73573-87-2

Usage

Uses

Used in Pharmaceutical Industry:
N-[2-Hydroxy-5-[1-hydroxy-2-[1-(4-methoxyphenyl)propan-2-ylamino]ethyl]phenyl]formamide is used as an internal standard for the quantification of Formoterol by GCor LC-mass spectrometry. It serves as a reference compound to ensure accurate and reliable measurements of Formoterol levels in various samples.
Used in Respiratory Medicine:
Formoterol, a compound related to N-[2-Hydroxy-5-[1-hydroxy-2-[1-(4-methoxyphenyl)propan-2-ylamino]ethyl]phenyl]formamide, is a useful compound for treating respiratory obstructive diseases. It acts as a bronchodilator, helping to relax and open the airways, making it easier for patients to breathe. N-[2-Hydroxy-5-[1-hydroxy-2-[1-(4-methoxyphenyl)propan-2-ylamino]ethyl]phenyl]formamide can be used in the development of medications and therapies for conditions such as asthma and chronic obstructive pulmonary disease (COPD).

Mechanism of action

Formoterol has 3′-formylamino and 4′-hydroxy ring R3 substitution pattern but also an alkoxyphenylethyl lipophilic group R1 on the nitrogen, similar to ritodrine. Although it is less lipophilic (log P = 1.6) than salmeterol, it has a 12-hour duration of action similar to that for salmeterol. It is administered as an inhaled dry powder, because it is unstable to heat and moisture. It is a mixture of (R,R)-(–)- and (S,S)-(+)-stereoisomers, with the (R,R)-isomer having approximately 1,000-fold more affinity for the β2-receptor than the (S,S)-isomer. Because of its high potency and low dose, however, there is no clinical advantage for using (R,R)-formoterol as bronchodilator compared to the racemate. Unlike salmeterol, formoterol has a faster onset of action as a result of its lower lipophilicity. It is also more potent; a 12-μg dose of formoterol has been demonstrated to be equivalent to a 50-μg dose of salmeterol.

InChI:InChI=1/C19H24N2O4/c1-13(9-14-3-6-16(25-2)7-4-14)20-11-19(24)15-5-8-18(23)17(10-15)21-12-22/h3-8,10,12-13,19-20,23-24H,9,11H2,1-2H3,(H,21,22)

Synthetic route

N-[5-[(1R)-Hydroxy-2-[[(1R)-methyl-2-(4-methoxyphenyl)ethyl](phenylmethyl)amino]ethyl]-2-(phenylmethoxy)phenyl]-formamide (188690-83-7) → (R,R)-formoterol (73573-87-2)

Conditions	Yield
With hydrogen; palladium 10% on activated carbon In ethanol at 25 - 30℃; under 2942.29 Torr; for 3h;	80%
With hydrogen; palladium on activated charcoal In ethanol
With hydrogen; palladium 10% on activated carbon In methanol
With palladium 10% on activated carbon; hydrogen In isopropyl alcohol at 35 - 36℃; Autoclave;

N-(2-Benzyloxy-5-{(R)-1-hydroxy-2-[(R)-2-(4-methoxy-phenyl)-1-methyl-ethylamino]-ethyl}-phenyl)-formamide (408497-91-6) → (R,R)-formoterol (73573-87-2)

Conditions	Yield
With hydrogen; 10% palladium on active carbon In ethanol at 20℃; Hydrogenolysis;

2-amino-1-(4-methyoxyphenyl)propane (64-13-1) → (R,R)-formoterol (73573-87-2)

Conditions	Yield
Multi-step reaction with 7 steps 1: Candida antarctica lipase B 2: 3M aq. KOH / Heating 3: dimethylsulfoxide / 87 h / 80 °C 4: neutral Al2O3 (activity III) 5: 67 percent / Fe turnings; 1M aq. HCl / methanol / 0.75 h / Heating 6: 69 percent / pyridine / 6.5 h / 60 °C 7: H2 / 10 percentPd/C / ethanol / 20 °C View Scheme

1-methoxy-4-((E)-2-nitroprop-1-enyl)benzene (37629-51-9) → (R,R)-formoterol (73573-87-2)

