Synthesis of 2-Amino-1-Phenyl-1-Propanol and Its Methyl at Ed Derivatives'

[CONTRIBUTION
FROM THEDEPARTMENTOF CHEMISTRY AND PURDUE

RESEARCH
FOUNDATION,
PURDlJE UNIVERSITY]
SYNTHESIS OF 2-AMINO-1-PHENYL-1-PROPANOL AND ITS

METHYLATED DERIVATIVES'
FRED W. HOOVER* AND HENRY B. HASS
Received January 22, 1947
Ephedrine is obtained commercially not only from extraction of the herb
mahuang but also by a synthetic process (1) in which l-l-hydroxy-l-phenyl-2-
propanone, obtained by action of benzaldehyde on fermenting sugar solutions,
is allowed to react with methylamine, and the resulting Schiff base is reduced
to 1-ephedrine. This process has the advantage that no resolution is necessary.
Propadrine hydrochloride, also called Mydriatine, is a racemic mixture, melt-
ing at 190-194". It is a mydriatic, diaphoretic, vasoconstrictor, and is used
like ephedrine hydrochloride or ephedrine sulfate but its action is more prolonged.
In 1929, Nagai and Kanao (4)reported the synthesis of ephedrine from benz-
aldehyde and nitroethane. A similar series of reactions has been used in this
work and offers a route to ephedrine.
(I) CtjHsCHO + CzHsNOz CsH5CHOHCHN0zCH3(Two Racemic Forms)
-+
(11) CeHSCHOHCHN02CH3+ Hz -
Raney Ni
-+ CeHijCHOHCHNHzCH3
(111) C6H5CHOHCHNH2CH3+ HCHO, then + HZ-
Raney Xi
--f
CeHsCHOHCH (NHCH,) CH,

The nitro alcohol mas obtained in good yield by the method of Vanderbilt and
Hass ( 5 ) , Kamlet (3), and Nagai and Kanao (4),but the method of Kamlet is
particularly desirable because of the speed of the reaction. This method involves
reaction between nitroethane and the sodium bisulfite addition product of
benzaldehyde. It requires only a few hours whereas the other methods require
several days.
The unmethylated amino alcohol was obtained by reduction of the nitro
alcohol either with zinc and sulfuric acid, tin and hydrochloric acid, sodium
amalgam and acetic acid, or by catalytic hydrogenation. Presumably many of
the ordinary metal-acid reducing agents can be used provided the temperature is
kept sufficiently low to prevent dehydration. There are, however, several by-
products of the reduction. When catalytic hydrogenation was selected as the
method, N-ethylbenzylamine was a by-product. It presumably forms by the
following reactions :
(I) C~H~CKOHCHNOZCH~ e CtjHsCHO CzHsNOz +
(11) CzHsNOz + Raney Ni
HP --+ CzHsXHz
(111) CtjHsCHO f CzHsKHz -+ CsHsCH :NC2Hs
(IV) CsHsCH:NCzH, 4- H2 -
Raney 2
C~H~CHZNHCZH,
1A portion of the doctoral thesis of Fred W. Hoover.
* Present address: Experimental Station, E. I . duPont de Nemours and Co., Wilming-
ton, Delaware.
506
SYNTHESIS OF 2-AM~NO-l-PHENYL-l-PROPANOL 507
This series of reactions postulates the formation of benzaldehyde and nitro-

