1.ApplicationNumber: US-2028160-A
1.PublishNumber: US-3058987-A
2.Date Publish: 19621016
3.Inventor: ALBRECHT HARRY ALLEN
PLATI JOHN THOMAS
WENNER WILHELM

4.Inventor Harmonized: ALLEN ALBRECHT HARRY()
THOMAS PLATI JOHN()
WILHELM WENNER()

5.Country: US
6.Claims:

7.Description:
(en)ilnited stares Parent @i 3,058,987 S-AWO-Z-AMINGMEIHYL-I-PIENYL-l- PRGPANOLS Harry Allen Albrecht, Nntley, John Thomas Plati, Rutherford, and Wilhelm Wenuer, Upper Montclair, NJ., assrgnors to Hoifmann-La Roche Tue, Nutley, NJ., a
corporation of New Jersey No Drawing. Filed Apr. 6, 1960, Ser. No. 20,281 4 Claims. (Cl. 260-2947) This invention relates to derivatives of diamino-isobutauol. More particularly, the invention relates to compounds which are represented by the structural formula .H .H(CH. N R (|)H \R 2 (I) wherein in the symbols R represent hydrogen, halogen,
lower alkyl or lower alkoxy and the symbols R represent lower alkyl groups or together with the nitrogen :Eorm a 5-6 membered saturated nitrogen heterocyclic,
and acid addition salts thereof.
In the formula above, either one or both of the symbols R may represent hydrogen or one of the enumerated substituent groups so that either an unsubstituted phenyl group or a phenyl radical bearing one or two substituent groups may be present. All four halogens are included Within the meaning of the symbol R. The lower alkyl groups include such groups as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, amyl, isoamyl and the like. The lower alkoxy groups include ether groups containing the same lower alkyl radicals as above.
The group represents an acyclic or cyclic tertiary amino group. The symbols R may represent lower alkyl groups such as those described so that a di-lower alkylamino radical is formed. The two symbols R may also together represent a tetramethylene, pentamethylene or oxytetramethylene group which together with the nitrogen atom forms a 5 or 6 membered saturated nitrogen heterocyclic radical such as pyrrolidyl, piperidyl, morpholinyl and the like.
The compounds of the structural formula set forth above are derived from acetophenone or halogen-, alkyl-, or alkoxy substituted acetophenones. By subjecting the acetophenone to the Mannich reaction one substituted aminomethyl group is introduced. Repetition of the reaction under alkaline conditions effects the introduction of a second aminomethyl group. The resulting ketone is then reduced to the alcohol of Formula I.
The first step of the procedure for forming the products of this invention involves reacting acetophenone or the appropriately substituted acetophenone with about one molar proportion of an amine such as dimethylamine, pyrrolidine, piperidine, or morpholine, or an acid salt thereof, and formaldehyde or paraformaldehyde. By conducting this reaction under acid conditions, e.g. in the presence of added hydrochloric acid, the introduction of one aminomethyl group is favored. Generally a well crystallized material results and a convenient method of purifying the intermediate is thus provided.
A second aminomethyl group is introduced by reacting the intermediate, substituted aminopropiophenone with a second molar proportion of the tertiary amine and formaldehyde or paraformaldehyde, this time under alkaline conditions, e.g. in the presence of sodium hydroxide or excess amine. In this manner a substituted di-aminoisobutyrophenone is obtained.
ice
The substituted di-aminoisobutyrophenone may be re duced to the alcohol, for example, with alkali metal hydrides such as sodium borohydride, preferably in an inert solvent such as alcohol.
The products of Formula I are basic compounds which form acid addition salts by reaction with about one or two molar proportions of inorganic or organic acid. Such acid addition salts as the hydrohalides, e.g. hydrochloride, hydrobromide, hydroiodide, hydrofluoride, other mineral acid salts such as sulfate, nitrate, posphate, and the like, alkyland mono-arylsulfonates such as ethanesulfonate, toluenesulfonate, benzenesulfonate, and the like, other organic acid salts such as acetate, tartrate, malate, citrate, benzoate, salicylate, ascorbate, etc., may in this way be obtained.
The compounds of Formula I are useful as diuretics and may be used in treating cardiac conditions such as cardiac edema or in treating hypertension. They may be administered orally by incorporating a therapeutic dosage of the base or a pharmacologically acceptable acid addition salt in a conventional oral dosage form such as tablets, capsules, elixirs, suspensions or the like.
The following examples illustrates the invention. peratures are expressed in degrees centr-igrade.
