GB2380996A - Hydroxy-nitrobenzene derivatives useful in the preparation of formoterol - Google Patents

Hydroxy-nitrobenzene derivatives useful in the preparation of formoterol Download PDF

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GB2380996A
GB2380996A GB0122608A GB0122608A GB2380996A GB 2380996 A GB2380996 A GB 2380996A GB 0122608 A GB0122608 A GB 0122608A GB 0122608 A GB0122608 A GB 0122608A GB 2380996 A GB2380996 A GB 2380996A
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protecting group
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Olivier Lohse
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Novartis AG
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    • C07D303/02—Compounds containing oxirane rings
    • C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
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    • C07C205/20—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups having nitro groups and hydroxy groups bound to carbon atoms of six-membered aromatic rings
    • C07C205/21—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups having nitro groups and hydroxy groups bound to carbon atoms of six-membered aromatic rings having nitro groups and hydroxy groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C205/22—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups having nitro groups and hydroxy groups bound to carbon atoms of six-membered aromatic rings having nitro groups and hydroxy groups bound to carbon atoms of the same non-condensed six-membered aromatic ring having one nitro groups bound to the ring
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    • C07C205/37—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system the oxygen atom of at least one of the etherified hydroxy groups being further bound to an acyclic carbon atom
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    • C07C205/35—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C205/36—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system
    • C07C205/38—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system the oxygen atom of at least one of the etherified hydroxy groups being further bound to a carbon atom of a six-membered aromatic ring, e.g. nitrodiphenyl ethers
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Abstract

Compounds of formula <EMI ID=1.1 HE=42 WI=57 LX=806 LY=816 TI=CF> <PC>where R is hydrogen or a hydroxy-protecting group, are useful in the preparation of optically pure enantiomers of formoterol.

