U.S. patent application number 12/005772 was filed with the patent office on 2008-06-05 for preparation of levalbuterol hydrochloride.
This patent application is currently assigned to Teva Pharmaceuticals USA, Inc. for Barbados.. Invention is credited to Stefano Bianchi, Paola Daverio, Silvia Mantovani, Valeriano Merli.
Application Number | 20080132579 12/005772 |
Document ID | / |
Family ID | 35456181 |
Filed Date | 2008-06-05 |
United States Patent
Application |
20080132579 |
Kind Code |
A1 |
Merli; Valeriano ; et
al. |
June 5, 2008 |
Preparation of levalbuterol hydrochloride
Abstract
Provided are processes for the preparation of (R)-SLB.D-DBTA
salt and levalbuterol hydrochloride. Also provided are levalbuterol
hydrochloride degradation products and processes for preparing
them. Pharmaceutical compositions comprising at least one
levalbuterol hydrochloride of the invention and at least one
pharmaceutically-acceptable excipient are also provided.
Inventors: |
Merli; Valeriano; (Cremella,
Lecco, IT) ; Mantovani; Silvia; (Lendinara, IT)
; Bianchi; Stefano; (Breccia, Como, IT) ; Daverio;
Paola; (Villasanta, Milano, IT) |
Correspondence
Address: |
KENYON & KENYON LLP
ONE BROADWAY
NEW YORK
NY
10004
US
|
Assignee: |
Teva Pharmaceuticals USA, Inc. for
Barbados.
|
Family ID: |
35456181 |
Appl. No.: |
12/005772 |
Filed: |
December 27, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11133721 |
May 20, 2005 |
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12005772 |
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60573025 |
May 20, 2004 |
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60577979 |
Jun 7, 2004 |
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60646803 |
Jan 25, 2005 |
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60577819 |
Jun 7, 2004 |
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60583777 |
Jun 28, 2004 |
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60583642 |
Jun 28, 2004 |
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60587673 |
Jul 13, 2004 |
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60632625 |
Dec 2, 2004 |
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Current U.S.
Class: |
514/653 ;
564/365 |
Current CPC
Class: |
A61P 11/00 20180101;
C07C 227/34 20130101; A61P 11/06 20180101; C07C 227/34 20130101;
C07C 217/48 20130101; A61P 43/00 20180101; C07C 229/38 20130101;
A61P 11/08 20180101; C07C 229/38 20130101; C07C 215/60
20130101 |
Class at
Publication: |
514/653 ;
564/365 |
International
Class: |
A61K 31/137 20060101
A61K031/137; C07C 215/20 20060101 C07C215/20 |
Claims
1-22. (canceled)
23. Levalbuterol hydrochloride characterized by at least one of an
enantiomeric excess of at least about 99.8%; having less than about
1700 ppm of residual C.sub.1-C.sub.4 alcohol; or having a pH of at
least about 4.3 in 1% aqueous solution at room temperature.
24. The levalbuterol hydrochloride according to claim 23, wherein
the residual alcohol is methanol.
25. The levalbuterol hydrochloride according to claim 23, wherein
the pH is about 4.5 to about 7.
26. Levalbuterol hydrochloride characterized by at least one of
having less than about 0.15% by area HPLC of at least one of
Compound A, Compound B, and Compound C; having less than about
0.10% by area HPLC of total unknown impurities; or having less than
about 0.25% by area HPLC of each impurities including Compound A,
Compound B, and Compound C, after being stored for three months at
40.degree. C. and 75% relative humidity.
27-28. (canceled)
29. A pharmaceutical composition comprising a therapeutically
effective amount of the levalbuterol hydrochloride according to
claim 26 and at least one pharmaceutically-acceptable excipient.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional application of U.S.
application Ser. No. 11/133,721, filed May 20, 2005, which claims
the benefits of U.S. Provisional Patent Application Nos.
60/573,025, filed May 20, 2004, 60/577,979, filed Jun. 7, 2004,
60/646,803, filed Jan. 25, 2005, 60/577,819, filed Jun. 7, 2004,
60/583,777, filed Jun. 28, 2004, 60/583,642, filed Jun. 28, 2004,
60/587,673, filed Jul. 13, 2004 and 60/632,625, filed Dec. 2, 2004,
the contents of all of which are incorporated herein by
reference.
FIELD OF THE INVENTION
[0002] The invention encompasses processes for the preparation of
(R)-SLB.D-DBTA salt, and levalbuterol hydrochloride. The invention
also encompasses levalbuterol hydrochloride degradation products
and processes for preparing them. Also provided are pharmaceutical
compositions comprising at least one levalbuterol hydrochloride of
the invention and at least one pharmaceutically-acceptable
excipient.
BACKGROUND OF THE INVENTION
[0003] Activation of .beta..sub.2-adrenergic receptors on airway
smooth muscle leads to the activation of adenylcyclase and to an
increase in the intracellular concentration of
cyclic-3',5'-adenosine monophosphate (cyclic AMP). This increase in
cyclic AMP leads to the activation of protein kinase A, which
inhibits the phosphorylation of myosin and lowers intracellular
ionic calcium concentrations, resulting in relaxation. Levalbuterol
relaxes the smooth muscles of the airways, from the trachea to the
terminal bronchioles. Levalbuterol acts as a functional antagonist
to relax the airway irrespective of the spasmogen involved thus
protecting against all bronchoconstrictor challenges. Increased
cyclic AMP concentrations are also associated with the inhibition
of release of mediators from mast cells in the airway. The chemical
name for levalbuterol HCl is
(R)-.alpha..sup.1-[[(1,1-dimethylethyl)amino]methyl]-4-hydroxy-1,3-benzen-
edimethanol hydrochloride.
[0004] Levalbuterol HCl has been synthesized using a variety of
synthetic schemes. For example, Great Britain patent No. 1298494
discloses synthesizing levalbuterol first by crystallizing the
alkyl acetate of the 4-carboxylate derivative (Formula 1) using
ditolyltartaric acid and isolating the selected crystalline
fraction. Thereafter, the crystal undergoes debenzylation
deprotection, followed by ester reduction to yield
levalbuterol.
##STR00001##
[0005] Several patents report synthetic routes using enantiomeric
separation, however, the synthetic routes result in low yields of
the enantiomerically pure product. Optically pure levalbuterol was
synthesized by the borane-methylsulfide reduction of the
enantiomerically pure precursor (Formula 2) as described in U.S.
Pat. No. 5,399,765. The reaction dissolved a mixture of enantiomers
of methyl
5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-hydroxybenzoate
and a chiral acid selected from (-)-di-toluoyl-L-tartaric acid and
(+)-di-toluoyl-D-tartaric acid in methanol, upon cooling one
stereoisomer crystallized, which was separated, and recrystallized
as a diastereomer from methanol, the diastereomer was separated,
treated with base, and upon reduction formed optically active
levalbuterol.
##STR00002##
[0006] U.S. Pat. No. 5,442,118 discloses the synthesis of optically
pure (R) or (S) levalbuterol by the asymmetric reduction of
.alpha.-iminoketones precursors. In particular, levalbuterol is
synthesized by the reduction with borane-methylsulfide complex in
the presence of chiral oxazaborolidines as catalysts.
[0007] During the synthesis of levalbuterol, D-dibenzoyltartaric
acid (D-DBTA) or D-ditoluoyltartaric acid (D-DTTA) have been used
for enantiomeric separation. Typically, during the enantiomeric
separation, at least one of the alcohol, ester, or amine functional
groups on levalbuterol is protected. The protecting group is
typically a benzyl group, which after separation is removed to
yield levalbuterol. See U.S. Pat. No. 5,545,745 and WO
95/32178.
