ZA200605947B - Preparation of levalbuterol hydrochloride - Google Patents

Description

PREPARATION OF LEVALBUTEROL HYDROCHLORIDE

Cross ~Reference To Related Applications

This application claim s the benefits of U.S. Provisional Patent Application Nos. 60/573,025, filed May 20, 2004, 60/577,979, filed June 7, 2004, 60/646,803, filed January 25, 2005, 60/577,819, filed June 7, 2004, 60/583,777, filed June 28, 2004, 60/583,642, filed June 28, 2004, 60/587,6773, filed July 13, 2004 andl 60/632,625, filed December 2, 2004, the contents of all of which are incorporated herein by reference.

Field of the Invention

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

Activation of B,-adrerergic receptors on airway smooth muscle leads to the activation of adenylcyclase amd 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 As, 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 ame also associated with the inhibition of release of mediators from mast cells in the airway . The chemical name for levalbuterol HCl is R)-a'-[[(1,1- dimethylethyl)amino]methyl J-4-hydroxy-1,3-benzenedimethanol hydrochloride.

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 acetates of the 4-carboxylate derivative (Formula 1) using ditolyltartaric acid and isolatiing the selected crystalline fraction. Thereafter, the crystal undergoes debenzylation deprotection, followed by ester reduction to yield levalbuterol.

o OH be

N

AKO KK

[e] “y Formula 1

Several patents report synthetic routes using enantiomeric separation, however, thes synthetic routes result in low yields of the enantiomerically puare product. Optically pumre levalbuterol was synthesized by the borane-methylsulfide re«duction of the enzntiomerically pure precursor (Formula 2) as described in U.S. patent No. 5,399,765.

Th ereaction dissolved a mixture of enantiomers of methyl 5-[2-[«(1,1- dirmethylethyl)amino}-1-hydroxyethyl]-2-hydroxybenzoate and a chiral acid selected from (9) —di-toluoyl-L-tartaric acid and (+)~di-toluoyl-D-tartaric acid in methanol, upon cooling on_e stereoisomer crystallized, which was separated, and recrystak lized as a diastereomer from methanol, the diastereomer was separated, treated with base, and upon reduction fommed optically active levalbuterol.

OH

H

K

Fon 02CH,

Formula 2

U.S. patent No. 5,442,118 discloses the synthesis of optically pure (R) or (S) } le~valbuterol by the asymmetric reduction of a-iminoketones precursors. In particular, le~valbuterol is synthesized by the reduction with borane-methylssulfide complex in the presence of chiral oxazaborolidines as catalysts.

During the synthesis of levalbuterol, D-dibenzoyltartaric acid (D-DBTA) or D- di_toluoyltartaric acid (D-DTTA) have been used for enantiomeri_c separation. Typically, during the enantiomeric separation, at least one of the alcohol, esster, 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. patent Mo. 5,545,745 and WO 95/32178.

The prior art has separated levalbuterol enantiomers using 4-benz¥y1 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 saltis <ebenzylated to yield either the (R) or (S) isomer of salbutamol as a sulphate salt.

Other publications have separated levalbuterol derivatives, such as WO 99/42460, by forming the ketal derivative of levalbuterol prior to enantiomeric sepaxation with an enantiomer of di-O-benzoy] 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 undesire«d enantiomer in the derivatize, resolve, and hydrolyze cycle to further enhance the overall yield of the desired enantiomer.

In Chinese patent No. 1,273,966, enantiomers of racemic salbutarmol 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 ID- dibenzoyltartaric acid is treated with potassium carbonate in water and am 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 HC! is synthesized by acid displacement from (R)-levalbuterol D- dibenzoyltartaric acid salt suspended in acetone and the addition of an ether solution of

HCL

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

The invention encompasses processes for preparing (R)-SLB.D-IDBTA comprising preparing a mixture of racemic salbutamol in a first C,-C, al cohol; adding D- dibenzoyltartaric acid to the mixture; crystallizing and isolating crude (IR)-SLB.D-DBTA; and recrystallizing the crude (R)-SLB.D-DBTA in a second C;-C, alcohol to obtain the (R)-SLB.D-DBTA, wherein the first or second alcohol is present in an azmount 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.

