IE44098B1 - Aminoalkylammonium compound - Google Patents

Description

Method I - Bromo - Ν,Ν,Ν - trimethyl - 1 - propanaminium halide is reacted with methylamine in an inert solvent, e.g., an alkanol such as ethanol or methanol, dimethyl5 formamide, water or mixture thereof at temperatures from 0°C. to 30°C. for from 4 to 24 hours. The term inert solvent used in this and following instances signifies that the solvent does not react with the other reactants or products thereof.

The product Ν,Ν,Ν - trimethyl -/3- (methylamino)_7 - 1 - propanaminium halide hydrobromide is suspended in a suitable inert solvent, preferably methanol, ethanol or water, and an equivalent of base, preferably an alkali metal or alkaline-earth metal hydroxide or an alkali metal carbonate, is added slowly during a period of from 10 minutes to 5 hours. The temperature is maintained at 0°C. to 50°C. during the addition of the base. The reaction mixture is concentrated to dryness under reduced pressure, and the product Ν,Ν,Ν - trimethyl 20 /3 - (methylamino)/1 - 1 - propanaminium halide is extracted. from the residue with a suitable solvent such as acetonitrile.

The product Ν,Ν,Ν - trimethvl -/3- (methylamino)/1 - 1 - propanaminium halide may be purified by recrystallization from an alkanol-ether solvent mixture, e.g., isopropanol-diethyl-ether, or it may be used without further purification in the next step, viz. treatment with oxetane. This step is preferably carried out in aqueous solution with from 1.1 to 3 equivalents of oxetane in a sealed vessel at a temperature of from 50°C. to 150°C. for a period of from 10 to 24 hours. The product is isolated by concentration of the reaction mixture to dryness and extraction into a suitable solvent such as acetonitrile from which it crystallizes on evaporation of the solvent. The product 3 - /S' - (3 - hydroxypropyl) - 5 - Ν' - methylamino/ - Ν,Ν,Ν - trimethyl - 1 - propanaminium halide, may be purified by recrystallization from acetonitrile.

Prior to the conversion of the 3 - hydroxypropyl to 3 - halopropyl, the intermediate 3 - £3' - 3 hydroxypropyl) - Ν' - methylamino/ - Ν,Ν,Ν - trimethyl 1 - propanaminium halide may suitably be converted to a propanaminium analogue, preferably one bearing the same halide counter anion as the halogen that will displace the hydroxyl function of the hydroxypropyl residue, although other counter anions Ya are suitable. The conversion is accomplished by passing an aqueous solution of the 1 - propanaminium halide acidified with an appropriate acid through an appropriate anion-exchange resin in the desired anionic form.

Alternatively, the halide anion of the intermediate may be exchanged for OH-, which in turn may be acidified with HY or exchanged for Ya by passage of an appropriately neutralized solution through an anion-exchange resin on the Ya cycle.

Concentration of the aqueous eluate to dryness yields the desired compound, which on treatment with an appropriate halogenating agent such as thionyl chloride, phosphorus oxychloride phosphorus pentachloride, thionyl bromide or phosphorus pentabromide yields a 3 - /Ν' - (3 - halopropyl) - Ν' - methylamino/ - Ν,Ν,Ν - trimethyl - 1 - propanammonium halide acid - addition salt. The product is usually purified by concentration of the reaction mixture and leaching of the residue with an appropriate ether solvent. The residue is taken up in water and the solution is treated with activated carbon. The aqueous solution is then filtered and concentrated to dryness under reduced pressure and crystallized from a mixed solvent such as isopropanol - acetone. 440S8 Method II In the second process, compound I is synthesized in one step by treating Ν,Ν,Ν - trimethyl -/3(methylamino)J7 - 1 - propanaminium halide with one equivalent of a 1,3 - dihalotrimethylene compound such as 3 - chloro - 1 - iodopropane, 3 - bromo - 1 chloropropane, or 1,3 - dibromopropane, in an inert solvent such as acetonitrile. Insoluble by-products are removed by filtration, the reaction mixture is concentrated to dryness, and the product is extracted from the residue vzith an appropriate solvent such as chloroform or methylene chloride. Counter anion exchange may be accomplished as described above and the product may be crystallized from isopropanol - ether or isopropanol acetone mixtures.