[0008] The prior art has separated levalbuterol enantiomers using
4-benzyl levalbuterol. See WO 02/48090. The synthesis uses tartaric
acid for enantiomeric separation and once the (L) tartaric acid
salt is formed and one enantiomer separated, then the salt is
debenzylated to yield either the (R) or (S) isomer of salbutamol as
a sulphate salt.
[0009] Other publications have separated levalbuterol derivatives,
such as WO 99/42460, by forming the ketal derivative of
levalbuterol prior to enantiomeric separation with an enantiomer of
di-O-benzoyl tartaric acid or di-O-(p-toluoyl)-tartaric acid. Thus,
after enantiomeric separation of the ketal, the derivative is
hydrolyzed to yield the desired levalbuterol enantiomer. The
process continuously recycles the undesired enantiomer in the
derivatize, resolve, and hydrolyze cycle to further enhance the
overall yield of the desired enantiomer.
[0010] In Chinese patent No. 1,273,966, enantiomers of racemic
salbutamol are separated using tartaric acid, D-DBTA, D-DTTA, or a
mixture thereof as a resolving agent. In the examples provided, the
ratios of reaction solvent to salbutamol were at least about 14
ml/g. Levalbuterol hydrochloride is isolated by acid-base work-up
or by solid-solid transformation in acetone. In one example, the
salt of (R)-levalbuterol D-dibenzoyltartaric acid is treated with
potassium carbonate in water and an organic solvent, such as
ethylacetate. After phase separation and extraction of the aqueous
layer, the organic layer is dried and the levalbuterol free base is
precipitated overnight. Levalbuterol HCl is synthesized by acid
displacement from (R)-levalbuterol D-dibenzoyltartaric acid salt
suspended in acetone and the addition of an ether solution of
HCl.
[0011] Despite the many attempts of the prior art to synthesize
enantiomerically pure levalbuterol, novel synthetic processes of
levalbuterol are still needed to reduce the steps necessary for
synthesis while maximizing synthetic yield without sacrificing
compound purity.
SUMMARY OF THE INVENTION
[0012] The invention encompasses processes for preparing
(R)-SLB.D-DBTA comprising preparing a mixture of racemic salbutamol
in a first C.sub.1-C.sub.4 alcohol; adding D-dibenzoyltartaric acid
to the mixture; crystallizing and isolating crude (R)-SLB.D-DBTA;
and recrystallizing the crude (R)-SLB.D-DBTA in a second
C.sub.1-C.sub.4 alcohol to obtain the (R)-SLB.D-DBTA, wherein the
first or second alcohol is present in an amount of about 2 ml/g to
about 7.5 ml/g of the salbutamol. In one embodiment, the first or
second alcohol is methanol. The crystallizing step is performed by
seeding with (R)-SLB.D-DBTA. In the process, the
D-dibenzoyltartaric acid is present in an amount of about 0.5 mol
to about 1.3 mol equivalents of the salbutamol.
[0013] Another embodiment of the invention encompasses
enantiomerically pure (R)-SLB.D-DBTA salt having an enantiomeric
excess of at least about 99.8%.
[0014] Yet another embodiment of the invention encompasses
processes for preparing levalbuterol hydrochloride comprising
preparing a first slurry of (R)-SLB.D-DBTA in a first solvent;
adding hydrochloric acid to the first slurry to form crude
levalbuterol hydrochloride; isolating the crude levalbuterol
hydrochloride; preparing a second slurry of the crude levalbuterol
hydrochloride in a second solvent; and isolating the levalbuterol
hydrochloride. In the process, the first or second solvent is at
least one of C.sub.3-C.sub.10 ester, C.sub.3-C.sub.10 ketone,
C.sub.3-C.sub.10 ether, C.sub.1-C.sub.4 alcohol, C.sub.6-C.sub.12
aromatic hydrocarbon, tetrahydrofuran, dimethylcarbonate,
dimethylsulfoxide, dimethylformamide, dichloromethane, or
acetonitrile. In particular, the first solvent is at least one of
ethylacetate, acetone, tetrahydrofuran, dimethylcarbonate,
acetonitrile, toluene, xylene, methanol, ethanol, isopropanol,
dimethylsulfoxide, or dimethylformamide. The second solvent is at
least one of methanol, ethanol, isopropanol, ethylacetate, butyl
acetate, DMF, acetone, toluene, isopropyl ether, diethyl ether,
methyl tert butyl ether, dichloromethane, or acetonitrile.
Optionally, the second solvent further comprises water, for
example, acetone and water. In one embodiment, the hydrochloric
acid is present in an amount of about 1 mol to about 1.3 mol
equivalents of the (R)-SLB.D-DBTA. The slurry may be cooled at a
temperature of about -20.degree. C. to about 110.degree. C. In the
process, the HCl may be added as a solution or a gas.
[0015] Another embodiment of the process encompasses where the
first or second solvent is at least one C.sub.3-C.sub.6 ester or a
mixture of at least one C.sub.1-C.sub.4 alcohol and C.sub.3-C.sub.6
ester. Preferably, the alcohol is methanol and the ester is
ethylacetate. Also, the first or second solvent has an alcohol to
ester ratio of about 15:85 by volume.
[0016] Yet another embodiment of the invention encompasses
levalbuterol hydrochloride characterized by at least one of an
enantiomeric excess of at least about 99.8%; having less than about
1700 ppm of residual C.sub.1-C.sub.4 alcohol; or having a pH of at
least about 4.3 in 1% aqueous solution at room temperature.
Preferably, the residual alcohol is methanol. In one embodiment,
the pH is about 4.5 to about 7.
[0017] Yet another embodiment of the invention encompasses
levalbuterol hydrochloride characterized by at least one of having
less than about 0.15% by area HPLC of total at least one of
Compound A, Compound B, or Compound C; having less than about 0.10%
by area HPLC of total unknown impurities; or having less than about
0.25% by area HPLC of total impurities including Compound A,
Compound B, and Compound C, after being stored for three months at
40.degree. C. and 75% relative humidity.
[0018] Another embodiment of the invention encompasses
N-(tert-butyl)-2-methoxy-2-(4-hydroxy-3-(hydroxymethyl)phen-1-yl-ethanami-
ne, Compound B, having the following structure:
##STR00003##
[0019] Another embodiment of the invention encompasses
N-(tert-butyl)-2-methoxy-2-(4-hydroxy-3-(methoxymethyl)phen-1-yl)-ethanam-
ine, or Compound C having the following structure:
##STR00004##
[0020] Yet another embodiment of the invention encompasses
pharmaceutical compositions comprising a therapeutically effective
amount of the levalbuterol hydrochloride of the invention and at
least one pharmaceutically-acceptable excipient.
DETAILED DESCRIPTION OF THE INVENTION
[0021] The invention encompasses enantiomerically pure
(R)-salbutamol.D-dibenzoyltartrate ("(R)-SLB.D-DBTA") salt,
levalbuterol hydrochloride in enantiomerically pure form, and
processes for their preparation. Typically, the processes require
fewer steps and result in higher yields and/or optical purity than
conventional processes. The invention also encompasses polymorphs
of levalbuterol and compounds synthesized during the preparation of
levalbuterol.
[0022] In particular, the invention encompasses processes for
separating racemic salbutamol enantiomers using D-dibenzoyltartrate
("D-DBTA") as a resolving agent. The processes do not require the
protection of the alcohol or amine functional groups and require
significantly less solvent than conventional processes to prepare
enantiomerically pure (R)-SLB.D-DBTA. The use of less solvent is
advantageous especially in industrial scale production due to cost,
efficiency, and pollution considerations. Furthermore, the
processes yield after two crystallization steps (R)-SLB.D-DBTA salt
in 40-43% yield and an enantiomeric excess of at least about 99.8%.
Enantiomerically pure (R)-SLB.D-DBTA salt is useful for preparing
levalbuterol hydrochloride with high optical purity. Not to be
limited by theory, it is believed that the (R)-SLB.D-DBTA salt
converts to levalbuterol hydrochloride in a solid-solid
transformation.
