzene and the resulting solution with acetone (170 ml.) and ice-cooling, more crystals. heated at 100 for 17 hours to precipitate the quaternary appeared. These were filtered off and dried under ether. salt. The cooled mixture was filtered and the precipitate More product was obtained by concentration of the mother washed several times with acetone to give essentially pure liquor and addition to ether. The product began to melt 2-methyl quaternary salt, M.P. 251-251.5 dec. Recrys at 150° C. This could be recrystallized from a nitro tallization from gave fine white crystals, M. P. benzeneacetone mixture. 75 259 dec. 2,763,648 Anal-Calcd. for C18H23CIN2: C, 69.00; H, 8.32; N, Analysis.-C32H50NaBra: , 10.05; Cl, 12.70. Found: C, 68.46; H, 8.73; N, 10.29; Cl, 12.14. Nitrogen, Bromine, The filtrate from the quaternary salt contained the 2 percent percent 5. - methyl chlorhexane unchanged. 25.8 0.378 mole (105.7 g.) of the 2-methyl quaternary was Calcd------23,3 suspended in 378 ml of undecanol (B. P. 225). The Found------4.57 mixture was heated to its reflux temperature with stirring, whereupon the solid dissolved with evolution of methyl EXAMPLE 1.5 chloride gas. The stirring and refluxing was continued ( 1,5-bis-(1,2-dimethyl-4-phenyl-azacycloheptane-onium)- until the evolution of gas was negligible. The Soiliigi penta- dibromide was cooled under nitrogen and extracted with 6 N-hydro 1,2-dimethyl-4-phenyl-azacycloheptane, 2.0 g (0.010 chloric acid. The acid extract was washed with ether, mole), 1,5-dibromopentane, 1.2 g (0.0050 mole), and basified, extracted with ether, the ether extract dried, nitrobenzene, 3 ml., were mixed and heated 20 hours at filtered, and the solvent removed. 100° C. The solution that resulted was cooled to 25 C. Distillation of the liquid residue gave the 2-methyl and diluted with acetone. By adding a large volume of cyano base, B. P. 123-6 (0.2 mm.), n° 1.5341, da? ether to this, the product was precipitated. After washing 1.019. Anal-Calcd. for C15H2ON2: C, 78.90; H, 8.83, and drying with ether, the desired product started to melt 20 at 75° C. M69.54.4-cyano-1,2-dimethyl-4-phenyl-azacycloheptane, Found: C, 78.50; H, 8.78; M69.40. 2.3 g. Analysis.-C33H52N2Br2: (0.010 mole), 1,4-dibromobutane, 0.86 g. (0.004 mole), Nitrogen, Brontine, and nitrobenzene, 7.5 ml., were mixed and heated 23 hours percent percent at 100° C. Crystals appeared. At room temperature, 50 ml. of dry ether was added with good stirring, the mix 2 5 Caled------ture was filtered, and the solid was washed with acetone Found------and then ether by trituration. After drying, there was obtained the desired product that began to melt at 200 C. EXAMPLE 16 Analysis.-C33H46N4Br2: - 1,4-bis-(1,3-dimethyl-4-phenyl-azacycloheptane-onium)- 30 tetra-methylene dibromide Nitrogen, Bromine, percent percent Following the procedure of Example 3, and starting with 0.05 mole (11.4 g.) 4-cyano-1,3-dimethyl-4-phenyl Calcd------8.50 24.3 azacycloheptane, the product obtained is 1,3-dimethyl-4- Found------7.34 21.6 35 phenylazacycloheptane, B. P. 98-100° C. (0.25 mm.), n° 1.5251. EXAMPLE 13 Anal.--Calcd. for C14H21N: C, 82.65; H, 10.40; N, 6.88. 1,5-bis-(4-cyano-1,2-dimethyl-4-phenyl-azacycloheptane Found: C, 82.06; H, 10.35; N, 6.60. onium)-pentamethylene dibromide 1,3-dimethyl-4-phenyl-azacycloheptane, 2.1 g (0.010 40 mole) 1,4-dibromobutane, 0.86 g. (0.0040 mole), and 4-cyano-1,2-dimethyl-4-phenyl-azacycloheptane, 2.3 g. nitrobenzene, 5 ml. were mixed and heated 21 hours at (0.010 mole), 1,5-dibromopentane, 0.92 g. (0.0040 mole), 100° C. After cooling the crystalline mass to 25 C., and nitrobenzene, 7.5 ml, were mixed and heated 23 hours it was mixed with a large volume of acetone and allowed at 100° C. No crystals: At room temperature, 50 ml. of to stand 16 hours. It was then filtered, and the solid was ether was added gradually with good stirring to precipitate 5 washed and dried under ether. The product melted at the product which was then reprecipitated from acetone 216-218 C. with decomposition. methanol (minimum) with ether and finally dried under Analysis.