Note: Descriptions are shown in the official language in which they were submitted.
1()7~32Z
Background of the Invention
Field of the Invention
This invention relates to an improved process for
making acid addition salts of 2-hydroxymethyl-3-hydroxy-
6-(1-hydroxy-2-t-butylaminoethyl)pyridine, a broncho-
dilator, which comprises hydrogenolysis of the benzyl-
idene acetal 2-phenyl-6-(1-hydroxy-2-t-butylaminoethyl)-
4H-pyrido~3,2-d]-1,3-dioxin, and conversion of the
resulting product to acid addition salts, especially to
the acetate salt, also a bronchodilator.
Description of the Prior Art
U~S. patent 3,948,919 issued April 6, 1976 describes
the preparation of 2-hydroxymethyl-3-hydroxy-6-~1-
hydroxy-2-t-butylaminoethyl)pyridine (known generically
as pirbuterol, formula IV), a bronchodilator, by the
following three related sequences:
1()743Z2
~Z
k o H ~; o 1_~\
U~ U~
0/l ~ /
a~ ~ ~; a~
~ U
1074;~22
In the above formulae each of R and R' is phenyi or
methyl; and Z is -CHOH-CH2-NH-C(CH3)3.
The reaction sequence IA to IB to IV affords good
yields of the final product (IV) having good quality but
suffers from the economic disadvantage of requiring
benzyl bromide, a relatively expensive substance, as
reactant for preparation of the benzyl ether (IA).
Hydrogenolytic removal of the benzyl group (IB to IV)
successfully eliminates the colored impuxities.
Reaction sequence IIIA to IIIB to IV is less
attractive from an economic standpoint than is sequence
IIA to IIB to IV because of the relatively high costs
realized in the preparation of reactant IIIA.
The sequence IIA to IIB to IV is free of the above
disadvantages. However, particularly on a large scale
operation it, as are the other two sequences, is subject
to the presence of colored impurities in the final
product (IV). These impurities arise during the prepa-
ration of intermediates IB, IIB and IIIB and, unless re-
moved prior to conversion of said compounds to IV,interfere in the isolation and purification of product
IV.
The protection of aliphatic hydroxyl groups by
converting them to benzylidene acetals has found ex-
tensive use in sugar and glyceride chemistry. Thebenzylidene group is removable by catalytic hydrogenoly-
sis using palladium-charcoal (Peat et al., J. Chem.
Soc., 1088, 1~8) or by hydrolysis with a mineral acid.
107432~
Fodor et al., Synthesis, 464-472 (1972) report the
use of the benzylidene group as protecting group for the
hydroxylic groups of 2-methyl-5-hydroxy-6-hydroxymethyl
pyridine and 2,6-bis-hydroxymethyl-3-hydroxypyridine,
intermediates in the synthesis of carpyrinic acid and
related pyridines. Catalytic hydrogenation of the
benzylidene acetal 2-phenyl-6-(11-tetrahydropyranyloxy-
dodecen-l-yl)-4H-pyrido[3,2-d]-1,3-dioxin at low pres-
sure over platinum oxide did not remove the benzylidene
group but only hydrogenated the olefin group.
U.S. patent 4,011,231, issued I~arch 8, 1977, des-
cribes the preparation of high quality pirbuterol dihy-
drochloride by a process which comprises reacting maleic
acid with 2-phenyl-6-(1-hydroxy-2-t-butylaminoethyl)-4H-
pyrido[3,2-d]-1,3-dioxin to produce the maleate salt
thereof, followed by hydrolysis of the dioxin with
excess hydrochloric acid. Conversion of the dihydrochlo-
ride salt thus produced to, for example, the acetate by
simple exchange is not practical.
Summary of the Invention
The process of this invention is a modification of
the sequence IIA to IIB to IV described in U.S. patent
3,948,919 and one which achieves significant improvement
in yield and purity in the large scale preparation of
plrbuterol. Increased economic advantage of this
process over the routes described in U.S. patent 3,948,919
is realized. The process comprises hydrogenolyzing the
benzylidene acetal 2-phenyl-6-(1-hydroxy-2-t-butylamino-
ethyl)-4~-pyrido[3,2-dl-1,3-dioxin IIB to pirbuterol.
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10~43Z'~
This process unexpectedly affords an advantageous,
economic, direct and industrially useful route to the
acetate salt, or to other acid addition salts, especially
of non-mineral acids, of pirbuterol.
Removal of the benzylidene protecting group from
by hydrolysis requires a strong acid, preferably a
mineral acid such as hydrochloric, hydrobromic or sul-
furic acid, to achieve satisfactory conversion to
pirbuterol. Acid hydrolysis fails to remove the colored
impurities present. These impurities are carried over
to the final product (IV) and are difficult to remove.