[0023] The process for preparing (R)-SLB.D-DBTA salt comprises
preparing a mixture of racemic salbutamol in a first
C.sub.1-C.sub.4 alcohol; adding D-dibenzoyltartaric acid to the
mixture; crystallizing and isolating crude (R)-SLB.D-DBTA salt; and
recrystallizing the crude (R)-SLB.D-DBTA salt in a second
C.sub.1-C.sub.4 alcohol to obtain the (R)-SLB.D-DBTA salt.
[0024] The first alcohol is present in any amount sufficient to
dissolve the racemic salbutamol and D-dibenzoyltartaric acid at
reflux. Preferably, the alcohol is present in an amount of about 2
ml/g to about 7.5 ml/g of the racemic salbutamol, more preferably
about 2 ml/g to about 5 ml/g, and most preferably about 4 ml/g to
about 5 ml/g. C.sub.1-C.sub.4 Alcohols include, but are not limited
to, at least one of methanol, ethanol, propanol, isopropanol,
butanol, isobutanol, or tert-butanol. The preferred alcohol is
methanol.
[0025] The D-dibenzoyltartaric acid may be present in any amount
sufficient to form the (R)-SLB.D-DBTA salt. Preferably, the
D-dibenzoyltartaric acid is present in an amount of about 0.5 mol
to about 1.3 mol equivalents of the salbutamol, and more preferably
about 1 mol equivalent.
[0026] The mixture of racemic salbutamol and a first alcohol may be
heated to form a solution, preferably at a temperature of at least
about 50.degree. C. More preferably, the mixture is heated at about
reflux temperature. Depending on the solvent used, the solution may
be heated at other suitable temperatures as long as the racemic
salbutamol and D-dibenzoyltartaric acid are sufficiently dissolved.
For example, where the reaction solvent is methanol, the mixture is
preferably heated at about 60.degree. C. to about 65.degree. C.
[0027] The crude (R)-SLB.D-DBTA may be crystallized by methods such
as seeding. Seeding may be carried out as soon as the solution is
cool enough not to dissolve the seeding material. Preferably, the
solution is cooled before seeding at a temperature below reflux,
and more preferably at a temperature of about 50.degree. C.
[0028] Preferably, the solution is seeded with (R)-SLB.D-DBTA
having an enantiomeric excess of at least about 99%. After seeding,
the solution is cooled at a temperature that permits crystal
formation without causing the solution to freeze. The solution may
be cooled at any rate that facilitates formation of the
(R)-SLB.D-DBTA salt. Preferably, the solution is cooled at a
temperature of about -20.degree. C. to about 10.degree. C., more
preferably at about -10.degree. C. to about 10.degree. C., and most
preferably at about -5.degree. C. The solution may be cooled to a
preferred temperature immediately after seeding, or cooled within a
period of about 15 hours. The crude (R)-SLB.D-DBTA salt may be
isolated by filtration and washed with additional solvent prior to
recrystallization.
[0029] The second C.sub.1-C.sub.4 alcohol used for
recrystallization can be the same as the alcohol used during the
reaction of salbutamol and D-dibenzoyltartaric acid, or it can be
different. The preferred alcohol for recrystallization is methanol.
The second alcohol is present in any amount sufficient to
crystallize (R)-SLB.D-DBTA salt. Preferably, the alcohol is present
in an amount of about 2 ml/g to about 5 ml/g of the racemic
salbutamol, and more preferably, in about 3 ml/g to about 4
ml/g.
[0030] The second alcohol is heated, preferably at reflux, to
dissolve the crude (R)-SLB.D-DBTA salt and form a solution. The
solution may be treated with charcoal and filtered, after which the
solution is further heated, followed by cooling, to precipitate the
enantiomerically pure (R)-SLB.D-DBTA salt. The precipitated
(R)-SLB.D-DBTA salt is preferably isolated by filtration and washed
with additional solvent.
[0031] The invention encompasses enantiomerically pure
(R)-SLB.D-DBTA. As used herein, "enantiomerically pure" refers to
an enantiomeric excess of at least about 99.8%. Enantiomeric
excess, as well as chemical purity, are determined by area percent
HPLC.
[0032] The invention also encompasses processes for preparing
levalbuterol hydrochloride. The process comprises preparing a first
slurry of (R)-SLB.D-DBTA in a first solvent; adding hydrochloric
acid to the first slurry to form crude levalbuterol hydrochloride;
and isolating crude levalbuterol hydrochloride. Optionally, the
process may further comprise preparing a second slurry of the crude
levalbuterol hydrochloride in a second solvent; and isolating the
levalbuterol hydrochloride.
[0033] A suitable first solvent is one in which levalbuterol
hydrochloride is insoluble and DBTA is soluble. The first solvent
includes, but is not limited to, at least one linear or branched
C.sub.3-C.sub.6 ester, C.sub.3-C.sub.10 ketone, C.sub.3-C.sub.10
ether, C.sub.1-C.sub.4 alcohol, C.sub.6-C.sub.12 aromatic
hydrocarbon, dimethylcarbonate, acetonitrile, dimethylsulfoxide, or
dimethylform amide. Preferably, the first solvent includes, but is
not limited to, at least one of ethylacetate, acetone,
tetrahydrofuran, dimethylcarbonate, acetonitrile, toluene, xylene,
methanol, ethanol, isopropanol, dimethylsulfoxide, or
dimethylformamide. More preferably, the first solvent is at least
one of ethylacetate, methanol, acetonitrile, or dimethylformamide.
When two solvents are used, the ratio of solvents is preferably
about 90 to about 10 by volume, or about 95 to about 5 by
volume.
[0034] Before addition of the hydrochloric acid, the first slurry
may be cooled, preferably at a temperature of about 10.degree. C.
to about -20.degree. C., and more preferably at about 0.degree. C.
to about 2.degree. C. The reaction may be carried out at
temperatures of about -10.degree. C. to about 40.degree. C.
[0035] The HCl may be added as a solution or a gas. For example,
methods for adding HCl include, but are not limited to, adding
aqueous HCl (37%), HCl gas, HCl in at least one C.sub.1-C.sub.4
alcohol, or HCl in dimethylformamide. Typically, when present as a
solution in an alcohol, the HCl is present in 5% concentration.
Typically, HCl is added in an amount of about 1 mol to about 1.3
mol equivalents of the (R)-SLB.D-DBTA, and preferably about 1.2 mol
equivalent.
[0036] The crude levalbuterol hydrochloride is isolated by
filtration and preferably washed with additional portions of the
first solvent prior to preparation of the second slurry.
[0037] When present, the second solvent for preparing the second
slurry includes, but is not limited to, at least one linear or
branched C.sub.3-C.sub.6 ester, C.sub.3-C.sub.10 ketone,
C.sub.3-C.sub.10 ether, C.sub.1-C.sub.4 alcohol, C.sub.6-C.sub.12
aromatic hydrocarbon, dimethylcarbonate, dimethylformamide,
dimethylsulfoxide, dichloromethane, or acetonitrile. Preferably,
the second solvent is at least one of methanol, ethanol,
isopropanol, ethylacetate, butyl acetate, DMF, acetone, toluene,
isopropyl ether, diethyl ether, methyl tert butyl ether,
dichloromethane, or acetonitrile. Water may be added to the second
solvent, preferably with acetone.
[0038] The slurry may be carried out at a temperature of about
-10.degree. C. to about the reflux temperature of the second
solvent. The second slurry may be carried out at room temperature,
or about 20.degree. C. to about 25.degree. C. The levalbuterol
hydrochloride is preferably isolated by filtration and washed with
additional portions of the second solvent. Optionally, the
levalbuterol hydrochloride is dried, such as at room temperature
under reduced pressure.