ethane by decomposition of 2-nitro-] -phenyl-1-propanol. It seemed logical t o
assume that this reaction was brought about by the catalytic effect of the basic
(amine) reduction products. This hypothesis is supported by the fact that use
of carbon dioxide in the Parr bomb reduces the yield of N-ethylbenzylamine t o
negligible quantities. Of those tested, the two best methods of reduction, from
the standpoint of both simplicity and yield, are that using zinc and sulfuric acid,
and that using acetic acid and sodium amalgam.
The amino alcohol which is an intermediate in the formation of Propadrine
is easily methylated by adding an equimolecular amount of aqueous formalde-
hyde and then reducing catalytically.
Each step in the synthesis provides good yields. Efforts to separate the
diastereoisomers were much less satisfactory. The method of Nag& and Kanao
(4)for resolving the hydrochloride of 2-amino-1-phenyl-1-propanol, using abso-
lute ethanol as the solvent, proved very inefficient, although enough of the de-
sired diastereoisomer, dl-nor-ephedrine hydrochloride, was obtained for identifi-
cation. The pressor action of these four stereoisomers has been studied by
Jaromski and Hartung (2).
EXPERIMENTAL
Preparation of 8-nitro-1-phenyl-f -propanol. (a) Method of Vanderbilt and Hass (5).
Benzaldehyde (13.25 g., 0.125 mole), nitroethane (9.38 g., 0.125 mole), and 50 ml. of 95%
ethanol were mixed, and 2 ml. of sodium hydroxide (25% solution) was added with cooling.
After allowing the mixture to stand for four days, the sodium hydroxide was neutralized
and most of the alcohol was removed under reduced pressure. The residue was dissolved
in ether, extracted with sodium bisulfite solution to remove unreacted benzaldehyde, and
then distilled (b.p. 120-130' at 2 to 4 mm.) conversion 25 g. (62%). Based on the benzalde-
hyde that reacted, the yield was almost quantitative.
(b) Method of Nagai and Ranao (4). Benzaldehyde (106 g., 1 mole), nitroethane (75
g., 1 mole), and 50 ml. of saturated sodium bicarbonate solution were vigorously stirred
for one week at room temperature (25-30"). The organic and aqueous layers were sepa-
rated, the organic layer was washed with sodium bisulfite solution and distilled (b.p. 120-
130" at 2 to 4 mm.), 90.5 g. resulted, conversion SO%, yield, based on benzaldehyde which
reacted, 90%.
(c) Method of Kamlet (3). Benzaldehydc (106 g., 1 mole) was vigorously agitated with
sodium bisulfite (110 g., 1.06 mole) in 500 ml. of water until the formation of the addition
compound was complete. Simultaneously, nitroethane (82.5 g., 1.10 mole) was dissolved
in a solution made from sodium hydroxide (48 g., 1.125 moles) dissolved in 200 ml. of water.
This solution was gradually added, with agitation and a t room temperature, to the addition
product of benzaldehyde and sodium bisulfitth. After stirring for a half hour, the mixture
WVRSallowed to stand overnight. The lower layer was discarded and the upper layer was
dissolved in ether and washed with sodium bisulfite solution. The ethereal solution was
dried over Drierite, and after removal of ether, distilled (b.p. 120-130' a t 2 4 mm.) The
usual conversion is 90-100 g. (50-55%) and the yield, based on benzaldehyde which reacts,
is nearly quantitative.
Preparation of 8-amino-1-phenyl-1-propanol. (a) With zinc and sulfuric acid. Sulfuric
acid (375 g. of 30y0 acid) was added with stirring to a mixture of 2-nitro-1-phenyl-1-propanol
(54.3 g., 0.3 mole), zinc dust (90 g., 1.37 mole of 80 mesh zinc), and 100 ml. of 95% ethanol.
The acid was added at such a rate that the temperature remained a t 45" or below. Usually
I O to 12 hours were required. Agitation was continued for 1-2 hours after completing the
508 FRED W. HOOVER AND HENRY B. HASS
addition of acid, then after extracting the acidic solution with ether to remove non-basic
materials, a large excess of sodium hydroxide (as 50% solution) was added. The product
which was freed was extracted with ether. Three extractions, with a total of 500 ml. of
ether, sufficed. The ether solution was dried, ether was removed, and the product was dis-
tilled (b.p. 122" at 4 to 5 mm.); 29-32 g. resulted (yield 65 to 70%). The viscousliquid solidi-
fied on standing, and m. 46-50'.
Anal. Calc'd for C~HlrCINO:C1, 18.91. Found: C1, 18.88.
(b) With sodium amalgam and acetic acid. Glacial acetic acid (160 g., 2.66 moles) and
3% sodium amalgam (1924 g., 2.5 moles) were added in small portions and with good agita-
tion to a solution of 2-nitro-1-phenyl-1-propanol (36.2 g., 0.2 mole) in 300 ml. of absolute
alcohol. Acetic acid was introduced at a rate sufficient to maintain an acidic reaction.
The rate of adding the amalgam was such that the temperature was maintained at 45" or
less. At the end of the reaction mercury was separated, water was added to dissolve the
sodium acetate, and the mixture was heated to remove the alcohol and concentrate the
solution. The cooled solution was extracted with ether to remove non-basic material and
then treated with excess sodium hydroxide (as 50% solution), and the product was taken
up in ether. After removing the ether and distilling, 18-21 g. of product resulted (b.p.
112" a t 2 to 3 mm.).
(c) Catalytic hydrogenation. A mixture of 2-nitro-1-phenyl-1-propanol (36.2 g., 0.2
mole), 100 ml. of absolute alcohol, and 4 g. of Raney nickel was placed in a Parr hydrogena-
tion bomb. Sufficient solid carbon dioxide was added to produce a pressure of 300 lbs./sq.
in., then hydrogen was introduced to bring the total initial pressure to 1800 lbs./sq.in.
Approximately four hours was required for complete reduction. On distilling, S-ethyl-
benzylamine (5%) and 2-amino-1-phenyl-1-propanol (877,) mere obtained. When no car-
bon dioxide was used, the yield of N-ethylbenzylamine approximated 45%.
N-ethylbenzylamine pias identified by its boiling point (198") and the melting point of
the hydrochloride (184") compared with an authentic sample prepared from benzaldehyde
and ethylamine.
Identification of 8-amino-1-phenyl-1-propanol. The product was a very viscous, colorless
liquid which solidified on standing, m.p. 46-50'. When dry hydrogen chloride was passed
into an ether solution, a gelatinous precipitate resulted, which hardened on standing. This
character of precipitate was attributed to the rather complex mixture of isomers, since an
authentic sample of I-ephedrine yielded well formed crystals. A better product could be
made from the base by treating it with concentrated hydrochloric acid to the end point of
methyl red indicator, evaporating under reduced pressure, and recrystallizing from buta-
nol-ether (50-50 mixture by volume). The white crystals (m.p. 134-137") gave 18.87 and
18.8970 chlorine by Fajan's method (theory 18.91%). The neutral equivalent of the free
amine was 155 (theory 151). The material is therefore believed to be a mixture of d l -
norephedrine and dl-norisoephedrine, These two compounds are diastereoisomers and
have the following constants:
dl -norephedrine dl-norisoephedrine
Free base m.p. 104-105' Free base m.p. 71"
Hydrochloride m.p. 192" Hydrochloride m.p. 169"
After four fractional crystallizations from absolute alcohol i t was possible to obtain a
hydrochloride m.p. 192". The melting point of a mixture of this compound and norephed-
rine hydrochloride was 192". Thus, i t is possible to separate the components of the mix-
ture by fractional crystallization but the yield is low.
The method of Nagai and Kanao (4),which utilizes the greater solubility in ether of
norisoephedrine to separate the isomers, was tried on the free base. After four crystalliza-
tions, the amino alcohol melted at 7275". Since the original base mixture melted at 46-
50", the difference in solubility is evidently not great.
The mixture of stereoisomers obtained in this synthesis was tested for physiological
action by two manufacturers of pharmaceuticals who compared i t with norephedrine hydro-
SYNTHESIS O F 2-AMIbiO- 1-PHENYL- 1-PROPANOL 509
chloride and found i t to have a similar effect on the blood pressure. The work of Jarowski
and Hartung already has been mentioned (2).
Preparation of 2-methylamino-l-phenyl-l~ propanol. Formaldehyde (0.3 mole of active
material as 37% solution) was added, with cooling, to 2-amino-l-phenyl-l-propanol (45.3
g., 0.3 mole) dissolved i n ethanol. After the mixture had stood for a half hour, the Schiff
base was reduced in a Parr hydrogenation bomb. Raney nickel (4 g.) was used as a cata-
lyst. Initial pressures of hydrogen from 600 to 1400 lbs./sq.in. were suitable. The product
was recovered by distilling the alcoholic solution with a Podbielniak column. There was a
small amount of material which boiled at 106" a t 5 mm., but the main portion of the dis-
tillate was collected at 115-120" at 5 111111. The yield of the more high-boiling product was
40 g. (8lyo).
Anal. Calc'd for CIOHISNO: N , 8.5. Feud: N,8.4.
This mixture presumably is norephedrine and norisoephedrine and their monomethylated
derivatives. This type of alkylation usually results in the formation of primary, second-
ary, and tertiary amines. Knowing that they usually result in such mixtures, we assume
that small amounts are present in spite of the good agreement of the percentage of nitrogen
with that required for CloHlsNO. Sampler; of this material were prepared for several
laboratories which specialize in techniques for separating isomers, but as yet no satisfac-
tory process has been devised.
~4CEL3'O%rLEDGXEKTS
The authors wish to acknowledge assistance from the Commercial Solvents