Conditions	Yield
Multi-step reaction with 8 steps 1: 78 percent / LiAlH4 / diethyl ether / 2 h / Heating 2: Candida antarctica lipase B 3: 3M aq. KOH / Heating 4: dimethylsulfoxide / 87 h / 80 °C 5: neutral Al2O3 (activity III) 6: 67 percent / Fe turnings; 1M aq. HCl / methanol / 0.75 h / Heating 7: 69 percent / pyridine / 6.5 h / 60 °C 8: H2 / 10 percentPd/C / ethanol / 20 °C View Scheme
Multi-step reaction with 6 steps 1.1: LiAlH4 / diethyl ether / 2 h / Heating 1.2: Candida antarctica lipase B; ethyl acetate; Et3N / 4 h / 30 °C 2.1: dimethylsulfoxide / 87 h / 80 °C 3.1: neutral Al2O3 (activity III) 4.1: 67 percent / Fe turnings; 1M aq. HCl / methanol / 0.75 h / Heating 5.1: 69 percent / pyridine / 6.5 h / 60 °C 6.1: H2 / 10 percentPd/C / ethanol / 20 °C View Scheme

4-benzyloxy-3-nitroacetophenone (14347-05-8) → (R,R)-formoterol (73573-87-2)

Conditions	Yield
Multi-step reaction with 9 steps 1: 82 percent / Br2 / CHCl3 / 25 °C 2: 87 percent / BH3*THF / tetrahydrofuran / -20 °C 3: lipase PS Celite-immobilized / various solvent(s) / 72 h / 37 °C 4: K2CO3 / methanol / 2.5 h / 20 °C 5: dimethylsulfoxide / 87 h / 80 °C 6: neutral Al2O3 (activity III) 7: 67 percent / Fe turnings; 1M aq. HCl / methanol / 0.75 h / Heating 8: 69 percent / pyridine / 6.5 h / 60 °C 9: H2 / 10 percentPd/C / ethanol / 20 °C View Scheme
Multi-step reaction with 8 steps 1.1: 82 percent / Br2 / CHCl3 / 25 °C 2.1: BH3*THF / tetrahydrofuran / -20 °C 2.2: 48 percent / lipase PS; vinyl acetate / various solvent(s) / 72 h / 37 °C 3.1: K2CO3 / methanol / 2.5 h / 20 °C 4.1: dimethylsulfoxide / 87 h / 80 °C 5.1: neutral Al2O3 (activity III) 6.1: 67 percent / Fe turnings; 1M aq. HCl / methanol / 0.75 h / Heating 7.1: 69 percent / pyridine / 6.5 h / 60 °C 8.1: H2 / 10 percentPd/C / ethanol / 20 °C View Scheme

4-benzyloxy-3-nitrophenacyl bromide (43229-01-2) → (R,R)-formoterol (73573-87-2)

Conditions	Yield
Multi-step reaction with 8 steps 1: 87 percent / BH3*THF / tetrahydrofuran / -20 °C 2: lipase PS Celite-immobilized / various solvent(s) / 72 h / 37 °C 3: K2CO3 / methanol / 2.5 h / 20 °C 4: dimethylsulfoxide / 87 h / 80 °C 5: neutral Al2O3 (activity III) 6: 67 percent / Fe turnings; 1M aq. HCl / methanol / 0.75 h / Heating 7: 69 percent / pyridine / 6.5 h / 60 °C 8: H2 / 10 percentPd/C / ethanol / 20 °C View Scheme
Multi-step reaction with 7 steps 1.1: BH3*THF / tetrahydrofuran / -20 °C 1.2: 48 percent / lipase PS; vinyl acetate / various solvent(s) / 72 h / 37 °C 2.1: K2CO3 / methanol / 2.5 h / 20 °C 3.1: dimethylsulfoxide / 87 h / 80 °C 4.1: neutral Al2O3 (activity III) 5.1: 67 percent / Fe turnings; 1M aq. HCl / methanol / 0.75 h / Heating 6.1: 69 percent / pyridine / 6.5 h / 60 °C 7.1: H2 / 10 percentPd/C / ethanol / 20 °C View Scheme
Multi-step reaction with 6 steps 1: 98 percent / oxazaborolidine from cis (1R,2S)-aminoindanol and trimethylboroxine, BH3 / tetrahydrofuran / -15 °C 2: 98 percent / aqueous sodium hydroxide / methanol / 0.5 h 3: 90 °C 4: H2 / PtO2 6: H2 / Pd-C / ethanol View Scheme

