AU686386B2 - Creation of Inventions and Patents with Artificial Intelligence

AU686386B2 – Enantioselective preparation of optically pure albuterol
– Google Patents

AU686386B2 – Enantioselective preparation of optically pure albuterol
– Google Patents
Enantioselective preparation of optically pure albuterol

Download PDF
Info

Publication number
AU686386B2

AU686386B2
AU25559/95A
AU2555995A
AU686386B2
AU 686386 B2
AU686386 B2
AU 686386B2
AU 25559/95 A
AU25559/95 A
AU 25559/95A
AU 2555995 A
AU2555995 A
AU 2555995A
AU 686386 B2
AU686386 B2
AU 686386B2
Authority
AU
Australia
Prior art keywords
enantiomer
amino
dimethylethyl
salt
methyl
Prior art date
1994-05-23
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

Expired

Application number
AU25559/95A
Other versions

AU2555995A
(en

Inventor
Yun Gao
Charles Melvyn Zepp
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Sunovion Pharmaceuticals Inc

Original Assignee
Sepracor Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
1994-05-23
Filing date
1995-05-23
Publication date
1998-02-05

1994-05-23
Priority claimed from US08/247,302
external-priority
patent/US5399765A/en

1995-05-23
Application filed by Sepracor Inc
filed
Critical
Sepracor Inc

1995-12-18
Publication of AU2555995A
publication
Critical
patent/AU2555995A/en

1998-02-05
Application granted
granted
Critical

1998-02-05
Publication of AU686386B2
publication
Critical
patent/AU686386B2/en

2015-05-23
Anticipated expiration
legal-status
Critical

Status
Expired
legal-status
Critical
Current

Links

Espacenet

Global Dossier

Discuss

Classifications

C—CHEMISTRY; METALLURGY

C07—ORGANIC CHEMISTRY

C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS

C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton

C—CHEMISTRY; METALLURGY

C07—ORGANIC CHEMISTRY

C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS

C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton

C07C213/10—Separation; Purification; Stabilisation; Use of additives

C—CHEMISTRY; METALLURGY

C07—ORGANIC CHEMISTRY

C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS

C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton

C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton

C07C215/56—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by hydroxy groups

C07C215/58—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by hydroxy groups with hydroxy groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain

C07C215/60—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by hydroxy groups with hydroxy groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain the chain having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring

C—CHEMISTRY; METALLURGY

C07—ORGANIC CHEMISTRY

C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS

C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton

C07C227/30—Preparation of optical isomers

C07C227/34—Preparation of optical isomers by separation of optical isomers

Abstract

The invention relates to a method for producing albuterol by the resolution of a mixture of enantiomers of methyl 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-(phenylmethoxy)benzoate or alpha -[[(1,1-dimethylethyl)amino]methyl]-4-(phenylmethoxy)-1,3-benzenedimethanol using a chiral acid such as (+/-) di-toluoyltartaric acid or (+/-) di-benzoyltartaric acid.