Another embodiment of the invention encompasses enantiomerically pure (R)-

SLB.D-DBTA salt having an enantiomeric excess of at least about 99.8%.

Yet another embodiment of the invention encompasses processes for preparing levalbuteros] 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 crud. levalbuterol hydrochloride in a second solvent; and isolating the levalbuterol hydrochloride. In the process, the first or second solvent is at least one of C3 -Cp ester,

C3-C0 ketone, C3-Cjg ether, C;-Cy alcohol, Cs-Ci2 aromatic hydrocarbon, tetrahydrofuran, dimethylcarbonate, dimethylsulfoxide, dimethylformamide, dichloromethane, or acetonitrile. In particular, the first solvent is at least one of ethylacetat €, 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, to luene, isopropyl ether, diethyl ether, methyl tert butyl ether, dichloromethane, or acetonitxile. Optionally, the second solvent further comprises water, for example, acetone and water. In one embodiment, the hydrochloric acid is present in am amount of about 1 molto about 1.3 mol equivalents of the (R)-SLB.D-DBTA. The slurry may be cooled at a temperature of about -20°C to about 10°C. In the process, the HCl may be added as a solution or a gas.

Another embodiment of the process encompasses where the first or second solvent is at least one C;-Cg ester or a mixture of at least one C,-C,4 alcohol and C3-C; 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.

Yet another embodiment of the invention encompasses levalbuterol Imydrochloride characterized by at least one of an enantiomeric excess of at least about 99.8%; having less than albout 1700 ppm of residual C;-C, alcohol; or having a pH of at leasst 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.

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, Cornpound 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 inclmding Compound A, Compound B, and Compound C, after being stored for three months at 40°C and 75% relative humidity.

Another embodiment of the invention encompasses N-(tert-butyl)-2-methoxy-2- (4-hydroxy-3-(hydroxymethyX)phen-1-yl-ethanamine, Compound B, having the following structure:

OCHg

H

N <

Ho jon

CH,OH

Compound B.

Another embodiment «of the invention encompasses N-(tert-butyl)-2-methoxy-2- (4-hydroxy-3-(methoxymethy/1)phen-1-y1)-ethanamine, or Compound C having the following structure:

OCH;

H

K

CH,0CH3

Compound C.

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

The invention encomppasses 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

S processes. The invention also ericompasses polymorphs of levalbuterol and compounds synthesized during the preparation of levalbuterol.

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.

The process for preparing (R)-SLB.D-DBTA salt comprises preparing a mixture of racemic salbutamol in a first C;-Cy4 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 ina a second C;-Cs alcohol to obtain the (R)-SLB.D-DBTA salt.

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 abowit 7.5 ml/g of the racemic salbutamol, more preferably about 2 ml/g to about 5 ml/g, zand most preferably about 4 ml/g to about 5 ml/g. Cy-C4

Alcohols include, but are not limited to, at least one of methanol, ethanol, propanol, isopropanol, butanol, isobutan«o], or tert-butanol. The preferred alcohol is methanol.

The D-dibenzoyltartari ¢ acid may be present in any amount sufficient to form the (R)-SLB.D-DBTA salt. Prefexably, the D-dibenzoyltartaric acid is present in an amount of about 0.5 mol to about 1.3 1mol equivalents of the salbutamol, and more preferably about 1 mol equivalent.

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°C. More preferably, the mixture is heated at about reflux temperature. Depending on the solvent used, the solution may be heated at other suitable tempexatures 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 °C to about 65 °C.

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°C.

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 -2€@ °C to about 10 °C, more preferably at about -10 °C to about 10 °C, and most preferably at about -5 °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.

The second C;-C, alcohol used for recrystallization can be the same as the alcohol used during the reaction of salbutamol and D-«libenzoyltartaric 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.ID-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.

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.

The invention encompasses enantiomerically pure (R)-SLB.D-DBTA. As used herein, “enantiomerically pure” refers to an emantiomeric excess of at least about 99.8%.

