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Патент USA US2407167

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Patented Sept. 3, 1946
2,407,167
‘PATENT “OFFICE 1 "
" ‘2,407,167
f-l DERIVATIVES ‘50F 1-HYDRUXYPHENYD-3
HAMINOBUTANE ANns-wmtocnssnszvnon
....rrnnm .‘PBQDUCTION
‘
,
iFi‘it‘z" Kiilz, Frankfort
@vested ‘in. the Alien Property'?ustodian
*NoiDra'iving; ‘1 Appli'cationi?ctober‘rmg11941, Serial
many1February<12Ip1940
.
i.
1‘
>
i
is from 1-hydroxypheny1-3-ha1ogenbutane, and
.The “invention concerns. new‘ ‘derivatives of. 1
:1.hydroxyphenyl-3earninobutane ‘and processes for
react this with a primary amine.
' ‘The new‘ "compounds may also-‘beobt‘ained by
‘1 their production.
starting from hydroxyben‘z‘yle‘a‘cetone, condensing
iIt'i isi ‘ known‘ ‘that: » 3B: (pehydro'xyphenylr). r-iso
5 -. same with a primary amineiorl-ammonia and hy
is xpropylamine "and, itsriderivati'ves ‘ are » character
nMannich has prepared the next higher homo
v-drogenatingnthe forming condensation products.
‘"lfwammoniatis used, the-obtained i-l-hydrogry
logue ‘ ‘amine, the’ 14hydroxyphényl-3-aminobu
:‘V-phenyl-BHaminQbutane -must be ~ treated with
ized by a special e?ect on circulation.
tane, from p-hydroxybenzcylacetone, by preparing
*"FVol‘;
Iand'rédU'cing‘
.265;"‘"(11'92'7)'¢,
‘the T123),
'ditim. i5 \"(Arc‘hiv
It has beenst‘ated
fiiri‘ Pharmazie‘,’
‘that
agents; which . are suitable ~ror \ introductiomoi
10‘ thehydrocarbonxresidue.
‘
.
Themostsimple methodlof producing. the .com
»‘ lf‘thisi‘icomp'ound 1m- (Jr-‘comparison’ l'with ' the -‘above
“pounds e according ~tom‘the ~ invention consists ‘ in
inam'ed'é‘ompound has ailess’di‘stinct eifect-‘on‘fcir
culation,‘ while analgesic properties‘ may 9be ‘just
~ condensing‘ 1 hydroxybenzalacetone ‘with- primary
t amineso-r-ammonia. vJAlso in this case condensation
. r-idetectable, ‘bu-tare far too-:weakttobe-suited- for‘ ' l?eproductsare obtained; thecarbon carbon. double
.. .bond and --the carbon nitrogen double bond ‘ of
practical purposes.
‘
P which-“maybe hydrogenated in asingle working
‘
It has been found that'alike the known nor
tqprocess, toreexample>~catalytica1ly~by hydrogen
‘base‘dei-ivatives" 70f ‘ 1-0; "-p- or -m'-'hyd-roxv
" --"phenyl'-3-*amiriobutane- ‘of "the" general formula
H 010 511413112740 HzZC H;C H3
r. in’ the presence ofeplatinumr» If ‘ ammonia :is em
20 ~p10yed. ufors the: production of .the ‘condensation
T-x-rt-H
- products-the forming 1ehydroxyphenyl-a-amino
~-=butane must.betreatedagain with agents, which
‘1 in‘ which‘ X‘ represents ‘alkyl,5 alkenyl=,'"‘cyclo viiLlkyl,
cyclo alkenyl, ar'a‘lkyll for aralkenyl "have no abil
i are suitable for ‘introduction . of the. \desired\ hy
_ ‘ 'drocarbon residue.
’
ity of‘v effectingcirculation; buteunlike-the known” 25' .‘The~ compounds according to thednvention
nor-base have .. excellent” analgesic
properties.
Among the alkyl derivatives; for example among
‘.Jmay also be prepared from l-phenyl-S-aminobu
--tanes substituted accordingly at .theHnitrogen by
" *the“ methyl-,~ *ethyl- v"“propyl-j " butyl-i "isobutylq
* -‘am'yl-; ‘is'oamyl-hderivatives "thebmet-hyll‘ "deriva-q. l. > or. .aralkenyl .by. ln-itration ‘in. the benzenegring, re
QQA .duction Yofflthe'. obtained. ‘nitro compound to.v the
"nary ‘efficacious"analgesic‘properties. ' “ ‘The other
amino compound, diaz'otizing of the amino group
alkyl derivatives have less outspoken analgesic
at 'the' benzene1 ring with ‘ nitrous‘ ‘acid ‘and con
verting into‘thei-idesired'hydroxy compounds by
. properties. \ .Qompoundsa- with an-alkyl. with‘ more
than 6 carbon atoms areless important for prac
‘boiling,
tical purposes. This rule is valid, independently"; 35 =Fina-llythe analgesics ‘according: to‘the inven
' of‘ the-"position :of’the OHegr‘oup'f that ‘ is' whether ncstion may be prepared ‘from- the corresponding
' it'is ‘in'Ithe'o-y p-"or‘f‘m-position.