Corporation, which provided financial aid to this program as Purdue Research
Foundation Fellowship 54338, and to 1)r. Elizabeth F. Riley, who assisted in
the preparation of the manuscript.
SUM&[ART
The synthesis of 2-amino-l-phenyl-l-propanol and of Z-methylamino-l-phenyl-
1-propanol has been effected in several ways, all utilizing economical inter-
mediates as initial materials. The mixture of diastereoisomers can be obtained
in good yield but the methods for separating the isomers are not yet entirely
satisf act ory .
LAFAYEWE,IND.
BIBLIOGRAPHY
(I) HILDEBRANDT AND KLAVEHN, U. S. Patent 1,956,950.
(2) JAROWSKI AND HARTUNG, J. Org. Chem., 5, 564 (1943).
(3) KAMLET,U. S. Patent 2,151,517.
(4) NAGAIAND KANAO,Ann., 470, 157 (1929)
(5) VANDERBILT, Doctoral Dissertation, Purdue University, 1937;
VANDERBILT AND HASS,Ind. Eng. Chem., 32, 34 (1940).

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[CONTRIBUTION

FROM THEDEPARTMENTOF CHEMISTRY AND PURDUE

SYNTHESIS OF 2-AMINO-1-PHENYL-1-PROPANOL AND ITS

CeHsCHOHCH (NHCH,) CH,

This series of reactions postulates the formation of benzaldehyde and nitro-

The authors wish to acknowledge assistance from the Commercial Solvents

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