Tem-
Example 1 Acetophenone g.), dimethylamine hydrochloride (106 g.), paraformaldehyde (39.6 g.), ethanol ml.), and 2 m1. of concentrated hydrochloric acid were refluxed for 2 hours. After the addition of 800 ml. of acetone, the product was allowed to crystallize in the cold, filtered, washed with acetone, and dried on the steam bath to obtain ,B-dimethylaminopropiophenone hydrochloride, M.P. 153-455".
{3-Dimethylaminopropiophenone hydrochloride (60 g.), 37% formaldehyde solution (22.8 g.), 25% dimethylamine in water (101 g.), and 360 ml. of ethanol were refluxed 1 hour. The solvent was distilled off in vacuo. Water (300 ml.) and excess 50% sodium hydroxide solution were added. The mixture was extracted with 400 ml. of ether. After drying with anhydrous sodium sulfate, the ether was evaporated in vacuo. The residual base was crystallized from 100 ml. of petroleum ether to yield a dimethylaminomethyl-fl-dimethylaminopropiophenone, M.P. 54-5 6.
a Dimethylaminomethyl-fl-dimethylaminopropiophenone dihydrochloride, M.P. 164l65, was obtained in crystalline form by adding a solution of hydrogen chloride in ethanol to an ethanolic solution of the base.
a Dimethylaminomethyl B dimethylaminopropiophenone (26.2 g.) was dissolved in 180 ml. of methanol and added to a solution of sodium borohydride (4.24 g.) in 500 ml. of 50% methanol, below 10. The addition required 8 minutes. The mixture was stirred for 1 hour while warming to room temperature, and then for 4 hours at 45-50. Most of the methanol was distilled 05 in vacuo. With cooling, 150 ml. of water and 30 ml. of 50% sodium hydroxide solution were added. The base was extracted with 2 portions of ether (250 ml. and 150 ml). After drying over sodium sulfate, the ether was evaporated in vacuo to yield eventually a crystalline residue. On crystallization from 50 ml. of petroleum ether, 3-dimethylamino-2-dimethylaminomethyl 1 phenyl-lpropanol, M.P. 6365, was obtained.
Addition of a solution of hydrogen chloride in ethanol to 4 g. of crude base obtained above in 10 ml. of ethanol gave the crystalline dihydrochloride, M.P. 225-227.
Example 2 Piperidine hydrochloride (69.3 g.), acetophenone (68.4 g.), paraformaldehyde (25.7 g.) and ml. of ethanol were refluxed for 30 minutes. Then, 34 g. of paraformalrefluxed for 2 hours.
dehyde was added, and refluxing continued for 17 hours.
On cooling, the product crystallized. It was filtered and washed with cold ethanol to obtain B-(l-piperidyDpropiophenone hydrochloride, M.P. 178-184.
13-(l-piperidyl)propiophenone hydrochloride (53 g.),
. of ethanol and a solution of hydrogen chloride in ethanol piperidine (35.6 g.), 37% formaldehyde solution (25.4
g.), and 300 ml. of ethanol were refluxed for 1 hour. The solvent was distilled off in vacuo. Water (200 ml.) was added, followed by excess 50% sodium hydroxide solution (50 ml.), with cooling. The :base was extracted with 300 ml. of benzene, washed with three 100 ml. portions of water, and dried over sodium sulfate. After dis tillation of the benzene in vacuo, the residue was dissolved in 2 liters of ether and acidified by addition of 180 ml.
or a solution of hydrogen chloride in ethanol (about 3 N). 3 (l-piperidyl)-2-(l-piperidylrnethyl)-1-phenyl-1- propanone hydrochloride precipitated as a gum. The ether 'Was decanted and 2500 ml. of hot ethyl acetate was to 30 and filtered to obtain crude dihydrochloride which, onheating, softened at 120 and meltedat 143-146. Crude dihydrochloride recrystallized from a mixture of 30 ml. of ethanol and .60 ml. of ether to give the pure product melting at 155-157.
Thebase was liberated from 40 g. of 3-(1-piperidyl)- 2-(l-piperidylmethyl) 1 phcnyl 1 propanone dihydrochloride by dissolving in 400 ml. of water and adding excess 50% sodium hydroxide solution. The oily base was isolated by extracting w'th ether, and evaporating the ether in vacuo. The base was dissolved in 150 m1. of methanol, cooled, and added to a solution of 3.91 g. of sodium borohydride in 200 ml. of 50% methanol below 10. After stirring in the cold for 5 minutes, themixture was allowed to warm to room temperature during 1 hour and 50 minutes. The mixture then was maintained at 45-5.0 for 2 /2 hours. Crystallization occurred on cooling. The product, 3-(l-piperidyl)-2-(1epiperidy1 methyl)-1-phenyl-1-propanol, was filtered and washed with cold 50% methanol, MP. 84-86".