Also alkenyb,
"“for- 'example"allyl-,' ‘cyclo‘ialkyl-f fon‘exam'rlle
1: r-alkoxy --compounds by splitting or? the ~ etheri?ed
.Joxygroupi for exampleby treatment withhydro
’cyclo"‘pe‘ntyl=" or “cycle 'heky1;"cyc1o 'ialkenylffor _
shalogenic
acid, >4 - especially » .hyd-robromic
acid.
example cyclo pentenyl or“"'cyclo" hexe'nylfar-W 40 Further ton-“they. are. obtained by -=saponi?cation
~- ialkyl-t' lforfr‘ex‘afnple'i- benzy1-, iipher‘iyl‘. "ie‘thyl-,~ -‘or
aralkenyl-, for"'~example>"phenyl allyl-derivatives,
“have good analgesicsproperties.
\ §ofethe compounds .acylatedatgtheoxygen and / or
li?theinitrogen.
EXAMPLES
.
“The: neW-canalgesics: mayilrbe-prepareddaccord-1; ,. 45
‘(ll
- wing? :to‘ ~various-‘rmethods. 1‘ ‘~-:1..-hydroxyphenyl‘-'3
.- :aminobutane :may iberitreatedr irri "kIlfOWII ‘manner
L'Withk "agentsjwhichlfare ‘suited for .aintroductionfof
"Ii'thefdesi-r'ed hydrocarbonzresiduetfor example‘ with
Prepar cation of 1—(p-hydro:cypheny1)-3'
“clZylamino-b'utane
2.0 grs. of allyl bromide are added to a hot
benzene" so1ution'“of ‘5.0" ‘grs; "0i 1- (p-h'ydroxy
ip‘h‘eiiyli '-»3-ainino-butane;' "prepared ‘according ‘to
“h'alogenides I-?of I'theii corresponding ‘ hydrocarbons” g
I‘:lorWiWitltfcorresponding ‘aldehydes‘ orf-ketoneaiiin
A (O N 4 v
~ which‘ latter: case‘the i'forining" Schiff’slbase must
'- » be hydrogenated?or according to Leuckarti'wal
lach.
‘
“ EtheIst‘arting famine
l?‘lteredi‘lwith suction. ‘T " The
$1mother“liqlioriv is">.conce'ntrated,‘ 'ifa necessary ?l
iii-One‘ ‘?-may; §:1Iiowever;’ir-proceedi vice- .versaiiizthat l oo- l'i'trat'ed againiifrom a: small ‘Iquantity for ‘anon-con
i/mm
r
2,407,167
3
4
verted starting base and evaporated to dryness.
melts after recrystallization from water at 170°
The 1- (p-hydroxyphenyl) -3-allylamino-butane,
C.
which is obtained in almost quantitative yield, is
converted with ethereal hydrobromic acid into
(6) Preparation of 1-(p-hydroxyphenyD-3
benzylamino-butane
the hydrobromide, which, after re-crystalliza
5.0 grs. of p-hydroxybenzylacetone are hydro
genated with a solution of 3.3 grs. of benzyl
amine in absolute alcohol according to Example
4 and are worked up according to Example 5.
tion from acetone, melts at 116—118° C. (uncor
rected).
(2) Preparation of I-(p-hydroxyphenyD-3
cyclopentyl-amino-butane
-
10 The hydrobromide of the l-(p-hydroxyphenyl) -
3-benzylamino-butane melts after re-crystalliza
5.0 grs. of l-(p-hydroxyphenyl) -3-aminobu
tane and 2.8 grs. of cyclo pentanone in methanol
with 0.3 gr. of platinum oxide are shaken in an
atmosphere of hydrogen. An amount of hydro
gen calculated for 1 mol. substance being taken
up in the course of about 2 hours, the substance
is ?ltrated from the catalyst. The methanol
is evaporated and the residue taken up in ether.
tion from water at 158° C.
(7) Preparation of 1-(o-hydroaryphenyD-3
n-butylamino-butane
8.1 grs. of o-hydroxybenzal-acetone are treated
with a solution of 3.7 grs. of n-butylamine. The
red solution is shaken with platinum black in an
atmosphere of hydrogen. 2 moles of hydrogen
The l-(p - hydroxyphenyl) -3-cyclopentylamino
butane is precipitated with ethereal hydrobromic 20 being taken up hydrogenation comes to a stand
still. The solution, now practically colorless, is
acid. It meltsafter re-crystallization from ace
?ltered from the catalyst, acidi?ed with diluted
tone at 173 to 174° C.
hydrochloric acid and evaporated to dryness.
(3) Preparation of 1-(p-hydroxyphenyD-3
allylaminobutane
l-(p-hydroxyphenyl)-3-brom-butane is pre
The residue is crystallized from acetone after a
25
pared by heating a mixture of 5.0 grs. of l-(p
small quantity of methanol is added. The hydro
chloride of the l-(o-hydroxyphenyl) -3-n-butyl
tane melts at 143° C.
hydroxyphenyl)-3-oxy-butane, obtained accord.
ing to Mannich and Merz, Arch. Pharm., vol.