Enantiomeric excess, as well as chemical purity, are determined by area percent HPLC.

The invention also encompasses processes for preparing levalbuterol hydrochloride. The process comprises preparing a first slurry of (R)-SLB.D-DBTA ina first solvent; adding hydrochloric acid to the first slurry to form crude levalbuterol hydrochloride; and isolating crude levalbutero 1 hydrochloride. Optionally, the process may further comprise preparing a second slurry of the crude levalbuterol hydrochloride in a second solvent; and isolating the levalbutero1 hydrochloride.

A suitable first solvent is one in which lewalbuterol hydrochloride is insoluble and

DBTA is soluble. The first solvent includes, but is not limited to, at least one linear or branched C,-Cg ester, C3-Cyo ketone, C3-Cho ethe, Ci-Cq alcohol, Ce-Ci2 aromatic hydrocarbon, dimethylcarbonate, acetonitrile, dirmethylsulfoxide, or dimethylformamide.

Preferably, the first solvent includes, but is not lizmited to, at least one of ethylacetate, acetone, tetrahydrofuran, dimethylcarbonate, acetonitrile, toluene, xylene, methanol, ethanol, isopropanol, dimethylsulfoxide, or dime-thylformamide. More preferably, the first solvent is at least one of ethylacetate, methamol, 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.

Before addition of the hydrochloric acid, the first slurry may be cooled, preferably at a temperature of about 10°C to about -20°C, and more preferably at about 0°C to about 2°C. The reaction may be carried out at temperatures of about -10°C to about 40°C.

The HCI may be added as a solution or a gas. For example, methods for adding

HClinclude, but are not limited to, adding aqueous HCI (37%), HCI gas, HCl in at least one C;-C; alcohol, or HCI 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.

The crude levalbuterol hydrochloride is i solated by filtration and preferably washed with additional portions of the first solvent prior to preparation of the second slurry.

When present, the second solvent for presparing the second slurry includes, but is not limited to, at least one linear or branched C3—Cs ester, C3-Cyo ketone, Ca-Cyg ether, C;-

C4 alcohol, C4-C;2 aromatic hydrocarbon, dimethylcarbonate, dimethylformamide, dimethylsulfoxide, dichloromethane, or acetonitrile. Preferably, the second solvent is at least one of methanol, ethanol, isopropanol, ethy/lacetate, 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.

The slurry may be carried out at a temperature of about -10°C to about the reflux temperature of the second solvent. The second slurry may be carried out at room temperature, or about 20°C to about 25°C. The levalbuterol hydrochloride is preferably isolated by filtration and washed with additional portions of the second solvent.

Optionally, the le~valbuterol hydrochloride is dried, such as at room temperature under reduced pressure.

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 C3-Cs ester or a mixtures of a C;-C; alcohol and a C3-Cg ester. C3-Cs Esters include, but are mot limited to, at leas# one of methylacetate, ethylacetate, isopropyl acetate, butyl acetate, or isobutyl acetate. ‘The preferred ester is ethylacetate. C,-Cs Alcohols include, but are mot 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.

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 shurry of enantiormerically pure (R)-SLB.D-DBTA in a first solvent.

The invermtion also encompasses levalbuterol hydrochloride degradation products useful for identifsing impurities within an levalbuterol hydrochloride sample. Isolated levalbuterol hydrochloride degradation products may be used to quantify an impurity content of a leval buterol hydrochloride sample. A sample of levalbuterol hydrochloride may be spiked with a known amount of the degradation product and analyzed by HPL.C 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 rmethanol, benzylic and secondary alcoholic functional groups undergo etherification to produce the following impurities:

OH H OCH, ’ OCHs q

Jr JE JE

CH,OCH3 CH,0H CH,0CH;

SLB-OMe prim SLB-OMe sec SLB-dI-OMe

Compound A Compound B Compound C.

One degradation product is N-(tert-butyl)-2-methoxy-2-(4-hydroxy-3- (hydroxymethyl)phen-1-yl-ethanam ine, or Compound B:

OCH, } fon

CH,OH

Compound B.