Additionally, the pirbuterol product is obtained as the
acid addition salt of the acid used for hydrolysis,
e.g., the dihydrochloride salt.
Conversion of the dihydrochloride salt, or other
mineral acid addition salt, to the acetate or other non-
mineral acid salt by simple exchange is not economically
practical or industrially useful. The present hydro-
genolysis process produces high quality pirbuterol as
the free base, thus permitting its direct conversion to
the acetate or any other desired acid addition salt.
~on-mineral acids such as acetic or other al~anoic acids
fail to achieve satisfactory removal of the benzylidene
protecting group from IIA and are, therefore, not
economically attractive for such purpose.
1~'743~Z
According to the invention, in the process for preparing pir-
buterol by removal of the benzylidene protecting group from 2-phenyl-6-(1-
hydroxy-2-t-butylaminoethyl)-4H-pyridor3,2-d]-1,3-dioxin, there is provided
the improvement which comprises hydrogenolyzing said compound over palladium
as a catalyst in a reaction-inert solvent in the presence of water.
Suitable reaction-inert solvents are alcohols, especially alkanols
having from one to four carbon atoms. Of these solvents, methanol îs pre-
ferred since it affords quantitative removal of the protecting group, is re-
latively inexpensive and available, and serves as reaction medium for subse-
quent salt formation. Other solvents such as tetrahydrofuran and dioxane can,
of course, be used either alone or in combination with each other and/or with
the above-mentioned alcohols. Higher boiling solvents can also be used, e.g.
ethylene glycol, dimethyl ether of ethylene glycol, but are not favored be-
cause more energy is required to remove them from the reaction mixture. The
solvent selected is desirably a water miscible solvent since, under the pre-
ferred conditions of this process, as is discussed below, water must be pre-
sent during the hydrogenolysis to minimize side reactions.
According to a preferred embodiment of the invention, in the process
for preparin~ pirbuterol acetate by removal of the benzylidene protecting
group from 2-phenyl-6-(1-hydroxy-2-t-butylaminoethyl)-4H-pyrido[3,2-d]-1,3-
dioxin, there is provided the improvement which comprises hydrogenolyzing
said compound over palladium-on-carbon in methanol at ambient temperature and
from about 15 to about 150 psi hydrogen in the presence of from about 1 to
about 30 equivalents of water, based upon the 2-phenyl-6-(1-hydroxy-2-t-butyl-
aminoethyl)-4H-pyrido[3,2-d]-1,3-di~an used,filtering and concentrating the hy-
drogenolyzed reaction mixture, and treating the concentrate with at least a
stoichiometric amount of acetic acid.
The reaction is generally conducted at a temperature of from about
20C. to 25C. since it proceeds smoothly and quantitatively to the desired
product, pirbuterol. ~urther, this temperature is essentially "ambient" tem-
perature and requires no cooling or heating. The reaction temperature is not
critical. Lower or higher temperatures, e.g. from about 10C.to about 100~.can
- 7 -
. .
~,.0743;~f~ .
be used but offer no advantages. On the contrary, from
a cost standpoint temperature outside the 20C. - 25C.
range are avoided.
The hydrogen pressure is not critical. Pressures
5 of from about 1 to about 200 psi (0.01 to about 140
kg./sq. cm.) can be used to remove the protecting group.
In actual practice, however, for reasons of economy and
ease of operation, pressures of from about 15 to about
150 psi (1 to about 10 kg./sq. cm.) are used.
As catalyst, palladium-carbon is particularly
effective in achieving rapid and complete removal of the
benzylidene group. Palladium itself can be used as
catalyst. .In addition, palladium on a carrier such as
barium sulphate can also be used as catalyst, as can
palladium black, palladium oxide (which is reduced to
palladium under the process conditions employed). Raney
nickel can also be used in this process as catalyst.
However, the preferred catalyst is palladium-carbon,
especially 5% palladium on charcoal.
The amount of catalyst used is not critical to suc-
cessful conduct of this process. In actual practice,
from about 0.01 to about 0.10 g. of palladium per gram
of benzylidene acetal have been found highly satisfac-
tory in effecting removal of the benzylidene group. In
terms of 5% palladium on charcoal, this is equivalent to
from about 0.2 to 2.0 g. of 5% palladium on charcoal pergram of benzylidene acetal.