The base obtained above (3 g.) was dissolved in 100 ml. or dry ether, and dry hydrogen bromide was passed in to precipitate the solid salt. On crystallization from ethanol, pure 3-( l-piperidyl)-2-(1-piperidylmethyl)lphenyl-l-propanol dihydrobromide, M.P. 140144, was
obtained. t
Example 3 4-chloroacetophenone (46.2 g.), piperidine hydrochloride (36.4 g.), paraformaldehyde'(l3.5 g.), ethanol (60 ml.) and 1 ml. of concentrated hydrochloric acid were On cooling, crystalline fi-(l-piperidyl)-p-chloropropiophenone hydrochloride, M.P. 19l- 192, was obtained. I
3 (l-piperidyl)-p-chloropropiophenone hydrochloride (39.3 g.), piperidine (23.3 g.), 37% formaldehyde solution (167 g.), and 200 ml.
1 hour. The solvent was distilled ofi in vacuo. With cooling, 200 ml. of water and 40 ml. of 50% sodium hydroxide solution were added. The mixture was extracted with 2 portions of ether (200 ml. and 1001111.).
The combined ether extracts were dried over sodium sulfate The .ether was evaporated in vacuo, and the residue was crystallized from a mixture of 120 ml. of methanol and ml. of water, to obtain 3-(1-piperidyl)-2-(1-piperidylrn'ethyl) 1-(4-chlorophenyl) -1-pIopanone, M1. 71-
Sodium borohydride (2.27 g.) -was dissolved in 40 ml. of 50% methanol below 10. 3-(1-piperidyl)-2-(l-piperidylmethyl) 1 (4- chlorophenyl )-l propanone (20.9 g.)
added. After thorough digestion, the mixture was cooled of ethanol were refluxed for was dissolved in 150 ml. of methanol and added with continned cooling below li0i After 5 minutes of stirring in the cold, the ice .bath was removed. After another 45 minutes, the mixture was warmed at 45-50 for 45 minntes. On a cooling, the product, 3-( 1-piperidyl)-2-( l-piperwas added. On dilution with ml. of ether, 3-(1-piperidyl) -2-( l-piperidylmethyl') -1-(4 chloropheuyl) 1' propanol dihydrochloride, M.P. 243-245, was obtained.
Example 4 p-Methoxyacetophenone (500 g.), piperidine hydrochloride (405 g.), paraformaldehyde g.), 650 ml. of ethanol, and 10 ml. of concentrated hydrochloric acid were refluxed for 2 hours. The product was allowed to crystallize at room temperaturefor-Z hours and then at the temperature of an ice bath. After filtering, washing with two 100 ml. portions of cold ethanol, and drying on a steam bath, the product, B-'(1piperidy1) -p-methoxypropiophenone hydrochloride, M.P. 210-212, was obtained.
B (l-piperidyl)-p-methoxypropiophenone hydrochloride (681 g.), 37% formaldehyde solution (292 g.), 95% piperidine (430 g.), and 2 liters of ethanol were refluxed for 1 hour. Most ofthe solvent was distilled off in vacuo while maintaining the inside temperature below 60. The residue was cooled, and 2 liters of water and 300 ml. of 50% sodium hydroxide solution were added." The mixture Was extracted with 2 portions of ether (800 ml. and 500 ml.). The combined ether extracts were dried C sodium sulfate. The ether was then distilled off in vacuo without heating the residue above 60. The residue was dissolved in 1100 ml. of petroleum ether, and allowed to crystallize at 0. The product, 3-(l-piperidyl)-2-(lpiperidylmethyl)-l-(4-rnethoxyphenyl)-1-propanone, was filtered and dried in the air, M.P. 54-57".
