US2642437A - Quaternary ammonium salts of x-sub - Google Patents

Quaternary ammonium salts of x-sub Download PDF

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US2642437A
US2642437A US2642437DA US2642437A US 2642437 A US2642437 A US 2642437A US 2642437D A US2642437D A US 2642437DA US 2642437 A US2642437 A US 2642437A
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
    • C07D213/16—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing only one pyridine ring
    • C07D213/20—Quaternary compounds thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
    • C07C255/59—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • This invention relates to quaternary ammonium salts of 4-substituted-2-(tertiary-aminoalkoxy) :benzonitriles and. to their preparation.
  • the quaternary ammonium salts of our invention have the general formula onlomona) 30 -CH2CH2CI'I2CH9 CH2CH (CH3) CH2, and the like.
  • the tertiary-amino radical I shown above as NRR comprehends dialkylamino radicals where R and R1 are lower alkylgroups, 35 alike or different, and each alkyl group having one to six carbon atoms, such dialkylamino radicals including dimethylamino, diethylamino, ethylmethylamino, diisopropylamino, ethyl-npropylamino, di-n-butylamino, di-n-hexylamino, and the like.
  • the tertiary-amino radical designated as NRR1 encompasses saturated N-heteromonocyclic radicals having five to six ring atoms, illustrated by examples such as 1- piperidyl; (lower alkylated)-1-piperidyl such as Z-methyl 1 piperidyl, 3-,ethyl-1-piperidyL4- methyl-l-piperidyl, 2,6-dimethyl-1-piperidyl; 1- pyrrolidyl; (lower alkylated) -1-pyrrolidyl such as Z-methyl-l-pyrrolidyl, 2,5-dimethyl-1-pyrrolidyl; l-morpholinyl; and the like.
  • 1- piperidyl such as Z-methyl 1 piperidyl, 3-,ethyl-1-piperidyL4- methyl-l-piperidyl, 2,6-dimethyl-1-piperidyl
  • 1- pyrrolidyl (lower alkylated)
  • the lower alkyl radical (designated as R2 below); has preferably one to six carbon atoms, including such radicals as methyl, ethyl, npropyl, n-butyl, isobutyl,- n-amyl, Z-amyl, nhexyl, and the like.
  • the lower hydroxyalkyl radical (designated as R2 below) has preferably two to six carbon atoms, including radicals such as 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 3-hydroxy-2-methylpropyl, 3-hydroxy- 2,2-dimethylpropyl, 2-hydroxybutyl, 4-hydroxybutyl, 3 hydroxyamyl, 5 hydroxyamyl, 6-hydroxyhexyl and the like.
  • R3 when representing lower alkyl has preferably one to six carbon atoms, including such radicals as methyl, ethyl,
  • the non-toxic anion, designated above as An which can be any anion, for instance, chloride, bromide, iodide, sulfate, benzene-sulfonata para-toluenesulfonate, and the like, has no appreciable pharmacological activity of its owniin'the high dilutions at which the quaternary ammonium salts as a whole are efiective.
  • the anions contribute nothing to theganglionic blocking activity which resides solelyin the remainder of the molecule.
  • .our invention comprehends quaternary ammonium salts of the above defined 4-substituted -2 (tertiary-aminoalkoxy)benzonitriles, said salts being-derived from lower. alkyl or benzyl esters of an" acid, either inorganic or Or ic. such esters havingthe formula Ra -An cedure represented by the following series of equations where X, NRRran'd R2 have the meanings given hereinabove and halogen is chlorine, bromine, iodine or fluorine:
  • step I 4-nitr0-2-hydroxybenzonitrile (A) is converted into a 4-nitro-2-(tertiaryaminoalkoxy)benzonitrile (C) by reaction with a tertiary-aminoalkyl halide (B).
  • Step I is carried out preferably using l nitro- 2-hydroxybenzonitrile in the form of af metal salt thereof, preferably an alkali metal salt, with the tertiary-aminoalkyl halide.
  • Step I can be carried out using 4 nitro -2-hydroxybenzonitrile itself, however, with a resulting decrease in yield of the 4-nitro-2- (t ertiaryaminoalkoxy) benzonitrile.
  • the reduction step II is carried out either by chemical methods or by catalytic hydrogenation.
  • Suitable chemical reducing agents include iron and hydrochloric acid, ferrous sulfate and am monia, tin and hydrochloric acid, sodium hydrosulfite, etc.
  • iron and hydrochloric 'fiid In practicing our invention, we preferably used iron and hydrochloric 'fiid.
  • Catalysts suitable when catalytic hydrogenation is employed include Raney nickel, platinum, palladium or other catalysts generally efiective to catalyze hydrogenation of nitro groups to amino groups.
  • step HI The alkylation of the 4 -amino-2-(tertiaryaminoalkoxy)benzonitriles (D); to produce the related 4-alkylamino or 4-h'ydrox'yalkylaminonitriles (step HI) where R2 has from three to six carbon atoms is preferably carried out by reductively alkylating the a l-amino compound with an alkanal or a hydroxyalkanal.
  • Illustrative of this reductive alkylation step is the formation of 4-n-amylamino-2 [3- l-piperidyl)'pr'opoxylbenzonitrile or 4 ('5 hydroxyamylamino) -2- [3- (l-piperidyl) propoxyl benzonitrile by treating a mixture of the corresponding 4-amino-2- [3-(1-piperidy1) propoxy] benzonitrile withpentanal (valeraldehyde) or 5-hydroxypentanal,
  • the alkylation step III can be carried out directly by heating a 4-nitro-2-(tertiary-aminoalkoxy)benzonitrile (D) with an alkylating agent such as methyl iodide, ethyl bromide, n-propyl bromide, isobutyl iodide, 2- hydroxyethyl bromide, 4-hydroxybutyl chloride, and the like, in the presence of a hydrogen halide acceptor, e. g., sodium bicarbonate, potassium carbonate, etc.
  • D 4-nitro-2-(tertiary-aminoalkoxy)benzonitrile
  • Step I can also be carried out stepwise, that is, by first haloalkylating 4-nitro-2-hydroxybenzonitrile (A) to form a 4-nitro-2-(haloalkoxylben zonitrile which is then treated with a secondary amine having the formula, HNRR1.
  • the first step can be accomplished by treating 4-nitro- 2-hydroxybenzonitrile or a metal salt thereof with a haloalkylating agent such as a haloalkyl para-toluenesulfonate, haloalkyl benzenesulfonate, dihaloalkane, etc.
  • .4 nitro-2-hydroxybenzonitrile is haloalkylated by treating its sodium salt with 2-chloroethyl .para-toluenesulfonate to form 4 nitro -2-(2- chloroethoxy) benzonitrile which then is treated with diethylamine or piperidine to form 4-nitro-2, -(2-diethylaminoethoxy) benzonitrile or 4-nitro-2-[2-(1-piperidyl) ethoxylbenzonitrile, respectively.
  • quaternary ammonium salts of our present invention are prepared preferably according'to the process as illustrated for-the methiodides by the following series of equations where X, NRR1 and R2 are defined as above:
  • Step IV a 4-nitro2- (tertiary-aminoalkoxy) benzonitrile (C) is treated with methyl iodide to yield the corresponding 4-nitro-2-(tertiaryaminoalkoxwbenz'onitrile methiodide (F).
  • step V the 4-nitro methiodide (F) is reduced to yield the corresponding 4-amino-2-tertiaryaminoalkoxy)benzonitrile methio-dide (G), which, in step VI,- is alkylated to produce the corresponding 4-alkylaminoor 4-hydroxyalklyamin 2 (tertiary aminoalkyoxybenzonitrile methiodide (H).
  • 4-nitro-2-(2-diethylaminoethoxy)'benzonitrile is treated'with methyl iodide to form 4 nitro 2 (2 diethylaminoethoxy benzonitrile methiodide, which is then reduced to yield the corresponding 4-amino-2- (Z-diethylaminoethoxy) benzonitrile methiodide, which, in turn, is alkylated toyield -n-butylamino 2 (2 diethylaminoethoxy) benzonitrile methiodide.
  • step IV When in step IV, other lower alkyl or benzyl esters of an acid is substituted for methyl iodide, the corresponding 4-nitro- (F) 4-amino(G) and 4-substituted-amino (H) quaternary salts are formed.
  • Other lower alkyl and benzyl esters that are suitable include those shown 'hereinabove.
  • the reduction step V is carried out preferably by catalytic hydrogenation using catalyst'such as Raney nickel, platinum, palladium or other cata lysts generally effective to catalyze nitro groups to amino groups.
  • catalyst' such as Raney nickel, platinum, palladium or other cata lysts generally effective to catalyze nitro groups to amino groups.
  • this reduction step can'be carried out by chemical methods.
  • Suitable chemical reducing agents include iron and a hydrohalic acid, tin and a hydrohalic acid, "etc. I V
  • the alkylation step VI. to produce the 4-alkylaminoor 4 hydroXyalkylamino- 2-(tertiary: aminoalkoxy) benzonitrile quaternary salts where the alkyl or hydroxyalkyl radical, designated as R2, has from three to six carbon atoms, is preferably carried out by reductivelyalkylating the corresponding 4-amino' quaternary salts with an alkanal or a hydroxyalkanal havingfrom three to six carbon atoms.
  • This reduction iscarried out preferably by catalytic hydrogenation using catalysts such as platinum, palladium, Raney nickel or other catalysts generally efiective in re duction alkylations'using alkanalsand hydroxy elkanals.
  • this reductive alkylation procedure can be carried out, but with lower yields, by chemical methods using chemical reducing agents such as zinc and acetic acid.
  • the alkylation step VI can be done directly by heating a 4- amino 2- (tertiary aminoalkoxy) benzonitrile quaternary salt with an alkylating agent such as methyl; iodide, ethyl bromide, n-propyl bromide, isobutyl iodide, Z-hydroxyethyl bromide, 4-hydroxybutyl chloride, andthe like,'in the presence of a hydrogen halide acceptor, e. g., sodium bicarbonate, potassium carbonate, etc.
  • an alkylating agent such as methyl; iodide, ethyl bromide, n-propyl bromide, isobutyl iodide, Z-hydroxyethyl bromide, 4-hydroxybutyl chloride, andthe like,'in the presence of a hydrogen halide acceptor, e. g., sodium bicarbonate, potassium carbonate, etc.
  • the 4-alkylaminoand 4-hy'droxyalklamino- 2- (tertiaryaminoalko-Xy) benzonitrile ,quaternary ammonium salts can also be prepared, but less preferably, bytreating a 4-a1kylaminoor 4-hydroxyalkylamino 2 (tertiary-aminoalkoxy) benzonitrile, designated above as (E), with an alkyl or benzyl ester. of an acid, said esters being of the type described above.
  • the 4-amino-2-(tertiary-aminoalkoxy)benaonitrile quaternary salts can be prepared by treating, preferably at room temperature, the corresponding 4-amino-2-(tertiaryaminoalkoxy) benzonitrile, designated above as (D), with an alkyl or benzyl ester of an acid of the type described hereinabove.