[0039] In a preferred embodiment, the first and second solvents may
be an ester, an alcohol, or a combination thereof. For example, the
first or second solvent is a C.sub.3-C.sub.6 ester or a mixture of
a C.sub.1-C.sub.4 alcohol and a C.sub.3-C.sub.6 ester.
C.sub.3-C.sub.6 Esters include, but are not limited to, at least
one of methylacetate, ethylacetate, isopropyl acetate, butyl
acetate, or isobutyl acetate. The preferred ester is ethylacetate.
C.sub.1-C.sub.4 Alcohols include, but are not limited to, at least
one of methanol, ethanol, propanol, or butanol. Methanol is the
preferred alcohol. When the first solvent is a mixture, the alcohol
to ester ratio is preferably about 15:85 by volume, and more
preferably about 5:95 by volume. When the second solvent is a
mixture, the alcohol to ester ratio is preferably about 15:85 by
volume, and more preferably about 1:9 by volume.
[0040] The above described process may prepare enantiomerically
pure levalbuterol hydrochloride by the use of enantiomerically pure
(R)-SLB.D-DBTA as a starting material. For example, the
levalbuterol hydrochloride is prepared by forming a first slurry of
enantiomerically pure (R)-SLB.D-DBTA in a first solvent.
[0041] The invention also encompasses levalbuterol hydrochloride
degradation products useful for identifying impurities within an
levalbuterol hydrochloride sample. Isolated levalbuterol
hydrochloride degradation products may be used to quantify an
impurity content of a levalbuterol hydrochloride sample. A sample
of levalbuterol hydrochloride may be spiked with a known amount of
the degradation product and analyzed by HPLC to identify the
impurities. An impurity level can be determined by comparing the
area percent by HPLC of a known impurity with the area percent of
the corresponding standard impurity injected in a known amount
within linearity range. When levalbuterol is prepared with
methanol, benzylic and secondary alcoholic functional groups
undergo etherification to produce the following impurities:
##STR00005##
[0042] One degradation product is
N-(tert-butyl)-2-methoxy-2-(4-hydroxy-3-(hydroxymethyl)phen-1-yl-ethanami-
ne, or Compound B:
##STR00006##
[0043] Another degradation product is
N-(tert-butyl)-2-methoxy-2-(4-hydroxy-3-(methoxymethyl)phen-1-yl)-ethanam-
ine, or Compound C:
##STR00007##
[0044] The invention further encompasses levalbuterol hydrochloride
having low residual alcohol content and/or a stabilizing pH in
aqueous solution. It has been found that residual alcohol content
and/or pH affect the stability of levalbuterol over time.
[0045] The levalbuterol hydrochloride made by the processes
described above typically has less than about 1700 ppm of residual
C.sub.1-C.sub.4 alcohol. Preferably, the levalbuterol hydrochloride
has 1600 ppm or less residual C.sub.1-C.sub.4 alcohol. Preferably,
the residual alcohol is methanol. Table 1 exemplifies the effect of
the first solvent used during the transformation of (R)-SLB.D-DBTA
in hydrochloride on the residual alcohol content of the final
product. For the examples of Table 1, the second solvent is a
mixture of methanol:ethylacetate at 1:9 by volume.
TABLE-US-00001 TABLE 1 First solvent and residual methanol content.
First solvent Residual Example (volume ratio) MeOH (ppm) 1
AcOEt-MeOH 85-15 5500 2 AcOEt-MeOH 90-10 5300 3 AcOEt-MeOH 90-10
7000 4 AcOEt-MeOH 90-10 6700 5 AcOEt-MeOH 92.5-7.5 1950 6
AcOEt-MeOH 95-5 1300 7 AcOEt-MeOH 95-5 1700 8 AcOEt-MeOH 95-5 1470
9 AcOEt-MeOH 95-5 1500 10 AcOEt-MeOH 95-5 1160 11 AcOEt-MeOH 95-5
1270 12 AcOEt 700 13 AcOEt 878 14 AcOEt 640 15 AcOEt 620
[0046] Table 1 illustrates that the alcohol present in the first
solvent has an effect on residual alcohol in the product. For
example, if the ratio of ester to alcohol is 95:5 or higher, then
the levalbuterol hydrochloride with a residual alcohol content has
less than about 1700 ppm of residual alcohol.
[0047] In another embodiment, the levalbuterol hydrochloride has a
pH of at least about 4.3 in 1% aqueous solution at room
temperature. Preferably, the pH is about 4.5 to about 7. The effect
of residual alcohol content and pH on the stability of levalbuterol
hydrochloride when stored at 70.degree. C. is exemplified in Table
2. Preferably, the levalbuterol hydrochloride of the invention has
less than about 1600 ppm or less of residual C.sub.1-C.sub.4
alcohol and a pH of at least about 4.3 in 1% aqueous solution at
room temperature.
TABLE-US-00002 TABLE 2 Stability of levalbuterol hydrochloride at
70.degree. C. Total Compound Compound Compound Unknown MeOH Sample
Time LVB.sup.a A B C Impurities pH.sup.b (ppm) White solid T = 0
99.9% 0.05% 0.02% n.d. 0.04% 4.41 300 White solid 1 week 99.8%
0.06% 0.02% n.d. 0.04% White solid T = 0 99.8% 0.03% 0.02% n.d.
0.10% 5.30 1500 White solid 1 week 99.7% 0.10% 0.06% 0.03% 0.07%
White solid.sup.c T = 0 99.4% 0.24% 0.18% 0.15% n.d. 3.97 3420 Pale
yellow 1 week 97.1% 0.72% 0.26% 0.18% 1.21% solid White solid T = 0
99.8% 0.04% 0.05% n.d. 0.06% 3.70 700 Yellow solid 1 week 98.9%
0.22% 0.06% 0.05% 0.45% White solid T = 0 99.8% 0.02% 0.01% n.d.
0.12% 3.50 878 Yellow solid 1 week 93.1% 0.27% 0.08% 0.07% 4.72%
.sup.aLevalbuterol hydrochloride. .sup.bMeasured at 22-23.degree.
C. in 1% aqueous solution. .sup.cMade according to Example 21.
[0048] Table 2 demonstrates that pH and/or residual alcohol content
affect the degradation of levalbuterol hydrochloride and/or the
presence of degradation products Compounds A, B, C, or other
impurities. At similar pH values, samples with greater residual
alcohol content resulted in higher levalbuterol hydrochloride
degradation. At lower pH values, greater levalbuterol hydrochloride
degradation occurred. In addition, it was observed that samples
with high residual methanol content or low pH values after storage
for 1 week at 70.degree. C. became yellow, whereas samples with low
residual methanol content and a pH of at least about 4.3 remained
as white solids. The effect of storage temperature on the stability
of levalbuterol hydrochloride is illustrated in Table 3.
TABLE-US-00003 TABLE 3 Stability of levalbuterol hydrochloride at
40-45.degree. C., 50-55.degree. C., and 25.degree. C. T Compound
Compound Total Unknown MeOH Sample Time (.degree. C.) LVB B A
Impurities (ppm) 1 T = 0 20.degree. C. 99.84% 0.035% 0.028% 0.097%
6700 2 20 hrs 40-45.degree. C. 99.30% 0.30% 0.11% 0.29% -- 3 20 hrs
55-60.degree. C. 98.17% 0.45% 0.23% 1.15% -- 4 32 hrs 55-60.degree.
C. 97.9% 0.45% 0.26% 1.39% -- 5 T = 0 25.degree. C. 99.90% 0.01%
0.02% 0.07% 2090 6 10 days 25.degree. C. 99.88% 0.01% 0.02% 0.09%
-- 7 1 month 25.degree. C. 99.87% 0.02% 0.03% 0.08% -- 8 2 months
25.degree. C. 99.82% 0.02% 0.04% 0.12% --
[0049] Table 3 illustrates that greater levalbuterol hydrochloride
decomposition occurred at elevated storage temperatures. The
invention encompasses levalbuterol hydrochloride where the amount
of each of Compound A, Compound B, or Compound C after storage for
three months at 40.degree. C. and 75% relative humidity is less
than about 0.15% by area HPLC. The percentage LVB, Compound B, or
Compound A is relative to the total amount of sample at time=T.