Method III In the third synthesis of compound I, 3 - aminopropanol is added to acrylontrile, yielding 3-(2cyanoethyl)aminopropanol, which in turn is converted in two steps to 3 - /8 - (2 - cyanoethyl) - N - fcrmylamino7propanol. The nitrile residue of the latter is catalytically reduced to a primary amine residue which in turn is exhaustively alkylated with a methyl halide to yield a 3 - /Ν' - formyl - Ν' - (3 - hydroxypropyl)amino/ - Ν,Ν,Ν - trimethyl - 1 - propanaminium halide. Reduction of the formyl residue in the latter to a methyl function is accomplished by treating this intermediate compound vzith a mixture of formic acid and formalin at 60°C. to 1OO°C. for 10 to 24 hours, followed by acidification with the appropriate aqueous hydrogen halide and concentration to dryness, yielding a 2 £l· -(3- hydroxypropyl) - Ν' - methylamino/ - Ν,Ν,Ν trimethyl - 1 - propanaminium halide hydrohalide. Conversion of this compound to 3-/N' -(3- halopropyl) Ν' - methylamino/ - Ν,Ν,Ν - trimethyl - 1 - propanamin44 0 9 8 ium halide hydrohalide is accomplished as described in Method I above, and anion exchange, if desired is effec· ted by any of the previously described procedures.

The following Examples, in which temperatures are on the Centigrade scale and Dowex and Celite are trade marks, are included as illustrative of the invent· ion.

EXAMPLE 1 Step 1-N,N,N - Trimethyl - /3 - (methylamino)/ - 1 propanaminium Bromide Hydrobromide To a stirred solution of 40% aqueous methylamine 229.57 g. (7.4 moles) cooled in an ice-water bath is added in three equal portions a solution of 3 - bromo Ν,Ν,Ν - trimethyl - 1 - propanaminium bromide (452.66 g., 1.78 moles) in 400 ml. of distilled water over a period of forty minutes. The ice-water bath is removed and the mixture is stirred for 4.0 hours. After this time the reaction mixture is evaporated under reduced pressure and the crystalline residue is dried in vacuo. Recrystallization of the residue from absolute ethanol gives 442.62 g. (87.6%) of product; m.p. 185°-189° + (dec.); NMR (D20) 8: 2.76 (3H, s, -NH2CH3); 3.16 (9H, S, + -N(CH3)3). Analysis calculated for c7H20N2Br2: c. 28.79; H, 6.90; N, 9.59; Br, 54.72. Pound: C, 28.63; H, 7.27; N, 9.47; Br, 54.49. Step 2-N, N,N - Trimethyl -/3- (methylamino)./ - 1 - propanaminium Bromide To a stirred suspension of 876.0 g. (3.0 moles) of Ν,Ν,Ν - trimethyl -/3- (methylamino)/ - 1 - propanaminium bromide hydrobromide in 2.75 litres of absolute methanol at room temperature is added a freshly prepared solution of sodium hydroxide (120.0 g., 3.0 moles) in 1.0 liter of absolute methanol over a period of 1.0 hour. The reaction mixture is evaporated under reduced pressure and the solid residue is shaken with 750 ml. of acetonitrile. The insoluble sodium bromide is removed by filtration and the filtrate is evaporated. The solid residue is dried in vacuo to give a quantitative yield of white, crystalline hygroscopic product which may be used without further purification or can be recrystallized from isopropanol - ether. NMR (DjO) δ: 2.28 + (3H, S, -NHCH3); 3.11 (9H, S, -N(CH3)3· Step 3-3 - /N’ - (3 - Hydroxypropyl) - Ν' - methylamino/ - Ν,Ν,Ν - trimethyl - 1 - propanaminium Bromide A mixture of 20 g. of oxetane (0.34 mole), 32.8 g. of Ν,Ν,Ν - trimethyl -/3- (methylamino)/ 1 propanaminium bromide (0.156 mole) and 22 ml. water is heated in a sealed tube at 100° for 15 hours. The solution is evaporated in vacuo and the residue is dissolved in 50 ml. of acetonitrile and filtered. Upon evaporation the desired product crystallizes. The product may be reerystallized from acetonitrile.