  • his mode of preparation is not desirable as the foregoing described method of reducing the corresponding 4 nitro -'2 L (tertiary aminoalkoxy)benzontirile quaternary ammonium-salts since here some alkylatio-n of the -amino radical might result, as a competing reaction Conditions more favorable for alkylation of the 4-amino radical were drogen halide acceptor.
  • N stands for total nitrogen as determined by the Dumas method.
  • V N stands for basic amino nitrogen as determined by titration with perchloric acid in glacial. acetic acid solution.
  • N stands for nitro nitrogen as determined by titra tion with standard titanous chloride in glacial acetic acid solution.
  • This compound is either 4-nitro-2-(z dimethylamino- 1-propoxy)benzonitrile (J) 'or 4-nitro-2-(3-dimethylamino-Z-propoxy)benzonitrile (K) having the following respective formulas IIFO: N Oz -'o-cnzonnccna)l --'or inoizm-r oizr-a)i on; i" 0H3 CN ON The hydrochloride of this basic nitrile (J or 212.1-'212.7 C. (cor.).
  • the ethyl "acetate insoluble red-precipitate, obtained above, was recrystallized several times from absolute ethanol-nehexa-ne or from isopropanol "containing Water.
  • the orange-form (a hydrate) was converted into 7 the anhydrous red formbn heating at '0.
  • nitro-2- (tertiary-aminoalkoxy) benzonitriles which can be prepared according to the foregoing procedures include the followmg: nitrile; 4-nitro-2- [2 (2,5-dimethyl-1-pyrrolidyl) ethoxylbenzonitrile; 4-nitro-2- (4 dimethylaminobutoxy) benzonitrile; 4.
  • the dihydrochloride salt was prepared by treating a solution of 20 g. of the 4- amino nitrile in 300 ml. of isopropanol with an sequently washed withhot ethanol. .The'combined filtrate and washings were concentrated by distilling in vacuo, thereby yielding, as an oil, the product, 4-amino-2- (2-diethylaminoethoxy) benzonitrile.
  • the foregoing preparation can be carried out using 4-nitro-2-(Z-diethylaminoethoxy)benz0nitrile in place of 4-nitro-2-(2-diethylaminoethoxy) benzonitrile hydrochloride.
  • the phosphate salt of the above 4-amino nitrile was prepared by dissolving about 12 g. of 4-ami- Ilo-2-(2-diethylaminoethoxy)benzonitrile in 100 excess of anhydrous ether containing 20% by weight of anhydrous hydrogen chloride and diluting the mixture with ether.
  • the thick, pale yellow oil that precipitated was separated by decanting the solvent mixture and was taken up in 400 ml. of boiling isopropanol and precipitated by the addition of 300 ml. of ethyl acetate, followed by cooling.
  • the product was filtered and recrystallized several times from isopropanolethyl acetate. There was thus obtained 4-amino-,
  • 4n-butylamino2- (Z-diethylaminoethoxy) benzonitrile was prepared as follows: To a hot stirred ,mixture of g. of 4-amino-2-(2-diethylaminoethoxy)benzonitrile, 22.5 g. of zinc dust, 21.2 g. of glacial acetic acid and 100 ml of dry benzene was added 7.5 g. of n-butanol (n-butyraldehyde) dissolved in ml. of dry benzene over a fifteen minute period. After the mixture had been stirred for one hour, an additional 1 ml. of nbutanal was added and stirring continued for an additionalfifteen minutes.
  • the zinc acetate was filtered oif and washed with hot dilute acetic acid and benzene.
  • the cooled filtrate was made basic to litmus with concentrated ammonium hydroxide, the benzene layer was separated and the aqueous solution was extracted three times with benzene. After the combined benzene layer and extracts had been dried over anhydrous potassium carbonate, the benzene was removed by distilling in vacuo, yielding, as a mobile yellow oil, 4-hbutylamino 2 (2-diethy1aminoethoxy)benzonitrile.
  • This oily product was converted into its monohydrochloride salt as follows: It was dissolved in propanol :and' recrystallized from a b s o l u t e ethanol-ethyl acetate. There was thus obtained, ascottony white needles, 4-n-butylamino-2-(2- diethylaminoethoxy) benzonitrile mono h y d r ochloride, M. P. 2l0.22l1.0 C. (cor.), [dried at C.in vacuo].
  • phosphate precipitated as a thick, orange-yellow oil Ether was added to the mixture which was then chilled. The supernatant liquid was separated from the oil by decantation and the oil was taken up in 100 m1. of acetone, whereupon the phosphate salt crystallized. To this mixture was added 100 ml. of ethyl acetate and theresulting mixture was chilled. The solid product that separated was recrystallized by dissolving it in about 100ml. of water, filtering and diluting the filtrate to a volume of about 450 ml. with absolute ethanol. There was thus obtained, after drying at 100 C. and 0.01 mm.
  • n-pentanal n-valeraldehyde
  • dry benzene n-pentanal
  • the phosphate of this compound was prepared by dissolving about 11.7 g. of.4-namylamino 2- [2 (2 -methyl-l-piperidyhethoxylbenzonitrile in; 150 ml. of acetone and adding to the resulting solution asolution of 4 g. of phosphoric acidin acetone.
  • the resulting mixture was diluted with ml. of acetone and 100 fml. of ethyl acetate, and chilledin ice, whereupon thereseparated a white crystalline precipitate.
  • the foregoing reductive alkylations can be carried out using, in place of zinc 'pylamino 2e [3 (4 methyl l-piperidyl) pro poxyl'benzonitrile; 4 isobutylamino 2- [2-(3- 18 r ethy1--1 piperidyllethoxylbenzonitrile; 4 nhexylamino 2 [3- (2methyl-I-pyrr0lidyl) pro:- poxylbenzonitrile; and the like.
  • the. 4-alkylaminoand 4-hydroxyalkylamino :2 J- (tertiary aminoa1koxy)- benzomtriles of our invention can be prepared by direct .alkylation of'the corresponding 4-amino 4'.
  • @Pm'tro-Z- (tertiary-aminoalkoxyl) benzomtrz'le quaternary ammonium salts I are prepared by treating the corresponding.4 nitro --2 (tertiary-aminoalkoxy)benz onitrile with an alkyl or 'benzyl ester of an inorganic or organic acid of the type described: hereinabove.
  • methiodides which can be prepared according to the foregoing procedure include the following: '4 nitro-2-(2 dimethylamino1 pro- .dyl) propoxyl ber-i'zonitrile methiodide 4-riitro-2- .IE2 (3. ethyl .1. piperidyl)ethoxylbenonitrile methiodide; 4 nitro 2-[3-.(2-methyll-pyrroli- :dyl)propoxylbenzonitrile methiodide; and the .like.
  • Additional 4-amino-2- (tertiary-aminoalkoxy) benzonitrile methiodides which can b prepared according to the foregoing procedure include the following 4-amino-2- (2-dimethylamino 1-pror poxy) benzonitrile methiodide; 4-amino-2- [3- 1'- pyrrolidyl)propoxylbenzonitrile methiodide, 4- amino-2- [2- (2,5-dimethyl- Vl :pyrrolidyl) ethoxy] benzonitrile methiodide; 4-aminov-2- (4-dimethy1- aminobutoxy benzonitrile methiodide; a-amino- 2 [2 (di n butylamino)ethoxylbenzonitrile methiodide; 4 amino-2- [3-(4-methyl- 1 -piperidyl) -propoxylbenzonitrile methiodide; 4-amino- 2-
  • 4-n-butylamino 2 (2 diethylaminoethoxy) benzonitrile methiodide can be preparedas follows: A mixture of 10 g. of 4-amino-2-(2-diethylaminoethoxy)benzonitrile methiodide, 5 g. of n-butanal (n-butyraldehyde), 0.5 g. of platinum oxide monohydrate and 150 ml. of absolute ethanol is treated at 50 C. with '50 lbs. (per sq. inch) pressure of hydrogen until hydrogeriis no longer taken up. The catalyst'is filtered off and the ethanol is removed from the filtrate by distilling in vacuo, leaving theproduct, l-n-butylamino 2 2 diethylaminoethoxy)benzonitrile methiodide.
  • the 4-alkylaminoand 4-hydroxyalkylamino-2 (tertiary-aminoalkoxy)benzonitrile quaternary ammonium salts can be prepared by treating the corresponding 4-a1kylaminoor l-hydroxyalkylamino 2 (tertiaryaminoalkoxy) benzonitrile with an' alkyl or benzyl ester of an inorganic or organic acid of the type described hereinabove.
  • This mode of preparation is illustrated by treating 4-methyla nino-2- (2 diethylaminoethoxy)benzonitrile, -ethyl amino-2-(2-diethylaminoethoxy) benzonitrile or 4-'(2-hydroxyethylamino) 2 (2 diethylaminoethoxy benzonitri1e with methyl iodide to yield, respectively, 4-methylarnino-2-(2-diethylaminoethoxy) -benzonitrile methiodide, 4-ethylamino 2-(2-diethy1amin0ethoxy) benzonitrile methiodide or 4- (2-hydroxyethylamino) -2.- (Z-diethylaminoethoxy) benzonitrile methiodide.-,
  • Additional 4-alkylaminoand ,4-hydroxyalky1- amino 2 (tertiary arr inoalkoxy) benzonitrile methiodides whichc'an be prepared according to the foregoing procedures include the following: -n-butylamino- 2 (2 dimethylamino 1 propoxy)benzonitrile' methiodide; 4-n-butylamino- 2-[3-(l-pyr'rolidyl) propoxylbenzonitrile meth iodide; 4- (fi hydroxyhexylamino) -2- [2- (2,5.-di-
  • a quaternary ammonium lsalt of fa, .4-amino- 2- (tertiary-aminoalkoxy) benzonitrile having the formula where X is a lower alkylene radical whose two free valence bonds are on different carbbnlacquisitionis, NRR1 is a l-pipe'fidyl radical, R3 is 'a'lower alkyl radical and A11 is a non-toxic aiiionof a strong acid.
  • a quaternary ammonium salt of'al-nitroa 2"-(dialkylaminoalkoxylbenzonitrile having the formula I NO'z where "X is a lower 'alkylene radical whose two free valence bonds are on 'difierent carbon atoms, Rois a lower alkyl radical and An is a non-toxic anion of a strong acid.
  • A'quaternary ammonium salt of a 4-nitro-2- ('di'ethyla mino alko'xy) benzonitrile having the formula Where X is a lower alkylene radical whose two free valence bonds areon differentcarbon atoms, R3 is a loweralkyl radical and An-is a non-toxic anion of a strong acid.
  • NRR1 is-a l-piperidyl radical
  • Rszis a lower :alkyl radical
  • An is a non-toxic anion of aistro'ng acid.
  • NRRi is a 2-methy1-1-piperidyl radical
  • R3 is a lower alkyl radical
  • An is a non-toxic anion 1 of a strong acid, which comprises treating the corresponding -4-nitro-2 (tertiary-aminoalkoxy) benzonitrile with an ester' having the formula.
  • N331 is a' member of the group consisting of zonitrile methiodide. e 21. 4 amino 2- [3-(1-pi'peridyDpropogy] benzonitrile methiodide.