With stirring and cooling below 10, 50 g. of sodium borohydride was added to 400 ml. of methanol and 100 ml. of water. A cold solution of 455 g. of 3-(1-piperidyl)- 2 (l piperidylmethyl) i 1 (4 methoxyphenyl)-1-pro panone in 1 liter of methanol was then added over a 25 minute period, with cooling below 10. After an additional 5 minutes of stirring in the cold, the ice bath was removed, 7 and stirring was continued with no further cooling. After 1 hour and 20 minutes, the reaction temperature rose to 33. Then, the mixture was warmed at 45-50 for 2 hours. On cooling in 'an'ice bath, the crystalline base, 3-( 1-piperidyl)-2-( 1-piperidylrnethyl)-1- (4-methoxypheny1)-1-propanol, was obtained. It was filtered, washed with dilute methanoLand dried in vacuo over potassium hydroxide, M.'P. 88-91".
263 g. ofthe base obtained above was dissolved in 1300 ml. of ethanol, and the solution was acidified by the addition of a solution of hydrogen chloride in ethanol (500 ml. of 3.33 N) with cooling below 25. The dihydrochloride was allowed to crystallizeat room temperature for several hours. After filtering, washing with two 100 ml. portions of cold ethanol, and drying in vacuo over potassium hydroxide, 3-( 1 piperidyl)-2- 1-piperidylmethy1) l-(p-methoxyphenyl)-l-propanol dihydrochloride, M.P.
to vary slightly according to -the rate of heating.
ExamplefS 4-acetylveratrole (60 g.) piperidine hydrochloride (40.6 g), paraformaldehyde .(15 g.), 60 ml. of ethanol, and 1 ml. of concentrated hydrochloric acid-were refluxed for 2 hours. The solution was filtered hot and allowed to crystallize in the cold. The product was filtered, washed with three 10ml. portions of cold ethanol, and dried in vacuo over potassium hydroxide to obtain 3-('l-piperidyl)- 1-(3,4-dimethoxyphenyl) l -propanone hydrochloride, M.P. 180-182.
*3 l. piperidyl) 1 (3,4 dimethoxyphenyl) 1- propanone hydrochloride (10 g.), 37% formaldehyde solution (3.88 g.), 95% piperidine (5.70 g), and 50 ml. of ethanol were refluxed for 1 hour. The solvent was distilled oif in vacuo. Water (50 ml.) and excess 50% sodium hydroxide solution ml.) were added with cooling. The base was extracted with 2 portions of ether (50 ml. and 30 ml.). The combined ether extracts were dried over sodium sulfate, and concentrated in vacuo. The residue was redissolved in 130 ml. of ether, and a solution of hydrogen chloride in ethanol was added to precipitate the solid 3-(1-piperidyl) -2-(1-piperidylmethyl) 1-( 3 ,4-dimethoxyphenyl) -l-propanone dihydrochloride, melting at 175-177". The mixed melting point with the starting material was depressed. On recrystallization from ethanol, the melting point rose to 183-185".
3 (l piperidyl) 2 (1 piperidylmethyl) 1 (3,4- dimethoxyphenyl)-1-pr0panoue dihydrochloride (9.7 g.) was dissolved in 80 ml. of water, and 5 ml. of 50% sodium hydroxide solution were added. The base was extracted with 100 ml. of ether. The ether was evaporated in vacuo. The residual base was dissolved in 30 ml. of methanol and added below 10 to a solution of 0.82 g. of sodium borohydride in 20 ml. of 50% methanol. The mixture was allowed to Warm to room temperature during 1 hour, and then warmed at 45-50" for 2 hours and 25 minutes. Most of the solvent Was distilled off in vacuo. Water (50 ml.) was added, and the mixture was extracted with ether (50 ml). After drying with sodium sulfate, the ether was evaporated in vacuo to leave 3-(1-piperidyl)- 2 (1 piperidylmethyl) 1 (3,4 dimethoxyphenyl) 1- propanol as a crude residue.
The residue was dissolved in 20 ml. of ethanol, and acidified by addition of a solution of hydrogen chloride in ethanol. The 3-(1-piperidyl)2-(1-piperidylmethyl)-l- (3,4-dimethoxyphenyl)-l-propanol dihydrochloride, which crystallized at room temperature, was filtered, washed with ethanol, and dried in vacuo over potassium hydroxide, M.P. 172-179". The dihydrochloride was solvated, and the melting point did not improve on recrystallization.
The free base was obtained again by dissolving the dihydrochloride (1 g.) in 20 m1. of water. Excess 10% sodium hydroxide solution was added, and the base was extracted with 30 ml. of ether. The ether was dried over sodium sulfate, and evaporated in vacuo. The residual oil was crystallized from 3 ml. of petroleum ether to yield the base, M.P. 64-66".