Description

<Desc/Clms Page number 1>
Organic Compounds This invention relates to organic compounds useful as intermediates in the preparation of optically pure enantiomers of formoterol and to the preparation of such compounds.
Formoterol, N-[2-hydroxy-S- (l-hydroxy-2- ( (2- (4-methoxyphenyl) -1-methylethyl) amino) - ethyl) phenyl] formamide, and its fumarate salt are selective beta 2-agonists which are useful as bronchodilators in the treatment of asthma.
It has now been found that certain novel compounds facilitate the production of optically pure enantiomers of formoterol without the need for complex chromatographic separation techniques.
Accordingly, the present invention provides in one aspect a compound of formula
where R is hydrogen or a hydroxy-protecting group.
Hydroxy-protecting groups are well known to those skilled in the art. R as a hydroxyprotecting group may be any known such group, for example as described in Protective Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, John Wiley & Sons Inc, Second Edition, 1991, particularly pages 10 to 174.
Preferably R as a hydroxy-protecting group is a group which can be removed by catalytic hydrogenolysis, for example using palladium on charcoal as catalyst. Examples of such groups are aryl-or aryloxy-substituted methyl groups such as benzyl, diphenylmethyl, triphenylmethyl and benzyloxymethyl. In an especially preferred compound of formula I, R is benzyl.
<Desc/Clms Page number 2>
The present invention provides, in another aspect, a process for the preparation of a compound of formula I which comprises asymmetric dihydroxylation of a compound of formula
where R 1 is a hydroxy-protecting group as hereinbefore described and, optionally, converting the protecting group Ru in the resulting compound of formula I into hydrogen.
The assymetric dihydroxylation of a compound of formula II may be carried out using known assymetric olefin dihydroxylation procedures, for example in the presence of an osmium-containing catalyst. In a convenient procedure, the compound of formula II is mixed with a chiral ligand, an organic solvent, water, an oxidant and an osmium-containing
catalyst. Suitable chiral ligands, organic solvents, oxidants, osmium-containing compounds, and reaction conditions for effecting such osmium-catalysed assymetric dihydroxylation are described in US Patents 4871855, 4965364, 5126494 and 5227543, and in Kolb et al Chem.
Rev. 1994,94, 2483-2547, which are incorporated herein by reference.
The osmium catalyst is usually osmium tetroxide or potassium osmate dihydrate, K2üsÜ2 (OH) 4. The amount of osmium catalyst may be, for example, from 0.1 to 1 mol%, e. g. 0.2 to 0.4 mol%, based on the molar amount of compound of formula II.
The chiral ligand may be, for example, a cinchona alkaloid derivative, usually a dihydroquinidine (DHQD) or dihydroquinine (DHQ) derivative, preferably a phthalazine (PHAL) or diphenylpyrimidine (PYR) derivative thereof, especially (DHQD) 2 ? HAL or (DHQ) 2 ? HAL. The amount of chiral ligand may be from about 0. 001M to 2M.
The organic solvent may be, for example, acetonitrile, a hydrocarbon such as hexane, cyclohexane or toluene, a ketone such as acetone or pinacolone, a tertiary alcohol such as tert-butanol or tert-amyl alcohol, an ether such as diethyl ether, tert-butyl methyl ether or tetrahydrofuran, or a mixture of two or more such organic solvents. In preferred
<Desc/Clms Page number 3>
embodiments of the invention, when the chiral ligand is (DHQD) 2PHAL or (DHQ) 2PHAL, the solvent is preferably tert-butanol or tert-amyl alcohol.
The oxidant may be, for example, hydrogen peroxide, an organic peroxy compound such as tert-butyl hydroperoxide, an amine oxide such as the commercially available Nmethylmorpholine N-oxide, an alkali metal hypochlorite such as sodium hypochlorite, an alkali metal chlorate, bromate or iodate such as Clos, KBr03 or KI03, an alkali metal ferricyanide such as potassium ferricyanide optionally together with a strong base such as potassium carbonate, or sodium hydroxide, or oxygen together with a suitable metal catalyst such as a copper, platinum or palladium catalyst. The amount of oxidant is generally from 100 to 500 mol% based on the molar amount of the compound of formula II.
Another suitable oxidant is a mixture of an alkali metal ferricyanide and sodium peroxodisulfate, NazSOg. Using this oxidant, the amount of ferricyanide can be reduced to a catalytic level, e. g. 10 to 50 mol %, such as 20 to 40 mol %, based on the molar amount of the compound of formula II while the amount of peroxydisulfate may be generally from 100 to 200 mol % based on the molar amount of the compound of formula II.