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Description

Patented June 16, 1953 PATENT OFF/ICE QUATERNARY AM'MONIUM SALTS OF 4-SUB- STITUTED -2- (TERTIARY-AIVIINOALKOXY) BENZONITRILES AND THEIR PREPARA- TION Raymond 0. Clinton, North Greenbush, and Stanley 0. Laskowski, Menands, N. Y.-, assignors to Sterlingv Drug Inc., New York, N. Y'., a corporation of Delaware No Drawing.
24 Claims. (01.
. 1 i This invention relates to quaternary ammonium salts of 4-substituted-2-(tertiary-aminoalkoxy) :benzonitriles and. to their preparation.
-The quaternary ammonium salts of our invention have the general formula onlomona) 30 -CH2CH2CI'I2CH9 CH2CH (CH3) CH2, and the like. The tertiary-amino radical I shown above as NRR comprehends dialkylamino radicals where R and R1 are lower alkylgroups, 35 alike or different, and each alkyl group having one to six carbon atoms, such dialkylamino radicals including dimethylamino, diethylamino, ethylmethylamino, diisopropylamino, ethyl-npropylamino, di-n-butylamino, di-n-hexylamino, and the like. Further, the tertiary-amino radical designated as NRR1 encompasses saturated N-heteromonocyclic radicals having five to six ring atoms, illustrated by examples such as 1- piperidyl; (lower alkylated)-1-piperidyl such as Z-methyl 1 piperidyl, 3-,ethyl-1-piperidyL4- methyl-l-piperidyl, 2,6-dimethyl-1-piperidyl; 1- pyrrolidyl; (lower alkylated) -1-pyrrolidyl such as Z-methyl-l-pyrrolidyl, 2,5-dimethyl-1-pyrrolidyl; l-morpholinyl; and the like. In the 50 Application September 5, 1951, Serial No. 245,247
2 l aboveformula, when Z stands for lower alkyl amino, the lower alkyl radical (designated as R2 below); has preferably one to six carbon atoms, including such radicals as methyl, ethyl, npropyl, n-butyl, isobutyl,- n-amyl, Z-amyl, nhexyl, and the like. When Z represents lower hydroxyalkylamin'o, the lower hydroxyalkyl radical (designated as R2 below) has preferably two to six carbon atoms, including radicals such as 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 3-hydroxy-2-methylpropyl, 3-hydroxy- 2,2-dimethylpropyl, 2-hydroxybutyl, 4-hydroxybutyl, 3 hydroxyamyl, 5 hydroxyamyl, 6-hydroxyhexyl and the like. R3 when representing lower alkyl has preferably one to six carbon atoms, including such radicals as methyl, ethyl,
n-propyl, n-butyl, isobutyl, n-amyl, n-hexyl, and the like. The non-toxic anion, designated above as An, which can be any anion, for instance, chloride, bromide, iodide, sulfate, benzene-sulfonata para-toluenesulfonate, and the like, has no appreciable pharmacological activity of its owniin'the high dilutions at which the quaternary ammonium salts as a whole are efiective. In particular, the anions contribute nothing to theganglionic blocking activity which resides solelyin the remainder of the molecule. Thus,.our invention comprehends quaternary ammonium salts of the above defined 4-substituted -2 (tertiary-aminoalkoxy)benzonitriles, said salts being-derived from lower. alkyl or benzyl esters of an" acid, either inorganic or Or ic. such esters havingthe formula Ra -An cedure represented by the following series of equations where X, NRRran'd R2 have the meanings given hereinabove and halogen is chlorine, bromine, iodine or fluorine:
Thus, in step I, 4-nitr0-2-hydroxybenzonitrile (A) is converted into a 4-nitro-2-(tertiaryaminoalkoxy)benzonitrile (C) by reaction with a tertiary-aminoalkyl halide (B). In'step II, the 4-nitro-2-(tertiary aminoalkoxy) benzonitrile (C) is reduced to yield the corresponding 4-amino-'2 (tertiary aminoalkoxy) benzonitrile (D), which is then alkylated to form the corresponding 4-alkylaminoor 4-hydroxyalkylami no-2- (tertiary-aminoalkoxy) benzonitrile (E) A specific illustration of this series of reactions is the formation of l-n-butylamino-2-(2-diethylaminoethoxy)benzonitrile by first reacting 4-mitro-2-hydroxybenzonitrile, preferably in the form of an alkali metal salt, with a 2-diethylaminoethyl halide, preferably the chloride, to yield 4-nitro-2- (Z-diethylaminoethoxy) benzonitrile, reducing this 4-nitro compound to yield the corresponding 4-amino -2-'(2- diethylaminoethoxy)benzonitrile and then alkylating this -amino compound to produce 4-n-butylami-no- Z-(Z-diethylaminoethoxy)benzonitrile.
Step I is carried out preferably using l nitro- 2-hydroxybenzonitrile in the form of af metal salt thereof, preferably an alkali metal salt, with the tertiary-aminoalkyl halide. Alternatively, Step I can be carried out using 4 nitro -2-hydroxybenzonitrile itself, however, with a resulting decrease in yield of the 4-nitro-2- (t ertiaryaminoalkoxy) benzonitrile. I
The reduction step II is carried out either by chemical methods or by catalytic hydrogenation. Suitable chemical reducing agents include iron and hydrochloric acid, ferrous sulfate and am monia, tin and hydrochloric acid, sodium hydrosulfite, etc. In practicing our invention, we preferably used iron and hydrochloric 'fiid. Catalysts suitable when catalytic hydrogenation is employed include Raney nickel, platinum, palladium or other catalysts generally efiective to catalyze hydrogenation of nitro groups to amino groups.
V The alkylation of the 4 -amino-2-(tertiaryaminoalkoxy)benzonitriles (D); to produce the related 4-alkylamino or 4-h'ydrox'yalkylaminonitriles (step HI) where R2 has from three to six carbon atoms is preferably carried out by reductively alkylating the a l-amino compound with an alkanal or a hydroxyalkanal. Thus, this 4 2-(tertiary-aminoalkoxy) benzonitrile and an alkanal or hydroxyalkanal, having from three to six carbon atoms, in a reducing medium. This reduction can be carried out either by chemical methods or by catalytic hydrogenation. Illustrative of this reductive alkylation step is the formation of 4-n-amylamino-2 [3- l-piperidyl)'pr'opoxylbenzonitrile or 4 ('5 hydroxyamylamino) -2- [3- (l-piperidyl) propoxyl benzonitrile by treating a mixture of the corresponding 4-amino-2- [3-(1-piperidy1) propoxy] benzonitrile withpentanal (valeraldehyde) or 5-hydroxypentanal,
respectively, with chemical reducing agents, such as zinc dust and acetic acid, iron and acetic acid, iron and hydrochloric acid, etc., or with hydrogen under pressure using catalysts such as platinum, palladium, Raney nickel or other catalysts generally effective in reductive alkylations using alkanals and hydroxyalkanals.
Alternatively, the alkylation step III can be carried out directly by heating a 4-nitro-2-(tertiary-aminoalkoxy)benzonitrile (D) with an alkylating agent such as methyl iodide, ethyl bromide, n-propyl bromide, isobutyl iodide, 2- hydroxyethyl bromide, 4-hydroxybutyl chloride, and the like, in the presence of a hydrogen halide acceptor, e. g., sodium bicarbonate, potassium carbonate, etc. Thus, such treatment of -4-am'ipreferred method ofalkylatingthe 4-amino n'i-' 1 no-2- (3-diethylaminopropoxy) benzonitrile with methyl iodide, ethyl bromide or 2hydroxy-ethyl bromide yields, respectively, 4-methylamino-2- (S-diethylaminopropoxy) benzonitrile, amino -2- (3-diethylaminopropoxy)benzonitrile or e- (Z-hydroxyethyl) amino-2- 3-diethylaminopropoxy)benzonitrile. Yields of the resulting 4-alkylaminotiary-aminoalkoxy) benzonitril'es obtained by this method are lower than those obtained by the foregoing described reductive alkylation procedure due to quaternary salt formation in this reaction.
Step I can also be carried out stepwise, that is, by first haloalkylating 4-nitro-2-hydroxybenzonitrile (A) to form a 4-nitro-2-(haloalkoxylben zonitrile which is then treated with a secondary amine having the formula, HNRR1. The first step can be accomplished by treating 4-nitro- 2-hydroxybenzonitrile or a metal salt thereof with a haloalkylating agent such as a haloalkyl para-toluenesulfonate, haloalkyl benzenesulfonate, dihaloalkane, etc. As illustrations of this stepwise procedure, .4 nitro-2-hydroxybenzonitrile is haloalkylated by treating its sodium salt with 2-chloroethyl .para-toluenesulfonate to form 4 nitro -2-(2- chloroethoxy) benzonitrile which then is treated with diethylamine or piperidine to form 4-nitro-2, -(2-diethylaminoethoxy) benzonitrile or 4-nitro-2-[2-(1-piperidyl) ethoxylbenzonitrile, respectively.
Another method of preparing the 4-nitro-2- (tertiary-aminoalkoxy)benzonitriles (C)- except those wherethe tertiary-amino radical NRR1 is dimethylamino is afforded bya rearrangement process by heatinga tertiary-aminoalkyl G-nitrobenzisoxazole-3-carboxylate or, alternatively, by heating a mixture; of a lower alkyl 6-nitro-' benzisoxazole-3-carboXylate with a tertiaryaminoalkanol which results in formation of the tertiary-aminoalkyl 6-nitrobenzisoxazole-3-carboxylate which then undergoes said rearrangement. This rearrangement process is disclosed and claimed in our copending applicationlSerial No. 245,250, filed September 5, 1951. The tertiaryaminoalkyl 6-nitrobenzisoxazole-3-carboxylates are also disclosed and claimed in our 'copending or 4-hydroXyalkylamino-2-(terapplication Serial No. 245,245, 5, 1951.
The quaternary ammonium salts of our present invention are prepared preferably according'to the process as illustrated for-the methiodides by the following series of equations where X, NRR1 and R2 are defined as above:
filed September In Step IV, a 4-nitro2- (tertiary-aminoalkoxy) benzonitrile (C) is treated with methyl iodide to yield the corresponding 4-nitro-2-(tertiaryaminoalkoxwbenz'onitrile methiodide (F). In step V, the 4-nitro methiodide (F) is reduced to yield the corresponding 4-amino-2-tertiaryaminoalkoxy)benzonitrile methio-dide (G), which, in step VI,- is alkylated to produce the corresponding 4-alkylaminoor 4-hydroxyalklyamin 2 (tertiary aminoalkyoxybenzonitrile methiodide (H). As a specific illustration of this series of reactions, 4-nitro-2-(2-diethylaminoethoxy)'benzonitrile is treated'with methyl iodide to form 4 nitro 2 (2 diethylaminoethoxy benzonitrile methiodide, which is then reduced to yield the corresponding 4-amino-2- (Z-diethylaminoethoxy) benzonitrile methiodide, which, in turn, is alkylated toyield -n-butylamino 2 (2 diethylaminoethoxy) benzonitrile methiodide. When in step IV, other lower alkyl or benzyl esters of an acid is substituted for methyl iodide, the corresponding 4-nitro- (F) 4-amino(G) and 4-substituted-amino (H) quaternary salts are formed. Other lower alkyl and benzyl esters that are suitable include those shown 'hereinabove.