~0743ZZ
A side-reaction of this hydrogenolysis process is
hydrogenolysis of the hydroxyl group on the t-butyl-
aminoethyl group at the 6-position. Minimization, and
even elimination, of this side reaction is achieved by
the presence of water during the hydrogenolysis reaction.
While the presence of water is critical, the amount of
water is not critical but can vary from about one
equivalent mole to as much as 30 equivalent moles, based
on the benzylidene acetal, the limiting factor being the
dilution effect of the added water on the rate of the
desired hydrogenolysis reaction. The favored amount of
water is from about 1 to about 20 equivalent moles. The
presence of smaller amounts of water serve to reduce
this side reaction but with less efficiency than does
the above-mentioned range. Larger amounts of water tend
to reduce the rate of the hydrogenolysis reaction as
noted.
The presence of water in the hydrogenolysis reaction
to minimize the above-mentioned side reaction is con-
veniently satisfied by using the palladium on charcoal
catalyst in the form of water wet material, e.g., 50~
water wet material. The above levels of catalyst then
become from about 0.4 to about 4.~ g. of 5% palladium on
charcoal, 50~ water wet, per gr~m of benzylidene acetal.
Alternatively, the water is added separately to the
reaction mixture.
~0743'~
The hydrogenolysis reaction mixture containing the
free base form of pirbuterol is concentrated, usually
under reduced pressure, to small volume to remove water
and by-product toluene. To more effectively dry the
concentrate, ethanol, generally from about 1-2 volumes,
is added and the resulting solution concentrated. This
step is repeated if necessary or desirable to more
completely remove water present. Complete removal of
all solvents and by-product toluene affords the free
base as a solid which is relatively stable at ambient
temperatures, e.g., 20C.-25C.
The desired acid addition salt of pirbuterol is
readily prepared by adding the appropriate acid, e.g.,
acetic acid, to the concentrate. At least a stoichio-
metric amount of acid is added. In actual practice up
to 10% excess of the acid is added to the concentrate.
To expedite precipitation of the acid addition salt, the
acid is usually added as a solution in a solvent, e.g.,
acetone, in which the acid addition salt is insoluble.
Alternatively, said solvent is added to the concentrate
before, after, or simultaneously with the acid.
The pirbuterol produced by this process is unex-
pectedly and surprisingly free of colored impurities.
Thus, the hydrogenolytic re~,oval of the benzylidene pro-
tecting group affords a quantitative yield of high
quality pirbuterol and, of course, permits preparation
of high quality acid addition salts of pirbuterol.
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10743ZZ
It permits the use of a crude benzylidene acetal and
achieves production of a pure debenzylated product. An
added feature of the hydrogenolytic removal of the
benzylidene protecting group is production of toluene,
a by-product easily removed from the reaction mixture.
In contrast, hydrolytic removal of the benzylidene group
produces benzaldehyde which is less easily removed from
the reaction mixture.
10743Z'~
EXAMPLE 1
Pirbuterol Acetate
A solution of 2-phenyl-6-(1-hydroxy-2-t-butylamino-
ethyl)-4H-pyrido[3,2-d3-1,3-dioxin (1.67 kg., 5.09
moles) in methanol (16.7 1.) is added to a glass-lined
reactor charged with 5% palladium-on-charcoal 50% water
wet catalyst (2.13 kg., 11.6 equivalent moles water).
The mixture is stirred and the reactor purged first with
nitrogen and then with hydrogen. Hydrogen is charged to
the reactor at 50 psi at 20C.-25C. and maintained at
this level throughout the 12 hour reaction period. The
reactor is depressurized and the reaction mixture
filtered through diatomaceous earth. (Thin layer
chromatography in the system methyl ethyl ketone:acetic
lS acid:water [6:1:1 v/v] on silica gel GF plates showed
hydrogenolysis to be complete.) The filter cake is
washed with methanol (3 x 500 ml.), the combined wash
and filtrate treated with activated charcoal (167 g.),
stirred at 20C.-25C. for one hour and then filtered.
A volume of filtrate containing one mole of pirbuterol
is removed and concentrated to about 1/3 volume under
reduced pressure. Ethanol (2550 ml.) is added to the
concentrate and the resulting solution concentrated to
1/3 volume under reduced pressure. The addition of
ethanol and concentration is repeated 3 or more times to
insure a water free concentrate of pirbuterol.
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~0743;~
The pirbuterol is converted ~o its acetate salt by
addition of a solution of glacial acetic acid (67.3 g.,
1.12 moles) in acetone (6125 ml.) to the concentrate.
The resulting mixture is stirred and heated to 50C.-
55C. and then cooled to room temperature in a waterbath. The acetate salt crystallizes out and is filtered,
washed with acetone (2 x 500 ml;) and dried in vacuo at
20C. to 25C. Yield = 222 g. (75%), m.p. 154C.-155C.