Example 6 Acetophenone (40 g.), morpholine hydrochloride (41.2 g.), paraformaldehyde g.), 60 ml. of ethanol and 1 ml. of concentrated hydrochloric acid were refluxed for 2 hours. The product, B-(4-morpholinyl)propiophenone hydrochloride, crystallized on cooling, M.P. 176-178".
fl-(4-morpholinyl)propiophenone hydrochloride (59.8 g.), 37% formaldehyde solution (28.5 g.), morpholine (40.7 g.) and 250 ml. of ethanol were refluxed for 1 hour. The solvent was distilled off in vacuo. With cooling, 300 ml. of water and 40 ml. of 50% sodium hydroxide solution were added. The mixture was extracted with 2 portions of ether (200 ml. and 100 ml). The combined ether extracts were Washed with 200 ml. of water, dried with sodium sulfate, and evaporated in vacuo to leave a residual oil.
This crude base was dissolved in 300 ml. of ethanol, and acidified by the addition of a solution of hydrogen chloride in ethanol. The crystalline product was filtered, washed with ethanol and dried in vacuo over potassium hydroxide to obtain 3-(4-morpholinyl) -2-(4-morpholinylmethyl)1-phenyl -1-propanone dihydrochloride, M.P.
3-(4-morpholiny1) -2-(4-morpholinylmethyl l-phenyll-propanone (50 g.) was dissolved in 300 ml. of water. Excess 50% sodium hydroxide solution was added, the base was extracted with 300 of ether, and the ether was evaporated in vacuo. The residue was dissolved in 150 ml. of methanol, and the solution was added below 10 to 4.84 g. of sodium borohydride in 40 m1. of meth- 6 anol plus 10 ml. of water. The reaction was allowed to warm to 35 After 1% hours, the reaction subsided, and the temperature of the mixture was maintained at 45-50" for 2% hours. Most of the solvent was distilled oif in vacuo, water (150 ml.) was added, and the oily base was extracted with ether (150 ml). After drying over sodium sulfate, the ether solution was concentrated in vacuo and the residue was crystallized from ml. of methanol plus 100 ml. of water to yield 3-(4-morpholinyl)-2-(4morpholinylmethyl)-1-phenyl 1 propanol, M.P. 98-101".
A solution of 20 g. of the base in 100 ml. of ethanol was acidified by the addition of a solution of hydrogen chloride in ethanol. The crystalline dihydroohloride melted at 237-238 Example 7 o-Methoxyacetophenone (45 g.), piperidine hydrochloride (36.5 g.), paraformaldehyde (13.5 g.), 60 ml. of ethanol, and 1 ml. of concentrated hydrochloric acid were refluxed for 2 hours. After several days of standing in the refrigerator, the crystalline product was obtained. It was filtered, washed with ethanol and dried in vacuo over potassium hydroxide to obtain [3 (1-piperidyl)-omethoxypropiophenone hydrochloride, M.P. 147-149".
5% l-piperidyl) -o-methoxypropiophenone hydrochloride (40 g.), 37% formaldehyde solution (17.2 g.), 95% piperidine' (25.2 g.), and 200 ml. of ethanol were refluxed for 1 hour. The solvent was distilled olf in vacuo. With cooling, 200 ml. of water and 40 ml. of 50% sodium hydroxide solution were added, and the base was extracted with ether (250 ml.). The ether solution was dried over sodium sulfate, and evaporated in vacuo. The crude base thus obtained, 3-(1-piperidyl)-2-(l piperidylmethyl)-1-(2-methoxyphenyl) 1 propanone, was dissolved in 1 liter of dry ether, and hydrogen chloride gas was passed in to precipitate the solid dihydrochloride. The crude dihydrochloride was extremely hydroscopic, and was purified by dissolving it in 200 ml. of ethanol and adding 500 ml. of ether, to obtain crystalline 3-(1- piperidyl)-2-(l-piperidylmethyl)-1 (2-methoxyphenyl)- l-propanone dihydrochloride, M.P. 138-140".
3-(1-piperidyl) -2-(l-piperidylmethyl) 1 (Z-methoxyphenyD-l-propanone dihydrochloride (20 g.) was dissolved in water, excess 50% sodium hydroxide solution was added, and the base was extracted with ether. The ether solution was evaporated in vacuo, the residual base was dissolved in 50 ml. of methanol, and the solution added below 10 to 1.81 g. of sodium borohydride in 40 ml. of methanol plus 10 ml. of Water. The mixture was stirred at room temperature for 1 hour and then for 2% hours at 45-50". The mixture was concentrated by distilling olf part of the solvent in vacuo, whereupon crystallization occurred. The :base, 3-(1-piperidyl) 2 (l piperidylmethyl)-l-(2-methoxyphenyl)-l propanol, was allowed to crystallize in the cold, filtered, washed with 50% methanol, and dried in vacuo over potassium hydroxide to obtain the pure product, M.P. 88-91".