The amount of water in the reaction mixture may generally be from about 10 to 20 mol, more usually from 12 to 15 mol, per mol of compound of formula II.
An additive which accelerates hydrolysis of osmate ester intermediates may optionally be included in the reaction mixture. This additive may be an acid or, preferably, a base, particularly a salt of a water-soluble carboxylic acid having an organic-solubilizing counterion such as a quaternary ammonium ion. Suitable such salts include tetramethylammonium acetate, tetraethylammonium acetate and benzyltrimethylammonium acetate. Another optional component of the reaction mixture is a sulfonamide such as methanesulfonamide, p-toluenesulfonamide or p-nitrobenzenesulfonamide.
The osmium-catalysed dihydroxylation may be carried out over a wide temperature range, the limits of which are determined primarily by the nature of the organic solvent. For
example, it may be carried out at a temperature from about-30 C to 50 C, preferably from 20 to 40 C. The product may be isolated from the reaction mixture using known procedures.
<Desc/Clms Page number 4>
The osmium-catalysed dihydroxylation is conveniently carried out, particularly for smallscale preparations, using a premix of KOsOOI- as catalyst, chiral ligand, and potassium ferricyanide and potassium carbonate as oxidant. Such premixes are commercially available from Aldrich Chemical Co. as AD-mix-ss, in which the ligand is (DHQD) 2PHAL and ADmix-a, in which the ligand is (DHQ) 2PHAL. AD-mix-p is preferred. For an AD-mix-P containing, by weight, 70% K3Fe (CN) 6,29. 4% KCOs, 0. 5% (DHQDhPHAL, and 0. 1% K2Os02 (OH) 4, it is convenient to use about 1. 4g of this mix per mmol of compound of formula II. The reaction procedure using such premixes may be, for example, as described by Kolb et al, op. cit. , or analogously as hereinafter described in the Examples.
The compound of formula II may be prepared by olefination of an aldehyde of formula
where R1 is a hydroxy-protecting group as hereinbefore defined. This olefination is preferably effected by a Wittig reaction, in which the aldehyde is reacted with a phosphorane, which may be generated in situ by reaction of a phosphonium salt with a base such as butyllithium, sodium amide, sodium hydride or a sodium alkoxide. The Wittig reaction may be carried out using known procedures, or variations thereof as described hereinafter in the Examples, for example in a solvent such as tetrahydrofuran (THF).
The aldehyde of formula III may be prepared by subjecting the corresponding unprotected hydroxy-substituted aldehyde to a protecting reaction to introduce the protecting group R1 using known procedures or variations thereof as described hereinafter in the Examples.
When R'is benzyl, for example, the free hydroxy aldehyde may be reacted with benzyl bromide in the presence of potassium carbonate and tetrabutylammonium iodide in isopropyl acetate.
In another aspect, the present invention provides the use of a compound of formula I as hereinbefore described for the preparation of an optically pure enantiomer of formoterol, particularly R, R-formoterol.
<Desc/Clms Page number 5>
The term"optically pure enantiomer"as used herein denotes an enantiomer which contains at least 95%, preferably at least 98%, especially at least 99%, by weight of an antipode with defined configuration, e. g. according to the known rules of sequencing of Kahn, Ingold and Prelog.
The compound of formula I may be converted into R, R-formoterol by (a) converting it into an epoxide of formula
where R 1 is a hydroxy-protecting group as hereinbefore described, (b) converting the compound of formula IV into a compound of formula
where R1 is a hydroxy-protecting group as hereinbefore described and R2 is an amineprotecting group, (c) reducing the compound of formula V to a compound of formula
<Desc/Clms Page number 6>
where R1 is a hydroxy-protecting group and R2 is an amine-protecting group, (d) formylating the compound of formula VI to give a compound of formula
where Ru ils a hydroxy-protecting group and R2 is an amine-protecting group, and (e) converting the protecting groups R and R in the compound of formula VII into hydrogen to give R, R-formoterol, which is recovered in free form or as a pharmaceutically acceptable salt thereof, preferably a fumarate salt.