(R)-(-)-p-methoxyamphetamine (58993-79-6) → (R,R)-formoterol (73573-87-2)

Conditions	Yield
Multi-step reaction with 5 steps 1: dimethylsulfoxide / 87 h / 80 °C 2: neutral Al2O3 (activity III) 3: 67 percent / Fe turnings; 1M aq. HCl / methanol / 0.75 h / Heating 4: 69 percent / pyridine / 6.5 h / 60 °C 5: H2 / 10 percentPd/C / ethanol / 20 °C View Scheme

4-methoxy-benzaldehyde (123-11-5) + (E/Z)-crotylstannane(1-)*Et4N(1+) → (R,R)-formoterol (73573-87-2)

Conditions	Yield
Multi-step reaction with 9 steps 1: 81 percent / ammonium acetate / 0.58 h / Heating 2: 78 percent / LiAlH4 / diethyl ether / 2 h / Heating 3: Candida antarctica lipase B 4: 3M aq. KOH / Heating 5: dimethylsulfoxide / 87 h / 80 °C 6: neutral Al2O3 (activity III) 7: 67 percent / Fe turnings; 1M aq. HCl / methanol / 0.75 h / Heating 8: 69 percent / pyridine / 6.5 h / 60 °C 9: H2 / 10 percentPd/C / ethanol / 20 °C View Scheme
Multi-step reaction with 7 steps 1.1: 81 percent / ammonium acetate / 0.58 h / Heating 2.1: LiAlH4 / diethyl ether / 2 h / Heating 2.2: Candida antarctica lipase B; ethyl acetate; Et3N / 4 h / 30 °C 3.1: dimethylsulfoxide / 87 h / 80 °C 4.1: neutral Al2O3 (activity III) 5.1: 67 percent / Fe turnings; 1M aq. HCl / methanol / 0.75 h / Heating 6.1: 69 percent / pyridine / 6.5 h / 60 °C 7.1: H2 / 10 percentPd/C / ethanol / 20 °C View Scheme

(+/-)-2-bromo-1-(4-benzyloxy-3-nitrophenyl)ethanol (299964-35-5) → (R,R)-formoterol (73573-87-2)

Conditions	Yield
Multi-step reaction with 7 steps 1: lipase PS Celite-immobilized / various solvent(s) / 72 h / 37 °C 2: K2CO3 / methanol / 2.5 h / 20 °C 3: dimethylsulfoxide / 87 h / 80 °C 4: neutral Al2O3 (activity III) 5: 67 percent / Fe turnings; 1M aq. HCl / methanol / 0.75 h / Heating 6: 69 percent / pyridine / 6.5 h / 60 °C 7: H2 / 10 percentPd/C / ethanol / 20 °C View Scheme

(R)-1-(4-benzyloxy-3-nitrophenyl)oxirane (188730-94-1) → (R,R)-formoterol (73573-87-2)

Conditions	Yield
Multi-step reaction with 5 steps 1: dimethylsulfoxide / 87 h / 80 °C 2: neutral Al2O3 (activity III) 3: 67 percent / Fe turnings; 1M aq. HCl / methanol / 0.75 h / Heating 4: 69 percent / pyridine / 6.5 h / 60 °C 5: H2 / 10 percentPd/C / ethanol / 20 °C View Scheme
Multi-step reaction with 4 steps 1: 90 °C 2: H2 / PtO2 4: H2 / Pd-C / ethanol View Scheme
Multi-step reaction with 4 steps 1.1: 20 h / 140 °C / Inert atmosphere 2.1: hydrogen / Ni-Raney / isopropyl alcohol; toluene / 20 h / 40 °C / 13680.9 Torr 3.1: acetic anhydride / 2 h / 50 °C / Inert atmosphere 3.2: 1 h / 0 °C 3.3: 0.25 h / 0 °C 4.1: hydrogen / 5% Pd(II)/C(eggshell) / ethanol / 20 h / 40 °C / 7600.51 Torr View Scheme
Multi-step reaction with 4 steps 1.1: 10 h / 20 - 110 °C 2.1: water; sodium dithionite / di-isopropyl ether; acetone; methanol / 20 - 60 °C 2.2: 25 - 60 °C / pH 9 - 9.5 3.1: polyethylene glycol-400 / 20 - 65 °C 3.2: pH 7 - 7.5 4.1: hydrogen / palladium 10% on activated carbon / methanol View Scheme