Analysis calculated£or c10H25N20Br: c, Found: 44.61; H, 9.36; N, 10.41; Br, 29.68. c, 44.59; H, 9.02; N, 10.27; Br, 29.84. Step 4-3 - /Ν' ~ (3 - Chloropropyl) - Ν' - methylamino/ - Ν,Ν,Ν - trimethyl - 1 - propanaminium Chloride Hydrochloride A sample of 44.4 g. of product from Step 3,344098 - 9 /Ν' - (3 - hydroxypropyl) - Ν' - methylamino/ - Ν,Ν,Ν trimethyl - 1 - propanaminium bromide,is dissolved in 500 ml. of water and acidified to pH 2 with concentrated hydrochloric acid. The solution is passed through a column of Dowex 1-X2 chloride from ion exchange resin and the eluant is evaporated under reduced pressure .

The residual viscous oil is dried in vacuo and treated with thionyl chloride (25 ml.) added dropwise with stirring during one hour. The solution is heated at 50° for 1.5 hours and then evaporated under reduced pressure.

The residue is washed with ether (2x200 ml.) and dried in vacuo. The crude product is dissolved in 100 ml. of water and 0.5 g. of charcoal is added. The mixture is heated to boiling and stirred while hot for one hour. After being filtered through Celite, the filtrate is evaporated under reduced pressure. To the residue is added 40 ml. of isopropanol, which is evaporated. Another 40 ml. of isopropanol is added and the evaporation is repeated until 10 ml. of isopropanol remains. At this point, 100 ml. acetone is added and the product is crystallized. The solid is chopped to a fine powder and collected by suction filtration. The solid is washed with 3sl/acetonesisopropanol (2x90 ml.) and acetone (90 ml.). The product is recrystallized from l:2/isopropanol:acetone to give 30 g. of desired product. Further purification provided the analytical sample.

Analysis calculated for C1OH25N2C12: C, 42.95; H, 9.01; N, 10.02; Cl, 38.03.

Found: C, 43.07; H, 9.30; N, 10.01; Cl, 38.15. - 10 EXAMPLE 2 - /Ν' - (3 - Chloropropyl) - Ν' - methylamino/ Ν,Ν,Ν - trimethyl - 1 - propanaminium Iodide To a stirred solution of 21o.2 mg. (1 mmole) of Ν,Ν,Ν -trimethyl - /3 - (methylamino)/ - 1 propanaminium bromide in 1.5 ml. of acetonitrile is added a solution of 205 mg. (1 mmole) of 3 - iodo - 1 chloropropane in 0.5 ml. of acetonitrile. The mixture is stirred at room temperature for 2.0 hours and the insoluble Ν,Ν,Ν - trimethyl -/3- (methylamino)/ “ - propanaminium bromide hydrobromide is removed by filtration. The filtrate is evaporated and the solid residue obtained is extracted with methylene chloride. The methylene chloride extract is evaporated to give the oily product which is recrystallized from isopropanol-ether to afford 90 mg. (52%) of product; m.p. 93° (dec.); NMR 5s 2.2 (3H, S, -NCH-g) ; 3.46 (9H, S, + -NMe3).

Analysis c, calculated for C1OH24N2C1I: 35.89; H, 7.23; N, 8.37; Cl, 10.59. Pound; - c, 35.75; H, 7.39; N, 8.36; Cl, 10.20.

EXAMPLE 3 - /Ν' - (3 - Chloropropyl) - Ν' - methylamino/ Ν,Ν,Ν - trimethyl - 1 - propanaminium Bromide Hydrobromide TO a stirred solution of 3.02 g. (14.3 mmoles) of Ν,Ν,Ν - trimethyl -/3- (methylamino)/ - 1 propanaminium bromide in 30 ml. of acetonitrile is added a solution of 2.25 g. (14,3 mmoles) of 3 bromo - 1 - chloropropane and the mixture is stirred at 4 0 9 8 - 11 room temperature under nitrogen for 3.5 hours. The mixture is cooled in an ice-water bath and then the insoluble material is removed by filtration. The filtrate is evaporated and dried in vacuo and is ex5 tracted with chloroform. The chloroform extract is evaporated and dried to give 2.05 g. (100%) of oily product; NMR fi: 2.2 (3H, S, -NCH3); 3.43 (9H, S, + -N(CH3)3).