The amine-protecting group R2 in compounds of formulae V, VI, VII and VIII may be any known such group, for example as described by Greene and Wuts, op. cit. , particularly pages 309-405. Preferably R2 is a group which can be removed by catalytic hydrogenolysis, for example using a palladium/charcoal catalyst. Such groups include triphenylmethyl, benzyloxycarbonyl and, preferably, benzyl.
Step (a) may be effected using known procedures for the stereospecific conversion of 1,2diols into epoxides, e. g. by reaction of the compound of formula I with a cyclic orthoacetate, such as trimethyl orthoacetate, and acetyl bromide, acetyl chloride or trimethylsilylchloride and base-mediated saponification of the product in methanol, as described by Kolb and Sharpless, Tetradedron 1992,48, 10515-30.
Step (b) may be carried out by reacting the compound of formula IV with a compound of formula
<Desc/Clms Page number 7>
where R2 is an amine-protecting group as hereinbefore described. This reaction may be carried out using known procedures for epoxide-amine reactions, for example by heating the compounds of formulae IV and VIII at elevated temperature, e. g. 90 to 110 C.
Step (c) may be carried out by known methods for reduction of aromatic nitro compounds to amines, for example by catalytic hydrogenation using a platinum/carbon catalyst using known procedures. Step (d) may be effected by known formylation procedures, e. g. by reaction of the compound of formula VI with a preformed mixture of formic acid and acetic anhydride, which mixture has preferably been prepared at least 3 hours before reaction with the amine of formula VI in order to avoid significant by-product formation. Step (e), the deprotection step, may be carried out using known procedures for the cleavage of protecting groups, for example as described by Greene and Wuts, op. cit. Preferably, where R1 and R2 are benzyl, step (e) is effected by catalytic hydrogenolysis using a palladium/charcoal catalyst in ethanol and known procedures. R, R-formoterol may be recovered in free form or may be converted into a fumarate salt thereof by, for example, reacting the free compound with fumaric acid, or reacting a sodium or potassium salt thereof with fumaric acid or the acid chloride thereof using known procedures.
The invention is illustrated by the following Examples.
Example 1 4- (Phenylmethoxy) -3-nitrobenzaldehyde - Intermediate I A 1. 5-liter flask is charged with 40. 45 g of 4-hydroxy-3-nitro-benzaldehyde (0.24 mol), 0. 4 L of isopropyl acetate and 0.885 g of tetrabutylammonium iodide. Benzyl bromide (62.1 g, 0.36 mol) is added in 5 minutes and the solution is heated to 70 C. A solution of potassium carbonate (50.2 g, 3.6 mol) in water (0.4 L) is added in 15 minutes. The suspension is stirred
at 70 C for 3. 5 hours before addition of another 24. 7 g (0. 14 mol) of benzyl bromide. After 20 hours at 70 C, the reaction mixture is cooled to 20 C and the phases are separated. The aqueous phase is extracted with isopropyl acetate (0.3 L) and the combined organic phases are washed twice with water (0.4 L). The organic phase is evaporated to dryness and the residue is dissolved at 50 C in isopropyl acetate (0.16 L) and n-hexane (0.14 L). 0.4 L of nhexane are slowly added and the suspension is cooled to 0 C in 3 hours. The solid is filtered
<Desc/Clms Page number 8>
and washed with cold n-hexane (0.12 L). After drying in vacuum, 4- (phenylmethoxy)-3- nitrobenzaldehyde is obtained as a yellow powder.
4-phenylmethoxy-3-nitrostyrene-Intermediate n A 1-liter flask is charged with 41.66 g (0.116 mol) of methyltriphenylphosphonium bromide and 200 mL of tetrahydrofuran under argon. The suspension is cooled to 0 C and 72.5 mL of a n-butyllithium solution (1.6 M) in hexane is added within 50 minutes. The solution is stirred at 0 C for 1.5 hours and a solution of Intermediate I (25 g, 0.097 mol) in 200 mL tetrahydrofuran is slowly added. The obtained suspension is warmed to 20 C, stirred for 1 hour and quenched by addition of 475 mL of water and 500 mL of toluene. The phases are separated and the aqueous phase is extracted twice with 100 mL of toluene. The combined organic phases are washed with 250 mL of brine and dried over sodium sulfate. The organic phase is evaporated to dryness and the residue is suspended at 45 C in 250 mL of ter-butyl methyl ether. The suspension is filtered and the resulting solution is concentrated under vacuum. Intermediate II crystallises out as a fine yellow powder. The mother liquors are purified by chromatography over silica gel, eluting with a heptane-ethyl acetate gradient to give Intermediate II as a yellow powder having a melting point of 95. 1 C.