[0050] In another embodiment, the levalbuterol hydrochloride has
total amount of unknown impurities after storage for three months
at 40.degree. C. and 75% relative humidity of less than about 0.10%
by area HPLC. The term "unknown impurities" refers to any impurity
in the sample other than Compound A, Compound B, or Compound C.
[0051] The invention also encompasses levalbuterol hydrochloride
where the total amount of impurities including Compound A, Compound
B, and Compound C after storage for three months at 40.degree. C.
and 75% relative humidity is less than about 1% by area HPLC.
[0052] Levalbuterol hydrochloride having at least one of the
impurity profiles described above preferably has less than about
1700 ppm of residual C.sub.1-C.sub.4 alcohol and/or a pH of at
least about 4.3 in 1% aqueous solution at room temperature and/or
less than 1% of impurities. Preferably, the levalbuterol
hydrochloride has less than 0.5% of impurities.
[0053] The invention encompasses pharmaceutical compositions
comprising at least one levalbuterol hydrochloride of the invention
and at least one pharmaceutically-acceptable excipient. The
pharmaceutical composition may contain a single levalbuterol
hydrochloride polymorphic form, a mixture of various crystalline
forms, and/or the amorphous form.
[0054] Any excipient commonly known and used widely in the art can
be used in the pharmaceutical composition. The excipients included
in the composition are determined primarily by the manner in which
the composition is to be administered. For example, a composition
to be administered in inhalant form can include a liquid carrier
and/or propellant. A composition to be administered in tablet form
can include a filler (e.g., lactose), a binder (e.g., carboxymethyl
cellulose, gum arabic, gelatin), an adjuvant, a flavoring agent, a
coloring agent, or a coating material (e.g., wax or a plasticizer).
A composition to be administered in liquid form can include, for
example, an emulsifying agent, a flavoring agent and/or a coloring
agent.
[0055] The pharmaceutical composition comprising the levalbuterol
hydrochloride can be administered by inhalation, by subcutaneous or
other injection, orally, intravenously, topically, parenterally,
transdermally, rectally or via an implanted reservoir containing
the drug. The form in which the drug will be administered (e.g.,
inhalant, powder, tablet, capsule, solution, emulsion) will depend
on the route by which it is administered.
[0056] If a conflict exists between a compound's nomenclature and
chemical structure, the chemical structure will define the
compound. While the invention is described with respect to
particular examples and preferred embodiments, it is understood
that the invention is not limited to these examples and
embodiments. The invention as claimed therefore includes variations
from the particular examples and preferred embodiments described
herein, as will be apparent to one of skill in the art.
EXAMPLES
[0057] Yields were determined by mass. Chemical purity was
determined by HPLC. The HPLC analysis was conducted using a column
POLARIS C18-A 250 mm.times.4.6 mm.times.5.0 mm (cat
n.2002-250.times.046) and a mobile phase. The mobile phase
comprised a phosphate buffer at pH 3.00 and acetonitrile in a
gradient. The eluent flow was 1.0 ml/min. The detector was set to a
wavelength of 230 nm, using an HPLC Hewlett Packard VWD detector HP
1100, as a detector.
[0058] Enantiomeric excess was determined by HPLC using a chiral
column. The column and packing was a CHIREX S-indoline-carboxylic
acid-R-.alpha.-naphtylethylamine 250 mm.times.4.60 mm (Phenomenex
cat. N 00G-3022-EO) and the diluent was a mobile phase. The mobile
phase was a mixture of n-hexane: CH.sub.2Cl.sub.2:
MeOH:CF.sub.3COOH (500:440:60:0.4 by volume, respectively). Each
chromatogram was run for to 20 minutes. The column temperature was
25.degree. C. and the flow rate was 1.5 ml/min. The detector was
set to UV at 280 nm.
[0059] The X-Ray diffraction (XRD) analysis was conducted using an
ARL X-Ray powder diffractometer (model X'TRA-030) equipped with a
Peltier detector, round standard aluminum sample holder with round
zero background, and quartz plate. The scanning parameters were
from a range of about 2-40 degree two 0 (+0.2 degrees) and a
continuous scan at a rate of about 3 degrees/min. One of ordinary
skill in the art understands that experimental differences may
arise due to differences in instrumentation, sample preparation, or
other factors.
[0060] Fourier transform infrared (FT-IR) spectroscopy was
conducted using a Perkin-Elmer Spectrum 1000 Spectrometer at about
4 cm.sup.-1 resolution with about 16 scans in the range of 4000-400
cm.sup.-1. Samples were analyzed in KBr pellet and the instrument
was calibrated using an empty cell as a background.
[0061] Differential scanning calorimetry (DSC) was conducted using
a Mettler Toledo DSC 822.sup.e/700 with a sample weight of about
3-5 mg, a heating rate of about 10.degree. C./min., using a 3 holed
crucible, under a stream of N.sub.2 at a flow rate of about 40
ml/min. The sample was scanned between a range of about 30.degree.
C. to about 250.degree. C. at a heating rate of about 10.degree.
C./minute.
[0062] Thermal Gravimetric Analysis (TGA) was conducted using a
Mettler Toledo TGA/SDTA 851.sup.e using a sample weight of about
7-15 mg, a heating rate of about 10.degree. C./min. under a N.sub.2
stream at a N.sub.2 flow rate of about 50 ml/min. The samples were
scanned at a range between about 30.degree. C. to about 250.degree.
C.
Example 1
Preparation of crude (R)-SLB.D-DBTA, or (R)(-)
.alpha..sup.1-[[(1,1Dimethylethyl)amino]methyl]-benzenedimethanol.(D)-Dib-
enzoyltartrate.
[0063] In a 2 L reactor equipped with a condenser, thermometer, and
mechanical stirrer at 20.degree. C. and under nitrogen, salbutamol
base (200 g), D-DBTA (150 g), and methanol (900 mL) were loaded.
The temperature increased from 20.degree. C. to 32.degree. C. to
form a solution. The solution was cooled to 25.degree. C., and a
second portion of D-DBTA (150 g) was loaded. The solution was
heated to 60-63.degree. C. The solution was cooled to 50.degree. C.
and seeded with pure (R)-SLB.D-DBTA (enantiomeric excess >99%,
0.350 g). Precipitation formed, and the mixture was maintained at
50.degree. C. for 30 min, cooled to -5.degree. C..+-.2.degree. C.
in 2 hours, and maintained at the temperature for 2 hours after
which a solid appeared. The solid was collected by filtration and
washed with cold methanol (2.times.100 mL).
[0064] Crude (R)-SLB.D-DBTA was obtained as a wet solid (319.14 g).
The wet product was crystallized according to the procedure
described in Example 2.
Example 2
Preparation of pure (R)-SLB.D-DBTA, or (R)(-).alpha..sup.1-[[(11
Dimethylethyl)amino]methyl]-benzenedimethanol.(D)-Dibenzoyltartrate.
[0065] In a 1 L reactor equipped with a condenser, thermometer, and
mechanical stirrer at room temperature and under nitrogen, a
suspension of wet (R)-SLB.(D)-DBTA (Loss on Drying 21.7%, 319.14 g)
in methanol (660 mL) was formed. The suspension was heated to light
reflux (62-63.degree. C.) until a solution formed. The solution was
cooled at 60.degree. C., and treated with charcoal (2.5 g). After
15 min at 60-62.degree. C. the charcoal was filtered off while the
solution was maintained at 60-62.degree. C. to avoid
crystallization.