The reduction step V is carried out preferably by catalytic hydrogenation using catalyst'such as Raney nickel, platinum, palladium or other cata lysts generally effective to catalyze nitro groups to amino groups. Alternatively, but less desirably, this reduction step can'be carried out by chemical methods. Suitable chemical reducing agents include iron and a hydrohalic acid, tin and a hydrohalic acid, "etc. I V
The alkylation step VI. to produce the 4-alkylaminoor 4 hydroXyalkylamino- 2-(tertiary: aminoalkoxy) benzonitrile quaternary salts where the alkyl or hydroxyalkyl radical, designated as R2, has from three to six carbon atoms, is preferably carried out by reductivelyalkylating the corresponding 4-amino' quaternary salts with an alkanal or a hydroxyalkanal havingfrom three to six carbon atoms. This reduction iscarried out preferably by catalytic hydrogenation using catalysts such as platinum, palladium, Raney nickel or other catalysts generally efiective in re duction alkylations'using alkanalsand hydroxy elkanals. Alternatively, this reductive alkylation procedure can be carried out, but with lower yields, by chemical methods using chemical reducing agents such as zinc and acetic acid.
, Alternatively, butless desirably, the alkylation step VI can be done directly by heating a 4- amino 2- (tertiary aminoalkoxy) benzonitrile quaternary salt with an alkylating agent such as methyl; iodide, ethyl bromide, n-propyl bromide, isobutyl iodide, Z-hydroxyethyl bromide, 4-hydroxybutyl chloride, andthe like,'in the presence of a hydrogen halide acceptor, e. g., sodium bicarbonate, potassium carbonate, etc. Thus, such treatment of 4-amino-2-(3-diethylaminopro- .poxy) benzonitrile methiodide with methyl iodide, ethyl bromideor Z-hydroxyethyl bromide yields, propoxy) benzonitrile methiod-ide, -ethylamino- 2 (3 diethylaminopropoxy) benzonitrile methiodide or 4- (2-hydroxyethylamino) -2- (3 -diethylaminopropoxy)benzontrile methiodide. Yields of the resulting e-alkylaminoand 4-hydroxyalkylamino 2 (teritary-aminoalkoxy)benzo nitrile, quaternary salts obtained by this method are lower than those obtained by the foregoing described reductive'alkylation procedure due to overalkylation and anionexchange reactions.
The 4-alkylaminoand 4-hy'droxyalklamino- 2- (tertiaryaminoalko-Xy) benzonitrile ,quaternary ammonium salts can also be prepared, but less preferably, bytreating a 4-a1kylaminoor 4-hydroxyalkylamino 2 (tertiary-aminoalkoxy) benzonitrile, designated above as (E), with an alkyl or benzyl ester. of an acid, said esters being of the type described above. Thus, treatment of 4n-amylaminoor 4-(5-hydroxyamylamino) -2- '[2 (2,6 dimethyl 1 p-iperidyl)ethoxylbenzo nitrile with methyl iodide results in the formation of 4n-amylamino;-2- [2- (2,6-dimethyl-1- piperidyl) ethoxy] benzonitrile niethiodide or 4* (5- hydroxyamylamino) --2 [2 (2,6 dimethyl-lpiperidyl) ethoxy1benzonitrile methiodide., Us
ing benzyl chloride in place of methyl iodide yields 4-n-amylamino-2- [2- (2,6-dimethy1-1-pi-v peridyDethoxyl-benzonitrile benzochloride or 4- (5 hydroxyamylamino) 2- [2 (2,6 dimethyl-l-piperidyl) ethoxylbenzonitrile benzochloride, respectively;
Similarly, the 4-amino-2-(tertiary-aminoalkoxy)benaonitrile quaternary salts can be prepared by treating, preferably at room temperature, the corresponding 4-amino-2-(tertiaryaminoalkoxy) benzonitrile, designated above as (D), with an alkyl or benzyl ester of an acid of the type described hereinabove. ment of 4,-amino-2-[3-(l-pyrrolidyllpropoxylbenzonitrile with methyl "iodide or benzyl chloride results in the formation of 4-amino-2-[3- (1.- pyrrolidyl) propoxylbenzonitrile methiodide or 4- amino 2 [3 (1 pyrro lidyl) propoxylbenzonitrile benzochloride, respectively. his mode of preparation is not desirable as the foregoing described method of reducing the corresponding 4 nitro -'2 L (tertiary aminoalkoxy)benzontirile quaternary ammonium-salts since here some alkylatio-n of the -amino radical might result, as a competing reaction Conditions more favorable for alkylation of the 4-amino radical were drogen halide acceptor.
Thus, treat-v 7 Specific embodiments of our invention areiillustrated by the following examples.
1. 4-m'tro-2-(tertiaiy-aminoalkomy) benzonitfil'es Preparation of the intermediate- 4-nitro-2- '(tertiary-aminoalkoxy)benzonitriles is illustrated. by the following alternative procedures, all of which involve alkylation of 4-nitro-2-hydro'xybenzonit'rile or 'a metal 'salt thereof "with a tertiary-aminoalkyl halide, or, stepwise, with a ha'loalkylating agent such as a halo'alkyl paratolue'nesulfonat'e to produce a 4-nitr0-'-'2- (haloalkoxy)benzonitrile' Whichis then treated with 'a 'se'condary amine to form the desired 4-nit'rc-2- (ter tiary-aminoalkoxy) ben'zon'itriles.
Procedure (a) .-To a warm solution of 8210 g. of 4-nitro 2-hydroxybenzonitrile and 1000 m1. of absolute ethanol'w'as added a solution of 11.5 g. of sodium in 500 ml. of absolute ethanol. To the resulting deep carmine-colo'r'ed solution was added 74.5 g. of 2-diethylaminoethyl chloride (the distilled free base can be conveniently replaced by the equivalent amount of 2-diethylaminoethyl chloride hydrochloride and an additional equivalent of sodium 'ethoxide), the mixture was refluxed with stirring for five hours, filtered While hot, and the filter cake was washed thoroughly with absolute ethanol. The combined filtrates were evaporated in vacuo, the residue was dissolved in ethyl acetate and the solution was filtered. To the filtrate was added an excess of 20% ethereal hydrogen chloride solution. There'sulting precipitate of 4-nitro-2- (2-diethylamin'oethoxy)benzonitrile hydrochloride was collected and recrystallized several times from absolute ethanol-ether. The yield of purified material was 112.0 g. (85%), M. P. 1932- 194.6 C. (cor.).
AnaZ.'Calcd. for C13H17N3O3'HC12 Cl, 11.83; N 14.02. Found: C1, 11.75; N 1402.
N stands for total nitrogen as determined by the Dumas method.
NBA, 5.32; NNOZ, 5.32. Found: C, 59.43; H, 6.58; NBA, 5.28; Nno 5.00. Y
V N stands for basic amino nitrogen as determined by titration with perchloric acid in glacial. acetic acid solution.
N stands for nitro nitrogen as determined by titra tion with standard titanous chloride in glacial acetic acid solution.
8 Instead eyclization of the '2-jdimethylamino ethyl chloride occurred exclusively, anda high yield of 1, 1,4,4-tetramethylpiperazinium 54-.(2- cyano-5-nitrophenolate) was: isolated, M. :P. 212.4--213.3. 6. (con) :with decomposition. l-Iowe ever,- 12-dimethylaminoethyl chloride can be used successfully in this a'lkylation by using a nonpolar solvent, such as benzene or toluene, in place of the polar solvent, ethanol, as described below in procedure (12).
l-dimethylamino-Z-propyl, chloride gave a mixture of products indicating that partial. cyclization of the basi'c'bhloride had occurred:
The ethanolic filtrate from the reaction (carried outas above) was evaporated in vacuo. The residual red oil was triturated with warm ethyl acetate and the insoluble red precipitate was removed by filtration. The ethyl acetate solution was decolorized and treated with an excess of ethereal hydrogen chloride. The resulting crystalline hydrochloride was collected, washed with ethyl acetate and reconverted to the base; the crystalline base as initially obtained melted at 56-59 C. Several recrystallizations from ne heptane and from dilute ethanol gave creamcolored leaflets, M. P. 75.6-77.0" C. (cor.). This compound is either 4-nitro-2-(z dimethylamino- 1-propoxy)benzonitrile (J) 'or 4-nitro-2-(3-dimethylamino-Z-propoxy)benzonitrile (K) having the following respective formulas IIFO: N Oz -'o-cnzonnccna)l --'or inoizm-r oizr-a)i on; i" 0H3 CN ON The hydrochloride of this basic nitrile (J or 212.1-'212.7 C. (cor.).
AnaZ.--Calcd. for C1'2H1sN3O3-HCI: Nn'o 4.90; Cl, 12.41. Found: M0,, 5.04 CI, 12.39. t
The ethyl "acetate insoluble red-precipitate, obtained above, was recrystallized several times from absolute ethanol-nehexa-ne or from isopropanol "containing Water. The compound crystallizedrin"clusters of slender red needles from the former solvent combination and in large thin rectangular orange plates from the latter solvent.
The orange-form (a hydrate) was converted into 7 the anhydrous red formbn heating at '0.
Quantitative degradation experiments; indicated that this compound was 1,1,2,4,4,5-hexamethyl= piperazinium di- (2-cyano-5-nitrophenolate) Procedure (b) ,A- mixture of 82.0 g. of i-nitro-j 2-hydroxybenzonitrile, 70.3 g. of powdered an hydrous potassium carbonate and. 2500 ml. of toluene was refluxed withstirringwunder a continuous water separatonfor three hours. During this period 4.5 ml. of water was collected. The continuous water separator was removed and there was added. 54.0 g. of z-dimethylam-i-noethyl' chloride. The mixture was refluxed with stirring for sixteen hours, treated. with an additional 10.8 g. of 2-dimethylaminoethyl chloride and refiuxed with stirring foranadditional eight hours. The'mixt'ur was filtered while hot, the insoluble material'was washed. with hottoluene andthe 9-1. combined filtrates were decolorized and evaporated in vacuo. The resulting solid was recrystallized several times from n-heptane, yielding 77.1 g. (65.7%) of purified 4-nitro-2-(2-dimethylaminoethoxy)benzonitrile, M. P. 83.1-
2 [2 (l-piperidyl)ethoxylbenzonitrile, respectively.