Description

WO 95/32178 PCT/US95/06539 -1- ENANTIOSELECTIVE PREPARATION OF OPTICALLY PURE ALBUTEROL CROSS-REFERENCE TO RELATED APPLICATION This application is a continuation-in-part of Application Serial No. 08/247,302 filed May 23, 1994.
TECHNICAL FIELD The present invention relates to a method of preparing optically pure and albuterol. More particularly, the present invention relates to the preparation and resolution of the albuterol precursor methyl 5-[2-[(l,l-dimethylethyl)amino]-lhydroxyethyl]-2-(phenylmethoxy) benzoate or dimethylethyl)amino]methyl]-4-(phenylmethoxy)-1,3benzenedimethanl with a chiral acid.
BACKGROUND OF THE INVENTION Albuterol, also referred to as dimethylethyl)amino]methyl]-4-hydroxy-l,3benzenedimethanol or as salbutamol, is a 8-2 agonist useful as a bronchodilator. It possesses a high degree of selectivity between B-l receptors (which are present in the heart) and B-2 receptors (which are present in bronchial tissue and elsewhere), for which reason it is widely used in the treatment of asthma, since in therapeutic doses it exhibits fewer cardiac side effects than many other B-agonists.
It is known that among many drugs having chiral centers one enantiomer of a racemic pair is often more active than the other in treating a medical WO 95/32178 PCT/US95/06539 -2condition. Recent data suggest that the levorotatory R-isomer of albuterol is approximately 80 times more potent than the dextrorotatory S-isomer (Hartley and Middlemis, J. Med. Chem. 14 895-896 (1971)), and preliminary research indicates that administration of the pure R-enantiomer may offer an improved therapeutic ratio.
SUMMARY OF THE INVENTION It is an object of the invention to provide a method for obtaining an optically pure isomer of albuterol from a phenolic precursor. It is a further object to provide a manipulatively simple synthesis of optically pure albuterol from a commercially available prochiral starting in only four steps involving one highly efficient resolution.
This and other objects, features and advantages are provided by the present invention which relates to a process for obtaining a single enantiomer of [2-[(1,1-dimethylethyl)amino]-l-hydroxyethyl]-2hydroxybenzoate, a precursor to albuterol, comprising the steps of: dissolving a mixture of enantiomers of methyl dimethylethyl)amino]-l-hydroxyethyl]-2hydroxybenzoate and a chiral acid selected from the group consisting of (-)-di-toluoyl-L-tartaric acid and (+)-di-toluoyl-D-tartaric acid in methanol by heating to form a solution; allowing said solution to cool, whereby a salt of primarily one stereoisomer crystallizes; separating said salt from said solution; recrystallizing said salt from methanol, whereby a diastereomeric salt having greater than 90% ee of an enantiomer of methyl 5-[2- WO 95/32178 PCT/US95/06539 -3- [(1,1-dimethylethyl)amino]-l-hydroxyethyl]-2hydroxybenzoate is obtained; separating said diastereomeric salt from the methanol solvent; and liberating said enantiomer of methyl dimethylethyl)amino]-l-hydroxyethyl]-2hydroxybenzoate from said diastereomeric salt by treatment with base.
In the process described above, a chiral acid such as (-)-di-toluoyl-L-tartaric acid will give the S enantiorer of methyl dimethylethyl)amino]-l-hydroxyethyl]-2hydroxybenzoate; (+)-di-toluoyl-D-tartaric acid will give the R enantiomer of methyl dimethylethyl)amino]-l-hydroxyethyl]-2hydroxybenzoate.
In addition, the invention encompasses a process for making optically pure albuterol from a mixture of enantiomers of 5-[2-[(1,l-dimethylethyl)amino]-lhydroxyethyl]-2-hydroxybenzoate. The process comprises steps through as described above, followed by reducing the enantiomer of methyl 5-[2- [(l,l-dimethylethyl)amino]-l-hydroxyethyl]-2hydroxybenzoate thereby forming optically active albuterol. The reduction may be accomplished with either borane-methyl sulfide or lithium aluminum hydride.
In a specific aspect the invention relates to a method for producing optically pure albuterol from methyl 5-acetylsalicylate comprising the resolution and reduction described above in combination with a method for producing 5-[2-[(1,l-dimethylethyl)amino]l-hydroxyethyl]-2-hydroxybenzoate. According to this WO 95/32178 PCT/US95/06539 -4aspect the methyl 5-[2-[(1,l-dimethylethyl)amino]-lhydroxyethyl]-2-hydroxybenzoate is obtained by: (a) reacting methyl 5-acetylsalicylate with hydrogen bromide in dimethyl sulfoxide, thereby forming a keto aldehyde; reacting said keto aldehyde with tertbutylamine, thereby forming an a-iminoketone; and (c) reducing said a-iminoketone to provide methyl 5-[2- [(1,l-dimethylethyl)amino]-l-hydroxyethyl]-2hydroxybenzoate.
The a-iminoketone may be reduced with either a hydride reducing agent, such as sodium borohydride, sodium cynaoborohydride, or sodium triacetoxyborohydride or by catalytic hydrogenation with a heterogeneous noble-metal catalyst, such as Pd/C, Pt/C or PtO 2 It is a further object of the invention to provide a method for obtaining an optically pure isomer of albuterol from a mono-protected albuterol precursor as well as to provide a manipulatively simple synthesis of optically pure albuterol from a commercially available prochiral starting material in only four steps involving one highly efficient resolution.
This and other objects, features and advantages are provided by the present invention which relates in one aspect to a process for obtaining a single enantiomer of albuterol, comprising: dissolving a mixture of enantiomers of methyl 5-[2-[(1,l-dimethylethyl)amino]-lhydroxyethyl]-2-(phenylmethoxy)benzoate and a chiral acid in methanol, ethanol or a mixture of WO 95/37178 PCT/US95/06539 the two by heating to form a solution, said chiral acid being selected from the group consisting of (-)-di-toluoyl-L-tartaric acid, (+)-di-toluoyl-D-tartaric acid, (-)-di-benzoyl- L-tartaric acid and (+)-di-benzoyl-D-tartaric acid; allowing said solution to cool, whereby a salt of primarily one enantiomer crystallizes; separating said salt from said solution; liberating the enantiomer from said salt by treatment with a base; reducing said enantiomer; debenzylating said enantiomer and recovering a single enantiomer of albuterol.
In a further aspect, the invention may be characterized as a process for making optically pure albuterol, comprising: dissolving a mixture of enantiomers of a- [[(l,l-dimethylethyl)amino]methyl]-4- (phenylmethoxy)-1,3-benzenedimethanol and a chiral acid in methanol, ethanol or a mixture of the two by heating to form a solution, said chiral acid being selected from the group consisting of (-)-di-toluoyl-L-tartaric acid, (+)-di-toluoyl-D-tartaric acid, (-)-di-benzoyl- L-tartaric acid and (+)-dibenzoyl-D-tartaric acid; WO 95/32178 PCT/US95/06539 -6allowing said solution to cool, whereby a salt of primarily one enantiomer crystallizes; separating said salt from said solution; liberating said single enantiomer from said salt by treatment with a base; debenzylating said enantiomer and recovering optically pure albuterol.
In either process described above, a chiral acid such as (-)-di-toluoyl-L-tartaric acid or benzoyl-L-tartaric acid will give the S enantiomer of albuterol; (+)-di-toluoyl-D-tartaric acid or benzoyl-D-tartaric acid will give the R enantiomer of albuterol.
DETAILED DESCRIPTION The present invention relates to a more economical and efficient process for making optically pure albuterol. The method is particularly economical and efficient because it proceeds via readily available and inexpensive starting materials, as set forth in Scheme A below: WO 95/32178 PCT/US95/06539 Scheme A
DMSO
aq HBr t-BuNH 2 0 NH-tBu HO Va COOMe NH-tBu NaBH 4 I l a NH-tBu
BH
3 -Me 2
S
The graphic represantations of racemic, ambiscalemic and scalemic or enantiomerically pure compounds used herein are taken from Mayer J. Chem.
Ed. 62, 114-120 (1985). Thus, solid and broken wedges are used to denote the absolute configuration of a chiral element; wedge outlines and dotted or broken lines denote enantiomerically pure compounds of unspecified absolute configuration (e.g.
structures Ib and IIIb). As usual, a wavy line indicates a mixture of enantiomers of indeterminate proportion, commonly a racemic mixture.
WO 951/32178 PCT/US95/06539 -8- Many organic compounds exist in optically active forms, they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and 1 or and are employed to designate the sign of rotation of plane-polarized light by the compound, with or 1 meaning that the Lompound is levorotatory. A compound prefixed with or d is dextrorotatory. There is no correlation between nomenclature for the absolute stereochemistry and for the rotation of an enantiomer. Thus, Dlactic acid is the same as lactic acid, and Llactic acid is Compounds having a single chiral center exist as a pair of enantiomers which are identical except that they are non-superimposable mirror images of one another. A one-to-one mixture of enantiomers is often referred to as a racemic mixture.
The term “enantiomeric excess” is well known in the art and is defined for a resolution of ab a+b as ee, (conc. of a conc. of b 100 S conc. of a conc. of b The term “enantiomeric excess” is related to the older term “optical purity” in that both are measures of the same phenomenon. The value of ee will be a number from 0 to 100, 0 being racemic and 100 being pure, single enantiomer. A compound which in the past might have been called 98% optically pure is now more precisely described as 96% ee. Processes that yield products of ee less than about 80% are not WO 95/32178 PCT/US95/06539 -9generally regarded as commercially attractive.
Processes that yield albuterol of ee greater than about 96% are particularly attractive because the eutectic of albuterol is about 96-97% and thus substantially pure single enantiomers can be obtained by simple recrystallization of the product.
“Optically pure” and “substantially optically pure” as u sd herein refer to albuterol of 96% ee or greater.
Arylglyoxals (IIa) are most conveniently prepared from acetophenone derivatives by the procedure of U.S. Patent 5,283,359, although other syntheses, well known to persons skilled in the art, are also suitable.
The starting material shown in Scheme A above, methyl 5-acetylsaiicylate, is commercially available.
Oxidation in DMSO (1.0 M) in the presence of 2 equivalents of aqueous HBr proceeds smoothly at 60 0
C
over 20 hours to give the arylglyoxal IIa in greater than 80% yield. However, prolonged reaction times and temperatures exceeding 70 0 C may result in lower yields. Without further purification, this compound is treated with 1.0-1.2 eq of t-butylamine in warm toluene or ethyl acetate to give the a-iminoketone Va in greater than 70% yield. The u-iminoketone can be further purified by recrystallization from toluene/heptane and is used in the reduction after drying. The overall yield from the salicylate is greeter than The a-iminoketone Va is dissolved in a suitable solvent such as methanol and cooled with ice water.
Approximately 2.5 equivalents of a hydride reducing WO 95132178 PCT/US95/06539 agent are added in portions and the mixture is stirred at room temperature overnight. Thereafter the mixture is concentrated, quenched with water, and extracted into a suitable solvent, washed and recrystallized from ethyl acetate-heptane in overall yield of about 78%. The product may be analyzed for purity by any one of many methods well known in the art, an example being HPLC analysis. If the solid amino-alcohol of formula III is not greater than area pure by HPLC analysis, recrystallization is preferably repeated until this level of purity is met prior to use of the same in the resolution step.