[0066] The filtrate, a clear solution, was cooled at 50.degree. C.
to obtain crystals. The solution was maintained at 50.degree. C.
for 30 min, cooled to -5.degree. C. in 2 hours, and maintained at
the temperature for 3 hours. The solid was collected by filtration
and washed with cold methanol (160 mL) and ethylacetate
(3.times.160 mL) to obtain a wet solid (253.6 g). The wet solid was
dried for 24 hours at 20-25.degree. C. under vacuum to obtain pure
(R)-SLB.D-DBTA (dry 213.5 g).
[0067] The crystallization yield was 87.6%. The overall yield from
racemic salbutamol was 42.7%. The enantiomeric excess of pure
(R)-SLB.D-DBTA was 99.8%.
Example 3
Preparation of Crude Levalbuterol Hydrochloride
[0068] In a 2 L reactor equipped with a condenser, thermometer, and
mechanical stirrer at room temperature and under nitrogen, a
suspension of pure (R)-SLB.D-DBTA (150 g, 0.25 mol), ethylacetate
(1710 mL), and methanol (90 mL) was formed. The suspension was
cooled to 0.degree. C..+-.2.degree. C., and HCl (37%, 29.44 g, 0.30
mol) was added in about 15 minutes. The temperature was maintained
at 0.degree. C..+-.2.degree. C. The suspension was stirred at
0.degree. C..+-.2.degree. C. for 1 hour. The solid was collected by
filtration and washed with an ethylacetate:methanol mixture (95:5,
80 mL), followed by washing with ethylacetate (2.times.80 mL).
[0069] The wet product (97.6 g) was slurried according to the
procedure described in Example 4.
Example 4
Preparation of Pure Levalbuterol Hydrochloride
[0070] In a 2 L reactor equipped with a condenser, thermometer, and
mechanical stirrer at 20.degree. C. and under nitrogen, a
suspension of wet levalbuterol hydrochloride (97.6 g), ethylacetate
(440 mL) and methanol (49 mL) was formed. The suspension was
stirred at 22.degree. C..+-.2.degree. C. for 4 hours. The solid was
collected by filtration and washed with an ethylacetate:methanol
mixture (90:10, 97 mL), and ethylacetate (2.times.97 mL). The
product was dried at 22.degree. C..+-.2.degree. C. under vacuum
(res. press. 40-45 mm Hg) for 24 hours to obtain 64.0 g (dry
weight) in 92.5% yield from pure (R)-SLB.D-DBTA. The overall yield
from racemic salbutamol to pure levalbuterol hydrochloride:
39.5%.
Example 5
Preparation of crude (R)-SLB.D-DBTA, or
(R)(-).alpha..sup.1-[[(1,1Dimethylethyl)amino]methyl]-benzenedimethanol.(-
D-Dibenzoyltartrate
[0071] In a 10 L reactor equipped with a condenser, thermometer,
and mechanical stirrer at 20.degree. C. and under nitrogen,
salbutamol base (800 g), D-DBTA (400 g), and methanol (3600 mL)
were loaded. The temperature increased from 20.degree. C. to
26.degree. C. A second aliquot of D-DBTA (400 g) was loaded and the
temperature increased to 31.degree. C. A third aliquot of D-DBTA
(400 g) was loaded, the temperature increased to 32.degree. C. and
a solution was obtained. The solution was heated to 60-63.degree.
C. The solution was cooled to 50.degree. C. and seeded with pure
(R)-SLB.D-DBTA (enantiomeric excess >99%, 1.404 g). The mixture
was maintained at 50.degree. C. for 30 min, then the solution was
cooled to -7.degree. C..+-.2.degree. C. in 2 hours, and maintained
at the temperature for 2 hours. The solid was collected by
filtration and washed with cold (-5.degree. C.) methanol
(2.times.400 mL). Crude (R)-SLB.D-DBTA was obtained as a wet solid
(1255 g, LOD=23.7% corresponding to 950 g Yield=47.5%). HPLC
purity=99.5%. Optical purity: R-levalbuterol vs
S-levalbuterol=95.8:4.2. The wet product was crystallized according
to the procedure described in Example 6.
Example 6
Preparation of pure (R)-SLB.D-DBTA, or
(R)(-).alpha..sup.1-[[(1,1-dimethylethyl)amino]methyl]-benzenedimethanol.-
(D)-Dibenzoyltartrate
[0072] In a 4 L reactor equipped with a condenser, thermometer, and
mechanical stirrer at room temperature and under nitrogen, a
suspension of wet (R)-SLB.(D)-DBTA (1245 g; LOD=23.7%, 950 g) in
methanol (2477 mL) was formed. The suspension was heated to gentle
reflux (62-63.degree. C.) until a solution formed. The solution was
cooled to 60.degree. C., and treated with charcoal (9.5 g). After
15 min at 60-62.degree. C. the charcoal was filtered off while the
solution was maintained at 60-62.degree. C. to avoid
crystallization.
[0073] The filtrate, a clear solution, was cooled at 50.degree. C.
to obtain crystals. The solution was maintained at 50.degree. C.
for 30 min, cooled to -8.degree. C. in 2 hours, and maintained at
the temperature for 3 hours. The solid was collected by filtration
and washed with cold methanol (607 mL) and ethylacetate
(3.times.588 mL) to obtain a wet solid (1061.8 g, assay=78.4%
corresponding to 832 g dry). The crystallization yield was 87.6%.
The overall yield from racemic salbutamol was 41.6%. HPLC
purity=99.5%; Optical purity: R-levalbuterol vs
S-levalbuterol=99.88:0.12
Example 7
Preparation of Crude Levalbuterol Hydrochloride
[0074] In a 10 L reactor equipped with a condenser, thermometer,
and mechanical stirrer at room temperature and under nitrogen, a
suspension of pure (R)-SLB.D-DBTA (823 g, 1.378 mol), ethylacetate
(9180 mL), and methanol (490 mL) was formed. The suspension was
cooled to 0.degree. C..+-.2.degree. C., and HCl (37%, 161 g, 1.634
mol) was added in 30 minutes. The temperature was maintained at
0.degree. C..+-.2.degree. C. The suspension was stirred at
0.degree. C..+-.2.degree. C. for 1 hour. The solid was collected by
filtration and washed with an ethylacetate:methanol mixture (95:5,
435 mL), followed by washing with ethylacetate (2.times.438 mL).
419.3 g of wet crude levalbuterol hydrochloride were obtained. HPLC
purity=99.6%. The wet product (419.3 g) was slurried according to
the procedure described in Example 8.
Example 8
Preparation of Pure Levalbuterol Hydrochloride
[0075] In a 4 L reactor equipped with a condenser, thermometer, and
mechanical stirrer at 20.degree. C. and under nitrogen, a
suspension of wet crude levalbuterol hydrochloride (414.3 g),
ethylacetate (2398 mL) and methanol (267 mL) was formed. The
suspension was stirred at 22.degree. C..+-.2.degree. C. for 4
hours. The solid was collected by filtration and washed with an
ethylacetate:methanol mixture (90:10, 533 mL), and ethylacetate
(2.times.533 mL). The product was dried at 25.degree. C. under
vacuum (res. press. 40-45 mm Hg) for 24 hours to obtain 357.3 g
(dry weight) in 93% yield from pure (R)-SLB.D-DBTA. The HPLC
purity=99.87%; compound A=0.01%; compound B=0.03%; compound C=n.d.
Total Unknown Impurities=0.09%; HPLC assay: 100.3%; Optical purity:
R-levalbuterol vs S-levalbuterol=99.9:0.1 by HPLC; e.e. =99.8;
pH=4.41; Residual solvents: EtOAc 880 ppm, MeOH 300 ppm, EtOH 65
ppm, and CH.sub.3COOH 160 ppm.
Example 9
Preparation of crude (R)-SLB.D-DBTA, or (R)(-).alpha..sup.1-[[(1,1
Dimethylethyl)amino]methyl]-benzenedimethanol.(D)-Dibenzoyltartrate.
