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Патент USA US2408346

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Patented Sept. 24, 1946
' 2,408,345
A, oomrosrrroufonm'rrnn AND METHOD.
Robert S. SheltomlMariernont, and Marcus G.
3 Van Campen, (in, Deer Park, Ohio, 'assignors to
The _Wm. S.._vMerrell Company, Cincinnati,
" 4'
Ohio, a'corporation of Ohio]
.No Drawing. ¢> Application ‘April is, ‘1942, i'
*1 '
gjserial No.438l,728 ;
is Claims,
(01. 260-5701;) ;
7-2 .
duction-‘of the resulting nitro compound to the
corresponding amino compound, but it had not
proven practical to directly eliminate the hy
This. invention relates ._to_novel chemical vcom
pounds, methods of<-'making .the. same, and to
pharmaceutical preparations in which: one or
droxy group. .
‘more of said compounds is anactive ingredient.
_0ne object voi the invention is'to produce novel _ 5
- r We have now
ane compound can be made. by catalytic reduc
and as intermediateslfiori manufacture ofv other
discovered that the desired beta
phenyl-alpha-alpha-dimethyl-alpha-amino eth-V
‘chemical compounds useful as pharmaceuticals
-' tionof thetcorresponding chloro compound, beta
I I‘ Another object‘ ofgthe invention, is to provide . phenyl-beta-chloro-alpha-alpha-dimethyl-alpha
ethane, advantageously in the presence of
‘effective vasopressor compositionshaving' little 10 amino
an alkali adaptedto react with the chlorine re
leased froin such compound by the reduction.
, 7 or Another
no stimulating
object effect.
of the invention
1 ...»
' to provide
, Surprisinglmthe resulting compounds, whether
a method of synthesizing alpha _di-substituted
amineorlin the form of the non-toxic
ethane amines‘, 1 and particularly beta-phenyl-.
salts, have proven'to be relatively inactive as cen
'ha-.alpha-dimethyhalpha-amino‘ ethane, (al 15 tral stimulants but very valuableas a vasopressor;
and thus, surprisingly, the synthesis of this com
It.‘ has been known, heretofore that manysubi , pound supplies an important need for a vaso
- Stltuted derivatives of.'betaephenyl-alphaamifm
ethanes, are activefpharmaceutical compounds 20'
‘exhibiting, vasopressorv or ‘vasodilat‘or, mydriatic,
sympathomimetic,v and/or
properties in varying degrees.
pressor' with only slight central stimulant effect.
Although we are giving below certain speci?c
; examplesof our invention and its application in
practical use and. are giving also certain modi?
central " stimulant
In many cases it
cations and alternatives, it should be understood
that these are not intended to be exhaustive nor
“ out others ;'thus,'in particularit is frequently de
limiting of the invention. On the contrary we
' sirable in cases of common cold and hay fever to 25 are giving- these as illustrations and are giving
is desirable to produce one of these effects with
~ shrink, the ‘nasal mucosa by application of ‘a vaso
constrictor “composition; whereas,‘ any : accom
herewith explanations in order fully to acquaint
others skilled in the art with» our invention and
panying ‘central stimulant e?ect maybe quite
the principles thereof ‘and a suitable manner of
its applicationv in practical use, so that others
undesirable, particularly as it interferes with
‘ By the present invention we have ‘made avail
30 skilled in the art may be enabled to modify the
invention and to adapt it and apply it in numer
able a vaso-pressor amine of the'substituted beta
phenyl-amino ethane type which has extraordi
narily good activity and duration as a vasopressor,
ous forms, each as may be best suited to the re
quirements of a particular use.»
I. As an example of the use of these materials
a composition particularly suitable for use as a
mydriatic, etc, but with only slight central'rstim
nasal inhalant may be made as follows:
e?orts to test this, however,’ we were
faced with great di?icultyqinv thatinone- of the
common reactions used, for producing other
amines of this general classmproved- satisfactory
for production" of thisparticular?amine; '
Analogous chlorides could be -made>bf1t,' pre
sumably due to stearic hindrance from the meth
yl groups on the alpha-‘carbon atom, the chloride '
could not be converted to the amine _by‘ordinary
_methods. - Also the beta-phenyl-betaehydroxy
alpha-alphaediémethyl-alpha-amino Methane ' is
known‘ and is ‘commercially available. 7 This
Menthol ____________________________ __'_____
' amino-‘ethane. .(as the free amine) _______ __
The camphor and menthol are dissolved inthe
amine and the-‘solution applied to a pledget of
cotton and placed in. an inhaler device. ' The pro
portions of menthol and camphor may be varied
rather widely and they may be replaced'by other
‘suitable aromatic or mixture of aromatic sub
product can be» made, for example, bylc'ondensa
tion of benzylaldehyde with nitroproparie, and re _.5o'stancessuchas euoalyptol', oil‘oi lavender, oil of
rose, etc. Likewise, the proportion of the amine
have no di?iculty in utilizing it in widely differ
may be increased or decreased substantially.
ent types of compositions and substituting it in
II. A suitable material for use as aqueous base
such compositions for previously used amines of
nose drops may be made as follows:
this general class.