-C32H5ON2Br2: ether. The product started to melt at 100° C. Analysis.-C34H48N4Br2: Nitrogen, Bromine, percent percent Nitrogen, Bronine, percent percent Caled------4.50 25.7 Found------4.24 25.8 Calcd------8, 32 23.8 Found------6.96 21.1 5 s EXAMPLE 17 1,5-bis-(1,3-dimethyl-4-phenyl-azacycloheptane-onium)- EXAMPLE 1.4 penta-methylene dibromide and sulfate 1,4-bis-(1,2-dimethyl-4-phenyl-azacycloheptane-onium)- tetra-methylene dibromide 60 1,3-dimethyl-4-phenyl-azacycloheptane, 2.1 g (0.010 mole), 1,5-dibromopentane, 0.92 g. (0.0040 mole), and In the same manner as taught in Example 3, and start nitrobenzene, 5 ml., were mixed and heated 21 hours at ing with 0.05 mole (11.4 g) of 4-cyano-1,2-dimethyl-4- 100° C. After cooling the crystalline mass to 25 C., phenyl-azacycloheptane, one may obtain the free base it was mixed with a large volume of acetone and allowed 1,2-dimethyl-4-phenylazacycloheptane, B. P. 106-108 C. to stand overnight. It was then filtered, and the solid was (0.2 mm.), n°7 1.5255. washed and dried under ether. The dibromide melted at Anal-Calcd. for C14H2N: C, 82.65; H, 10.40; N, 6.88. 213-215 C. with decomposition. Found: C, 82.25; H, 10.35; N, 6.66. Analysis.-C33H52N2Br2: 1,2-dimethyl-4-phenyl-azacycloheptane, 2.0 g (0.010 0 mole), 1,4-dibromobutane, 1.1 g (0.0050 mole), and Nitrogen, Bronine, nitrobenzene, 3 ml., were mixed and heated 20 hours at percent percent 100° C. The crystalline mass was cooled down to room temperature, mixed with acetone, and filtered. The solid was washed and dried under ether. The product started to melt at 80° C. . 75 2,768,648 9 10 Silver sulfate, 0.31 g (0.0010 mole), in 75 ml. of warm 20 hours at 80-100° C. After cooling down to room distilled water was added dropwise with stirring to 0.65 g. temperature, it was diluted with acetone, filtered, and the (0.0010 mole) of 1,5-bis-(1,3-dimethyl-4-phenyl-azacyclo clear filtrate added dropwise with good stirring to a large heptane-onium)-pentamethylene dibromide in 20 ml. of volume of dry ether. The white precipitate was washed distilled water at room temperature. After stirring 15 well with ether by trituration and dried over P2O5. The minutes more, the mixture was filtered. The water of the product started to melt at 140 C. clear filtrate was removed under a pressure of 10 mm. and Analysis for C41H64Br2N2O4: heated with a hot water bath. The residue was dissolved in an acetone-methanol mixture, filtered through carbon Nitrogen, Bronine, black, and the clear filtrate added dropwise with stirring O percent percent to a large volume of ether. The precipitate was made granular by trituration with dry ether. After filtering and Calcd------3.46 19.8 drying over P2O5 at 25 C. (5 mm.), the water-soluble Found------3, 60 8.7 sulfate salt was obtained which started to melt at 70° C. Analysis for C33H52N2O4S: We claim: 1. A quaternary salt containing the cation Carbon Hydrogen Nitrogen. Sulfur COO-lower alkyl lower alkyl-oo: Caled------89.3 9.6 4.90 5.60 Found------65.9 9,37 4, 35 4.9 20 CH-C-OH,-c.N-alk-N uchi-OH,--C.H. 1 N CH-CH-CHCH C CH-CH-CH EXAMPLE 18 wherein "alk' stands for an alkylene radical of 6 to 10 1,6-bis-(1,2-dimethyl-4-phenyl-azacycloheptane-onium)- carbon