The free base obtained above was dissolved in ethanol (30 ml.), and the solution was acidified by the addition of a solution of hydrogen chloride in ethanol. On standing, crystalline 3- 1-piperidy1)-2-(l-piperidylmethyD-l- (2-rnethoxyphenyl)-1 propanol dihydrochloride, M.P. 138-151", was obtained.
Example 8 m-Methoxyacetophenone (25 g.), piperidine hydrochloride (20.3 g.), paraformaldehyde (7.5 g.), 35 ml. of ethanol and 0.5 ml. of concentrated hydrochloric acid were refluxed for 2 hours. On cooling, crystalline fi-(lpiperidyl)-m-methoxypropiophenone hydrochloride, M.P. 135-144", was obtained. Recrystallization from ml. of ethanol gave the pure material, M.P. 154.
/8-( 1-piperidyl) -m-methoxypropiophenone hydrochloride (18.5 g.), 95% piperidine (11.7 g.), 37% formalde 7 (p-tolyl) -'1-propanol,
hyde solution (7.92 g. and 90 ml. of ethanol were .re-
fluxed for 1 hour. The solvent was distilled off in vacuo.
.over anhydrous sodium sulfate, and the ether evaporated in vacuo. The crude base, 3-(1-piperidyl) -2-(1-piperidylmethyl) -1- (3 -methxyphenyl) -1 -propanone,
was dissolved in 30 ml. of ethanol and acidified by the addition of a solution of hydrogen chloride in ethanol. On addition of 100 ml. of ether, the crystalline dihydrochloride, M.P. 155-157", was obtained. 7
The base was obtained from 12.5 g. of 3-(1-piperidyl)- 2-(l-piperidylmethyl)-1-(3-methoxyphenyl) 1 propanone dihydrochloride by dissolving it in water (100 ml.), adding excess 50% sodium hydroxide solution, extracting with 2 portions of ether (80 ml. and 40 ml.), and evaporating the-ether in vacuo. The base was dissolved in 50 mLof methanol and added below to 1.14 g. of sodium borohydride in 40 ml. of methanol and 10 ml. of Water. The mixture was allowed to warm to room temperature with stirring during 1 hour, and then warmed at 45-50 for 2% hours. Most of the solvent was distilled off in vacuo. Water (50 ml.) was added to the residue, and the base was extracted with ether (250 ml). On evaporating the ether in vacuo, the solid base, 3-(1- piperidyl)-2-(1-piperidylmethyl)-l-(3 methoxyphenyl)- l-propanol, M.P. 103-105", was obtained. Recrystallization from methanol gave 'a product melting at 105- 106.5". A solution of 8 g. of the free base obtained above in 20 m1. of ethanol was acidified by addition of a solution of hydrogen chloride in ethanol. Onaddition of 40 ml. of ether, the crystalline dihydrochloride was obtained. The dihydrochloride was solvated, and the melting point depended upon the rate of heating. A sample, heated very slowly in the apparatus, melted at 208-212, after slight preliminary shrinking.
Example 9 Methyl p-tolyl ketone (40.2 g.), piperidine hydrochloride (36.5 g.), paraformaldehyde 13.5 g.), 60 ml. of ethanol, and 1 ml. of concentrated hydrochloric acid were refluxed for 2 hours. On cooling, crystalline 3-(1-piperidyl)-l-(p-tolyl)-1 propanone hydrochloride, M.P. 172.5- 174.5 was obtained. V I i 3( l-piperidyl) -l-'(p-tolyl) -1-propanone hydrochloride (45 g.),,.9.5% piperidine (30.1 g.),. 37%,formal'del 1-yde fsolution' (20.4 g.), and 200 ml. of ethanol were refluxed for lhour. The solvent was distilled off in vacuo. With cooling, 200 mLof water and 40 ml. of 50% sodium hydroxide solution were added, and the base was extracted with 2 portions of ether (150 ml. and 75 ml.) The combined ether extracts were dried over sodium sulfate and evaporated in vacuo. The solid residue was crystallized from a mixture of 125 ml. of methanol and 34 ml. of water to give practically pure 3-(1-piperidyl)-2 (l-piperidylmethyl)-1-(p-tolyl)-1-propanone, M.P. 70-72.. I
3 (1 piperidyl) 2.- (1 piperidylmethyl) -1 (ptolyl)-1-propanone (20 g.) Was'dissolved in 80ml. of
'methauol, and the solution was added below 10 to a solution of 2.30 g. of sodium borohydride, 40 ml. of methanol, and 101111; of water during 20 minutes. After an additional five minutes in the cold, the mixture was allowed to warm with stirring to room temperature during '1 hour. I he temperature reached 32 before the reaction subsided. The mixture was warmed for 2 hours at 45-50".