Analysis: Calc'd for C12H20O3N2.C2 4 2
H, 8.05; N, 9.33 ~; Found: C, 56.60; H, 8.16; N, 9.56%.
Recrystallization from ethanol affords an analytical
sample: Analysis: Found: C, 56.04; H, 8.05; N, S.33 %.
The remaining methanol solution of pirbuterol is
concentrated in the manner described above and the
ethanol-pirbuterol concentrate treated with a stoichio-
metric amount of fumaric acid and the mixture stirredand heated to 60C. The fumarate salt precipitates and
the slurry is stirred and allowed to cool to 25C. It
is then cooled in an ice bath to 5C., granulated for 30
minutes and then filtered. The filter cake is ~lashed
with ethanol and dried in a forced air oven at 50C.
(73~ yield based on an assumption of 4.09 moles pir-
buterol in the concentrate). The product is the hemi-
fumarate monoethanolate salt. M.P. 135C.-136C.
(dec.~.
~ 12 20 3 2 / 4 4 4 2 5
C, 55.80; H, 8.19; N, 8.14 ~; Found: C, 55.72; H, 8.25;
N, 8.06 %.
1074;3~;~
EXAMPLE 2
The procedure of Example l is repeated but using
0.049 moles of 2-phenyl-6-(l-hydroxy-2-t-butylaminoethyl)-
4H-pyrido~3,2-d]-1,3-dioxin, 160 ml. methanol as solvent,
20.38 g. of 5% palladium-on-charcoal, 50% water wet
(11.5 equivalent les water), a hydrogen pressure of 50
p8i at 22C. for 22.5 hours to give 100% conversion to
pirbuterol.
Treatment of the ethanol concentrate, o~tained
according to the procedure of Example l with 0.055 moles
glacial acetLc acid affords a 73% yield of pirbuterol
acetate.
EXAMPLE 3
Pirbuterol Acetate (Via Hydrogenolysis
Using one equivalent mole water)
A solution of 2-phenyl-6-(1-hydroxy-2-t-butylamino-
ethyl)-4H-pyrido[3,2-d]-1,3-dioxin (8.046 g., 0.0245
mole) in methanol (80 ml.) is added to a 500 ml. high
pressure bottle charged with dry 5~ palladium-on-charcoal
catalyst (5.095 g.) and water (0.45 ml., one equivalent
mole). The mixture is stirred and the reactor purged
first with nitrogen and then with hydrogen. Hydrogen is
charged to the reactor at 50 psi at 20C.-25C. and
maintained at this level throughout the 24 hour reaction
period. The reactor is depressurized and the reaction
mixture filtered through diatomaceous earth. The filter
cake is washed with methanol (2 x 30 ml.), the combined
~0743ZZ
wash and filtrate treated with activated charcoal (0.6
g.), stirred at 20C.-25C. for 15 minutes and then
filtered through diatomaceous earth. The filter cake is
washed with ethanol ~2 x 12.5 ml.) and the combined
filtrate and wash concentrated under reduced pressure to
a volume of about 25 ml.
Glacial acetic acid (1.618 g., 0.02695 mole) in
acetone (1.50 ml.) is added to the concentrate and the
resulting mixture stirred and heated to 50C.-55C. It
is then cooled at room temperature overnight and then to
0C.-5C. The solution is then concentrated under
reduced pressure to an oil (since crystallization did
not occur) and chloroform (100 ml.) added to the oil.
The mixture is stirred at room temperature for 2 hours
and the acetate salt filtered, washed with chloroform (2
x 15 ml.) and dried. Yield = 7.0 g. (95.1%); m.p.
152C.-154C.
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1~)7432;~
EXAMPLE 4
The procedure of Example 3 is repeated but using
the levels of water indicated below.
Equivalent (C.) % yield of pir-
ml. water moles water M.P. buterol acetate
a) 13.23 30 153-55 60%* good
quality
b) --- --- 148-51 64%** inferior
quality
10 c) 0.1 0.23 148-51 61.8%**
inferior
quality
*The acetate crystallized from the concentrate on
cooling. The relatively low yield is due to incom-
15 plete removal of the water from the concentrate prior toformation of the acetate salt.
**NMR shows presence of 2-hydroxymethyl-3-hydroxy-
6-(2-t-butylaminoethyl)pyridine as impurity.
EXAMPLE 5
The procedure of Example 2 is repeated but using
the following conditions of hydrogen pressure, time,
temperature, catalyst and water:
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107432Z
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