Alternatively, the compound of formula IIIa may also be prepared directly from the corresponding aiminoketone Va by the catalytic reductive amination with t-butylamine in the presence of heterogeneous noble-metal catalysts such as Pd/C, Pt/C, or PtO,.
The precursor IIIa is resolved with a chiral acid such as or di-p-toluoyltartaric acid.
This may be accomplished by dissolving the phenolic precursor liIa and the chiral acid in refluxing methanol. Although this solvent may alternatively comprise ethanol or a methanol/ethanol mixture, methanol is the preferred solvent. The methanol solution is then cooled and stirred at 20-25 0 C for 3 to 20 hours, preferably 2 to 3 hours, thereby forming a tartrate salt in the form of a white solid. The salt is filtered off, washed with ethyl acetate to remove impurities and then dried. At this point the diastereomeric salt may represent approximately a yield, of 93% ee. The solid is preferably dissolved again in refluxing methanol and the resulting solution cooled to room temperature and stored at 00 WO 95/32178 PCT/US95/06539 -11to 5°C for 10 to 20 hours. The white solid is again collected by means known in the art, such as by filtration, and dried to produce a diastereomeric salt of approximately 98.5% ee, from which the product 5-[2-[(1,1-dimethylethyl)amino]-lhydroxyethyl]-2-hydroxybenzoate may be obtained by treatment with base, extraction, and, if desired, recrystallization from ethyl acetate.
The salicylic ester IIIa is reduced to substantially optically pure albuterol by treatment with 20 to 3 equivalents of borane-methyl sulfide complex (BH, 3 Me 2 S) in a suitable solvent, such as dichloromethane or toluene at temperatures from 500 to 600C. It is preferred that the reaction is not heated over 60 0 C since higher temperatures may result in overreduction of the product. In addition, these steps are preferably performed under a dry nitrogen or argon atmosphere and the reactants and products protected from light. The reaction is quenched with methanol and worked up as usual in the art.
The highly efficient synthesis shown in Scheme A is made possible by the surprising discovery that the free phenol of formula IIIa can be resolved in good yield in a single recrystallization employing a relatively inexpensive chiral acid. Previous syntheses required either more expensive starting materials or additional protection and deprotection steps, because arriving at unresolved IIIa was considered a synthetic dead end.
In a further embodiment, optically pure albuterol may be economically and efficiently made by similarly starting with inexpensive starting WO 95132170 PCTU$95O 6539 -12materials and proceeding via a process that further minimizes the requisite steps. This alternative embodiment may be seen in reference to Scheme B as set forth below: Scheme B If H -1190 1HO1 H 0 H-tOU O N -tBu OnNH-tau COOkme W Oe lb fib I I Ib HO H Ho H HO H NH-teu NHj-t8U NH-tsu On a’ n O HO Coome CH20H HO MI Vb H1O1
H
HOO
(l1,l-dimethylethyl)amino]-l-hydroxyethyl]- 2-(phenylmethoxy)-benzoate (structure lb and hereinafter “compound IbI”) may be prepared by procedures well known to persons skilled in the art.
The starting material shown in scheme B above, compound Ib, is commercially available from Cipla (Bombay, India).
WO 95/32178 I’CTIUS95/06539 -13- Without further purification compound lb is resolved with a chiral acid such as or di-ptoluoyltartaric acid or or di-benzoyltartaric acid. This may be accomplished by dissolving compound Ib and the chiral acid in refluxing methanol. The solvent may alternatively comprise ethanol or a methanol/ethanol mixture. Resolution of compound Ib may be accomplished with either about 1 mole equivalent of the tartaric acid derivative or with about 0.5 mole equivalent of the chiral acid (structure IIb and hereinafter “compound IIb salt”) in the form of a solid. Compound IIb salt is filtered off, washed with ethyl acetate to remove impurities and then dried.
Table-1 Resolution of racemic compound Ib Scale of Yield of Compound compound Chem.
Ib Conditions IIb Purity ee 3 mmol 1.0 eq of D-Ta 31.6% N.D. 10.0% mmol 0.5 eq of (D)-TA 23.0% N.D. 10.6% 200 mmol 0.5 eq of D-DBTA 28.7% 99.9% 99.3% area 100 mmol 0.5 eq of D-DBTA 37.2% 99.9% 99.0% area 3 mmol 1.0 eq of D-DTTA 37.2% N.D. 84.3% The solid, compound IIb salt, is preferably dissolved again in refluxing methanol and the resulting solution cooled to room temperature and stored at 00 to 5 0 C for 10 to 20 hours. The solid is again collected by means known in the art, such as by filtration, and dried to produce a diastereomeric
I
WO 95/32178 PCT/US95/06539 -14salt of approximately 99.0% ee, from which optically active or methyl 5-[2-[(1,1-dimethyl ethyl)amino]-l-hydroxyethyl-2-(phenylmethoxy)benzoate (structure IIIb and hereinafter “compound IIIb”) may be obtained by treatment with base and, if desired, recrystallization from ethyl acetate.
Compound IIIb is reduced to substantially optically pure a-[[(1,1-dimethylethyl)amino]methyl]- 4-(phenylmethoxy)-1,3-benzenedimethanol (structure IIc and hereinafter “4-benzyl albuterol”), by treatment with 2 to 3 equivalents of borane-THF solution (BH 3 -THF) in a suitable solvent, such as tetrahydrofuran (THF). The solution may be refluxed and then cooled and quenched with methanol. In addition, these steps are preferably performed under anhydrous conditions, such as a dry nitrogen or argon atmosphere, and the reactants and products protected from light. The reaction is quenched with methanol and then worked up as usual in the art.
Table-2 Reduction of resolved compound IIIb Isolated Scale of yield of Chem.
compound IIIb Reagent compound IVb Purity ee 33.3 mmol BH 3 -THF 73.8% 99.8% 99.4% 33.3 mmol BH 3 -THF 54.7% 97.7% 99.8% The oj ically pure 4-benzyl albuterol (structure IVb), may then be debenzylated to provide optically pure albut-rol (structure IVa). For example, 4benzyl albuterol may undergo debenzylation with hydrogen in the presence of a catalytic amount of WO 95/32178 PCTIUS95/06539 Pd/C in methanol or ethanol at ambient temperature under 50 psi of hydrogen for several hours. After debenzylation the catalyst may be removed by filtration. Optically pure albuterol (structure IVa) may then be further purified and readily obtained from the filtrate as acid salt (structure Vb) by treating the albuterol with an appropriate acid, such as anhydrous HCl, in an ethanol and ether solution.
Table-3 Debenzylation and hydrochloride salt formation Scale of Yield of Chem. ee albuterol HCI(%)a purity 20.0 mmol 83.5 (4.60) 99.3 99.6 (99.4) 15.0 mmol 80.4 (3.33) 99.4 99.8 (99.8) a. Yield after recrystallization.
The highly efficient synthesis shown in Scheme B is made possible by the surprising discovery that the mono-protected ether of compound Ib can be resolved in good yield in a single recrystallization employing a relatively inexpensive chiral acid. Previous syntheses required either more expensive starting materials or additional protection and deprotection steps.
In an alternative embodiment, optically pure albuterol may be economically and efficiently made by similarly starting with inexpensive starting materials and proceeding via a process that further minimizes the requisite steps. This alternative embodiment may be seen in reference to Scheme C as set forth below: WO 95/32178 PCT/US95/06539 -16- Scheme C HO H HO H HO H *D-DBTA HH-1Bu NH-tS ‘u NH-tBu en BnO ?lnO Ho 3 H 2 OH
H
H
IIc IVb HO H HO P HO H IVb Ia Vb The alternative embodiment begins with a mixture of enantiomers of dimethylethyl)amino]methyl] -4-(phenylmethoxy)-1,3benzenedimethanol (structure Ic and hereinafter “4benzyl albuterol”). As with the compound Ib above, racemic 4-benzyl albuterol (Ic) is commercially available from Cipla (Bombay, India). Alternatively, compound Ic (racemic 4-benzyl albuterol) can be prepared by reduction of racemic Ib with borane or LiAlH 4 Racemic 4-benzyl albuterol, as well as non one-to-one mixtures of enantiomers, may be resolved using about 1 equivalent of a chiral acid such as or di-p-toluoyltartaric acid (DTTA) or or dibenzoyltartaric acid (DBTA). The solvent may comprise ethanol or ethyl acetate, although ethanol is a preferred solvent when using dibenzoyltartaric acid as the resolving agent. The resolved chiral acid salt (structure IIc) is isolated as a solid and I I WO 95/3178 PCT/US95/06539 -17is treated with a base, such as 5 wt% aqueous Na 2
CO
3 in the presence of ethyl acetate in order to obtain the resolved free base of 4-benzyl albuterol (structure IVb). The resolved free base of 4-benzyl albuterol may be further purified by crystallization from ethyl acetate and heptanes in order to achieve 99.8% chemical purity and a 98% ee.
Table-4 racemic benzyl albuterol: Resolution of Entry Scale of Conditions Yields of ee compound Ic compound IIc 1 30.0 mmol 1 eq of D- 32.5% 98.4%
DBTA
ethanolb 2 90.0 mmol 1 eq of D- 34.0% 99.6%
DBTA
3 2 mmol 1 eq of D- 21.7% 94.4% DBTAc 4 2 mmol 1 eq of D- 50.0% 83.5%
DBTA
2 mmol 1 eq of D- 46.0% 75.9% DTTA ethyl acetate a. Yield is based upon racemic 4-benzyl albuterol compound.
b. Denatured ethanol.
c. 95% ethanol.
The free base of optically pure 4-benzyl albuterol (IVb) may then be debenzylated to form optically pure albuterol (IVa) and recrystallized in the form of an acid salt (structure Vb) as described above in reference to Scheme B.
WO 95/32178 PCT/US95/06539 -18- Debenzylation of compound IVb and hydrochloride salt formation Yield of albuterol Chem.
Entry Scale purity ee(%) 9.7 mmol 1 (98.4) 80.9 (2.17) 99.6 99.6 10.0 mmol 2 (99.6) 78.3(2.16) 99.6 99,4 10.0 mmol 3 (99.6) 80.5(2.22) 99.4 99.8 EXAMPLE 1 The synthesis of the keto aldehyde hydrate IIa was performed using a 500 mL three neck flask charged with 150mL of dimethyl sulfoxide (DMSO) and methyl acetylsalicylate (39g, 0.2 mol). Ag. HBr (48%, 46mL, 0.4 mol. 2.0 eq) was added dropwise over min. After addition, the solution was heated at for ca. 20 hours (followed by TLC) until no starting material remained. The yellow mixture was poured onto 400 g of ice, stirred for 30 minutes, collected by filtration, and washed with 2×50 mL of cold water to give the keto aldehyde hydrate (IIa) (yield >80% based on dried material). The wet solid was dried at room temperature under vacuum for 4 hours and used for the next step without further purification.
The wet solid (1.0 eq, based on 0.2 mol, 100% yield) and 1.1 eq of t-butylamine (0.22 mol, 23 mL) were dissolved in 200 mL of toluene. The solution was heated at reflux for ca. 2 hours. The solution was then cooled to room temperature and washed with WO 95/32178 PCT/US95/06539 -19water (2×50 mL) and concentrated to dryness under vacuum to give crude ketoimine Va as yellow solid (33.4 g, 63% yield from methyl The crude ketoimine can be further purified for use in the NaBH 4 reduction. In this case, it was reduced directly with NaBH 4 in methanol (MeOH).
The crude ketoimine (10.6 g, 25mmol) was dissolved in 100 mL of MeOH and cooled with icewater.
Solid NaBH 4 (2.5 g, 62.5 mmol, 2.5 eq) was added in portions with caution due to hydrogen evolution. The resulting mixture was stirred at room temperature overnight (TLC: completed) and then concentrated to dryness. The residue was quenched with 20 mL of water and extracted with 2×150 mL of ethyl acetate.
The ethyl acetate solution was washed with 25 mL of NaHCO 3 and 25 mL of water. The solution was then concentrated to ca. 40 mL to give a slurry. The slurry was-heate’d”‘to dissolve the solid, and heptane (ca. 30 mL) was added. The solution was cooled to room temperature, and then stored at 3°C overnight.