265, p. 22 (1927) and hydrogen bromide in glacial 30
acetic acid for 3 hours to 100° C. After the
glacial acetic acid has been distilled o? in vacuo
the obtained substance is puri?ed by taking up
in ether, shaking of the ethereal solution with a
' '
(8) Preparation of Z-(o-hydroztyphenyD-3
n-propylamtno-butane
8.1 grs. of o-hydroxybenzal-acetone was treated
with 3.0 grs. of n-propylamine and worked up as
described in Example 7. The hydrochloride of
the 1 - (o-hydroxyphenyl) -3-n-propylamino~bu
solution of bicarbonate, drying and evaporation 35 tane melts at 143° C. '
of the ether. This starting material is heated to
(9) Preparation of I-(m-hydrozcyphenyD-Ii-n
batyZamino-butane
120-130” C. with allyl amine in great excess in
a bomb tube for ?ve hours. The excess allyl
amine is evaporated. The residue is taken up
8.1 grs. of m-hydroxybenzal-acetone are
treated with butylamine and worked up as de
scribed in Example 7, a di?erence only consisting
in not using diluted hydrochloric acid but diluted
in diluted hydrochloric acid, and, in order to
remove neutral bodies, extracted with ether. The
acid solution is rendered alkaline by help of bi
hydrobromic acid for acidi?cation. The hydro
The obtained base is taken up in
bromide of the '1- (m-hydroxyphenyl) -3-n-butyl
‘
The ether
is evaporated. The residue,,
after having been distilled in high vacuo (boiling 45 amino-butane melts at 117° C.
carbonate.
ether.
point 145-150° C. under 0.05 mm. pressure) is'
(10) Preparation of 1-(p-hydromyphenyD-3
ethyZamino-butane
converted into the hydrobromide, which melts
after re-crystallization from acetone at 116-118°
8.1 grs. of p-hydroxybenzal-acetone are, ac
C. Adding on hydrobromide of same constitu
cording to Example 9, converted with 2.3 grs. of
tion prepared according to Example 1 there is 50 ethylamine and worked up. The hydrobromide of
no depression of the melting point to be observed.
the l-(p-hydroxyphenyl) -3-ethylamino - butane
(4) Preparation of 1-(p-hydroxyphenyD-3
. melts at 130° C.
methyZamino-butane
(11) Preparation of 1-(p-hydromyphenyD-3-n
propyl-amino-butane
5.0 grs. of p-hydroxybenzyl-acetone are shaken 55
with 0.95 gr. of methylamine, solved in abso
8.1 grs. of p-hydroxybenzal-acetone are con
lute alcohol in the presence of platinum black
verted with 3.0 grs. of n-propylamine and worked
in an atmosphere of hydrogen. An amount of
up according to Example 9. The hydrobromide
hydrogen being taken up which corresponds to
1 mol. substance the substance is worked up ac
cording to Example 2. The hydrobromide of the
of the l-(p-hydroxyphenyl)~3-n-propylamino
60 butane melts at 138° C.
(12) Preparation of 1-(p-hydroxyphen1/D-3-n
1- (p-hydrolxyphenyl) - 3 - methylamino - butane
amyZamz‘no-butane
melts after re-crystallization from water at 143°
C.
5.0 grs. of l-(p-methoxyphenyl) -3-n-amyl
(Si Preparation of I-(p-hydroxyphenyD-3
n-butylamz'no-butane
65
amino-butane obtained by catalytic hydrogena
tion of a mixture consisting of p-methoxy
benzal-acetone and n-amylamine in alcohol and
5.0 grs.‘ of p-hydroxybenzylacetone and 2.3 grs.
puri?ed by distillation (boiling point 192/ 194° C.
of n-butylamine solved in absolute alcohol are
bath under vacuo, in order to remove some re
at 20 mm.) were heated to boiling under reflux
with the ten-fold amount of constant boiling hy
drobromic acid. After evaporation to dryness
the residue is crystallized from water. The hy
drobromide of the 1-(p-hydroxyphenyl)-3-n
maining butylamine. The hydrobromide of the
amylamino-butane melts at 125° C.
hydrogenated and worked up according to Ex
ample 4. The residue, after evaporation of the
alcohol, is heated for some time in the water
- _ 1 - (p ,- hydroxyphenyl) -3-n-butylamin0 -_' butane
.
Having now particularly described and ascer
2,407,167
2‘. 1- (p-hydroxyphenyl) -3-n-buty1amino - bu
tane of the formula
tained the nature of my said invention and. in
what manner it is to be performed I declare that
what I claim is:
om-cm-cn-om
H-—N-—CHn—CH2—-CHz-—CH|
1. 1 -(o-hydrou(ypheny1) -3-n - butylamino-bu
tane of the formula
-
OH
5
HO
3. A substituted butylamino-butane oi the for
CHrCHr-CH-GH:
H-—N-—-CHr-C HrCHr-CH:
mula
H—N—OHg-—CHz—OHz-OH:
in which X is a hydroxyphenyl'radical.
v
FRITZ K?LZ.
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