Procedure ((1) .--A solution of 16.4 g. of 4-nitro- 2-hydroxybenzonitrile and 14.2 g. of 2-diethyl- 5 aminoethyl chloride in 150 ml. of anhydrous iso- 84.0 0. (con) propanol was refiuxed for five hours. On work- AnaZ.Ca1cd. for 011141317305: NBA, 5.95; Nno ing up there was obtained 8.5 g. (28% yield) of 5.95. Found: NBA, 5.98; NN0 6.25. 4-nitr0 2 (Z-diethylaminoethoxy)benzonitrile 4 nitro 2 (2-dimethylaminoethoxy)benzohydrochloride,"M.P. and mixed M. P. 193-194 C. nitrile in the form of its hydrochloride salt melts (con). I at 229.5230.3 C. (c0r.). Procedure (e).-A- solution of 6.2 g. of 6- AnaZ.Calcd. for 011111317303: Cl, 13.05; Nno nitrobenzisoxazole-3-carboxylic acid and 5.4 g. of 5.16. Found: Cl, 12.79; Nno 5.28. a Z-diethylaminoethyl chloridein 100 ml. of an- Procedure (0) .A mixture of 82.0 g. of 4-nitrohydrous isopropanol was refluxed forv one hour. 2-hydroxybenzonitrile, 76.0 g. of powdered an-- During initial dissolution of the acid in the alcohydrous potassium carbonate, 141.0 g. of 2- hol-amine mixture an orange color developed chloroethyl para-toluenesulfonate and 1350-1201. and carbon dioxide was vigorously evolved. On of meta-xylene was refluxed with stirring: under working up there was obtained 5.2 g. (58% yield) a continuous water separator for seventy-eight of purified 4-nitro-2-(2-diethylaminoethoxy)- hours. The mixture was filtered while hot and benzonitrile.hydrochloride, M. P. and mixed M. P. the insoluble material was washed thoroughly 1932-1946 C. (con). with hot toluene. The combinedfiltrates were Anal.Calcd. for CisHi'rNzOs-HClt C, 52.09; concentrated to dryness in vacuo and the. residual H, 6.05 Np, 14.02; Nuo 4.67; 01, 11.83. Found: solid was recrystallized from absoluteethanol. C, 52.29;1-1, 5.91; ND, 14.07; NNO2, 4.55; Cl, 11.79. There was thus obtained a 67.5 yield of purified Alternatively, this procedure can be modified 4 nitro 2 (2 chloroethoxy)-benzonitrile, as 5 by isolating the Z-diethylaminoethyl G-nitroslender, pale yellow needles, M. P. l27.4128.5 C. benzisoxazole-3-carboxy1ate first formed and (cor). then heating this ester to, produce 4-nitro-2 AnaZr-Calcd. for C9H7C1N203t NNO2, 6.18; Cl, (Z-diethylamino'ethoxy)benzonitrile. 15.65. Found: Nno 6.30; Cl, 15.30. The foregoing process as illustrated by proce- The reaction of 4-nitro-2-(2-chloroethoxy) dure (e) is disclosed and claimed in our copending benzonitrile with a secondary amine in aqueousapplication Serial Number 245,250, filed Septemethanolic solution containing sodium iodide gave ber 5,, 1951;, now Patent No. 2,626,261, granted fair to pooryields ofthe-corresponding 4-nitro- January 20, 1953. 2-tertiary-aminoethoxy)benzonitriles, given be- ,Additional 4-nitro-2-(tertiary-aminoalkoxy)- low in Table 1;. Thus, reactionw-ith dimethylbenzon-itriles,prepared.accordingto the above deam-ine; diethylamine or piperidine gave 4-nitroscribed proceduresaregiven in Table I.
Table I- Q.( Hz)NR 1 V 7 Analyses, Percent 12 NNR| j C Formula Nlm N110:
coined; TEound c5155. Found 3 NKGJHM 53.0-55.0 f 01515151505, 5.105 5. 01 5.05 4.92 2" "NcaHao 1181-1192 614111101503; 1 5. 00; 5.07 5.09 5.05 2 NC Hflh. 1332430 2 o,1.ri N305 .4.84 -.,4:82' 14.52 14.24 2 C'lHm 2 3318. CmHaiNaQa 4.62 4.65 4.62 4.76 J "'3; NC5H'1u 102-21028 CmHmNaOa 4:84 4:87 1 4.84 4.80 J. '3. NQaHnP. ,a 02.5-93.5 01611211503 v 4.62 rer- 4. 62 4. 2 10041180. 125.5-127.5 CitHnNaO; 5. 05 5.07" 5. 05-" 5.05
3 NClHBO" 11004115 'C14H17N304"' 4.81 4.82 4.01 4.30,
B CalcdJ. C, 62.26
0.02. Found: 0 02.38351", 6.53..
2;.daimfittysamoahqxabananas; 4-5150,-
. I-I ydroch1oride addition-salts of the compounds 2-(zmiethylaminoethoxylb nz n trile or 4-.nitroll; of. Tab1e.I' '.'-are given in Table I1.
TABLE II (CHaL-NRRr-HCI Analyses, Percent o V n NRR; 5 Formula 01 NR0,
Calcd. Found Calcd Found 3 N(CH5)z 2 10. 2-210. 9 C H aN O3.HCl 11. 11. 30 4. 46 4. 58 2 NCsHm B C 4H17N3O3.HC1 11. 37 11. 33 4. 49 4. 64 2 NCaHu 192. 7-193. 7 01511511951303.1101 10. 83 10. 80 d 12, 90 d 13. 04 2 NC H 214. 6-215. 3 GMHZINSOLHC]. 10. 43 10. 3O 4. 12 4. 26 3 NC H 0 194. 0-194. 9 CuHnNzOaHCl 10. 88 10. 83 4. 3O 4. 30 3 Noel 1 187. 1-188. 0 cwHmNaoaHol 10. 43 10. 27 12. 37 d 12. 12 2 N 0 11 0 214. 6-215. 5 C13H15N304.HC1 11. 30 11. 31 4. 47 4. 35 3 NG4H80 215. 0-215. 8 C 4H17N3O4.HC1 10. 82 10. 85 4. 27 4. 19
b Sintered at 197 0., slowly decomposed and turned black above 199 C.
c N C H =2methyl-l-piperidyl. 4 Total nitrogen by the Dumas method (Np). e NC H1 =2,6-dimethy1-l-piperidyl.
1 N 0411 0 =4-morpholinyl.
Additional 4 nitro-2- (tertiary-aminoalkoxy) benzonitriles which can be prepared according to the foregoing procedures include the followmg: nitrile; 4-nitro-2- [2 (2,5-dimethyl-1-pyrrolidyl) ethoxylbenzonitrile; 4-nitro-2- (4 dimethylaminobutoxy) benzonitrile; 4. nitro-2- [2- (di-n-butylamino) ethoxy] benzonitrile 4-nitro-2- [3- (4- methyl 1 piperidyl) propoxy] benzonitrile; 4 nitro 2 [2-(3-ethyl-1-piperidyl) ethoxylbenzonitrile; 4-nitro-2- [3- (2-methyl-l-pyrrolidyl) pro poxylbenzonitrile; and the like.
2. 4-amino 2 (tertiary-aminoalkoxy) benzonitriles ture was stirred for an additional ten minutes and then filtered through a filter aid which was sub- 4-nitro-2- [3- (l-pyrrolidyl) propoxyl benzo- The resultant mix- H ml. of hot isopropanol, adding tothis solution a solution of 6 g. of 85% phosphoric acid in ml. of hot isopropanol and chilling the resulting mixture. The separated product was filtered, washed with isopropanol and recrystallized several times by dissolving it in a small amount of water, filtering the aqueous solution and diluting the filtrate with acetone. There was thus obtained as white prisms, 4-amino-2-(2-diethyl aminoethoxy) benzonitrile phosphate, M. P. 213.5-
214.5 C. (con), [after drying at 100 C. and 0.01
AnaZ.-Calcd. for C13H19N3O'H3PO4: H3PO4, 29.59; ND, 12.68. Found: H3PO4, 29.70; ND, 12.52.
Alternatively, the dihydrochloride salt was prepared by treating a solution of 20 g. of the 4- amino nitrile in 300 ml. of isopropanol with an sequently washed withhot ethanol. .The'combined filtrate and washings were concentrated by distilling in vacuo, thereby yielding, as an oil, the product, 4-amino-2- (2-diethylaminoethoxy) benzonitrile.
Alternatively, the foregoing preparation can be carried out using 4-nitro-2-(Z-diethylaminoethoxy)benz0nitrile in place of 4-nitro-2-(2-diethylaminoethoxy) benzonitrile hydrochloride.
, The phosphate salt of the above 4-amino nitrile was prepared by dissolving about 12 g. of 4-ami- Ilo-2-(2-diethylaminoethoxy)benzonitrile in 100 excess of anhydrous ether containing 20% by weight of anhydrous hydrogen chloride and diluting the mixture with ether. The thick, pale yellow oil that precipitated was separated by decanting the solvent mixture and was taken up in 400 ml. of boiling isopropanol and precipitated by the addition of 300 ml. of ethyl acetate, followed by cooling. The product was filtered and recrystallized several times from isopropanolethyl acetate. There was thus obtained 4-amino-,
2 2-diethylaminoethoxy)benzonitrile dihydrochloride. The above reduction of the 4-nitro-2-(tertiary- 'aminoalkoxy)benzonitriles to yield the corresponding 4-amino nitriles can be carried out by catalytic hydrogenation as illustrated by the following general preparation: Ten grams of the 4- nitro 2 (tertiary-aminoalkoxy)benzonitrile inml. of ethanol is hydrogenated using 50 lbs. pressure of hydrogen at 25 C. in the presence of 2 g. of Fancy nickel. After the rapid exothermic reaction, the catalyst is filtered 01f and the filtrate evaporated to dryness. The resulting residue is dissolved in ethyl acetate and ethereal hydrogen chloride is added as above. Alternatively, other catalysts can be employed as exemplified in aminoalkoxy)benzonitrile, which isextracted 7 with ethyl acetate. The ethyl acetate extract is dried and treated with phosphoric acid, a'sabove, H
to give the 4-amino-2-(tertiary-aminoalkoxy) 7 benzonitrile in the form of its phosphate.
When the procedure given alcovev for the reduction of 4-nitro-2-(Z-diethylaminoethbxy)benzonitrile was followed but using 72.5 g. of 4-nitro-2- [2- (-morpholinyl) ethoxyl benzonitrile hydrochloride, 80 g. of powdered iron, 1 ml. of concentrated hydrochloric acid, 300 m1. of ethanol and 50 ml. of water, there was obtained as the product, 4-amino-2- [2- l-morpholinyl) ethoxy] benzonitrile, which recrystallized from benzene as rosettes of long flat white needles, M. P. 130.6- 132.8C. (cor.) [dried at 80 C. in a vacuum oven for six hours].
AnaZ.-Calcd. 'for C13H17N302Z ND, 17.00., Found: ND, 17.09. i
The preparation of this 4-amino nitrile. in the form of its monohydrochloride salt was accomplished as follows-:' To a solution of 5 g. of 4- amino 2 [2-(4-morpholinyl)ethoxylbenzonitrile dissolved in 100 ml. of-- warm ethyl acetate was added an excess of ethereal hydrogen chloride, thereby yielding an amorphous white precipitate. The precipitate was-filtered, washed well withethyl acetate and-recrystallized by dissolving it in a minimum quantity of hot absolute ethanol and then adding to this hot solution about two volumes of ethyl acetate.-'The preethanol.
cipitated dihydrochloride was. collected, washed with ethylacetate and dissolved in 100. ml. of hot To. thissolution was added 6 g. of 4- amino 2 [2 (4-morpholinyl)ethoxylbenzonitrile and the solution was heated until dissolution of the 4-amino nitrile was complete. The resulting solution was cooled, and then diluted to about 1 liter with 1:1 ethyl acetate-ether. The gummy; material that separated was boiled with absolute ethanol and the hot mixture treated with 2 volumes of ethyl acetate. On cooling, there senarateda. crystalline pr cipitate w i w o lected and recrystallized once from ethanolethyl acetate and once from absolute ethanol,
thereby yielding, as large transparent prisms, 4-
, amino 2 [2-(4-morpho1inyl)ethoxylbenzonitrile monohydrochloride, M. P. 222.2-223.5 C.