Another degradation product is N-(tert-butyl)-2-methoxy-2-(4-hydroxy-3- (methoxymethyl)phen-1-yl)-ethanaznine, or Compound C:

OCH,

H

N <

HO or

CH,OCH3

Compound C.

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.

The levalbuterol hydrochloride made by the processes described above typically has less than about 1700 ppm of residual C,-C, alcohol. Preferably, the levalbuterol hydrochloride has 1600 ppm or less residual C;-Cs 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 1. First solvent and residual methanol content. volume ratio MeOH (ppm

A cOEt-MeOH 85-15 5500 : A_cOFt-MeOH 90-10 5300

A _cOEt-MeOH 90-10 7000

A_cOEt-MeOH 90-10 6700

AcOEt-MeOH 92,5-7,5 1950 6 | AcOEt-MeOH 95-5 1300

AcOEt-MeOH 95-5 1700 8 | AcOEt-MeOH 95-5 1470 9 | AcOEt-MeOH 95-5

AcOEt-MeOH 95-5 1160

AcOFEt-MeOH 95-5 1270

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 alcobol is 95:5 or higher, then the levalbuterol hydrochloride with a residual alcohol content has less than about 1700 ppm of residual alcohol

In another embodiment, th e levalbuterol hydrochloride has a pH of at least about 4.3 in 1% aqueous solution at roorn 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°C is exemplified in Table 2. Preferably, the levalbuterol hydrochloride of the invention hass less than about 1600 ppm or less of residual C;-C,4 alcohol and a pH of at least about 4.3 in 1% aqueous solution at room temperature.

Table 2. Stability of levalbouterol hydrochloride at 70°C.

Sample | Time | LVB® | Compound | Compound | Compound Total * | MeOH

A B C Unknown (ppm)

Impurities [White solid [1 week 199.8%] 006% | 002% | nd [| 004% 99.8%] 003% | 002% | nd | 010% 530] 1500 0.M0% | 006% 1 003% | 007% 1 99.4% edd ll A IL I solid 998%] 0.04% | 005% | nd | 006% [3.70] 700

White solid |T=0__ [99.8%] 0.02% [ 001% | nd | 012% [350] 878

Yellow solid [1 week [93.1%] 0.27% | 0.08% | 007% | 472% * Levalbuterol hydrochloride. b Measured at 22-23°C in 1% aqueous solution. © Made according to Example 21. }

Table 2 demonstrates that pH and/or residual alcohol content affect the degradation of levalbutero! 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”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 3. Stability of levalbuterol hydrochloride at 40-45°C, 50-55°C, and 25°C.

Sample | Time T LVB | Compound | Compound Total MeOH

CO) B A Unknown (ppm)

Impurities 99.84% 40-45°C| 99.30% | 030% | 011% [| 029% [ - 98.17% | 045% | 023% | 115% | - [4 [32hrs |55-60°C| 97.9% | 045% | 026% | 139% | - 99.90% 6 |i0days | 25°C [99.88% | 001% | 002% | 009% [| - 0.08% | ~~ 8 [2months| 25°C [99.82% | 0.02% | 004% | 012% | -

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°C and 75% relative humidity is less than about 0.15% by area

HPLC. The percentage VB, Compound B, or Compound A is relative to the total amount of sample at time =T.

In another embodiment, the levalbuterol hydrochloride has total amount of unknown impurities aftex storage for three months at 40°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.

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°C and 75% relative humidity is less than about 1% by area

HPLC.

Levalbuterol hydrochloride having at least one of the impurity profiles described above preferably has less than about 1700 ppm of residual C-Cs 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 haas less than 0.5% of impurities.

The invention encompasses pharmaceutical compositions comprising at least one levalbuterol hydrochloride of the invention and at least csne pharmaceutically-acceptable excipient. The pharmaceutical composition may contairm a single levalbuterol hydrochloride polymorphic form, a mixture of various crystalline forms, and/or the amorphous form.