The solid was collected by filtration to give the first crop. The mother liquor was concentrated and recrystallized to give a second crop. Total recovery of the phenolic solid was 6.9 g (78% yield) as white solid.
EXAMPLE 2 Resolution of the phenolic precursor IIIa was performed with (-)-di-p-toluioyl-L-tartaric acid and (+)-di-p-toluoyl-D-tartaric acid, respectively.
In a representative case (examples 2.4 and 2.4a), a mixture of the phenolic precursor IIIa WO 95/32178 PCT/US95/06539 (1.33g, 5 mmol) and (+)-di-p-toluoyl-D-tartaric acid (1.93 g, 5 mmol) was dissolved in refluxing MeOH mL). The solution was then cooled and stirred at room temperature for 16 hours. The white solid was collected by filtration and washed with 5 mL of ethyl acetate and dried (0.86 g, 53% yield, 93% ee). The solid was then dissolved again in 18 mL of refluxing MeOH. The resulting solution was cooled to room temperature and stored at 3 0 C for 15 hours (overnight). The white solid was collected by filtration and dried (0.53 g, 33% yield, 98.5% ee).
Results obtained analogously are summarized in the following tables: Chiral Time at Room Time at Example acid Solvent Temperature 30 C 2.1 EtOAc/ 15 MeOH 2.2 EtOAc/ 15 MeOH 2.3 EtOH/ 6 MeOH 2.3a MeOH 2 2.3b MeOH 3 2.4 MeOH 16 2.4a MeOH 3 MeOH 3 MeOH 3 WO 95/32178 PCT/US95/06539 -21ee% of Yield Example solid of solid ee% of ML 2.1 90(s) 50 27 2.2 77(R) 66 2.3 75(R) 75 2.3a 95(R) 45 2.3b 98(R) 31 2.4 93(R) 53 2.4a 99(R) 33 90(R) 54 38(S) 2.5a 99(R) 33 Examples identified as a or b indicate the results of an additional recrystallization of the solid obtained from the preceding crystallization. The optically pure $a4trate salt can be obtained after just one more recrystallization in over 30% yield based on available isomer.
The absolute configuration of the salt from resolution with (+)-di-p-toluoyl-D-tartaric acid was correlated to R-albuterol according to the following procedure: a small amount of the slat was neutralized with saturated aqueous NaHCO 3 in the presence of ethyl acetate. The ethyl acetate phase was concentrated to dryness to give the enriched free base material of formula IIIa which was then reduced with BH 3 *Me 2 S in CH 2 C12 to give optically active albuterol. HPLC analysis in comparison with authentic (R)-albuterol confirmed that the salt has (R)-configuration at the benzyl OH group.
i I I I WO 95/32178 11CUUM/00539G53 -22- EXAMPLE 3 A 500 mL three-necked flask equipped with a mechanical stirrer was charged with 200 mL of DMSO ACS reagent grade) and methyl acetylsalicylate Schweizerhall, 39.6 g, 0.2 mol, 1.0 eq). Aqueous hydrobromic acid ACS reagent grade, 34 mL, 0.3 mol, 1.5 eq) was added dropwise with stirring over 15-20 minutes. The solution was then heated at 60-65 0 C for 24-26 hours with stirring. Refluxing of the solution occurred at ca. 60 0 C. The reaction was followed by HPLC and heating was stopped when the ratio of product to starting material was greater than 95:5 by area HPLC.
A ABondapak C18, 10 pm, 30 cm x 3.9 mm (Waters) column with a mobile phase consisting of 0.01 M Na 2
H
2
PO
4 0.002 M Octanesulfonic acid, sod-um salt (pH (75:25) was used to monitor the reaction at a TJV detection wavelength of 220 nm.
Prolonged reaction times and higher temperatures (over 70 0 C) resulted in lower yield. The solution was slowly poured onto 500 g of ice with v.gorous stirring. A yellow solid precipitated out of the solution with some sticky solids being present. The mixture was stirred at 10 0 C for 2 hours until a fine slurry was formed during which time most of the sticky solid changed to a fine powder or small pieces. The slurry was filtered through a Buchner funnel using filter paper or DMSO-compatible filter cloth to recover the arylglyoxal product of formula II in the form of a yellow powder. The flask and solids were washed twice with 50 mL of cold water 0 C) followed by dual washes with 15 mL of cold toluene (5-10 0 The powder was retrieved and held under a vacuum for ca. 1 hour which removed most of WO 95/32178 PCITUS95/06539 the solvent, no additional drying was required. The powder was used without further purification having a crude yield of ca. 80% when dry with the average weight of the arylglyoxal solid falling in the range of 55-65 g.
The arylglyoxal solid (the 55-65 0.2 mol) obtained from the preceding process was then transferred to a second 500 mL three-necked flas charged with 300 mL of ethyl acetate ACS reagent) thereby forming a yellow slurry. The amount of crude arylglyoxal was based on 100% yield on step one. Tertiary-butylamine Aldrich, 31.4 mL, 0.3 mol, 1.5 eq) was added to the slurry over 15-20 minutes with stirring, thereby dissolving the solids within the slurry and forming an orange solution.
The mixture was heated at 40-45 0 C for 2-3 hours. The reaction was followed by TLC (silica gel plate pretreated with 10:l(v/v) hexane: Et31; eluting with
CH
2 Cl 2 :MeOH (20:1, v/v) containing 2 volume of EtN 3 starting material: 0.55, ketoimine: 0.68; UV).
Tne reaction was worked up when the starting material was almost invisible by UV detection. The solution was cooled to 20-25°C (room temperature) and separated from the dark aqueous phase. The organic phase was washed twice with 30 mL of saturated aqueous sodium chloride solution. The combined aqueous phase was not extracted and the amount of ketoimine product in the aqueous phase was ca. 5-6% of the overall yield. The organic phase was then concentrated to dryness and further dried under vacuum for 2-3 hours at room temperature yielding a yellow solid of crude ketoimine of formula Va (31-35 g, 75-82% crude yield). The crude product was used WO 95/32178 PCT/US95/06539 -24without further drying and purification in the reduction step set forth below.
A 500 mL three-necked flask was charged with the crude ketoimine from above (32 g, 0.122 mol, 1.0 eq) and 300 mL of methanol (99% ACS reagent grade) and cooled to 10-15 0 C. Sodium borohydride (NaBH 4 98%, reagent grade) 11.6 g, 0.31 mol, 2.5 eq) was dissolved in 50 M1 of 0.2% sodium hydroxide solution and added to the ketoimine solution at 10-20 0 C with vigorous stirring over 30-40 minutes. This is an exothermic reaction and H 2 is released during addition, both of which may be controlled by using a cooling bath and by controlling the rate of addition.
A slurry was formed during addition which was then stirred at 10-15 0 C for 20-25 minutes. The reaction usually completes after addition of the NaBH 4 The reaction was followed by TLC (silica gel, mobile phase:2 v/v% Et 3 N in 20:1 CH 2 Cl 2 /MeOH; UV, R: ketoimine, 0.44; product, 0.29) or HPLC as described hereinabove. The reaction was worked up when no arylglyoxal starting material waq detected by TLC or HPLC. The slurry was concentrated below 35 0 C under vacuum to ca. 100-120 Ml thereby forming a dense slurry. 800 ml of ethyl acetate and 150 mL of distilled water were added to the dense slurry, stirred at 20-25°C for 30-40 minutes and allowed to settle. Although some solid slurry was present in the aqueous phase it did not affect phase separation.
After separating out the aqueous phase the organic phase was washed with 50 mL of distilled water, then mL of saturated NaCl solution. The organic phase was concentrated to dryness yielding a yellowish solid, weighing ca. 20-35 g greater than 95 area pure by HPLC. The crude product was dissolved in WO 95/32178 PCT/US95/06539 150-200 mL of ethyl acetate under refluxing.
Thereafter, 50 mL of heptane was added to the hot solution. The weight/volume ratio of crude product to ethyl acetate is ca. 0.2:1. The volume ratio of ethyl acetate to heptane is 3:1. Although solids started to form at 40 0 C, the mixture was stirred and cooled to 20-25 0 C over 2 hours and then at 0-5 0 C for 4 hours. The mixture was filtered to recover the product and the flask and solids washed with 50 mL of ethyl acetate/heptane v/v) and dried under vacuum thereby forming a white solid (33 78.5% yield, 97.7 area by HPLC). The white solid was a racemic amino-alcohol of formula IIIa. Typically the yield after recrystallization is in the range of 70% and more product can be recovered from the filtrate. The product was analyzed by HPLC and should be greater than 95 area pure for use in the resolution step and, if not, then recrystallization should be repeated.
A 500 mL three-necked flask was charged with 304 mL of methanol and (+)-di-p-toluoyl-D-tartaric acid or its monohydrate (greater than 38%) (30.6 g., 76 mmol, 1.0 eq) and heated to 60-65 0 C with the stirring. The racemic amino-alcohol (20.0 76 mmol, 1.0 eq) was added in one portion to the heated solution with stirring. The heating is necessary for the formation of the salt and the production of a homogeneous solution. The solution was then cooled to room temperature over about 1.5 hours and held at room temperature (22 0 C) for 4 hours, then at 0°C.
The solid formed was recovered by filtration and the flask and cake rinsed with ca. 30 mL of ethyl acetate. The recovered solid was then dried under vacuum to give (21.2 g) of a white solid as the WO 95/32178 PCT/US95/06539 -26tartrate salt (80% ee in favor of the R-isomer, 42.7% yield or 85.4% yield based on available isomer). The ee was determined by HPLC on the free base, which was formed after neutralization with 5 weight Na 2
CO
3 in the presence of ethyl acetate. HPLC for optical purity may be conducted using a sumichiral OA 4900, 4.6 x 250 mm column and a mobile phase of 240(hexane):140(dichloromethane):20(methanol): l(trifluoacetic acid) and a UV detection wavelength of 280 nm. The ee of the mother liquor was 69.3% in favor of the S-isomer. The tartrate salt was dissolved in 374 mL of methanol at reflux. The concentration of the salt in methanol was about 5.7% w/v (the range of salt concentration is 5.5-6.0% w/v in methanol). The solution was cooled to room temperature (22°C) over 1.5 hours with stirring and then stirred at room temperature for an additional 4hours. The solution was further cooled to a temperature of 0°C for 1-2 hours. The solids were collected by filtration and washed with 25 mL of ethyl acetate and dried at 40°C at 28 inches of Hg for 2 hours to give the enriched tartrate salt (14.0 g, 99.1% ee of the R-isomer, 56% yield based on available isomer). The enriched salt was greater than 90% area pure by HPLC. Additional enriched salt was recovered from the filtrate by concentrating it to dryness and dissolving the residue in methanol at reflux to make a 5.0-5.5% w/v solution which was cooled at room temperature over 1.5-2 hours and stirred at room temperature for 3-4 hours at 0°C for 1 hour. The solids were recovered as above to give an enriched salt in 14% yield greater than 98% ee.
The solids were combined and transferred to a flask to which 375 mL of ethyl acetate was added thereby forming a slurry. 91.2 mL of Na 2
CO
3 solution WO 95/32178 PCT/US95/06539 -27weight aqueous solution) was added to the slurry with stirring at room temperature (22-25 0 C) for minutes. The amount of Na 2
CO
3 solution used represents two equivalents of Na 2
CO
3 for each equivalent of tartrate salt. The pH of the aqueous solution is preferably ca. 9-10 (pH paper or pH meter), if the pH is less than 9, more sodium carbonate should be added to the solution to obtain the preferred pH.
The solution was then heated to ca. 300C and the aqueous phase separated out. The organic phase was washed with 40 mL of Na 2
CO