(R)-2-Hydroxy-2-(4'-phenylmethoxy-3'-nitrophenyl)-ethanol-Compound1 A 200-mL flask is charged with 11,2 g of AD mix-ss (Aldrich), 40 mL of water and 40 mL of tert-butanol. The mixture is stirred for 30 minutes at 20 C and 2.04 g (8 mmol) of Intermediate II are added. The suspension is stirred at 20 C for 48 hours and quenched by addition of sodium sulfite (0.3 g). The phases are separated and the aqueous phase is extracted three times with 100 mL of ethyl acetate. The combined organic phases are washed with brine (50 mL) and dried over sodium sulfate. The solution is evaporated and the crude diol dried in vacuum to yield a white solid containing 98.5% of the R-isomer.
Recrystallization of the diol in ethyl acetate/n-heptane (1: 1) improves the purity to 99. 2% Risomer (mp 80 C, [a]D20 -41. 6 (c=l, CHCL ;)).
Example 2 (R)-[3-nitro-4-(phenylmethoxy)phenyl]-oxirane - Compound 2
<Desc/Clms Page number 9>
A 100-mL flask under argon is charged with 3.76 g of Compound I (0.013 mol), 20 mL of dichloromethane, 2.3 mL (0.018 mol) of trimethylorthoacetate and 32.5 mg of paratoluenesulfonic acid. The mixture is stirred for 1 hour at 20 C and concentrated under vacuum. The residue is dissolved in 26 mL of dichloromethane and acetyl bromide (1.17 mL, 0.0158 mol) is added. The reaction mixture is stirred for 1.75 hours at 20 C before addition of 52 mL of methanol and 3.12 g (0.0226 mol) of potassium carbonate. The suspension is stirred for 30 minutes and quenched by addition of 100 mL of saturated aqueous ammonium chloride. The phases are separated and the aqueous phase is extracted three times with 100 mL of ethyl acetate. The combined organic phases are washed with 80 mL of water, dried over sodium sulfate and evaporated to dryness. The epoxide is dried in vacuum to yield Compound 2 as a grey powder having a melting point of 74. 6 C (99% (R)-isomer, [a] o- 13.3 (c=l, CHC13)).
(R, R) -a-[[[2- ( 4-Methoxyphenyl) -1-methylethyl] (phenylmethyl) amino ]methyl]-3-nitro-4- (phenylmethoxy)-benzenemethanol-Compound 3 A 10 mL flask under argon is charged with 2.71 g (0.01 mol) of Compound 2 and 3.36 g (0.013 mol) of an amine of formula VIII in which R2 is benzyl. The flask is closed and the mixture is heated at 100 C for 13 hours. The crude product is purified by chromatography over silica gel, eluting with a heptane/ethyl acetate gradient. Compound 3 is recovered as an oil.
(R, R)-3-ammo-a- [ [ [2- (4-methoxyphenyl)-l-methylethyl] (phenylmethyl) ammo] methyl]-4- (phenylmethoxy)-benzenemethanol-Compound 4 A solution of 3.307 g (6.28 mmol) of Compound 3 in 160 mL of tetrahydrofuran is hydrogenated in a Parr hydrogenator in the presence of 1 g of platinum on charcoal (5%) catalyst at 45-50 psi for 10-24 hours until hydrogen uptake ceases. The reaction mixture is filtered over a bed of diatomaceous earth and concentrated to dryness. The product is dried in vacuum to yield crude Compound 4 as an oil.
N-[5-[(1R)-Hydroxy-2-[[(1R)-methyl-2-(4-methoxyphenyl)ethyl] (phenylmethyl) amino ethyl]- 2-(phenylmethoxy)phenyl]-formamide - Compound 5
<Desc/Clms Page number 10>
A 100-mL flask under argon is charged with 2.296 g (4.62 mmol) of Compound 4,20 mL of toluene and 20 mL of tetrahydrofuran. A mixture of 0.505 mL (5.28 mmol) of acetic acid anhydride and 0.367 mL (7.92 mmol) of formic acid is stirred for 3 hours prior to addition to the solution of Compound 4. The reaction mixture is allowed to stir for 15 minutes and then diluted with toluene and evaporated to dryness. The crude product is purified by chromatography over silica gel eluting with a methylene chloride/ethyl acetate gradient.
Compound 5 is obtained as an oil.
N- [2-Hydroxy-5- [ (lR)-l-hydroxy-2- [ [ (lR)-2- (4-methoxyphenyl)-l- methylethyl] amino] ethyl] phenyl]- formamide- (R, R)-Formoterol A solution of 0.940 g (1.79 mmol) of Compound 5 in 43 mL of ethanol is hydrogenated in a Parr hydrogenator in the presence of 0.1 g of palladium on charcoal (10%) catalyst at 45-50 psi for 3-4 hours until hydrogen uptake ceases. The reaction mixture is filtered over a bed of diatomaceous earth and concentrated to dryness. The product is dried in vacuum to yield (R, R)-formoterol. HPLC analysis indicates an enantiomeric purity higher than 99% (S, Senantiomer not detectable).