Per cent 5
The corresponding secondary amine is simi
Beta-phenyl-alpha - alpha -dimethyl-alpha
larly valuable for the same purposes.
amino ethane (calculated as free
The following example will illustrate a method
amines) ____________________________ __
of preparing this compound in accordance with
my invention although, as will be evident to those
Molecular equivalent of inorganic Or or
ganic acid such as hydrochloric, sulfuric,_
lactic, gluconic, isoasror'bic, levulinic and
the like.
skilled in the art, various equivalent substances
may be used. in place of those mentioned and
various equivalent procedures may be used in
Cetyl pyridinium chloride ______________ __ 0.033
. stead of the particular steps described:
0.05 '
Sorbitol ______________________________ __ 4
Distilled water, q. s.
Preparation of beta-phenyl-beta-chZoro-alpha
' aminoalpha-alpha-di-methyl ethane
We prefer to use organic acidsalts rather. than _, 1'3“: .Amiktlire ‘of ‘equal parts by Weight of beta_
mineral acid salts, since in general they are. less
irritating. The sorbitol in this composition? 'fphe‘riyllbetaehydroxy-alpha-amino-alpha-methyl
serves to make the product isotonic and should. 2o__propane hydrochloride and thionyl chloride are
be in amount adjusted to eiTect‘ that result. "Tl‘l?f 1; allowed'to stand‘at ordinary temperature (25
7 735° C.) for 10 to 15 hours, then warmed to 70° C.
pH of the solution is adjusted to approximately"
‘I. The surface tension of the material is approx; ~The solid which results is then powdered and
washed‘with 200 to 300 cc, of ligroin, and ?nally
imately 34.5 dynes per sq. centimeter.
III. A suitable composition _'f01‘ wusejasian oil 25 dried over soda lime. The resultingbeta-phenyl
beta-chloro-MDhal-amino l-alpha-‘methyly-propane
base nose'drop may be made as follows;
hydrochloride is aboutv 95% pure: and is often
satisfactory for‘ use in. the next step‘,jbut is ad
vantageously puri?ed beforeljfurtherr user' For
amino ethane _______________________ ___ 0.5
Oil of eucalyptus __________ _a__i____,___i____ 1.0 30 puri?cation '60 parts ofthe crude material is dis
solved in 120 parts of; hOtf?lCOhOlf and {poured
Mineral oil _________________________ __,____ 98.5
into 360 parts of ether, cooled, and thepurejhy
The free amine may be used in this composition
drochloride Salt ?ltered and dried. Tné ‘yield 5]
Beta-phenyl-alpha — alpha-dimethyl-alpha
or any of itsoil soluble, e.lg.', fatty acid, salts,
such as the oleate, palmitate, etc. The oil of 35
eucalyptus may, of course, be replaced by other
of puri?ed material lS_‘abOl,lt_80% ‘of‘the theory.
Preparation '0} beta-phenylealiihaeaminoealphae
aromatics commonly used in nose drops, such
as varying proportions of menthol, camphor,
thymol, etc., and the mineral oil may be replaced
by a vegetable oil such as peanut oil, ‘cotton
seed oil, sesame oil, etc.
v -
d -
Per cent
Beta - phenyl - alpha - alpha + dimethyl-
Methyl salicylate ____________ __'...‘. _____ __
1.5 parts of the above beta-phenyllbeta-chloroe
_' ethane .hy
hol, and 5 parts ,of palladiniz'ed .‘calciumfca‘rbon
ate added. 'The mixtures ‘then reduced in a ‘
conventional hydrogenation apparatus with'hy
_ drog'en at 50-'80° C. and under-.50 lbs. pressure“v
the solutionis removed, the. palladiniz'edcalcium
carbonate ?ltered andthe' ?ltratev evaporated.
The residue is‘ dissolvedin'dilutehydrochloric j
Cetyl Dyridinium chloride/W.’ _____ __I__7_-_: " 0.1
____________ __j ____ ___ ____ __l
45 When'hydrogeh is no 3 longer readily absorbed,
alpha-amino ethane ________ __>________» 0.5
40 drochloride, are dissolved iii-150 partslofalcoé- i
, IV. A nasal jelly may be prepared as follows:
Eucalyptol ______________ __ ___________ __
Oil dwarf pine needles ________________ __
Distilled water _________ __-__ _________ ___ 83.25
V. For internal administration the compound
may be included in tablets of suitable composi
tion, for example:
Beta-phenyl-alpha - alpha - dimethyl-alpha
amino ethane __________ __mgs. per tablet__ 25
Mixed in a base consisting of approximately:
50. Theacid
acid, shaken
with is
made. alkaline,
ether "discarded.
as with '
sodium ‘hydroxide, and the-amine? extracted with
ether. The ether solution-v may ‘(1), be dried‘ and
distilled to give the desired 'a-ben'zyl isopropyl
amine, B. P. 205° at ‘750 mm. or 100° at
55 or (2) the ether solution may be dried and ‘sat
urated with‘ hydrogen chloride an'd‘the precip_
itated hydrochloride recrystallizedfroma mix
ture of 50 parts alcohol and 100- parts of acetone.