Upon. the addition of 18ml. of water and cooling, the
crystalline base, 3-(1 piperidyl) -2 l-piperidylmethyl) -1- M.P. 68-71, wasiobtained. The base (12.3 g.) in ethanol '(25 ml.) was acidified 'by the addition cat a solution of hydrogen chloride in ethanol (35 ml. of approximately 3 N). Ether (200 ml.) was added to give, the crystalline dihydrochloride, M.P.
Cir
.Eixamp'le 10 i m-Chloroacetophenone (26.5 g.), piperidine hydrochloride (20.8 g.), paraformaldehyde (7.7 g.), ethanol (35 ml.), and 0.6 ml. of concentrated hydrochloric acid were refluxed for 2 hours. On cooling, crystalline 5-(1- piperidyl)-m-chloropropiophenone hydrochloride, M.P. 180-182", was obtained.
;3-( lpiperidyl -m'chloropropiophenone hydrochloride (25.2 g.), piperidiue (15.7 g.), 37% formaldehyde solution (-10.7g.) and ml. of ethanol were refluxed for 1 hour. The solvent was distilled off in vacuo. With cooling, 125 ml. of water and 20 m1. of 50% sodium hydroxide solution were added. The mixture was extracted with ml. of ether. The ether extract was dried over sodium sulfate and evaporated in vacuo to obtain the crude product, 3 (1 piperidyl) 2 (1 piperidylmethyl) 1- (3-chlorophenyl)-l-propanone, which was reduced directly with sodium borohydride.
Sodium borohydride (3.3 g.) was dissolved in 50 ml. of methanol plus 15 ml. of Water, below 10. 'A cold solution ofthe crude ketone obtained as described above in 200 ml. of methanol was added below 10, over a 15 minute period. The mixture was stirred for 1 hour while warming to room temperature and 20 minutes at 50. On cooling, 16.9 g. of crystalline 3-(1-piperidyl)-2-(1- piperidylmethyl) 1 (3 chlorophenyl) 1 propanol, M.P. 9699, was obtained. Y
The base (10 g.) was dissolved in 30 ml. of ethanol, and a solution of hydrogen chloride in ethanol was added.
, The 3-(l-piperidyl)-2-(l-piperidylmethyl) 7 1 (3-chloro- Hydrogen chloride gas was passed into a solution of 39.3 g. of pyrrolidine in 100 ml. of ethanol, until the mixture was just slightly acidic. :Then, 83 g. of p-methoxyacetophenone, 24.9 g. of paraformaldehyde, and 1 ml. of concentrated hydrochloric acid were added. The mixture was refluxed for 2 hours. On cooling, crystalline fl-(lpyrrolidyl)-p-methoxypropiophenone hydrochloride was obtained, melting at -182. i v
' fi-( l-pyrrolidyl)-p-methoxypropiophenone hydrochloride (45 g.), pyrrolidine (24 g.), 37% formaldehyde solution (20 g.), and 20 ml. of ethanol were refluxed for 1 hour. The solvent was distilled oil in vacuo. With cooling, 200 ml. of water and 40 ml. of 50% sodium hydroxide solution were added to the residue. Thebase solidified, was crushed, filtered, and washed with water. Without drying, the crude base was dissolved in 125 ml. of methanol at room temperature, and water (85 ml.).added to slight turbidity. On cooling, crystalline. B H-pyrrolidyl)- 2 -(-1'- pyrrolidylmethyl) 1 (4 methoxyphenyl) 1- propanone, melting at 8688, was obtained.