(con), [dried at. C. in vacuoior sixhoursl. Anal.-.Calcd. for CnHnNsOrHCl: ND, 14.81; Cl, 12.49. Found: ND, 14.77; C1, 1221.
Treatment of the compound obtained above by reacting the sodium salt, of 4-nitro-2-hydroxybenzonitrile with 1 dimethylamino- 2 propyl chloride, with a reducing agent according tobthe. foregoing procedures yields a compound that is either 4-amino-2-(2-dimethylamino,-1-propoxy)'- benzonitrile (L) or 4-amino-2-(3-dimethylamino-2-propoxy) benzonitrile (M) having the following respective formulas TABLE III ,NC H =l-piperidyl. b N C H 2methyl-l -piperidyl.
- N 0 Hazfi-dimethyl-l-piperidyl.
;-Bas1 c amino nitrogen as determined; by titration with perchloric acid in-glacia), aceticacid solution.
' 1 fNCi-HaO=4-inor pholinyl;
TABLE IV o (CH2)..NR 11.-Hm o.
a '116 whereupon a precipitate readily-formed; The precipitate was collected,- washed withhold iso- Analyses I 'n N RR. g- Formula H3130; ND
Calcd. rou d Calcd. Found 3 NwgHaz 237. -233. 2 C14H21Na0. Hare. 28.39 28. 1 12. 11 11. 92 2 N (3511 0 198. 0-198. 7 CHHIQNSO. H3PO4' v 28. 55 28. 60 12. 24 12. O5 2 Noun. 192. e194. 0 olsnnNao. HsPOl 27. 43 27. so 11. 76 11. 5e 2 NC7H14 193. 5-195. 5 O1GH23N30. H3PO4 26. 40 26. 10 11. 31 11. 19 3 NC5H105, 202. 1-203. 3 (jml lmN ao. H3P04 27. 43 27. 83 11. 76 11. 60 3 No.11. 214. 8-216. 7 01611231230. H3PO4 26. 40 26,40 11. 31 11.20 3 NO4HO 190. e192. 2 C14H19N3Oz. H3PO4 27.28 27. 52 11. e9 11. 55
3. 4-al7tylaminoand 4-hydroacyaZlcylamino-2 (tertiary-aminoalkoxy) benzonitriles These compounds are produced by alkylation of the corresponding 4-amino-2-(tertiary-aminoalkoxy) benzonitriles described above. This alkylation is run preferably by reductive alkylation procedures as illustrated in the following examples.
4n-butylamino2- (Z-diethylaminoethoxy) benzonitrile was prepared as follows: To a hot stirred ,mixture of g. of 4-amino-2-(2-diethylaminoethoxy)benzonitrile, 22.5 g. of zinc dust, 21.2 g. of glacial acetic acid and 100 ml of dry benzene was added 7.5 g. of n-butanol (n-butyraldehyde) dissolved in ml. of dry benzene over a fifteen minute period. After the mixture had been stirred for one hour, an additional 1 ml. of nbutanal was added and stirring continued for an additionalfifteen minutes. The zinc acetate was filtered oif and washed with hot dilute acetic acid and benzene. The cooled filtrate was made basic to litmus with concentrated ammonium hydroxide, the benzene layer was separated and the aqueous solution was extracted three times with benzene. After the combined benzene layer and extracts had been dried over anhydrous potassium carbonate, the benzene was removed by distilling in vacuo, yielding, as a mobile yellow oil, 4-hbutylamino 2 (2-diethy1aminoethoxy)benzonitrile.
This oily product was converted into its monohydrochloride salt as follows: It was dissolved in propanol :and' recrystallized from a b s o l u t e ethanol-ethyl acetate. There was thus obtained, ascottony white needles, 4-n-butylamino-2-(2- diethylaminoethoxy) benzonitrile mono h y d r ochloride, M. P. 2l0.22l1.0 C. (cor.), [dried at C.in vacuo].
AnaZ.-Ca1cd. for C17H27N30'HC1Z C, 62.67; H, 8.36; N 12.90; 01, 10.90. Found: C, 62.72; H. 8.47; ND, 12.95; Cl, 10.76.
When the above procedure is followed but using 4-hydroxybutana1 or 5-hydroxypentanal in place of n-butanal, the resulting products are 4-(4-hydroxybutylamino) 2 2-diethylaminoethoxy) benzonitrile and 4-(5-hydroxyamino) -2-(2-diethylaminoethoxy) benzonitrile, respectively.
When the above procedure is followed but using 4 amino-2-(2-diethylamino-1-propoxy) benzonitrile (L) or 4-amino-2-(3-dimethylamino-2-propoxy)benzonitrile (M), shown above, in place of 4 amino-2-(Z-diethylaminoethoxy) benzonitrile, the resulting product is 4-n-butylamino-2-(2-dimethylamino-l-propoxy)benzonitrile (N) or 4-hbutylamino 2 (B-diethylamino-Z-propoxy) benzonitrile (0) having the following respective formulas mom-n moan-n CH; CN
15.2 g. of zinc dust, 14.3 g. of glacial acetic acid,
150 m1. of dry benzene and 5.0 g. of n-butanal. The product, 4-n-butylamino-2-[2-(2-methyl-1- piperidyl)ethoxylbenzonitrile, was obtained as a thick, viscous, pale orange oil. The phosphate salt of this product was prepared by dissolving about 14 g. of the oil in 100 ml. of hot ethyl acetate and isopropanol and the resulting solution was treated treating the solution with a solution of 6.5 g. of phosphoric acid in 25 ml. of acetone. The
phosphate precipitated as a thick, orange-yellow oil. Ether was added to the mixture which was then chilled. The supernatant liquid was separated from the oil by decantation and the oil was taken up in 100 m1. of acetone, whereupon the phosphate salt crystallized. To this mixture was added 100 ml. of ethyl acetate and theresulting mixture was chilled. The solid product that separated was recrystallized by dissolving it in about 100ml. of water, filtering and diluting the filtrate to a volume of about 450 ml. with absolute ethanol. There was thus obtained, after drying at 100 C. and 0.01 mm. for four hours, 4-n-butylamino 2- [2-(2-methyl-1-piperidyl) ethoxylbenzonitrile phosphate, M. P. 194.4-195.3 C. (con). AnaZ.Calcd. for C19H29N3O-H3PO4: ND, 10.16; H3PO4, 23.17. Found; ND, 10.11; H3PO4, 23.28.
When the above procedure is followed but using, in place of 4-amino-2-[2-(Z-methyl-l-piperidyl) ethoxylbenzonitrile, 4-amlno-2- [3- l-piperidyl) propoxylbenzonitrile, 4 amino"- 2,.= l2 (2,fi-.-di methyl 1 piperidyl) ethoxylbenzonitrile or 4- amino-2- [2- (4-morpholinyl) ethoxylb'enzonitrile, there is obtained, in the form of their phosphates, 4 n-butylamino-Z-[3:(1-piperidyl) propoxy] benzonitrile, 4-n-butylamino-2- [2- (2,6-dimethyl-l-piperidyl)ethoxylbenzonitrile or 4-nbutylamino 2-[2-(4-morpho1inyl)ethoxylbenzonitrile, respectively. 1
, 4 n amylamino 2 l2-(2-vmethyl-l-piperidyl ethoxylbenzonitrile was obtained, as a vis-- g. of zinc dust, 9.5 g. of glacial acetic acid, 4.0 g.
of n-pentanal (n-valeraldehyde) and 100 ml. of dry benzene. The phosphate of this compound was prepared by dissolving about 11.7 g. of.4-namylamino 2- [2 (2 -methyl-l-piperidyhethoxylbenzonitrile in; 150 ml. of acetone and adding to the resulting solution asolution of 4 g. of phosphoric acidin acetone. The resulting mixture was diluted with ml. of acetone and 100 fml. of ethyl acetate, and chilledin ice, whereupon thereseparated a white crystalline precipitate. This precipitate was recrystallizedby dissolving it 111,250 of boiling ethanol, filtering the solution and adding to the filtrate ml. of hot isopropanol. This recrystallization was repeated. There was, thus obtained, after drying for four hours at 100 C. and 0.01 mm., 4 n-amylamino-2-[2-(2-methylel-piperi-dyl)ethoxy]benzonitrile-phosphate, M. 1?. 178.0- 179.5 ,C. (con).
. AnaZ.-Calcd. forCzoHsiNso-HzPOlz ND, 9.33;
H3PO4, 22.93. Found: N '9.90 H3PO4, 22.58.
Alternatively, the foregoing reductive alkylations can be carried out using, in place of zinc 'pylamino 2e [3 (4 methyl l-piperidyl) pro poxyl'benzonitrile; 4 isobutylamino 2- [2-(3- 18 r ethy1--1 piperidyllethoxylbenzonitrile; 4 nhexylamino 2 [3- (2methyl-I-pyrr0lidyl) pro:- poxylbenzonitrile; and the like.
Alternatively, the. 4-alkylaminoand 4-hydroxyalkylamino :2 J- (tertiary aminoa1koxy)- benzomtriles of our invention can be prepared by direct .alkylation of'the corresponding 4-amino 4'. @Pm'tro-Z- (tertiary-aminoalkoxyl) benzomtrz'le quaternary ammonium salts I are prepared by treating the corresponding.4 nitro --2 (tertiary-aminoalkoxy)benz onitrile with an alkyl or 'benzyl ester of an inorganic or organic acid of the type described: hereinabove.
by the following examples.
-4- nitro 2- (-2- diethylaminoethoxy)benzonitrile methiodide was prepared as follows: To a solution of 5 g. of 4-nitro-2-(2-diethylaminoethoxy benzonitri1e in 100 of ethyl acetate was added 15 ml. ofmethyl iodide, resultingfirst in a clear solution which rapidly yielded a crystalline precipitateat room temperature. Toinsure completion of the reaction, the mixture was then/refluxed for ,fifteenminutes, whereupon the mixturejturned bright orange in color and heavy precipitation resulted. The precipitate was collected, washedlwell, with ethyl acetate and recrystallized front absolute ethanol-ethyl ace etate. to yield, as. rosettes of. long slender orange needles, .4enitroe2 (ZediethyIaminoethoX'y) benzonitrilemethiodide, M. P. 185.8-187.0 C. (cori) when driedatQO Clin vacuoforsix hours.