atoms. hexamethylene dibromide 25 2. The compound, 1,6-bis-(4-carbethoxy-1-methyl-4- 1,2-dimethyl-4-phenyl-azacycloheptane, 1.6 g. (0.0080 phenyl-azacycloheptane-onium)-hexamethylene dihalide. mole), 1,6-dibromohexane, 0.97 g. (0.0040 mole), and 3. The compound, 1,7-bis1(4-carbethoxy-1-methyl-4- nitrobenzene, 2.5 ml., were mixed and heated 17 hours phenyl-azacycloheptane-onium)-heptamethylene dihalide. at 100° C. After cooling down to room temperature it 4. The compound, 1,8-bis-(4-carbethoxy-1-methyl-4- was stirred and treated with 50 ml. of acetone to give a 30 phenyl-azacycloheptane-onium) -octamethylene dihalide. gummy precipitate. After decanting the supernatant 5. The compound, 1.9-bis-(4-carbethoxy-1-methyl-4- solution, the gum was washed with acetone, dissolved in phenyl-azacycloheptane-onium)-nonamethylene dihalide. acetone-methanol (minimum), filtered through carbon 6. The compound, 1,10-bis-(4-carbethoxy-1-methyl-4- black, and added dropwise with stirring to 200 ml. of dry phenyl-azacycloheptane-onium)-decamethylene dihalide. ether. The solid precipitate was triturated with and dried 7. The process comprising dissolving in an inert highly under ether. This gave the desired product that began to polar organic solvent an azacycloheptane reactant having melt at 95 C. the formula Analysis.-C34H54N2Br2: go O-lower alkyl

Nitrogen, Bromine, 40 C.H.--CH-ceN-CH percent percent / CH-CH-CH Calcd------4.3 24.6 and an alkylene dihalide reactant having from 6 to 10 Found------4.93 24.3 carbon atoms, said solvent having a boiling point above 45 about 70° C. and a dipole moment of at least about EXAMPLE 19 2.5 Debye units, heating the reactants to a temperature in the range of about 70 to about 100° C. thereby form 1,4-bis-(4-carbethoxy-1-methyl-4-phenyl-azacycloheptane ing as a desired product a quaternary ammonium salt onium)-1-methyl-tetramethylene dibromide containing the cation 4-carbethoxy-1-methyl-4-phenyl-azacycloheptane, 2.6 g. (0.010 mole), 1,4-dibromopentane, 1.1 g (0.0050 mole), 50 g O O-lower alkyl lower alkyl O og CH-C-CH-CH CE-CIH-C-CFs and nitrobenzene, 4.0 ml., were mixed and heated 20 N+ +/ hours at 90-100° C. After cooling down to room tem N-alk-N perature, it was diluted with 25 ml. of acetone. The clear 1. N yellow solution was added dropwise with stirring to CEI-CH-Ca CH-CH-CH 200 ml. of anhydrous ether over a period of 2 hours to 55 CE: CH precipitate a solid product. The supernatant solution was wherein "alk” stands for an alkyleen radical of 6 to 10 decanted, and the yellow solid was washed and dried under carbon atoms, ether for 2 days. After drying at 25 C. (5 mm.) over 8. The process of claim 7, wherein the reaction products P2O5 the product obtained began to melt at 70 C. 60 are commingled with a relatively non-polar solvent thereby precipitating the desired product. 9. The process of claim 8, wherein the reaction products Nitrogen, Bromine, are gradually added to said relatively non-polar solvent. percent percent 65 References Cited in the file of this patent Calcd------3.73 21.3 Found------4.37 21. UNITED STATES PATENTS 2,666,050 Diamond et al. ------Jan. 12, 1954 EXAMPLE 20 2,667,493 Slack et al. ------Jan. 26, 1954 1.9-bis-(4-carbethoxy-1-methyl-4-phenyl-azacyclo 70 heptane-onium)-nonamethylene dibromide OTHER REFERENCES MacArdle: "Use of Solvents in Synthetic Org. Chem." 4-carbethoxy-1-methyl-4-phenyl-azacycloheptane, 1.3 g. (Van Nostrand) pp. 151-5 (1925). (0.0050 mole), nonamethylene dibromide, 0.70 g. (0.0025 Collier et al.; Nature, vol. 164, pp. 491-2 (1949). mole), and nitrobenzene, 2.0 ml., were mixed and heated 75 Jones, Chem. Abst., vol. 45, col. 619 (1951).