EXAMPLE 4 JO 3 - /Ν' - (3 - lodopropyL) - Ν' - methylamino/ Ν,Ν,Ν - trimethyl - 1 - propanaminium Iodide To a stirred solution of 216.2 mg. (1 mmole) of Ν,Ν,Ν - trimethyl -/3- (methylamino^- 1 propanaminium bromide in 1.5 ml. of acetonitrile is added a solution of 296 mg. (1 mmole) 1,3 - diiodopropane in 0.5 ml. of acetonitrile. The mixture is stirred at room temperature for 2.0 hours and the insoluble Ν,Ν,Ν - trimethyl -/3- (methylaminoJJ7 1 - propanaminium bromide hydrobromide is removed by filtration. The filtrate is evaporated and the solid residue obtained is extracted with methylene chloride. The methylene chloride extract is evaporated to give the oily product which is recrystallized from isopropanol-ether .

EXAMPLE 5 _ /ν' - (3 - Bromopropyl) - 11' - methylamino7 Ν,Ν,Ν - trimethyl - 1 - propanaminium Bromide hydrobromide To a stirred solution of 3.02 g. (14.3 mmoles) of Ν,Ν,Ν - trimethyl - /T - (methylaminotf - 1 propanaminium bromide in 30 ml. of acetonitrile is added a solution of 2.88 g. (14.3 mmoles) of 1,3 dibromopropane and the mixture is stirred at room 4409 8 - 12 temperature under nitrogen for 3.5 hours. The mixture is cooled in an ice-water bath and then the insoluble material is removed by filtration. The filtrate is evaporated and dried in vacuo and is extracted with chloroform. The chloroform extract is evaporated and dried to give the product.

EXAMPLE 6 Step 1-3 -(2- Cyanoethyl)aminopropanol A solution of 75 g. (1 mole) of 3-aminopropanol is stirred while 54 g. (1 mole) of acrylonitrile is added dropwise. After being allowed to stand at room temperature for several hours and preferably overnight, the reaction mixture is concentrated under reduced pressure at 50° yielding 3-(2- cyanoethyl)aminopropanol .

Step 2-Formate Ester of 3 - /N - (2 - Cyanoethyl) N - formylamino/propanol A solution of 127.7 g. of 3-(2-cyanoethyl)aminopropanol in 1 liter of 99% formic acid is heated at 85°C for 15 hours. The reaction mixture is concentrated under reduced pressure at 80° and the residue is taken up in 60 ml. of methylene chloride-ethyl acetate (1:1).

A 1500 g. silica gel G column packed in methylene chloride-ethyl acetate is prepared, and the product is purified by adsorption on silica gel G followed by elution using the 1:1 methylene chloride-ethyl acetate system. Concentration of the combined eluates yields the formate ester of 3 - /Ϊ5 - (2 - cyanoethyl) - N formylamino/propanol.

Step 3-3 - /Ν “ (2 - Cyanoethyl) - N - formylamino/propanol - 13 A solution of 55.7 g. of the formate ester of - ZR ” (2 - cyanoethyl) - N - formylamino/propanol in 300 ml. of methanol is treated with 820 mg. of sodium methoxide at room temperature. After 30 minutes, the reaction mixture is concentrated to dryness under reduced pressure and the residue is taken up in 500 ml. of methylene chloride. The methylene chloride solution is filtered and the filtrate is concentrated under reduced pressure yielding 3 - /N - (2 - cyanoethyl) - N - formylaming7propanol.

Step 4-3 - /Ν' - Formyl - Ν' - (3 - hydroxypropyl)aminq/ - 1 - propanaminium Chloride A solution of 15.6 g. (100 mmoles) of 3 - /5 (2 - cyanoethyl) - N - formylamins/ - propanol in 225 ml. of water is treated with 100 ml. of 1 H hydrochloric acid and reduced over 3.8 g. of platinum at room temperature and 40 psi of hydrogen. The reaction mixture is filtered and concentrated under reduced pressure yielding 3 - /S' “ formyl - Ν' - (3 - hydroxypropyl) amine/ - 1 - propanaminium chloride.

Step 5-3 - /8' - Formyl - Ν' - (3 - hydroxypropyl)amino/ - Ν,Ν,Ν - trimethyl - 1 - propanaminium Chloride To a suspension of 3.6 g. of 3 - /Ν' - formyl Ν' - (3 - hydroxypropyl)amino/ - 1 - propanaminium chloride in 25 ml. of dimethylformamide is added 10.7 g. of anhydrous sodium carbonate and 33 g. (15 ml.) of iodomethane. The mixture begins to reflux gently. When the initial reaction appears to have subsided, the mixture is stirred and heated at 50° for eighteen hours. The reaction mixture is filtered and the filter cake is washed with 3x10 ml. portions of dimethylformamide. The combined filtrate and washes is concentrated 4098 - 14 to dryness under reduced pressure and the residue is taken up in methanol and concentrated to dryness under reduced pressure. The residue is triturated with hot isopropanol and the mixture is filtered. The product is converted to the chloride-ion-containing product by passage of a 5% aqueous solution of the iodide-containing product through a column of AG1-X2 ion-exchange resin (Cl cycle) and concentrating the aqueous eluate.