AnaZ.Calcd;-ifor TCMHZOINBOBZ- C, 41.46;. H, 4.97:; ,NNo ,3.46;. I,5 3,1.32.;..F0und: C, 41.46; iI-I, 4.78; NNO2, 3.22; I, 31.18. j M i -.When the .above procedure is followed but using, in place of methyl iodide, methyl bromide, ethylchl oride, n-propyl iodide, benzyl chloride or ethyl" para toluenesulfonata there is obtained, respectively, "4 1 nitro--" 2 (2 diethylaminoethoxy)..benzonitrile.methobromide, 4 nitro 2 (2 .-,.diethylaminoethoxy)'benzonitrile ethochlo- .-ride,:4.-.,nit ro 2 (2-diethylaminoethoxy)ben- ,zonitrile" 'n-propiodide, 4-nitro-2- (2-diethylaminoethoxylbenzonitrile :benzochloride or 4-nitro- 2 (2 diethylaminoethoxy).benzonitrile ethoparatoluenesulfonater 3:1 v
4 L nitro -2-[35('l-piperidyl) propoxylbenzonitrile methio'dide wasprepared following the above procedure butfusing 5 g; of 4 mtro-2-[3'-:(1
piperidyl)propoxylbenzonitrile methiodide, "100 1 ml; of ethyl acetate and 15ml. of methyl iodide,
and a refluxperi'od of thirty minutes." The product was' recrystallized by suspending itin boiling ethanolfand adding hot water dropwi'se until dissolution; the hot" solution was filtered; andthe filtrate was diluted with-hot absolute ethanol and some hot ethyl acetatei 0h cooling there separated, as large canary-yellow, feathery The eaction is illustrated rapid, taking about fifteen minutes. lyst wasfiltered off and washed with absolute ethanol; and the filtrate was taken to dryness solvent was takenoff in "vacuo; this procedure was repeated once more; The resulting thick,v
gummy residue was taken up with about '50 ml. of hot absolute :ethanol and'the alcohol solution cooled, whereupon" there separated a precipitate;
in part, an, oil, whichsolidified; Ehe precipitate was filtered and washed with ethyl acetate. This material was recrystallized once from absolute ethanol-ethyl acetate andlonce from absolute ethanol alone, yielding as white prisms, 4-amiiio Analyses, Percent Q ..o NH H n NR-R. 5.5 Formula I I v i1 No,
Q I Calcd Found Calcd. Found 2 Mont}. arcasm cerium. c5 33. e0 3. 11 a. %2 3. N (@2115)? 29z0-23L-0] 15H22 NQZ 3Q T 9- 9 3. 34 3. 32 2. i N CtHm? 3238.0-240 QuHzoINaQa 30. 42 30. 30 3. 36 3. 34 2 NCHiz 2211 221.? CiHizIN'xOz 29; 43 29. 40 3. 3. 24 Qi ilZ 322 1-2222 G17 i-iIN3Q 2 w 61 3 3 i NQaH12.. 2310-239 OwHuINiQa 2s. 50 2s. 37 3.15 3. a4 2' s 'N C4Hg0 223.0-225 CixHfgIN304 30; 27 29. 9O 3. 34 35 29 3 NCrHgO 236.02 38 .5 0151120137304 L 29. 29 29. 00 3. 23 3. 15
Additional 4-nitro-2-( tertiaryeaminoalkoxy) b'enzonitrile. methiodides which can be prepared according to the foregoing procedure include the following: '4 nitro-2-(2 dimethylamino1 pro- .dyl) propoxyl ber-i'zonitrile methiodide 4-riitro-2- .IE2 (3. ethyl .1. piperidyl)ethoxylbenonitrile methiodide; 4 nitro 2-[3-.(2-methyll-pyrroli- :dyl)propoxylbenzonitrile methiodide; and the .like.
' T5. mama-2:demafi-ammodzkaew b'enzem:
These compound are prepared preferably by reducing the above described 4.-nitro-2'-(tertiaryaminoalkoxy) benzcnitrile quaternary ammonium salts. by catalytic hydrogenation methods, as illustrated by thefollowing examples.
Preferably... the reduction is carried out 4 amino--2-(2-diethylaminoethoxy).benzonitri-le methiodide was prepared as follows: 4-
vnitrc e 2 f (-2 diethylaminoethoxy)benzonitrile methicdide (7.9 g.) was mixed with 200 mg. of
platinum oxide monohydrate, diluted to a total volume of 150 ml. with 80% aqueous ethanol and was hydrogenated at room temperature using 50 lbs. pressure of hydrogen. The reduction was The catain vacuo. A 1:1 mixture of absolute ethanol- -ethyl acetate was added to the residue andrthe LI. 215 aerie;-
oxy) benzonitrile methiodide, "4-nitro 2 (Z-diethylaminoethoxy)benzonitrileinethobromid. 4'- nitro 2 (2 diethylaminoethoxy)benzonitiile ethoehloride, 4.-nitr'o -2 42-diethy1an inceth6xyJ aminoethoxy)benzonitrile benzochloride or 4- nitro 2 (2-diethylaminomethoxy)benzonitrile etho-para-toluenesulfonate, there is obtained.
respectively, 4-amino-2- 2-'diethylaininoethoxy) benzonitrile methobromide, 4-amino-'2-(2-'-'diethylaminoethoxy)benzonitrile ethochlor-ide, 4-'
amino-2- (2-diethyl'aminoethoxy) benz'ohitrile npropiodi'de, 4 amino=2e (2=diethylami'noethoxy) benzonitrile. benzochloride or 4-amino-2-(2-d iethylaminoethoky) benzonitrile ethopara-toluenesulfonate.
4 amino-2 [3 (l-piperidyl)propoxylbenzo nitrile methiodide, was prepared. following the above procedure ,but' using 7.7g. of 4--nitro-2- [3- ('1 piperidyl)propoxylbenzonitrile methiodide,
200 mg. of platinum oxide monohydrate, 60% aqueous ethanoL a totalreaction mixture volume .of; ml. and-a reaction temperature of 45? C. There was thus obtained,- when recrystallized once from absolute ethanolethyl acetate and once from absolute ethanol,;the product, taming-2- [-3- 1 piperidyl)propoxylbenzonitrile methiodide,
.as rosettes of white needles,- M. P. 162.9-164.2
s ag er;
When the above procedure is followed but using, in place of 4-nitro-2-[3-(l-piperidyllpropoxylbenzonitrile methiodid e, 4 -nitro-,-2- (2 I methyl-l-piperidyl)ethoxylbenzonitrile methio;
dide r 4-nitro-2- 3- (4-morpholinyl) propoxy] benzonitrile methiodide, there 'is obtained, respectively, 4-amino-2-(2-dimethylaminoethoxy) benzonitrile methiodide, 4-amino-2- [2- (Z-methyll-piperidyl)ethoxylbenaonitrile methiodide, 4- amino 2 -[2-(2,6-dirnethyl-1 piperidyl) ethoxylbenzonitrile methiodide or l-amino-2-[3-(4- morpholinyl) propoxylbenzonitrile methiodide. v
-amino 2 -(3-diethylarninopropoxy)benzonitrile methiodide was prepared following" the above procedure described for the preparation of 4-amino- 2 2 -diethylaminoethoxy)benzonitrile methiodide but using 63 g. of 4-nitro-2-(3-diethylaminopropoxy)benzonitrile methiodide in place of the 4-nitro-2-(Z-diethylaminoethoxy)'- benzonitrile methiodide. The product, 4-amino- 2- (3-diethylaminopropoxy) benzonitrile methiodide, melted at 146.4-147.7 C. (cor).
Anal.Calcd. for C15H24IN3O1' ND, 10.80; I, 32.60. Found: ND, 10.90; 1 32.44.
Additional 4-amino-2- (tertiary-aminoalkoxy) benzonitrile methiodides which can b prepared according to the foregoing procedure include the following 4-amino-2- (2-dimethylamino 1-pror poxy) benzonitrile methiodide; 4-amino-2- [3- 1'- pyrrolidyl)propoxylbenzonitrile methiodide, 4- amino-2- [2- (2,5-dimethyl- Vl :pyrrolidyl) ethoxy] benzonitrile methiodide; 4-aminov-2- (4-dimethy1- aminobutoxy benzonitrile methiodide; a-amino- 2 [2 (di n butylamino)ethoxylbenzonitrile methiodide; 4 amino-2- [3-(4-methyl- 1 -piperidyl) -propoxylbenzonitrile methiodide; 4-amino- 2-[2-(3 ethyl 1 piperidyliethoxy] benzonitrile methiodide; 4-amino-2- [3- (2-methyl-l-pyrrolidyDpropoxylbenzonitrile methiodide; and the like.
6. -alkylaminoand 4-hydrogvyalkylammo -2 d These compounds where the 4-alkyl-*o'r 4- hydroxyalkyl radical, designated hereinabove as R2, has from three to six carbon atoms are prepared preferably by reductively alkylating the corresponding 4-amino-2- (tertiaryaminoalkoxy) benzonitrile quaternary ammonium salts with hydrogen under pressure and an alkanal or a hydroxyalkanal having threeto six carbon atoms, in the presence of a hydrogenation catalyst. This preparation and the products obtained thereby are illustrated by the following examples.
4-n-butylamino 2 (2 diethylaminoethoxy) benzonitrile methiodide can be preparedas follows: A mixture of 10 g. of 4-amino-2-(2-diethylaminoethoxy)benzonitrile methiodide, 5 g. of n-butanal (n-butyraldehyde), 0.5 g. of platinum oxide monohydrate and 150 ml. of absolute ethanol is treated at 50 C. with '50 lbs. (per sq. inch) pressure of hydrogen until hydrogeriis no longer taken up. The catalyst'is filtered off and the ethanol is removed from the filtrate by distilling in vacuo, leaving theproduct, l-n-butylamino 2 2 diethylaminoethoxy)benzonitrile methiodide.
Following the above procedure but using 5- hydroxypentanal in place ofvn-butanal the re- 22; sulting product obtained is 4-(5- hydroxyamylamino) 2 (2 diethylaminoethoxy)benzonitrile methiodide.
When the above procedure. is followed but,
, using, in place of 4-amino-2e(2 diethylaminoethoxy)benzonitrile methiodide, the corresponding 4 amino- 2 -(2-diethylamirioethoxy) benzonitrile methobromide, ethochloride, n-propiodide, benzochloride or etho para toluenesulfonate, there is obtained, respectively: 4-n-butylamino- 2- (2-diethylaminoethoxy)benzonitrile methobro m rn-b trl m r e lamino s i benzonitrile; ethochloride, 4-n -buty1amino 2 (2 th m n ethqxylbe z ni e. r ro odis e;
.. h nh usinain Place; '-of; ,F am g-2%Z-die Y minQe ethoxy benzonitrile methiodide, 4-amino-2-(2-.
dimethylarninoethoxy)benzonitrile methiodide,
- methyl-l-piperidyl) ethoxylbenzenitrile methiodide or 4-amino-2- [3-(4-morpholinyl) propoxyl benzonitrile 'methiodide, and using in place of n-butanal, the appropriate respective alkanal or hydroxyalkanal; there is-obtained, respectively, 4-npropylamino- 2 -(2 dimethy1aminoethoxy)- benzonitrile methiodide, 4n-hexylamino2-[2- (Z-methyl-l-piperidyl) ethoxy] benzonitrile methiodide, 4- (4-hydroxybutylamino) 2 '-.[2+(2,6-di'- methyl-lr-piperidyl) ethoxy] benzonitrile methiodide or 4- (5-hydroxyamylamino) -2[3- (4-m0r: pholinyl) propoxylbenzonitrile' methiodide.