Any excipient commonly known and used widely in the art can be used in the pharmaceutical composition. The excipients included im 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 ar abic, gelatin), an adjuvant, a flavoring agent, a coloring agent, or a coating material (€.g., wax or a plasticizer). A composition to be administered in liquid form can inclucle, for example, an emulsifying agent, a flavoring agent and/or a coloring agent.

The pharmaceutical composition comprising the levalbuterol hydrochloride can be administered by inhalation, by subcutaneous or other inj ection, 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.

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 thee art.

Examples

Yields were determined by mass. Chemical purity was determined by HPLC.

The HPLC analysis was conducted using a column POL_ARIS C18-A 250 mm X 4.6 mm

X 5.0 mm (cat n.2002-250 x 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 mI/min. The detector was set to a wavelength of 230 nm, wsing an HPLC Hewlett

Packard VWD detector HP 1100, as a detector.

Enantiomeric excess was determined by HPLC using a chiral column. The column and packing was a CHIREX S-indoline-carboxylic aci«d-R-o-naphtylethylamine 250 mm x 4.60 mm (Phenomenex cat. N* 00G-3022-EO) and whe diluent was a mobile phase. The mobile phase was a mixture of n-hexane : CHCl, : MeOH : CF;COOH (500 : 440 : 60 : 0.4 by volume, respectively). Each chromato ggram was run for to 20 minutes. The column temperature was 25°C and the flow rate was 1.5 mI/min. The detector was set to UV at 280 nm.

The X-Ray diffraction (XRD) analysis was conducted msing an ARL X-Ray powder diffractometer (model X TRA-030) equipped with a P eltier 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 6 (+ 0.2 degrees) and a continuous scan at a rate of about 3 degrees/min. One of ordiraary skill in the art understands that experimental differences may arise due to differences in instrumentation, sample preparation, or other factors.

Fourier transform infrared (FT-IR) spectroscopy was c-onducted using a Perkin-

Elmer Spectrum 1000 Spectrometer at about 4 cm’! resolution with about 16 scans in the range of 4000-400 cm’. Samples were analyzed in KBr pellet and the instrument was calibrated using an empty cell as a background.

Differential scanning calorimetry (DSC) was conducte-d using a Mettler Toledo

DSC 822°/700 with a sample weight of about 3-5 mg, a heatin grate of about 10 °C/min., using a 3 holed crucible, under a stream of N; at a flow rate ofS about 40 ml/min. The sample was scanned between a range of about 30 °C to about 2250 °C at a heating rate of about 10 °C/ minute.

Thermal Gravimetric Analysis (TGA) was conducted rising a Mettler Toledo

TGA/SDTA 851° using a sample weight of about 7-15 mg, a Ineating rate of about 10 °C/ min. under a N stream at a N, flow rate of about 50 ml/min. “The samples were scanned at a range between about 30 °C to about 250 °C.

Example 1. Preparation of crude (R)-SLB.D-DBTA, or R)(-D» a'~ [[(1.1Dimethylethyl)aminolmethyl]-benzenedimethanol.(D)-Dibenzoyltartrate.

In a 2 L reactor equipped with a condenser, thermometer, and mechanical stirrer at 20°C and under nitrogen, salbutamol base (200 g), D-DBTA (150 g), and methanol (900 mL) were loaded. The temperature increased from 20°C to 32°C to form a solution.

The solution was cooled to 25°C, and a second portion of D-DEBTA (150 g) was loaded.

The solution was heated to 60-63°C. The solution was cooled te 50°C and seeded with pure (R)-SLB.D-DBTA (enantiomeric excess > 99%, 0.350 g). Precipitation formed, and the mixture was maintained at 50°C for 30 min, cooled to -5°C =t 2°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 x 100 mnL).

Crude (R)-SLB.D-DBTA was obtained as a wet solid (3 19.14 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)(-) ol [[(L.1Dimethylethyl)amino]methyl]-benzenedimethanol.(D)-Dilbenzoyltartrate.