3 solution (5 weight and 28 mL of saturated NaCl solution. The solution was kept at ca. 30 0 C to prevent the free amino alcohol from crystallizing out from the ethyl acetate solution. The removal of the di-toluoyl-D-tartaric acid by sodium carbonate extraction was followed by the HPLC method described hereinabove. The amount of tartaric acid left should be 0% area by HPLC and if it exceeds this amount, the organic phase is preferably washed again with a sodium carbonate solution. The organic phase was dried with 10 g of anhydrous Na 2
SO
4 and the organic solution concentrated to dryness which gave the free base as a white solid. The white solids were dissolved in mL of ethyl acetate under reflux and thereafter cooled to room temperature over 1 hour with stirring.
The solution remained at room temperature (22-250C) with stirring for 1 hour and then at 0°C for 2-3 hours. The white solid formed was recovered by filtration and dried at 400C (28 inches of Hg) for 2 hours to give an enriched R-amino-alcohol (5.0 g, 87.7% yield, greater than 99% ee, chemical purity greater than 99% area).
WO 95/32178 PCT/US95/06539 -28- The R-amino-alcohol (2.67 g, 10 mmol, 1.0 eq) was added to a 100 mL flame-dried three-necked flask previously charged with 20 mL of ethylene glycol dimethyl ether (DME) anhydrous, water less than 0.005%, This reaction and all subsequent operations were performed under dry nitrogen or argon and the reaction solutions and final products protected from light. Borane dimethyl sulfide complex (BH 3 eMe 2 S) (10 M, aldrich grade) 1.6 mL, mmol, 1.6 eq) was added dropwise to the above slurry over 5 minutes with stirring. Hydrogen is released and the reaction slightly exothermic (from 25°C to ca. 30 0 The solution is then heated at ca. 55 0
C
for 3 hours. The reaction is followed by HPLC and if after 3 hours of reaction starting material is still greater than 0.3% area, it is preferred that an additional 0.1 eq of BH 3 *Me 2 S be added and the solution heated at ca. 55 0 C for an additional hour.
It is preferred that the reaction is not heated over 60 0 C since higher temperatures may result in overreduction of the product. Once the reaction has progressed to the desired point heating was stopped and the solution cooled to 5-100C with use of an ice water bath. 40 mL of methanol was heated at reflux for 1 hour to destroy excess borane by forming trimethyl borane, freeing the albuterol product.
mL of solvent was distilled out at 60-66 0 C/1 atm and then an additional 20 mL of methanol was added.
Another 20 mL of the solvent was distilled out at 660/1 atm. The methylborate was removed azeotropically with methanol at 60-66 0 C. 70 mL of DME was then added followed by distilling out the solvent until the temperature reached 85°C. An additional ca. 10 mL of DME was added at 80-850C to maintain the solvent volume at 40-45 mL during WO 95/32178 PCT/US95/06539 -29distillation. The leftover methanol was removed azeotropically with the DME. The additional DME was added slowly at reflux to prevent precipitation of solids. The final solvent volume is preferably ca.
40-45 mL. The solution was checked by HPLC: the boron-complex (tRo 17.0 minutes) should be less than 0.4 area on HPLC otherwise additional DME should be added and distillation continued. Then 25 mL of cyclohexane was added slowly over 10 minutes, to prevent oil-out, at ca. 80 0 C. Heating was then stopped and the solution cooled to ca. 20-25°C (room temperature) over 1 hour and then to 0-5 0 C over 1 hour and maintained at this temperature for an additional 3 hours with stirring. The solution was cooled slowly to prevent oil-out. The white powder formed was recovered by filtration. The flask and solids underwent dual washings with 10 mL of cyclohexane, the solids were dried at 50-60 0 C/28 inches of Hg for over 12 hours. This yielded a white powder, (R)-albuterol of formula IVa (weight 1.9 g, yield, 98.4% area, 98% ee).
EXAMPLE-4 Racemic compound Ib (1.07g, 3 mmol) and di-p-toluoyltartaric acid (D-DTTA) (1.21 g, 3 mmol) are dissolved in 36 mL of methanol and refluxed for min. The resulting solution is then cooled to room temperature and stirred for about 4 hours. The white solid formed is isolated by filtration and dried under vacuum to give (R)-compound IIb, the chiral acid salt of compound IIIb (0.83 g, 37.2% yield). The salt is neutralized with 5 wt% aq. Na 2
CO
3 and extracted with ethyl acetate to give optically active form of compound Ic, the free base of WO 95/32178 PCT/US95/06539 compound IIb, as a white solid with 84.3% ee. The optical purity (ee) is determined by chiral HPLC (Column Sumichiral OA 4900, 5A, 4.6 x 230 mm column; Mobile phase: 240 (hexane): 140 (dichloromethane): (methanol): 1 (trifluoroacetic acid) (vol); UV detection: 280 nm).
(+)-D-dibenzoyltartaric acid (D-DBTA) (17.9g, mmol, 0.5 eq) is dissolved in 200 mL of methanol with heating to reflux. A solution of racemic compound Ib (35.7g, 100 mmol, 1.0 eq) in 200 mL of methanol is added to the above solution over 5-10 min. After addition, a white slurry is formed rapidly which is refluxed for 2 hours. The white slurry is then cooled to room temperature and stirred overnight.
The solid is collected by filtration and dried under vacuum (20% ee). The solid is then re-slurried in 600 mL of methanol under reflux for 2 hours and cooled to room temperature and stirred for 4 hours.
The solids are collected by filtration and dried under vacuum at room temperature for 2 hours to give a chiral acid salt, the form of compound IIb (23.8 g, 94.8% ee). The salt (21.5g, 40.1 mmol) is then treated with 100 g of 5 wt% aq. Na 2
CO
3 in 300 mL of ethyl acetate. After phase separation, the ethyl acetate phase is washed with 50 mL each of saturated aq. NaHC03 and NaC1 solutions and concentrated to dryness to give the free base of compound IIb, (R) form of compound Ib, as a white solid. The crude free base is then recrystallized from 15 mL of methanol and 30 mL of ethyl acetate to give purified form of compound IIIb as a white solid (12.0 g, 37.2% yield from racemic compound Ia, 99.0% ee and 99.9% purity).
WO 95/32178 PCT/US95/06539 -31- EXAMPLE-6
BH
3 -THF solution (1.OM in THF, 100 mL, 3.0 eq) is added dropwise over 30 minutes to a mixture of the form of compound IIIb taken from Example-2 (12.0 g, 33.3 mmol, 1.0 eq) and 50 mL THF at room temperature under nitrogen atmosphere. The resulting solution is refluxed for 23 hours and cooled and quenched with 30 mL of methanol. The solution is concentrated to ca. 20 mL in volume and diluted with 250 mL of ethyl acetate. The solution is stirred with 40 mL of 5 wt% aq. Na 2
CO
3 at room temperature for minutes. After removal of the aqueous layer, the organic phase is washed with 40 mL each of saturated aq. NaHCO 3 and NaCl solution and concentrated to dryness to give a crude (R)-4-benzyl albuterol (compound IVb) as an oily foam. The crude 4-benzyl albuterol is then recrystallized from 20 mL of ethyl acetate and 20 mL of n-heptane to give pure benzyl albuterol as white solid (8.1 g, 73.8% yield, 99.4% ee, 99.8% purity).
EXAMPLE-7 A mixture of (R)-4-benzyl albuterol from Example-3 (6.6g, 20 mmol) and 10% Pd/C (1.32 g) in mL of ethanol (denatured with 5 vol% 2-propanol) is shaken on a Parr-hydrogenator under 50 psi of hydrogen at room temperature for 2-3 hours. The catalyst is removed by filtration and the filtrate is concentrated to give crude (R)-albuterol (compound IVa). The crude albuterol (20 mmol) is dissolved in 20 mL of ethanol and treated with anhydrous HCl in ether (1.0 M, 19 mL, 0.95 eq) at 0-5 0 C. After 30 min at room temperature, 20 mL of methyl t-butyl ether WO 95/32178 PCT/US95/06539 -32- (MTBE) is added to the mixture and the resulting mixture is stirred at room temperature for 30 min and at 0-50C for 2 hours. The white solid (R)-albuterol hydrochloride (compound Vb) is collected by filtration and recrystallized from 52 mL of ethanol and 26 mL of MTBE to give pure (R)-albuterol hydrochloride as a white powder (4.6 g, 83.5% yield, 99.6% ee, 99.3% purity).
EXAMPLE-8 Racemic 4-benzyl albuterol (compound Ic) (0.66g, 2 mmol) and D-DTTA (0.81 g, 2 mmol) are dissolved in mL of ethyl acetate with heating. The solution is then cooled to room temperature and stirred for 4 hours. The resulting white solid is collected by filtration and dried under vacuum to give the (R) form of the chiral acid salt, compound IIc (0.66 g, 46% yield, 75.9% ee). The optical purity (ee) is determined on the free base by HPLC as in Example-4.
EXAMPLE-9 Racemic 4-benzyl albuterol (compound Ic) (0.66 g, 2 mmol) and (D-DBTA) (0.72 g, 2 mmol) are dissolved in 4 mL of ethyl acetate with heating at reflux for 10 min. The solution is then cooled to room temperature and stirred for 3 hours. The resulting solid is collected by filtration and dried to give form of the chiral acid salt, compound IIc (0.07 g, 50% yield, 83.5% ee).
WO 95/32178 PCT/US95/06539 -33- Racemic 4-benzyl albuterol (compound Ic) (0.66 g, 2 mmol) and D-DBTA (0.72 g, 2 mmol) are dissolved in 3.3 mL of 95% ethanol. The solution is heated at reflux for 10 min. and cooled to room temperature and stirred for 7 hours after seeding. The resulting solid is collected by filtration and dried to give the form of the chiral acid salt, compound IIc (0.30 g, 21.7% yield, 94.4% ee).
EXAMPLE 11 D-DBTA (32.2 g, 90 mmol, 1.0 eq) is added to a hot solution of racemic 4-benzyl albuterol (compound Ic) (29.6 g, 90 mmol, 1.0 eq) in 180 mL of anhydrous denatured ethanol (type 3A, denatured with 5 vol% 2propanol). The resulting solution is refluxed for min. and cooled to room temperature over 40 min and seeded with 99% ee (R)-4-benzyl albuterol D-DBTA salt (compound IIc). The mixture is cooled to 5-100 C and stirred for 1 hour. The white solid is collected by filtration and dried at 400C and 28 inches of Hg for 1 hour to give (R)-4-benzyl albuterol D-DBTA salt (compound IIc) (31.8 g, 50% yield, 83.6% ee). The solid is redissolved in 240 mL of ethanol at 55-60 0
C
and the solution is cooled to room temperature and stirred at room temperature for 2 hours and at 0-5 0
C
for 1 hour. The resulting solid is collected by filtration and dried at 400C and 28 inches of Hg for 2 hours as (R)-4-benzyl albuterol D-DBTA salt (22.9 g, 37.1% yield, 99.3% ee). The salt (22.9 g) is then treated with 204 mL of 5 wt% aq. Na 2
CO
3 solution in 570 mL of ethyl acetate. The solid is worked-up, and recrystallization from 30 mL of ethyl acetate and
-I
WO 95/32178 PCT/US95/06539 -34mL of n-heptane gives optically pure (R)-4-benzyl albuterol free base (compound IVb) as a white powder (10.1 g, 34.1% yield from racemic Compound Ic, 99.6% ee and 99.8% purity).
EXAMPLE 12 A mixture of (R)-4-benzyl albuterol as a free base (compound IVb) from Example 8 (3.2 g, 9.73 mmol) and 10% Pd/C (0.64 g) in 24 mL of ethanol (denatured with 5 vol% 2-propanol) is shaken on a Parrhydrogenator under 50 psi of hydrogen at room temperature for 3 hours. The catalyst is removed by filtration and the filtrate is concentrated to ca. 9 mL in volume containing crude (R)-albuterol (compound IVa) and treated with anhydrous HCl in ether (1.0 M, 9.5 mL, 0.98 eq) at 0-5°C. After 30 min. at room temperature, 9 mL of MTBE is added to the mixture and the resulting mixture is stirred at room temperature for 30 min. and at 0-5 0 C for 2 hours. The white solid (R)-albuterol hydrochloride is collected by filtration and recrystallized from 25 mL of ethanol and 12.5 mL of MTBE to give pure (R)-albuterol hydrochloride (compound Vb) as a white powder (2.17 g, 80.9% yield, 99.6% purity).
While the invention has been particularly shown and described with reference to preferred embodiments thereof, it will be understood by those skilled in the art that other changes in form and details may be made therein without departing from the spirit and scope of the invention.