Sodium borohydride (2.40 g.) was dissolved in 40 ml. of methanol and 10ml. of water below 10. A solution were added to the residue. fIhe petroleum ether was evaporated in vacuo to leave a viscous, partly crystalline residue, 3 (1 pyrrolidyl) 2 (-1 pyrrolidylmethyl).-
The crude base obtained as described abovewas dissolved in 200 m1. of ether. A solution of hydrogen chloride in ethanol was added. After settling in the cold, the
supernatant liquid was decanted, and the gum crystallized from 50 ml. of 'isopropanol to obtain. 3-(l-pyrrolidyl)-2- panol .dihydrochloride melting at 191-194. Recrystallization raised the melting point'to 199-201.
9 Example 12 p-Methoxyacetophenone (50 g.), dimethylamine hydrochloride (35.3 g.), paraformaldehyde (15 g.), 70 ml. of ethanol and 0.7 ml. of concentrated hydrochloric acid were refluxed for 2 hours. While cooling, 200 ml. of acetone were added. The crystalline product, fl-dimethylamino-p-methoxypropiophenone hydrochloride, M.P. l82-184, was separated by filtration.
B-Dimethylamino p-methoxypropiophenone hydrochloride (68 g.), 25% dimethylamine in water (101 g.), 37% formaldehyde solution (34 g.) and 300 ml. of ethanol were refluxed for one hour. The solvent was evaporated in vacuo. The residue was chilled and 300 n11. of water and 40 ml. of 50% sodium hydroxide solution were added below 20. The mixture was extracted twice with ether (250 ml., of 100 ml.), the ether extracts were combined and dried over sodium sulfate. The ether was then evaporated in vacuo and the crude residue was crystallized from 210 ml. of petroleum ether. The 3-dimethylamino-2-dimethy1aminomethyl-1- (4-methoxyphenyl)-1-propanone melted at 5461.
Sodium borohydride (6.87 g.) was dissolved in 20 ml. of water and 60 ml. of methanol below 3-dimethylamino-2 dimethylaminomethyl-l (4-methoxyphenyl)- l-propanone (48 g.) was dissolved in 100 ml. of methanol and added to the sodium borohydride solution over a 10 minute period below 10. The mixture Was stirred while cold for 10 minutes, then 1 hour and minutes at room temperature and 2% hours at 4550. The solvent was distilled in vacuo. 200 ml. of Water were added to the residue. This was extracted with 200 ml. of ether and the ether extracted was dried over sodium sulfate. Then the solvent was evaporated in vacuo. The residue was dissolved in 200 ml. of ethanol and acidified with a solution of hydrogen chloride in ethanol. 3-dirnethylamino 2 dimethylaminomethyl-l- (4-methoxyphenyl) l-propanol dihydrochloride crystallized. The product was recrystallized from ethanol, M.P. 2265-227".
10 We claim: 1. A compound selected from the group consisting of bases represented by the formula R ()H R 1 wherein R represents a member of the group consisting of hydrogen, halogen, lower alkyl and lower alkoxy, and the symbols R represent a member of the group consisting of lower alkyl individually, and collectively, together with the nitrogen atom, pyrrolidyl, piperidyl, and morpholinyl and pharmacologically acceptable acid addition salts thereof.
2. A compound represented by the formula 2,514,380 Duschinsky July 11, 1950 2,835,676 Sprague et a1 May 20, 1958 2,962,501 Cutler et a1 Nov. 29, 1960 OTHER REFERENCES Cardwell: Journal of the Chemical Society, 1950, page Williams et al.: Journal of the American Chemical Society, vol. 74, 3875 and 3876 (1952).
Hach et a1.: Chemical Abstracts, vol. 51, page 10403]: (1957).
UNITED STATES PATENT OFFICE CERTIFICATE OF CORECTION atent No, 8,058,987 October 16 1962 Harry Allen Albrecht et ale It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.
Column 2, line 10, for "'posphate" read phosphate 9 :olumn 6, line 38, for "hydroscopic" read hygroscopic :olumn 9, line 16, strike out "of"; column l0 lines 4 to 7 ;he right-hand portion of the formula should appear as shown elow instead of as in the patent:
.ines 22 to 24, the center portion of the formula should appear 15 shown below instead of as in the patent:
ame column 10 under the heading 'UIJITED STATES PATENTS" dd the following:
2,934,534 Morren mew-w) Apr. 26 1960 ame column 10, above "OTHER REFERENCES insert:
FOREIGN PATENTS 840,496 Great Britain July 6 1960 Signed and sealed this 21st day of May 1963 SEAL) ttest:
RNEST W, SW-IDER 7 DAVID L, LADD ttesting Officer Commissioner of Patents