In a 1 L reactor equipped with a condenser, thermometenr, 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. Tkne suspension was heated to light reflux (62-63°C) until a solution formed. The solution wvas cooled at 60°C, and treated with charcoal (2.5 g). After 15 min at 60-62°C the charcoal was filtered off while the solution was maintained at 60-62°C to avoid crystallization.

The filtrate, a clear solution, was cooled at 50°C to obtain crystals. The solution was maintained at 50°C for 30 min, cooled to -5°C in 2 hours, amd maintained at the temperature for 3 hours. The solid was collected by filtration armd washed with cold methanol (160 mL) and ethylacetate (3 x 160 mL) to obtain a weet solid (253.6 g). The wet solid was dried for 24 hours at 20-25°C under vacuum to obwtain pure (R)-SLB.D-

DBTA (dry 213.5 g).

The crystallization yield was 87.6%. The overall yield from racemic salbutamol was 42.7%. The enantiomeric excess of pure (R)-SLB.D-DBT Aa was 99.8%.

Example 3. Preparation of crude levalbuterol hydrochloride.

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°C + 2°C, and HC (37%, 29.44 g, 0.30 mol) was added in about 15 minutes. The temperature was maintained at 0°C + 2°C. The suspension was stirred at 0°C + 2°C for 1 hour. The solid was collected by filtration and washed with an ethylacetatte : methanol mixture (95:5, 80 mL), followed by washing with ethylacet-ate (2 x80mL).

Th.e wet product (97.6 g) was slurried according to the procedure described in

Example 4.

Example 4_ Preparation of pure levalbuterol hydrochloride.

In a2 L reactor equipped with a condenser, thermometer, and mechanical stirrer at 20°C and under nitrogen, a suspension of wet levalbuterol hydrochloride (97.6 g), ethylaceta te (440 mL) and methanol (49 mL) was formed. The suspension was stimred at 22°C + 2° C for 4 hours. The solid was collected by filtration and washed with an ethylaceta te : methanol mixture (90:10, 97 mL), and ethylacetate (2 x 97 mL). Time product was dried at 22°C + 2°C under vacuum (res. press. 40-45 mm Hg) for 24 Inours to obtain 64. 0 g (dry weight) in 92.5% yield from pure (R)-SLB.D-DBTA. The overall yield froma racemic salbutamol to pure levalbuterol hydrochloride: 39.5%.

Example 5S. Preparation of crude (R)-SLB.D-DBTA, or (R)(-) al- [i(1,1Dimmethylethyl)amino]methyl]-benzenedimethanol.(D)-Dibenzoyltartrate

In a 10 L reactor equipped with a condenser, thermometer, and mechanical stirrer at 20°C arad under nitrogen, salbutamol base (800 g), D-DBTA (400 g), and methanol (3600 m1.) were loaded. The temperature increased from 20°C to 26°C. A second aliquot of" D-DBTA (400g) was loaded and the temperature increased to 31°C. A third aliquot of D-DBTA (400g) was loaded, the temperature increased to 32°C and a solution was obtaimed. The solution was heated to 60-63°C. The solution was cooled to SO°C and seeded with pure (R)-SLB.D-DBTA (enantiomeric excess > 99%, 1.404 g). The mixture was maintained at 50°C for 30 min , then the solution was cooled to -7°C + 2°C im 2 hours, and maintained at the temperature for 2 hours. The solid was collected by filtration snd washed with cold (-5°C) methanol (2 x 400 mL). Crude (R)-SLB.D~DBTA was obtaimed as a wet solid (1255 g, LOD= 23.7% corresponding to 950g 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)-SLIEB.D-DBTA, or (R)(-) al-[[(1L.1- dimethylethyl)aminolmethyl]-benzenediimethanol.(D)-Dibenzoyltartrate

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 (1245g;

LOD = 23.7%, 950 g) in methanol (24777 mL) was formed. The suspension was heated to gentle reflux (62-63°C) until a solution formed. The solution was cooled to 60°C, and treated with charcoal (9.5 g). After 15 ruin at 60-62°C the charcoal was filtered off while the solution was maintained at 60-62°C to avoid crystallization.