[0076] In a 3 L reactor equipped with a condenser, thermometer, and
mechanical stirrer at 20.degree. C. and under nitrogen, salbutamol
base (265 g), D-DBTA (199 g), and methanol (1190 mL) were loaded.
The temperature increased from 20.degree. C. to 35.degree. C. The
mixture was cooled to 28.degree. C. A second portion of D-DBTA (199
g) was loaded and the suspension was heated to 60-63.degree. C. The
solution was cooled to 50.degree. C. and seeded with pure (R)
--SLB.D-DBTA (enantiomeric excess >99%, 0.46 g). The mixture was
maintained at 50.degree. C. for 30 min, cooled to -5.degree. C. in
2 hours, and maintained at the temperature for 1.6 hours. The solid
was collected by filtration and washed with cold methanol
(2.times.139 mL).
[0077] Crude (R)-SLB.D-DBTA was obtained as a wet solid (395 g;
LOD=22% corresponding to 308 g of dry product; yield=46.5%). HPLC
purity=99.0%; Optical purity: R-levalbuterol vs
S-levalbuterol=97.3:2.7. The wet product was crystallized according
to the procedure described in Example 10.
Example 10
Preparation of pure (R)-SLB.D-DBTA, or
(R)(-).alpha..sup.1-[[(1,1-dimethylethyl)amino]methyl]-benzenedimethanol.-
(D)-Dibenzoyltartrate.
[0078] In a 2 L reactor equipped with a condenser, thermometer, and
mechanical stirrer at room temperature and under nitrogen, a
suspension of wet (R)-SLB.(D)-DBTA (395 g; LOD=22%, 308 g dry) in
methanol (815 mL) was formed. The suspension was heated to gentle
reflux (62-63.degree. C.) until a solution formed. The solution was
cooled to 60.degree. C., and treated with charcoal (3 g). After 15
min at 60-62.degree. C. the charcoal was filtered off while the
solution was maintained at 60-62.degree. C. to avoid
crystallization.
[0079] The filtrate, a clear solution, was cooled at 50.degree. C.
to obtain crystals. The solution was maintained at 50.degree. C.
for 30 min, cooled to -8.degree. C. in 2 hours, and maintained at
the temperature for 2 hours. The solid was collected by filtration
and washed with cold methanol (197 mL) and ethylacetate
(3.times.191 mL) to obtain a wet solid (336.4 g; assay=82.3%
corresponding to 277 g of dry product). The crystallization yield
was 89.9%. The overall yield from racemic salbutamol was 41.8%.
HPLC purity=99.0%; Optical purity: R-levalbuterol vs.
S-levalbuterol=99.9:0.1.
Example 11
Preparation of Crude Levalbuterol Hydrochloride
[0080] In a 4 L reactor equipped with a condenser, thermometer, and
mechanical stirrer at room temperature and under nitrogen, a
suspension of pure (R)-SLB.D-DBTA (wet=331 g; assay=82,3%; 0.4559
mol), ethylacetate (3060 mL), and methanol (163 mL) was formed. The
suspension was cooled to 0.degree. C..+-.2.degree. C., and HCl
(37%, 53.7 g, 0.545 mol) was added in 30 minutes. The temperature
was maintained at 0.degree. C..+-.2.degree. C. The suspension was
stirred at 0.degree. C..+-.2.degree. C. for 1 hour. The solid was
collected by filtration and washed with an ethylacetate:methanol
mixture (95:5, 146 mL), followed by washing with ethylacetate
(2.times.146 mL). The wet product (137.5 g; 122 g dry) was slurried
according to the procedure described in Example 12. HPLC
purity=99.6%; Optical purity: R-levalbuterol vs
S-levalbuterol=99.92:0.08.
Example 12
Preparation of Pure Levalbuterol Hydrochloride
[0081] In a 4 L reactor equipped with a condenser, thermometer, and
mechanical stirrer at 20.degree. C. and under nitrogen, a
suspension of wet levalbuterol hydrochloride (133 g), ethylacetate
(799 mL) and methanol (89 mL) was formed. The suspension was
stirred at 22.degree. C..+-.2.degree. C. for 4 hours. The solid was
collected by filtration and washed with an ethylacetate:methanol
mixture (90:10, 178 mL), and ethylacetate (2.times.178 mL). The
product was dried at 25.degree. C. under vacuum (res. press. 40-45
mm Hg) for 24 hours to obtain 116 g (dry weight) in 92.3% yield
from pure (R)-SLB.D-DBTA.
[0082] HPLC purity=99.91%; compound A=0.02%; compound B=0.01%;
compound C=n.d.; Total Unknown Impurity=0.06%; HPLC assay: 100.3%;
Optical purity: R-levalbuterol vs S-levalbuterol=99.93:0.07 by
HPLC; e.e. =99.86; pH=4.86; Residual solvents: EtOAc 830 ppm; MeOH
430 ppm; EtOH 56 ppm; and CH.sub.3COOH 152 ppm.
Example 13
Preparation of crude (R)-SLB.D-DBTA, or (R)(-).alpha..sup.1-[[(1,1
Dimethylethyl)amino]methyl]-benzenedimethanol.(D)-Dibenzoyltartrate.
[0083] In a reactor equipped with a condenser, thermometer, and
mechanical stirrer at 20.degree. C. and under nitrogen, salbutamol
base (44 Kg), D-DBTA (66 g, added in three portions), and methanol
(200 L) were loaded. The temperature was kept below 32.degree. C.
The mixture was heated to 60-63.degree. C. for 30'. The solution
was cooled to 50.degree. C. and seeded with pure (R)-SLB.D-DBTA
(enantiomeric excess >99%, 0.08 Kg). The mixture was maintained
at 50.degree. C. for 30 min, cooled to -7.degree. C..+-.2.degree.
C. in 2 hours and 15 minutes, and maintained at the temperature for
2 hours. The solid was collected by filtration and washed with cold
(-5.degree. C.) methanol (2.times.44 L). Crude (R)-SLB.D-DBTA was
obtained as a wet solid (67.9 Kg, LOD=20.5% corresponding to 53.98
Kg). The wet product was crystallized according to the procedure
described in Example 14.
Example 14
Preparation of pure (R)-SLB.D-DBTA, or
(R)(-).alpha..sup.1-[[(1,1-dimethylethyl)amino]methyl]-benzenedimethanol.
(D)-Dibenzoyltartrate.
[0084] In a reactor equipped with a condenser, thermometer, and
mechanical stirrer at room temperature and under nitrogen, a
suspension of wet (R)-SLB.(D)-DBTA (67.9 Kg wet; 53.98 Kg dry) in
methanol (140 L) was formed. The suspension was heated to light
reflux (62-63.degree. C.) until a solution formed. The solution was
cooled to 60.degree. C., and treated with charcoal (2 Kg) and
dicalite (3 Kg). After 15 min at 60-62.degree. C. the charcoal was
filtered off while the solution was maintained at 60-62.degree. C.
to avoid crystallization; the filter was washed with hot methanol
(10 L).
[0085] The filtrate, a clear solution, was cooled at 50.degree. C.
to obtain crystals. The solution was maintained at 50.degree. C.
for 30 min, cooled to -5.degree. C. in 2.5 hours, and maintained at
the temperature for 2 hours 15 min. The solid was collected by
filtration and washed with cold methanol (32 L) and ethylacetate
(3.times.100 L) to obtain a wet solid (54 Kg, assay=85.5%
corresponding to 46.2 Kg dry product).
Example 15
Preparation of Crude Levalbuterol Hydrochloride
[0086] In a reactor equipped with a condenser, thermometer, and
mechanical stirrer at room temperature and under nitrogen, a
suspension of pure (R)-SLB.D-DBTA (45.3 Kg), ethylacetate 517 L),
and methanol (22 L) was formed. The suspension was cooled to
0.degree. C..+-.2.degree. C., and HCl (37%, 9.2 Kg) was added in 30
minutes. The temperature was maintained at 0.degree.