Claims (19)

  1. Claims 1. A compound of formula
    where R is hydrogen or a hydroxy-protecting group.
  2. 2. A compound according to claim 1, in which R is a group which can be removed by catalytic hydrogenolysis.
  3. 3. A compound according to claim 2, in which R is a group which can be removed by catalytic hydrogenolysis using palladium on charcoal as catalyst.
  4. 4. A compound according to claim 1, in which R is an aryl-or aryloxy-substituted methyl group.
  5. 5. A compound according to claim 1, in which R is benzyl.
  6. 6. A process for the preparation of a compound according to claim 1, which comprises asymmetric dihydroxylation of a compound of formula
    where R1 is a hydroxy-protecting group as defined in any of claims 1 to 5 and, optionally, converting the protecting group Ru in the resulting compound of formula I into hydrogen.
    <Desc/Clms Page number 12>
  7. 7. A process according to claim 6, in which the assymetric dihydroxylation of a compound of formula II is carried out in the presence of an osmium-containing catalyst.
  8. 8. A process according to claim 7, in which the compound of formula II is mixed with a chiral ligand, an organic solvent, water, an oxidant and an osmium-containing catalyst.
  9. 9. A process according to claim 8, in which the osmium catalyst is osmium tetroxide or potassium osmate dihydrate, KOstOH) .
  10. 10. A process according to any one of claims 7 to 9, in which the chiral ligand is a dihydroquinidine (DHQD) or dihydroquinine (DHQ) derivative.
  11. 11. A process according to claim 10 in which the chiral ligand is a phthalazine (PHAL) derivative of DHQD or DHQ, especially (DHQDPHAL or (DHQ) 2PHAL.
  12. 12. A process according to any one of claims 7 to 11, in which the organic solvent is acetonitrile, a hydrocarbon, a ketone, a tertiary alcohol, an ether, or a mixture of two or more such organic solvents.
  13. 13. A process according to claim 12, in which the solvent is tert-butanol or tert-amyl alcohol.
  14. 14. A process according to any one of claims 7 to 13, in which the oxidant is hydrogen peroxide, an organic peroxy compound, an amine oxide, an alkali metal hypochlorite, an alkali metal chlorate, bromate or iodate, an alkali metal ferricyanide optionally together with a strong base, oxygen together with a metal catalyst, or a mixture of an alkali metal ferricyanide and sodium peroxydisulfate, Na2S20s.
  15. 15. A process according to any one of claims 6 to 14, which is carried out at a temperature from 20 to 40 C.
  16. 16. A process according to any one of claims 8 to 15, in which K2Os02 (OH) 4 as catalyst, (DHQD) 2PHAL as ligand, and potassium ferricyanide and potassium carbonate as oxidant are used in the form of a premix.
    <Desc/Clms Page number 13>
  17. 17. The use of a compound according to any one of claims 1 to 5 for the preparation of an optically pure enantiomer of formoterol.
  18. 18. Use according to claim 17, in which the enantiomer is R, R-formoterol.
  19. 19. A method of converting a compound according to any one of claims 1 to 5 into R, Rformoterol which comprises (a) converting a compound according to any one of claims 1 to 5 into an epoxide of formula
    where Ru ils a hydroxy-protecting group as defined in any one of claims 1 to 5, (b) converting the compound of formula IV into a compound of formula
    where R1 is a hydroxy-protecting group as defined in any one of claims 1 to 5 and R2 is an amine-protecting group, (c) reducing the compound of formula V to a compound of formula
    <Desc/Clms Page number 14>
    where R1 is a hydroxy-protecting group as defined in any one of claims 1 to 5 and R2 is an amine-protecting group, (d) formylating the compound of formula VI to give a compound of formula
    where Ru ils a hydroxy-protecting group as defined in any one of claims 1 to 5 and R2 is an
    amine-protecting group, and (e) converting the protecting groups R 1 and R 2 in the compound of formula VII into hydrogen to give R, R-formoterol, which is recovered in free form or as a pharmaceutically acceptable salt thereof.
GB0122608A 2001-09-19 2001-09-19 Hydroxy-nitrobenzene derivatives useful in the preparation of formoterol Withdrawn GB2380996A (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009147383A1 (en) * 2008-06-02 2009-12-10 Cipla Limited Process for the synthesis of arformoterol
CN106565527A (en) * 2016-11-02 2017-04-19 北京万全德众医药生物技术有限公司 Preparation method of arformoterol tartrate methanamide intermediate
CN111018902A (en) * 2019-12-02 2020-04-17 苏州凯瑞医药科技有限公司 Formoterol important intermediate and synthetic method thereof

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998021175A1 (en) * 1996-11-11 1998-05-22 Sepracor, Inc. Process for the preparation of optically pure isomers of formoterol

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998021175A1 (en) * 1996-11-11 1998-05-22 Sepracor, Inc. Process for the preparation of optically pure isomers of formoterol

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Tetrahedron: Asymmetry (2000), 11(13), 2705-2717 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009147383A1 (en) * 2008-06-02 2009-12-10 Cipla Limited Process for the synthesis of arformoterol
US9029421B2 (en) 2008-06-02 2015-05-12 Cipla Limited Process for the synthesis of arformoterol
CN106565527A (en) * 2016-11-02 2017-04-19 北京万全德众医药生物技术有限公司 Preparation method of arformoterol tartrate methanamide intermediate
CN111018902A (en) * 2019-12-02 2020-04-17 苏州凯瑞医药科技有限公司 Formoterol important intermediate and synthetic method thereof

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