Claims (25)

1. A method for obtaining a single enantiomer of methyl 5-[2-[(1,1-dimethylethyl)amino]-l- hydroxyethyl]-2-hydroxybenzoate comprising the steps of: dissolving a mixture of enantiomers of methyl 5-[2-[(1,1-dimethylethyl)amino]-l- hydroxyethyl]-2-hydroxybenzoate and a chiral acid selected from the group consisting of di-toluoyl-L-tartaric acid and (+)-di-toluoyl-D- tartaric acid in methanol by heating to form a solution; allowing said solution to cool, whereby a salt of primarily one stereoisomer crystallizes; separating said salt from said solution; recrystallizing said salt from methanol, whereby a diastereomeric salt having greater than 90% ee of an enantiomer of methyl

5-[2-((1,1-dimethylethyl)amino]-l-hydroxyethyl]- 2-hydroxybenzoate is obtained; separating said diastereomeric salt from the methanol solvent; and liberating said enantiomer of methyl 5-[2-[(l,l-dimethylethyl)amino]-l-hydroxyethyl]- 2-hydroxybenzoate from said diastereomeric salt by treatment with base. AMFNDED SHEET LIN rUl/US -b U b) -p iui 18 DEC 1995 -36- 2. A method for making optically pure albuterol comprising the steps of: dissolving a mixture of enantiomers of methyl 5-(2-[(1,1-dimethylethyl)amino)-l- hydroxyethyl]-2-hydroxybenzoate and a chiral acid selected from the group consisting of di-toluoyl-L-tartaric acid and (+)-di-toluoyl-D- tartaric acid in methanol by heating to form a solution; allowing said solution to cool, whereby a salt of primarily one stereoisomer crystallizes; separating said salt from said solution; recrystallizing said salt from methanol, whereby a diastereomeric salt having greater than 90% ee of an enant’irer of methyl 5-[2-[(l,l-dimethylethyl)amino]-l-hydroxyethyl]- 2-hydroxybenzoate is obtained; separating said diastereomeric salt from the methanol solvent; liberating the enantiomer of methyl [2-[(l,l-dimethylethyl)amino]-l-hydroxyethyl]-2- hydroxybenzoate from said diastereomeric salt by treatment with base; and reducing said enantiomer of methyl [2-[(1,1-dimethylethyl)amino]-l-hydroxyethyl]-2- hydroxybenzoate thereby forming optically active “‘4u 1 8 DEC1995 -37- albuterol. 3. The method of claim 2 wherein said enantiomer of 5-[2-[(,l-dimethylethyl)amino]-l- hydroxyethyl]-2-hydroxybenzoate is reduced with borane-methyl sulfide. 4. The method of claim 2 wherein said enantiomer of 5–[2-[(1,1-dimethylethyl)amino]-1- hydroxyethyl]-2-hydroxybenzoate is reduced with lithium aluminum hydride. The method of claim 2 wherein said mixture of enantiomers of methyl dimethylethyl)amino]-l-hydroxyethyl]-2- hydroxybensoate is obtained by the steps of: reacting methyl acetylsalicylate with hydrogen bromide in dimethyl sulfoxide, thereby forming a keto aldehyde; reacting said keto aldehyde with tert butylamine, thereby forming an a-iminoketone; and reducing said a-iminoketcne to provide methyl 5-[2-[(l,l-dimethylethyl)amino]-l- hydroxyethyl]-2-hydroxybenzoate.

6. A method according to claim 5 wherein said a-iminoketone is reduced with a hydride reducing agent.

7. The method of claim 5 wherein said hydride reducing agent is selected from the group consisting AMF~lcf S1-4FT PTUS 95 U653 9 IO C DEC 1995 -38- of sodium borohydride, sodium cyanoborohydride, and sodium triacetoxyborohydride.

8. A method according to claim 5 wherein said a-iminoketone is reduced by catalytic hydrogenation.

9. A method according to claim 8 wherein said catalytic hydrogenation is carried out over a heterogeneous noble-metal catalyst. The method of claim 9 wherein said heterogeneous noble-metal catalyst is Pd/C.

11. The method of claim 9 wherein said heterogeneous noble-metal catalyst is Pt/C.

12. The method of claim 9 wherein said heterogeneous noble-metal catalyst is PtO 2

13. A method for obtaining a single enantiomer of albuterc.l, comprising: dissolving a mixture of enantiomers of methyl 5-[2-[(1,l-dimethylethyl)amino]-l- hydroxyethyl]-2-(phenylmethoxy)benzoate and a chiral acid in methanol, ethanol or a mixture of the two by heating to form a solution, said chiral acid being selected from the group consisting of (-)-di-toluoyl-L-tartaric acid, (+)-di-toluoyl-D-tartaric acid, (-)-di-benzoyl- L-tartaric acid and (+)-di-benzoyl-D-tartaric acid; allowing said solution to cool, whereby a salt of primarily one enantiomer crystallizes; TII-_. «mncn CUCCT PGT/US^)5/Q6539 PTaS 5 18 EC199 -39- separating said salt from said solution; liberating the enantiomer from said salt by treatment with a base; reducing said enantiomer; debenzylating said enantiomer and recovering a single enantiomer of albuterol.

14. The method of claim 13 wherein said enantiomer is reduced with a borane complex. A method for obtaining a single enantiomer of albuterol, comprising: dissolving a mixture of enantiomers of a- [[(1,1-dimethylethyl)amino]methyl]-4- (phenylmethoxy)-1,3-benzenedimethanol and a chiral acid in methanol, ethanol or a mixture of the two by heating to form a solution, said chiral acid being selected from the group consisting of (-)-di-toluoyl-L-tartaric acid, (+)-di-toluoyl-D-tartaric acid, (-)-di-benzoyl- L-tartaric acid and (+)-dibenzoyl-D-tartaric acid; allowing said solution to cool, whereby a salt of primarily one enantiomer crystallizes; separating id salt from said solution; liberating said single enantiomer from said salt by treatment with a base; POUS 9 1 5 3 9′ debenzylating said enantiomer and recovering optically pure albuterol.