Step 6-3 - /S' - (3 - Hydroxypropyl) - Ν' - methyl10 amino/ - Ν,Ν,Ν - trimethyl - 1 - propanaminium Chloride Hydrochloride A mixture of 2 g. of 3 - /Ν' - formyl - Ν' (3 - hydroxypropyl)aming/- Ν,Ν,Ν - trimethyl - 1 propanaminium chloride 4 g. of 99% formic acid and 2 ml. of formalin is stirred and heated at 100° for seventeen hours. To the cooled mixture is added 11 ml. of concentrated hydrochloric acid and the reaction mixture is concentrated under reduced pressure. The product is taken up in 35 ml. of IN hydrochloric acid and the solution is filtered and concentrated to dryness under reduced pressure yielding 3 - /N1 - (3 - hydroxypropyl) - N’ - methylamino/ - Ν,Ν,Ν - trimethyl - 1 - propanaminium chloride hydrochloride.

Claims (9)

1. A3-/N-(3-X- propyl)methylamine/ “ Ν,Ν,Ν - trimethyl - propan - 1 - aminium compound of the formula: 5 CIi 3 x-ch 2 -ch 2 -ch 2 -n p CH 2 + n( ch 3) 3 where X is halo or hydroxy, Y is a pharmaceutically acceptable anion, a is the anionic charge on Y, and m is a number such that the product of m and a is 1; and acid addition salts thereof. 10

2. A compound as claimed in Claim 1 in which the formula Y is a chloride, bromide or iodide anion.

3. 3 - /N - (3 - chloropropyl)methylamino/ Ν,Ν,Ν - trimethyl - propan - 1 - aminium chloride hydrochloride. 15

4. 3 - /N - (3 - chloropropyl)methylamino/ Ν,Ν,Ν - trimethyl - propan - 1 - aminium bromide hydrobromide.

5. 3 - /N - (3 - bromopropyl)methylamino/ Ν,Ν,Ν - trimethyl - propan - 1 - aminium bromide 20 hydrobromide. 4409 8 - 16

6. The method that comprises reacting Ν,Ν,Ν trimethyl -/3- (methylaminotf - 1 - propanaminium halide with oxetane to form a 3 - /8 -hydroxypropyl)methylamino/ - Ν,Ν,Ν - trimethyl - propan - 1 5 aminium halide of the formula: HOCH 2 CH 2 CH 2 NCH 2 CH 2 CH 2 N + (CH 3 ) 3 . xch 3 where X- is a halide anion; and optionally reacting the latter compound with a halogenating agent thereby forming a 3-/N-(3-halopropyl)methylamino/ - Ν,Ν,Ν - tri10 methyl - propan - aminium/ compound of the formula: H l + XCH 2 CH 2 CH 2 N + CH2CH2CH2N + (CH3) 3 . 2Xwhere X is a halogen atom and X- is as above-defined; and optionally exchanging the anion X- of the latter compound with another pharmaceutically acceptable anion 15 Y a , where a is the anionic charge on Y, to form a 3 /N - (3 - halopropyl)methylamino/ - Ν,Ν,Ν - trimethyl - propan - 1 - aminium compound of the formula: H XCH 2 CH 2 CH 2 N+CH 2 CH 2 CH 2 N + (CH 3 ) 3 . 2rn¥ a where X, Y and a are as above defined, and m is a number 20 such that the product of m and a is 1.

7. A method of preparing a compound of the formula: CII, XCH 2 CII 2 CII 2 N CH, CII, CH 2 + n(ch 3 ) 3 that comprises reacting H 5 CH 3 — N-CH 2 -CH 2 --CH 2 --N + (CH 3 ) 3 . Br’ with at least one equivalent of X— ch 2 —ch 2 —ch 2 -1 where X is chlorine, bromine or iodine.

8. A method of preparing a compound as claimed 10 in Claim 1, substantially as hereinbefore described in any one of the Examples.

9. A compound as claimed in Claim 1, when prepared by a method as claimed in any one of Claims 6 to 8.