The filtrate, a clear solution, was cooled at 50°C to obtain crystals. The solution was maintained at 50°C for 30 min, coo led to -8°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 x 588 mL) to obtain a wet solid (1061.8 g, assay = 78.4% corresponding to 832 g dry). Thee 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 levalbsuterol hydrochloride.

In a 10 L reactor equipped with a condenser, thermometer, and mechanical stirrer at room temperature and under nitrogem, 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°C x 2°C, and HC1 (37%%, 161g, 1.634 mol) was added in 30 minutes. The temperature was maintained at 0°C + 2=C. The suspension was stirred at 0°C + 2°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 x 438 mL). 419.3 g of wet crude levalbuterol hydrochloride w ere obtained. HPLC purity= 99.6%. The wet product (419.3 g) was slurried accordin g to the procedure described in Example 8.

Example 8. Preparation of pure levalbuterol hydrochloride.

In a 4 L reactor equipped with a. condenser, thermometer, and mechanical stirrer at 20°C and under nitrogen, a suspension «f wet crude levalbuterol hydrochloride (414.3g), ethylacetate (2398 mL) and methanol (267 mL) was formed. The suspension was stirred at 22°C = 2°C for 4 hours. The solid was collected by filtration and washed with an ethylacetate : methanol mixture (90:10, 533 mL), and ethylacetate (2 x 5 33 mL). The . product was dried at 25°C under vacuum (res. press. 40-45 mm Hg) for 224 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

S 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;COOH 160 ppm.

Example 9. Preparation of crude (R)-SLB.D-DBTA, or (R)(-) &'- [[(1.1Dimethylethyl)aminolmethyl]-benzenedimethanol.(D)-Dibenzoylt artrate.

In a 3 L reactor equipped with a condenser, thermometer, and mechanical stirrer at 20°C and under nitrogen, salbutamol base (265 g), D-DBTA (199 g), an_d methanol (1190 mL) were loaded. The temperature increased from 20°C to 35°C- The mixture was cooled to 28°C. A second portion of D-DBTA. (199 g) was loaded and the suspension wvas heated to 60-63°C. The solution was cooled to 50°C and seeded wi th pure (R)-

SLB.D-DBTA (enantiomeric excess > 99%, 0.46 g). The mixture was ruaintained at 50°C for 30 min, cooled to -5°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 x 139 mL).

Crude (R)-SLB.D-DBTA was obtained as a wet solid (395 g; LOD=22% corresponding to 308g of dry product; yield= 46.5%). HPLC purity = 9 9.0%; 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)(-) a'-[[(1.1 - dimethylethyl)amino]methyl]-benzenedimethanol.(D)-Dibenzoyltartrates.

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 (395g;

L.OD= 22%, 308 g dry) in methanol (815 mL) was formed. The suspension was heated to gentle reflux (62-63°C) until a solution formed. The solution was coole=d to 60°C, and treated with charcoal (3 g). After 15 min at 60-62°C the charcoal was filtered off while the solution was maintained at 60-62°C to avoid crystallization.

The filtrate, a clear solution, was cooled at S0°C to obtain crystals. The solution “was maintained at 50°C for 30 min, cooled to -8°C in 2 hours, and maimtained at the temperature for 2 hours. The solid was collected by filtration and washesd with cold

Claims (29)

CLAIMS What is claimed is:

1. A process for preparing (R)-SLB.D-DBTA comprising: (2) preparing a mixture of racemic salbutamol in a first C,-C, alcohol; (b) adding D-dibenzoyltartaric acid to the mixture; (©) crystallizing and isolating crude (R)-SLB.D-DBTA; and (Jd) recrystallizing the crude (R)-SLB.D-DBTA in a second C;-C, 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.

2. The process according to claim 1, wherein the first or second alcohol is methanol,

3. The process according to claim 1, wherein the D-dibenzoyltartaric acid is present in an amount of about 0.5 mol to about 1.3 mol equivalents of the salbutamol.

<4. The process according to claim 1, wherein the mixture of racemic salbutamol in a first C;-C4 alcohol is heated to a temperature of at least about 50°C.