16. A method according to claim 13 or wherein said enantiomer is debenzylated by catalytic hydrogenation.

17. The method of claim 13 or 15 further comprising forming a slurry of said salt in methanol, ethanol or a mixture of the two and refluxing said slurry and allowing said slurry to cool, whereby a salt of primarily one enantiomer crystallizes.

18. A method for obtaining a single enantiomer of methyl 5-[2-[(l,l-dimethylethyl)amino]-l- hydroxyethyl]-2-(phenylmethoxy)benzoate comprising: dissolving a mixture of enantiomers of methyl 5-[2-[(1,1-dimethylethyl)amino)-l- hydroxyethyl]-2-(phenylmethoxy)benzoate and a chiral acid in methanol, ethanol or a mixture of the two by heating to form a solution, said chiral acid being selected from the group consisting of (-)-di-toluoyl-L-tartaric acid, (+)-di-toluoyl-D-tartaric acid, (-)-di-benzoyl- L-tartaric acid and (+)-di-benzoyl-D-tartaric acid by heating to form a solution; allowing said solution to cool, whereby a salt of primarily one stereoisomer crystallizes; separating said salt from said solution; r \Jl~d3ISDEC 19,~ -41- recrystallizing said salt from the alcohol solvent, whereby a diastereomeric salt having greater than 90% ee of an enantiomer of methyl 5-[2-[(1,1-dimethylethyl)amino]-i- hydroxyethyl]-2-(phenylmethoxy)benzoate is obtained; separating said diastereomeric salt from the alcohol solvent; and liberating said enantiomer of methyl [2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2- (phenylmethoxy)benzoate from said diastereomeric salt by treatment with base.

19. A method for obtaining a single enantiomer of a-[([(1,1-dimethylethyl)amino]methyl]-4- (phenylmethoxy)-1,3-benzenedimethanol comprising: dissolving a mixture of enantiomers of a-[[(1,1-dimethylethyl)amino]methyl]-4- (phenylmethoxy)-1,3-benzenedimethanol and a chiral acid in methanol, ethanol or a mixture of the two by heating to form a solution, said chiral acid being selected from the group consisting of (-)-di-toluoyl-L-tartaric acid, (+)-di-toluoyl-D-tartaric acid, (-)-di-benzoyl- L-tartaric acid and (+)-di-benzoyl-D-tartaric acid in methanol by heating to form a solution; allowing said solution to cool, whereby a salt of primarily one stereoisomer crystallized; AAAMOMM uCrr PrU- CT 95/0653 9 z 11 IS DEC 1995 -42- separating said salt from said solution; recrystallizing said salt from the alcohol solvent, whereby a diastereomeric salt having greater than 90% ee of an enantiomer of a-[[(1,1-dimethylethyl)amino]methyl]-4- (phenylmethoxy)-1,3-benzenedimethanol is obtained; separating said diastereomeric salt from the alcohol solvent; and liberating said enantiomer of dimethylethyl)amino]methyl]-4-(phenylmethoxy)- 1,3-benzenedimethanol from said diastereomeric salt by treatment with base. A method according to any of claims 1, 2, 13, 15, 18 or 19 wherein said chiral acid is toluoyl-D-tartaric acid and said enantiomer is the R enantiomer.

21. A method according to any of claims 1, 2, 13, 15, 18 or 19 wherein said chiral acid is benzoyl-D-tartaric acid and said enantiomer of is the R enantiomer.

22. A method according to claim 19 wherein said chiral acid is (+)-di-benzoyl-D-tartaric acid, said solvent ethanol and said enantiomer the R enantiomer. .rrn (1aa K i I I 43

23. A method for obtaining a single enantiomer of methyl dimethylethyl)amino]-l-hydroxyethyl]-2-hydroxybenzoate, substantially as hereinbefore described with reference to any one of the examples.

24. A method for making optically pure albuterol, substantially as hereinbefore described with reference to any one of the examples. A method for obtaining a single enantiomer of albuterol, substantially as hereinbefore described with reference to any one of the examples.

26. A method for obtaining a single enantiomer methyl dimethylethyl)amino]-l-hydroxyethyl]-2-(phenylmethoxy)benzoat,, substantially as hereinbefore described with reference to any one of the examples.

27. A method for obtaining a single enantiomer of dimethylethyl)amino]methyl]-4-(phenylmethoxy)-1,3-benzenedimethanol, substantially as hereinbefore described with reference to any one of the examples.

28. Methyl 5-[2-[(1,1-dimethylethyl)amino]-l-hydroxyethyl]-2-hydroxybenzoate, whenever prepared by the method of any one of claims 1 or 20 to 21 or 23.

29. Albuterol, whenever prepared by the method of any one of claims 2 to 17, to 21, 24 or

30. Methyl 5-[2-[(1,1-dimethylethyl)amino]-l-hydroxyethyl]-2- (phenylmethoxy)benzoate, whenever prepared by the method of any one of claims 18, S 20 to 21 or 26.

31. a-[[(1,1-dimethylethyl)amino]methyl]-4-(phenylmethoxy)-l,3- S benzenedimethanol, whenever prepared by the method of any one of claims 19 to 22 or 27. :Dated 10 December, 1996 25 Sepracor, Inc. Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON [n:\libc]00860:MEF IN~TE RNATIONAL SEARCH REI*’)R’r Int~roationttl applicAtion No. PCT/US95106S39 A. -CLASSJFICATION OF SUBJE& MA’TTER IPC(6) :CO7C 209/44, 227734 US CL :5601 42. 564/304, 356, 365 Accordinig’io lntcemationo! Patent Classification (IPC) or to both national classification anti IPC B. FIELDS SEARCHED Minimum documentation sew hed (clas-,ification system followed by classification symbols) U.S. :560/42; 564/304, 356, 365 Documentation searched othe;r than minimum documentation to thc cxtent that such documents arc included in thc fields searched Electronic data base consulted during the international search (name of data base and, where practicable, search terms used) C. DOCUMENTS CONSIDERED TO BE RELEVANT Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. A J. Med. Chem., Volume 14, issued 17 April 1971, Hartley et 1-31 al., “Absolute Configuration of the Optical Isomers of Salbutamol”, pages 895-896. A WO, A, 92/04314 (SCHERING CORPORATION) 19 March 1-31

1992. D Further documents are. istced in the continuation of Box C. D See patent family annex. Special catiegories of cited document do mtu udefining; the general stame of the ant which is not considered to be of particular relevance earlier document published on or after the international iling date document which may throw doubts on priority claim(s) or which is cited to establish the publication date of another citation or. other special reason (as specified) document referring to sn oral disclosure. use, exhibition or other document published prior to the international iling date but Inter than the priority, date claimed T later document published after the international riling date or priority date and not in conflict with the application but cited to understand the principle or theory Underlying the nvenoon document of particular relevance; the claimed invention cannot be considered novel or cannot be considered to involve an inventive se when the document is taken alone .Y document of particular relevance; the claimed invention cannot be considered to involve an inventive step when th~e document is combined with one or more other such documents, such combination being obvious to a person skilled in the sin docuzmetwsbcr of the same patent family— Date of the actual completion of the international search Date of 07 JULY 1995 Name and mailing address of the ISA/US Commissioner of Patents and Trademarks Blox PCT Washington, D.C. 2023 Facsimile No. (703) 305-3230 t cpho Form PCT/ISAI210 (srcond shct)(July 1992)*

AU25559/95A
1994-05-23
1995-05-23
Enantioselective preparation of optically pure albuterol

Expired

AU686386B2
(en)

Applications Claiming Priority (5)

Application Number
Priority Date
Filing Date
Title

US247302

1994-05-23

US08/247,302

US5399765A
(en)

1994-05-23
1994-05-23
Enantioselective preparation of optically pure albuterol

US08/376,072

US5545745A
(en)

1994-05-23
1995-01-20
Enantioselective preparation of optically pure albuterol

PCT/US1995/006539

WO1995032178A1
(en)

1994-05-23
1995-05-23
Enantioselective preparation of optically pure albuterol

US376072

1999-08-16

Publications (2)

Publication Number
Publication Date

AU2555995A

AU2555995A
(en)

1995-12-18

AU686386B2
true

AU686386B2
(en)

1998-02-05

Family
ID=26938588
Family Applications (1)

Application Number
Title
Priority Date
Filing Date

AU25559/95A
Expired

AU686386B2
(en)

1994-05-23
1995-05-23
Enantioselective preparation of optically pure albuterol

Country Status (11)

Country
Link

US
(1)

US5545745A
(en)

EP
(1)

EP0763010B1
(en)

JP
(1)

JP3826208B2
(en)

AT
(1)

ATE195931T1
(en)

AU
(1)

AU686386B2
(en)

DE
(1)

DE69518646T2
(en)

DK
(1)

DK0763010T3
(en)

ES
(1)

ES2151065T3
(en)

GR
(1)

GR3034982T3
(en)

PT
(1)

PT763010E
(en)

WO
(1)

WO1995032178A1
(en)

Families Citing this family (44)

* Cited by examiner, † Cited by third party

Publication number
Priority date
Publication date
Assignee
Title

US6136327A
(en)

1997-12-01
2000-10-24
Alza Corporation
Stereospecific delivery of a drug using electrotransport

US6365756B1
(en)

1998-02-20
2002-04-02
Fine Chemical Corporation Limited
Process for the production of optically enriched (R)- or (S)-albuterol

ZA994264B
(en)

1998-07-01
2000-01-25
Warner Lambert Co
Stereoisomers with high affinity for adrenergic receptors.