C..+-.2.degree. C. The suspension was stirred at 0.degree.
C..+-.2.degree. C. for 1.5 hour. The solid was collected by
filtration and washed with an ethylacetate:methanol mixture 95:5
(23 L), followed by washing with ethylacetate (2.times.25 L). The
wet product (24.2 Kg) was slurried according to the procedure
described in Example 16. HPLC purity=99.8%.
Example 16
Preparation of pure levalbuterol hydrochloride
[0087] In a reactor equipped with a condenser, thermometer, and
mechanical stirrer at 20.degree. C. and under nitrogen, a
suspension of wet levalbuterol hydrochloride (24.2 Kg),
ethylacetate (156 L) and methanol (15 L) was formed. The suspension
was stirred at 22.degree. C..+-.2.degree. C. for 4.5 hours. The
solid was collected by filtration and washed with an ethylacetate:
methanol mixture (90:10, 30 L), and ethylacetate (2.times.30 L).
The product was dried at 22.degree. C. under vacuum for 18 hours to
obtain 17.9 Kg (dry weight) of pure levalbuterol hydrochloride.
HPLC purity=99.86%; compound A=0.01%; compound B=0.02%; compound
C=n.d.; Total Unknown Impurity=0.11%; HPLC assay: 100.3%; Optical
purity: R-levalbuterol vs S-levalbuterol=99.9:0.1 by HPLC; e.e.
=99.8; pH=5.30; Residual solvents: EtOAc 480 ppm; MeOH 1600 ppm;
EtOH 180 ppm; and CH.sub.3COOH 170 ppm.
Example 17
Stability Comparison of Sample at 40.degree. C. and 75% RH
[0088] Using the products of the previous examples, a stability
study at 40.degree. C. and 75% RH was carried out. Table 4
summarizes the results.
TABLE-US-00004 TABLE 4 Stability Comparison of Sample at 40.degree.
C. and 75% RH Exam. Comp. Comp. Comp. Total Unknown MeOH No. Time
LVB A B C Impurities (ppm) pH 8 T = 0 99.87% 0.01% 0.03% n.d. 0.09%
300 4.41 8 3 months 99.85% 0.03% 0.07% n.d. 0.05% -- 8 6 months
98.81% 0.03% 0.07% n.d. 0.09% -- 12 T = 0 99.91% 0.02% 0.01% n.d.
0.06% 430 4.86 12 3 months 99.85% 0.02% 0.06% n.d. 0.07% -- 12 6
months 99.83% 0.02% 0.06% n.d. 0.09% -- 16 T = 0 99.86% 0.01% 0.02%
n.d. 0.11% 1600 5.30 16 3 months 99.75% 0.06% 0.09% 0.04% 0.08% --
16 6 months 99.72% 0.07 0.13% 0.05% n.d. --
Example 18
Preparation of crude (R)-SLB.D-DBTA, or
(R)(-).alpha..sup.1-[[(1,1-Dimethylethyl)amino]methyl]-benzenedimethanol.-
(D)-Dibenzoyltartrate.
[0089] In a 10 L reactor equipped with a condenser, thermometer,
and mechanical stirrer at 20.degree. C. and under nitrogen,
salbutamol base (1257 g), D-DBTA (1887 g, in three portions), and
methanol (5657 mL) were loaded. The temperature was kept below
32.degree. C. The mixture was heated to 60-63.degree. C. and a
solution was obtained, which was cooled to 50.degree. C. and seeded
with pure (R)-SLB.D-DBTA (enantiomeric excess >99%, 2.2 g). The
mixture was maintained at 50 C for 30 min, cooled to -7.degree.
C..+-.2.degree. C. in 2 hours, and maintained at the temperature
for 2 hours. The solid was collected by filtration and washed with
cold (-5.degree. C.) methanol (2.times.627 mL). Crude
(R)-SLB.D-DBTA was obtained as a wet solid (1879 g, LOD=19%
corresponding to 1522 g dry). The wet product was crystallized
according to the procedure described in Example 19. Optical purity:
R-levalbuterol vs S-levalbuterol=96.9:3.1.
Example 19
Preparation of pure (R)-SLB.D-DBTA, or
(R)(-).alpha..sup.1-[[(1,1-dimethylethyl)amino]methyl]-benzenedimethanol.-
(D)-Dibenzoyltartrate.
[0090] The solid obtained in example 18 was divided in two
portions, each was treated as reported below.
[0091] In a 5 L reactor equipped with a condenser, thermometer, and
mechanical stirrer at room temperature and under nitrogen, a
suspension of wet (R)-SLB.(D)-DBTA (747 g) in methanol (2019 mL)
was formed. The suspension was heated to gentle reflux
(62-63.degree. C.) until a solution formed. The solution was cooled
to 60.degree. C., and treated with charcoal (7.4 g). After 15 min
at 60-62.degree. C. the charcoal was filtered off while the
solution was maintained at 60-62.degree. C. to avoid
crystallization. The cake was washed twice with hot methanol (77
ml).
[0092] The filtrate was cooled at 50.degree. C. to obtain crystals.
The solution was maintained at 50.degree. C. for 30 min, cooled to
-8.degree. C. in 2 hours, and maintained at the temperature for 3
hours. The solid was collected by filtration and washed with cold
methanol (478 mL) and ethylacetate (3.times.462 mL) to obtain a wet
solid (810 g, assay=79.8% corresponding to 646 g dry). The
crystallization yield was 86.5%. Optical purity: R-levalbuterol vs
S-levalbuterol=99.8:0.2.
Example 20
Preparation of Crude Levalbuterol Hydrochloride
[0093] In a 10 L reactor equipped with a condenser, thermometer,
and mechanical stirrer at room temperature and under nitrogen, a
suspension of pure wet (R)-SLB.D-DBTA (810 g), ethylacetate (7174
mL), and methanol (388 mL) was formed. The suspension was cooled to
0.degree. C..+-.2.degree. C., and HCl (36%, 130 g) was added in 15
minutes. The temperature was maintained at 0.degree.
C..+-.2.degree. C. The suspension was stirred at 0.degree.
C..+-.2.degree. C. for 1 hour. The solid was collected by
filtration and washed with an ethylacetate:methanol mixture (95:5,
344 mL), followed by washing with ethylacetate (2.times.334 mL).
The wet product (406 g) was slurried according to the procedure
described in Example 21. HPLC purity=99.9%. Optical purity:
R-levalbuterol vs S-levalbuterol=99.8:0.2.
Example 21
Preparation of Pure Levalbuterol Hydrochloride
[0094] In a 10 L reactor equipped with a condenser, thermometer,
and mechanical stirrer at 20.degree. C. and under nitrogen, a
suspension of wet levalbuterol hydrochloride (846.7 g),
ethylacetate (3810 mL) and methanol (423 mL) was formed. The
suspension was stirred at 22.degree. C..+-.2.degree. C. for 4
hours. The solid was collected by filtration and washed with an
ethylacetate:methanol mixture (90:10, 821 mL), and ethylacetate
(2.times.821 mL). The product was dried at 22.degree. C. under
vacuum (res. press. 40-45 mm Hg) for 18 hours to obtain 580 g (dry
weight) in 40% yield from racemic salbutamol. HPLC purity=99.82%;
compound A=0.07%; compound B=0.04%; compound C=n.d.; Total Unknown
Impurity=0.06. %; HPLC assay: 99%;
R-levalbuterol:S-levalbuterol=99.8:0.2 by HPLC; e.e. =99.6%;
pH=3.97; Residual solvents: EtOAc 870 ppm; MeOH 3420 ppm; and EtOH
490 ppm.
* * * * *