Patent GB-673509-A (GB)
Title: ª‰-haloalkylamines
Filed: 1950-05-25
Abstract: The invention comprises compounds of the formula <FORM:0673509/IV (b)/1> where A is aryl, Y is O or S, R is alkyl, R1 and R11 are H or alkyl (1-6 carbon atoms), X is chlorine or bromine, n is 1-6 and Z is alkyl, alkenyl, aralkyl, aryloxyalkyl, cyclohexylalkyl or thienylalkyl, and organic and inorganic salts thereof.  The aromatic and thiophene nuclei may carry substituents such as alkyl, alkoxy, acylamino, alkylamino (these 4 groups not containing more than 4 carbon atoms), hydroxy, benzyloxy, chlorine, bromine, amino, phenylamino (which may be nuclearly substituted), cyclohexyl, phenyl and aralkyl.  These compounds are prepared in the form of their hydrochlorides or hydrobromides by treating the corresponding alcohols (X=OH) with thionyl chloride or bromide.  The free bases are then liberated with alkali and may be converted into other salts, e.g. sulphate, sulphamate, phosphate, glycollate, oxalate, maleate or camphorsulphonate.  In the examples, compounds are made as above where A is phenyl, o-, m- and p-tolyl, 3 : 4-dimethylphenyl, o-ethylphenyl, o-propylphenyl, o- and p-isopropylphenyl, o-butylphenyl, o-isobutylphenyl, o-and p-sec. butylphenyl, o- and p-tert. butylphenyl, thymyl, p - cyclohexylphenyl, p-xenyl, o- and p-benzylphenyl, o-, m- and p-anisyl, p - allyl - o - anisyl, p - benzyloxyphenyl (hydrolysed to p-hydroxyphenyl), o-and p-chlorophenyl, o-bromophenyl, m-aminophenyl, p - dimethylaminophenyl, m - diethylaminophenyl, p - anilinophenyl, p - acetaminophenyl and a -naphthyl; n is 1 and 2; R is methyl and ethyl; R1 and R11 are hydrogen and methyl; Z is ethyl, allyl, cyclohexylmethyl, benzyl, o-methylbenzyl, p-methoxybenzyl, 3 : 4 - dimethoxybenzyl, p - chlorobenzyl, 2 : 4- and 3 : 4-dichlorobenzyl, p-aminobenzyl, p - dimethylaminobenzyl, o-acetaminobenzyl, b  - phenoxyethyl, b  - (m-hydroxyphenoxy) - ethyl, b  - (o - methoxyphenoxy) - ethyl, b  - (p - chlorophenoxy)-ethyl, b  - (o - bromophenoxy) - ethyl, b  - (p-aminophenoxy) - ethyl, b  - (p - dimethylaminophenoxy) - ethyl, b  - (p - acetaminophenoxy)-ethyl, b -phenoxyisopropyl, a - and b -thienylmethyl and 5-chlor-a -thienylmethyl.  Alkanolamines of the above formula where X=OH and the other symbols are as defined above are made by (1) reacting A-Y-(CH2)n-CHR-OH successively with thionyl chloride or bromide and NH.CHR1.CHR11.OH to give A-Y-(CH2)n-CHR-NH-CHR1-CHR11.  OH which is then N-alkylated with ZHal; (2) hydrogenating a mixture of A-Y-(CH2)n-CO-R and NH2-CHR1-CHR11-OH to give the same product as above which is N-alkylated with ZHal; (3) Hydrogenating a mixture of A-Y-(CH2)n-CHR-NH2 and the appropriate aldehyde or ketone to give A-Y-(CH2)n-CHR-NHZ which yields the alkanolamine on treatment with a halohydrin or alkylene oxide; (4) hydrogenating a mixture of A-Y-(CH2)n-CO-R and ZNH2 to give A-Y-(CH2)n-CHR-NHZ which is treated as in (3). Hydrohalide salts of the alkanolamines are mentioned.  In the examples, compounds are prepared with groups as listed above for p  the halo-alkylamines (and also Z=p-nitrobenzyl).  These are made by the above 4 methods, and in addition an amino group may be produced by hydrolysis of an acylamino group or reduction of a nitro group.  Intermediates of the formula A-O-(CH2)n-CHR-NH-CHR1-CHR11-OH with similar groups for A, R, R1 and R11 are also listed.  The thio-analogue C6H5S.CH2.CH(CH3).NH.CH2 CH2OH is made similarly from b -phenylthioisopropyl chloride and ethanolamine.  Bis - (b  - phenoxyisopropyl) - amine is prepared by hydrogenation of the ketimine from phenoxyacetone and b -phenoxy-isopropylamine.  N - (b - phenoxyisopropyl) - p - dimethylamino - benzylamine is made by hydrogenating a mixture of phenoxyacetone and p-dimethylamino-benzylamine.  Aryloxy - alkanols A-O-(CH2)n-CHR-OH and the halides A-O-(CH2)n-CHR-Hal are prepared from (1) the sodium phenolate A-ONa and an alkylene halohydrin or alkylene oxide, or (2) catalytic hydrogenation of the corresponding ketone, followed in each case by treatment with a halogenating agent such as thionyl chloride or bromide.  Such compounds are made in the examples with A and R as listed above for the haloalkylamines. p-Nitrobenzoates of some of the alkanols are mentioned.  Arylthio-alkanols A-S-(CH2)n-CHR-OH and the halides A-S-(CH2)n-CHR-Hal are made as above, e.g. C6H5SNa with propylene chlorhydrin gives b  - phenylthio - isopropanol which is converted into its chloride with thionyl chloride.  p - Dimethylaminophenoxyethyl bromide is prepared by treating the sodium salt of p-dimethylaminophenol with ethylene dibromide.