5. The process according to claim 1, wherein the crystallizing step is performed by seedling with (R)-SLB.D-DBTA.

6. The process of claim 1, wherein after seeding with (R)-SLB.D-DBTA, the solution is cooled to a temperature of about -20°C to about 10°C.

“7. The process according to claim 1, wherein the second C;-C; alcohol is heated to about reflux temperature.

8. The process according to claim 7, further comprising cooling.

9. Enantiomerically pure (R)-SLB.D-DBTA salt having an enantiomeric excess of at least about 99.8%.

10. A process for preparing levalbuterol hydr ochloride comprising the steps of: (a) preparing a first slurry of (R)-SLB.D-DBTA in a first solvent; (b) adding hydrochloric acid to the first slurr=y to form crude levalbuterol hydrochloride; (c) isolating the crude levalbuterol hydrochloride; (d) preparing a second slurry of the crude lev-albuterol hydrochloride in a second solvent; and (e) isolating the levalbuterol hydrochloride.

11. The process according to claim 10, wherein the first or second solvent is at least one of C3-Ciq ester, C3-Cio ketone, C3-Cyo ether, C;-C; alcohol, Cs-Cy2 aromatic hydrocarbon, tetrahydrofuran, dimethylcarbonate, dimmethylsulfoxide, dimethylformamide, dichloromethane, or acetonitrile.

12. The process according to claim 10, whereein the first solvent is at least one of ethylacetate, acetone, tetrahydrofuran, dimethylcarbonate, acetonitrile, toluene, xylene, methanol, ethanol, isopropanol, dimethylsulfoxide, or dimethylformamide.

13. The process according to claim 10, wherein the second solvent is at least one of methanol, ethanol, isopropanol, ethylacetate, buty-1 acetate, DMF, acetone, toluene, isopropyl ether, diethyl ether, methyl tert butyl ether, dichloromethane, or acetonitrile.

14. The process according to claim 10, wherein the second solvent further comprises water.

15. The process according to claim 10, wherein the first or second solvent is at least one Cs-Cg ester or a mixture of at least one C,-#C, alcohol and C;-C; ester.

16. The process according to claim 15, wherein the alcohol is methanol and the ester is ethylacetate.

17. The process according to claim 15, whemrein the first or second solvent has an alcohol to ester ratio of about 15:85 by volume.

18. The process according to claim 10, where prior to step (b) the slurry is cooled to a tem:perature of about -20°C to about 10°C.

19. The process according to claim 10, wherein the hydrochloric acid is added as a solution.

20. The process according to claim 10, wherein the hydrochloric acid is added as a gas.

21. The process according to claim 10, wherein the hydrochloric acid is present in an amount of about 1 mol to about 1.3 mol equivalents of the (R)}-SLB.D-DBTA.

22. The process according to claim 10, wherein prior to step (¢) the slurxy is cooled at a temperature of about -10°C to about reflux temperature of the second solvent.

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,-C4 alcoholg or having a pH of at least about 4.3 in 1% aqueous solution at room tenaperature.

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 1 ess than about 0.15% by area HPLC of at least one of Compound A, Compound B, and Compound C; havimg less than about 0.10% by area HPLC of total unknown impurities; or having less tham about 0.25% by area HPLC of each impurities including Compound A_, Compownd B, and Compound C, after being stored for three months at 40°C an«d 75% relative humidity.

27. N-(tert-butyl)-2-methoxy-2-(4-hydroxy-3-(hydroxymethyl)phen-1-yl- ethanamine, Compound B, having the following structure: OCH, i HO CH,OH Compound B.

28. N-(tert-butyl)-2-methoxy-2-(4-hydroxy-3-(methoxymethyl)phen-1-yi)- ethanamine, or Compound C having the following structure: OCH; Ho o> CH,OCH, Compound C.

29. A pharmaceutical composition comprising a therapeutically effective amount of the levalbuterol hydrochloride according to claim 27 and at least one pharmaceutically- ’ 10 acceptable excipient.