US7232837B2
(en)

1999-06-29
2007-06-19
Mcneil-Ppc, Inc.
Stereoisomers with high affinity for adrenergic receptors

US6451289B2
(en)

2000-03-24
2002-09-17
Sepracor Inc.
Albuterol formulations

GB0030171D0
(en)

2000-12-11
2001-01-24
Cipla Ltd
Process for preparing isomers of salbutamol

US6596686B2
(en)

2001-03-12
2003-07-22
International Flavors & Fragrances Inc.
Use of dihydropyrans as fragrance Material

US7407955B2
(en)

2002-08-21
2008-08-05
Boehringer Ingelheim Pharma Gmbh & Co., Kg
8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions

EP1572622B1
(en)

2002-12-10
2006-04-26
Sepracor Inc.
use of levalbuterol L-tartrate in the production of a metered dose inhaler

WO2004101592A1
(en)

2003-05-19
2004-11-25
Taisho Pharmaceutical Co., Ltd.
Process for production of erythromycin a derivatives

US20050020692A1
(en)

2003-07-24
2005-01-27
Ciofalo Vincent B.
Treatment of heaves

EP1684593A4
(en)

2003-11-20
2010-02-10
Alteragon Pty Ltd
Method of decreasing fat deposits and body weight in mammals and birds

JP2006528203A
(en)

2004-05-20
2006-12-14
テバファーマシューティカルファインケミカルズソチエタレスポンサビリタリミテ

Levalbuterol hydrochloride polymorph A

DE102004054054A1
(en)

2004-11-05
2006-05-11
Boehringer Ingelheim Pharma Gmbh & Co. Kg

Process for preparing chiral 8- (3-amino-piperidin-1-yl) -xanthines

RU2440972C2
(en)

2004-12-17
2012-01-27
Сипла Лимитед
Crystalline levosalbutamol sulfate, method of its obtaining and pharmaceutical composition, which contains it

EP2311793A1
(en)

2004-12-17
2011-04-20
Cipla Ltd.
Crystalline levosalbutamol sulphate (Form II)

EP1832572A1
(en)

2006-03-08
2007-09-12
Stirling Products Limited
Process for the enantiomeric enrichment of salbutamol and salbutamol precursors

EP1852108A1
(en)

2006-05-04
2007-11-07
Boehringer Ingelheim Pharma GmbH & Co.KG
DPP IV inhibitor formulations

CN107235980A
(en)

2006-05-04
2017-10-10
勃林格殷格翰国际有限公司
Polymorphic

PE20080251A1
(en)

2006-05-04
2008-04-25
Boehringer Ingelheim Int

USES OF DPP IV INHIBITORS

ES2431844T3
(en)

2006-08-02
2013-11-28
Aarti Healthcare Limited

Process for the preparation of (R) – (-) – optically pure salbutamol and its pharmaceutically acceptable salts

EP1935872A1
(en)

2006-12-11
2008-06-25
Stirling Products Limited
Process for obtaining the R-enantiomer of salbutamol

AU2008331928B2
(en)

2007-12-03
2012-08-16
Bridge Pharma, Inc.
Use of RR/SR-ractopamine

PE20140960A1
(en)

2008-04-03
2014-08-15
Boehringer Ingelheim Int

FORMULATIONS INVOLVING A DPP4 INHIBITOR

UY32030A
(en)

2008-08-06
2010-03-26
Boehringer Ingelheim Int

“TREATMENT FOR DIABETES IN INAPPROPRIATE PATIENTS FOR THERAPY WITH METFORMIN”

KR20200118243A
(en)

2008-08-06
2020-10-14
베링거 인겔하임 인터내셔날 게엠베하
Treatment for diabetes in patients inappropriate for metformin therapy

CA2741700A1
(en)

2008-10-24
2010-04-29
Biolink Life Sciences, Inc.
Stable, water-insoluble r-(+)-.alpha.-lipoic acid salt useful for the treatment of diabetes mellitus and its co-morbidities

WO2010072776A1
(en)

2008-12-23
2010-07-01
Boehringer Ingelheim International Gmbh
Salt forms of organic compound

AR074990A1
(en)

2009-01-07
2011-03-02
Boehringer Ingelheim Int

TREATMENT OF DIABETES IN PATIENTS WITH AN INAPPROPRIATE GLUCEMIC CONTROL THROUGH METFORMIN THERAPY

WO2011064352A1
(en)

2009-11-27
2011-06-03
Boehringer Ingelheim International Gmbh
Treatment of genotyped diabetic patients with dpp-iv inhibitors such as linagliptin

JP6034781B2
(en)

2010-05-05
2016-11-30
ベーリンガーインゲルハイムインターナショナルゲゼルシャフトミットベシュレンクテルハフツング

Combination therapy

ES2953123T3
(en)

2010-06-24
2023-11-08
Boehringer Ingelheim Int

Diabetes therapy

US9034883B2
(en)

2010-11-15
2015-05-19
Boehringer Ingelheim International Gmbh
Vasoprotective and cardioprotective antidiabetic therapy

JP5876150B2
(en)

2011-07-15
2016-03-02
ベーリンガーインゲルハイムインターナショナルゲゼルシャフトミットベシュレンクテルハフツング

Substituted quinazolines, their preparation and their use in pharmaceutical compositions

US9555001B2
(en)

2012-03-07
2017-01-31
Boehringer Ingelheim International Gmbh
Pharmaceutical composition and uses thereof

WO2013171167A1
(en)

2012-05-14
2013-11-21
Boehringer Ingelheim International Gmbh
A xanthine derivative as dpp -4 inhibitor for use in the treatment of podocytes related disorders and/or nephrotic syndrome

WO2013174767A1
(en)

2012-05-24
2013-11-28
Boehringer Ingelheim International Gmbh
A xanthine derivative as dpp -4 inhibitor for use in modifying food intake and regulating food preference

JP6486358B2
(en)

2013-08-15
2019-03-20
アラーガン、インコーポレイテッドＡｌｌｅｒｇａｎ，Ｉｎｃｏｒｐｏｒａｔｅｄ

(−)-(2R, 3S) -2-amino-3-hydroxy-3-pyridin-4-yl-1-pyrrolidin-1-yl-propan-1-one • (L)-(+) tartrate; Its manufacturing method and use

WO2015128453A1
(en)

2014-02-28
2015-09-03
Boehringer Ingelheim International Gmbh
Medical use of a dpp-4 inhibitor

EP3042892A1
(en)

2015-01-09
2016-07-13
Deva Holding Anonim Sirketi
Amorphisation of levosalbutamol tartrate

EP3468562A1
(en)

2016-06-10
2019-04-17
Boehringer Ingelheim International GmbH
Combinations of linagliptin and metformin

KR20230081285A
(en)

2021-11-30
2023-06-07
주식회사 브이에스팜텍
Preparation method for single isomer with high purity

CN115286521B
(en)

2022-07-11
2023-11-03
上海医药集团(本溪)北方药业有限公司
Synthesis method of levosalbutamol hydrochloride

CN116836069A
(en)

2023-06-02
2023-10-03
山东锐顺药业有限公司
Preparation method of levosalbutamol hydrochloride

Family Cites Families (1)

* Cited by examiner, † Cited by third party

Publication number
Priority date
Publication date
Assignee
Title

CA2091352C
(en)

1990-09-11
1996-12-03
Chou-Hong Tann
Process for preparing albuterol, acetal, hemi-acetal, and hydrates of arylglyoxal intermediates thereof

1995

1995-01-20
US
US08/376,072
patent/US5545745A/en
not_active
Expired – Lifetime

1995-05-23
JP
JP53051395A
patent/JP3826208B2/en
not_active
Expired – Lifetime

1995-05-23
EP
EP95919913A
patent/EP0763010B1/en
not_active
Expired – Lifetime

1995-05-23
DE
DE69518646T
patent/DE69518646T2/en
not_active
Expired – Lifetime

1995-05-23
AU
AU25559/95A
patent/AU686386B2/en
not_active
Expired

1995-05-23
DK
DK95919913T
patent/DK0763010T3/en
active

1995-05-23
ES
ES95919913T
patent/ES2151065T3/en
not_active
Expired – Lifetime

1995-05-23
WO
PCT/US1995/006539
patent/WO1995032178A1/en
active
IP Right Grant

1995-05-23
PT
PT95919913T
patent/PT763010E/en
unknown

1995-05-23
AT
AT95919913T
patent/ATE195931T1/en
active

2000

2000-11-24
GR
GR20000402605T
patent/GR3034982T3/en
unknown

Also Published As

Publication number
Publication date

ATE195931T1
(en)

2000-09-15

AU2555995A
(en)

1995-12-18

EP0763010B1
(en)

2000-08-30

PT763010E
(en)

2000-12-29

JP3826208B2
(en)

2006-09-27

DE69518646T2
(en)

2001-04-19

GR3034982T3
(en)

2001-02-28

EP0763010A1
(en)

1997-03-19

DK0763010T3
(en)

2001-01-08

ES2151065T3
(en)

2000-12-16

EP0763010A4
(en)

1997-07-16

DE69518646D1
(en)

2000-10-05

US5545745A
(en)

1996-08-13

WO1995032178A1
(en)

1995-11-30

JPH10500954A
(en)

1998-01-27

Contact information