-> The pure hydrochloride’is thus obtained as’ a
Parts 60 white crystalline substance in yieldsf60%, of the
theoretical and having a,M,.P.. of 195-106." C..unc.
Milk sugar ________________________ _;_- 50
» Talc
__________________________ __
- Stearic acid ________________________ __'
And compressed into anuncoated tablet ‘of ap
Other halogeno compoundsjmay. be usedinstead
> _
Instead of'palladinized calcium‘ carbonate other
hydrogenation catalysts may be used. Palladium
and/or; platinum absorbed on ' a basic. carrier‘such
proximately 2.8 grains.
.as an alkaline earth oxide Or carbonate (especial
Instead of compounding'the amine in a tablet
the substituted phenyl-ethane. . Platinum and
lyi calcium or magnesiumi jgivesthe be'sti yield of
base it may be added to a suitable syrup or other 70 platinum,‘ oxide. (Adams), alone, palladium‘ on
vehicle for internal administration.
As will be appreciated from‘ the above the use
of this amine compound is'very similar to other
,vasopressor amines and in‘ general may be used
charcoal, and Raney nickelmay also. be em
ployed, but the yield of the, beta-phenyl'—alpha
alpha-'-dimethypalphaeaimino "ethane Y compound
is a smallerportion of‘ the total-product. while
in the same manner. Those skilled in the art will 75 at the same time there is produced a substantial
‘ thereof which comprises hydrogenating beta
yield of the novel product, beta-cyclohexyl-alpha
alpha-dimethyl-alpha-amino ethane.
phenyl - beta - chloro - alpha - alpha - dimethyl
amino-ethane hydrochloride in solution in the
Accordingly, regardless of which of two types
of catalysts is employed, the method is utilizable‘
for the production of a beta-cyclo-alpha-alpha
dimethyl-amino ethane, a catalyst of the former
type being chosen when the “cyclo” radical is to
be kept as anunsaturated nucleus and. the latter
type being suitable when it is desired to saturate
the ring.
presence of palladium absorbed on calcium car
4. The method-of preparing beta-phenyl-al
pha-alpha-dimethyl-alpha-amino ethane and the
amine salts thereof which comprises hydrogenat
The solution during hydrogenation should not
be su?iciently alkaline to remove the hydrochloric
ing the corresponding beta-phenyl-beta-beta
chloro-alpha-methyl-alpha-amino propane at
elevated temperature and pressure in alcoholic
solution in the presence of palladinized calcium
. acid from the amine group as thatwould permit
carbonate dispersed therein.
. with the class of vasopressor amines they may
thereof which comprises hydrogenating beta
5. The method of preparing beta-phenyl-alpha
the amino-ethane compound to react with itself.
As indicated above and as generally recognized 15 alpha-alpha-amino ethane and the amine salts
be used either as free amines or as amine salts
and as primary or secondary amines.
phenyl-beta-chloro-alpha-methyl - alpha - amino
; propane at atemperature between about 50-80°
C.v andpa hydrogen pressure about 50 lbs. per
What is claimed is:
’ ,
1. The method of preparing beta-phenyl-al 20 square inch and in alcoholic solution with ?nely
pha-alpha-dimethyl-aminp ethane and the amine
salts thereof which comprises hydrogenating the
alpha-dimethyl-amino ethane compound in so-‘ .
lution in the presence of a catalytic metal of the
‘ class consisting of platinum and palladium ab
sorbed on a basic carrier.
2. The method of preparing beta-phenyl-al
divided palladinized calcium carbonate dispersed
'6. The method of preparing beta-phenyl-beta
chloro-alpha-alpha-dimethyl-amino ethane and
the amine salts thereof which comprises mixing
a corresponding beta-phenyl-beta-hydroxy-al
pha-alpha-dimethyl-amino ethane compound and
thionyl chloride, allowing the same to react,
pha-alpha-dimethyl-amino ethane and the amine
salts thereof which comprises hydrogenating-beta
warming, washing, and drying.
7. Beta-phenyl-alpha-alpha-dimethyl - alpha
ethane hydrochloride in solution in the presence
of palladium absorbed 0n magnesium carbonate.
amino ethane.
8. Beta-phenyl-alpha-alpha-dimethyl - alpha
amino‘ethane and the salts thereof.
3. The method of preparing beta-phenyl-alpha
alpha-dimethyl-amino ethane and the amine salts 35
Certi?cate of Correction
Patent No. 2,408,345. -
September 24, 1946.
It is hereby certi?ed that errors appear in the printed speci?cation of the above
numbered patent requiring correction as follows: Column 4, line 37, after “alpha
dimethy ” insert ethane; column 6, line 9, claim 4, after “phenyl-” strike out beta-;
line 15, claim 5, for “alpha-alpha” read alpha-dimethyl-alpha; and that the said Letters
Patent should be read with these corrections therein that the same may conform to
the record of the case in the Patent Office.
Signed and sealed this 8th day of April, A. D. 1947.
First Assistant Oonwnissioner of Patents.
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