Alternatively,} the 4-alkylaminoand 4-hydroxyalkylamino-2 (tertiary-aminoalkoxy)benzonitrile quaternary ammonium salts can be prepared by treating the corresponding 4-a1kylaminoor l-hydroxyalkylamino 2 (tertiaryaminoalkoxy) benzonitrile with an' alkyl or benzyl ester of an inorganic or organic acid of the type described hereinabove. This mode of preparation is illustrated by treating 4-methyla nino-2- (2 diethylaminoethoxy)benzonitrile, -ethyl amino-2-(2-diethylaminoethoxy) benzonitrile or 4-'(2-hydroxyethylamino) 2 (2 diethylaminoethoxy benzonitri1e with methyl iodide to yield, respectively, 4-methylarnino-2-(2-diethylaminoethoxy) -benzonitrile methiodide, 4-ethylamino 2-(2-diethy1amin0ethoxy) benzonitrile methiodide or 4- (2-hydroxyethylamino) -2.- (Z-diethylaminoethoxy) benzonitrile methiodide.-,
Additional 4-alkylaminoand ,4-hydroxyalky1- amino 2 (tertiary arr inoalkoxy) benzonitrile methiodides whichc'an be prepared according to the foregoing procedures include the following: -n-butylamino- 2 (2 dimethylamino 1 propoxy)benzonitrile' methiodide; 4-n-butylamino- 2-[3-(l-pyr'rolidyl) propoxylbenzonitrile meth iodide; 4- (fi hydroxyhexylamino) -2- [2- (2,5.-di-
methyl-l-pyrrolidyl) ethoxylbenzonitrile" methiodide; 4-(3-hydroxy-1-butylamino) 2 (l-dimethylaminobutoxy{benzonitrile methiodide; ,4- (3"- hydroxypropylamino) 2 [2 (di n-butylamino) ethoxylbenzonitrile methiodide; 4-n-pro pylamino-2- [3-(4-methyl-1-piperidyl) propoxyl- "We'cl'aim: 1. A quaternary'ammonium salt having the formula where X is a lower alkylen'e raxlical whose two free valence bonds are on :difierent carbon atoms, R3 is a lower alkyl radical and An isa non-toxic anion-of a'strong acid.
3. Aguaternalfy ammonium salt of adv-amino- Z-fidiethylaminoalkoxy) benzonit'rile having the orm a v =H 2 whereX is a :lower'alkyleneradical whose two free valence bonds are on difierentaarbon atoms, R3 is a lower alkyl'radical and Anis -a1-non=.toxic anion of a strong acid. V
4. A quaternary ammonium lsalt of fa, .4-amino- 2- (tertiary-aminoalkoxy) benzonitrile having the formula where X is a lower alkylene radical whose two free valence bonds are on different carbbnlatoriiis, NRR1 is a l-pipe'fidyl radical, R3 is 'a'lower alkyl radical and A11 is a non-toxic aiiionof a strong acid.
5. A quaternary ammonium salt of'al-nitroa 2"-(dialkylaminoalkoxylbenzonitrile "having the formula I NO'z where "X is a lower 'alkylene radical whose two free valence bonds are on 'difierent carbon atoms, Rois a lower alkyl radical and An is a non-toxic anion of a strong acid.
6. A'quaternary ammonium salt of a 4-nitro-2- ('di'ethyla mino alko'xy) benzonitrile having the formula Where X is a lower =alkylene radical whose two free valence bonds areon differentcarbon atoms, R3 is a loweralkyl radical and An-is a non-toxic anion of a strong acid. I v
'7. 1A quaternary ammonium saltof a 4-nitro-2- (tertiary-aminoalkox-y)benzonitrile having the formula where -X is a lower alkyl'ene radic'al whose two free valence bonds "are 'on different carbon atoms, NR'Ri is a (lower alky1ated)'-l-piperidy-l radical, R3 is :a lower alkyl radical and An is a non -"toxic anion of a strong acid.
'8. A quaternary ammonium salt of a imitro- 2'- (tertia'ry-aminoalkoky)benzonitrile having the formula where X is a lower alkylene radical whose two free 'valencebonds are on differentc'arbon atoms, NRR1 is a 2-methyl-1-piperidy-1radical, R3 is a lower alkyl radical and An is a non-toxic anion of astrong acid.
9. vAquaternary ammonium salt of 'a ll-nitro- 2-(tertiary-aminoalkoxy)benzonitrile having the formula where is a lower alkylen'e radical whose two free valence bonds are ondifierent .carbon atoms,
NRR1 is-a l-piperidyl radical, Rszis a lower :alkyl radical and An is a non-toxic anion of aistro'ng acid.
10. A process of preparing a quaternary am"- monium salt of a 4'-iamino-2-(tertiary-'amifim alkoxy-lbenzonitrile having ,the .formula where X is a lower alkylene radical whose two free valence bonds are on diiferent carbon atoms,
' 4 nitro 4 2 tertiar animcalkoxyibenzonitr e quaternary ammonium saltQwith. a reducing agent. g
11. A process of preparing a quaternary ammonium salt of a 4-amino-2-(dialkylaminoalkoxy)benzonii'rile havingthe formula 7' 4 -"X,l 1'(lowralkyl)n n 0N 4 .t'i i where X is a lower alkylene radical whose two free valence bonds are on diiferent carbon atoms, R3 is a lower alkyl radical and An is a non-toxic anion of a strong acid, which comprises treating the corresponding 4 nitro 2 (dialkylaminoalkoxy benzonitrile with an ester having the formula, R3An and. treating the resulting 4 nitro 2 (dialkylaminoalkoxy)benzonitrile quaternary ammonium salt with a reducing agent. I
.12. A process of preparing a quaternary ammonium salt of a 4-amino-2-(diethylaminoalkoxy)benzonitrile having the formula where X is a lower alkylene radical whose two where X is a lower alkylene radical whose two free valence bonds are on different carbon atoms, NEE is a 1piperidyl radical, R3 is a lower alkyl radical and A11 is a non-toxic anion of a strong acid, which comprises treating the corresponding 4 nitro 2 (tertiary-aminoalkoxy)benzonitrile with an ester having the formula R3An and treating the resulting 4-nitro-2-(tertiary-amino-- alkoxy)benzonitrile with an alkoxy)benzonitrlle quaternary ammonium salt withareducing agent. V I
14. A process of preparing a quaternary ammonium salt of a 4 nitro"- 2 (dialkylaminoalkoxy benzonitrile having the formula where X is a lower alkylene radical whose two free/valence bonds'are on'different carbon atoms, R3 is: a-lower alkylradical and An is a non-toxic anion of a'strongacid, which comprises treating where X is a lower alkylene radicalwhose two free valence bonds are on different carbon atoms, Rsis a lower alkyl radical and An is a non-toxic anion of a strong acid,'which comprises treating the corresponding 4-nitro-2-(diethylaminoalk-p oxy)benzonitrile with an ester having the formula Rs-An.
16. A process of preparing a quaternary ammonium salt'of a 4-nitro-2-(tertiary-aminoalkoxy)benzonitrile having the formula I Ra O,XII\IRR1 l n ON where X is a lower alkylene radical whose two free valence bonds are on different carbon atoms, NRR1 is a (lower alkylatedl-l-piperidyl radical, R3 is a lower alkyl radical and An is a non-toxic anion of a strong acid, which comprises treating the corresponding 4-nitro-2-(tertiary-aminoester having the formula Rz-An. V 17. A process of preparing a quarternary ammonium salt of a'4-nitro-2-(tertiaryaminoalkoxy)benzonitrile having the formula lia O-XNRR1 where X is a lower alkylene'radical whose two free valence bonds are on different carbon atoms,
NRRi is a 2-methy1-1-piperidyl radical, R3 is a lower alkyl radical and An is a non-toxic anion 1 of a strong acid, which comprises treating the corresponding -4-nitro-2 (tertiary-aminoalkoxy) benzonitrile with an ester' having the formula.
ama es 2.7 18. A process of preparing a quaternary ammonium salt of a 4-nitro-2:(tertiary-aminoalkoxy)benzon itrile having the formula where X is a loweralkylene radical Whose two free valence bonds are on different carbon atoms, NRRlis a l-piperidyl radical, R3 is a lower alkyl 'radial and An is'a non-toxic anion of a strong acid, which'comprises treating the corresponding 4 nitro 2 (tertiaryeaminoalkoxy) benzonitrile with an ester having the formula Rz-An.
19. A process of preparing a quaternary ammonium salt of a 4-nitro-2-(tertiary-aminoalkoxy)benzonitrile having the formula 28 where X is a lower alkylene radical whose two free valence bonds are on difierent carbon atoms,
N331 is a' member of the group consisting of zonitrile methiodide. e 21. 4 amino 2- [3-(1-pi'peridyDpropogy] benzonitrile methiodide.
2'2. 4 nitro 2 -(3-diethylaminopropoxy)benzonitrile methiodide. j
23. 4-nitro-2-[2f-(2-methyl 1 piperidyDethoxyJbenzonitrile methiodide.
241'. 4-nitr0-2- [2- l-piperidyl) ethoxy] benzonitrile methiodide. r v
RAYMOND O. CLINTON. STANLEY C.- LASKOW SKI.
No references cited.

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1. A QUATERNARY AMMONIUM SALT HAVING THE FORMULA
US2642437D Quaternary ammonium salts of x-sub Expired - Lifetime US2642437A (en)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3012033A (en) * 1957-08-15 1961-12-05 Hydrierwerk Rodleben Veb New substituted phthalazines and process for their preparation
US3459782A (en) * 1963-08-26 1969-08-05 Boehringer Sohn Ingelheim 1-substituted phenoxy-2-hydroxy-3-isopropylamino-propanes
US3876640A (en) * 1969-08-13 1975-04-08 Sandoz Ag 2-cyano-morph olino-substituted anilines
US20050256340A1 (en) * 2002-08-01 2005-11-17 Basf Aktiengesellschaft Method for producing aminoalkoxy benzylamines and aminoalkoxy benzonitriles as intermediates

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
None *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3012033A (en) * 1957-08-15 1961-12-05 Hydrierwerk Rodleben Veb New substituted phthalazines and process for their preparation
US3459782A (en) * 1963-08-26 1969-08-05 Boehringer Sohn Ingelheim 1-substituted phenoxy-2-hydroxy-3-isopropylamino-propanes
US3876640A (en) * 1969-08-13 1975-04-08 Sandoz Ag 2-cyano-morph olino-substituted anilines
US20050256340A1 (en) * 2002-08-01 2005-11-17 Basf Aktiengesellschaft Method for producing aminoalkoxy benzylamines and aminoalkoxy benzonitriles as intermediates
US7256312B2 (en) * 2002-08-01 2007-08-14 Basf Aktiengesellschaft Method for producing aminoalkoxy benzylamines and aminoalkoxy benzonitriles as intermediates

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