(R)-2-bromo-1-(4-benzyloxy-3-nitrophenyl)ethanol (188690-82-6) → (R,R)-formoterol (73573-87-2)

Conditions	Yield
Multi-step reaction with 6 steps 1: K2CO3 / methanol / 2.5 h / 20 °C 2: dimethylsulfoxide / 87 h / 80 °C 3: neutral Al2O3 (activity III) 4: 67 percent / Fe turnings; 1M aq. HCl / methanol / 0.75 h / Heating 5: 69 percent / pyridine / 6.5 h / 60 °C 6: H2 / 10 percentPd/C / ethanol / 20 °C View Scheme
Multi-step reaction with 5 steps 1: 98 percent / aqueous sodium hydroxide / methanol / 0.5 h 2: 90 °C 3: H2 / PtO2 5: H2 / Pd-C / ethanol View Scheme
Multi-step reaction with 5 steps 1.1: potassium carbonate / toluene; methanol / 20 h / 40 °C 2.1: 20 h / 140 °C / Inert atmosphere 3.1: hydrogen / Ni-Raney / isopropyl alcohol; toluene / 20 h / 40 °C / 13680.9 Torr 4.1: acetic anhydride / 2 h / 50 °C / Inert atmosphere 4.2: 1 h / 0 °C 4.3: 0.25 h / 0 °C 5.1: hydrogen / 5% Pd(II)/C(eggshell) / ethanol / 20 h / 40 °C / 7600.51 Torr View Scheme

(R)-N-[1-(o-methoxyphenyl)propan-2-yl]ethanamide (86073-42-9) → (R,R)-formoterol (73573-87-2)

Conditions	Yield
Multi-step reaction with 6 steps 1: 3M aq. KOH / Heating 2: dimethylsulfoxide / 87 h / 80 °C 3: neutral Al2O3 (activity III) 4: 67 percent / Fe turnings; 1M aq. HCl / methanol / 0.75 h / Heating 5: 69 percent / pyridine / 6.5 h / 60 °C 6: H2 / 10 percentPd/C / ethanol / 20 °C View Scheme

Acetic acid (S)-1-(4-benzyloxy-3-nitro-phenyl)-2-bromo-ethyl ester (299964-37-7) → (R,R)-formoterol (73573-87-2)

Conditions	Yield
Multi-step reaction with 6 steps 1: K2CO3 / methanol / 2.5 h / 20 °C 2: dimethylsulfoxide / 87 h / 80 °C 3: neutral Al2O3 (activity III) 4: 67 percent / Fe turnings; 1M aq. HCl / methanol / 0.75 h / Heating 5: 69 percent / pyridine / 6.5 h / 60 °C 6: H2 / 10 percentPd/C / ethanol / 20 °C View Scheme

(R)-1-(3-Amino-4-benzyloxy-phenyl)-2-[(R)-2-(4-methoxy-phenyl)-1-methyl-ethylamino]-ethanol (299964-43-5) → (R,R)-formoterol (73573-87-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: 69 percent / pyridine / 6.5 h / 60 °C 2: H2 / 10 percentPd/C / ethanol / 20 °C View Scheme

(R)-1-(4-Benzyloxy-3-nitro-phenyl)-2-[(R)-2-(4-methoxy-phenyl)-1-methyl-ethylamino]-ethanol (245759-61-9) → (R,R)-formoterol (73573-87-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: 67 percent / Fe turnings; 1M aq. HCl / methanol / 0.75 h / Heating 2: 69 percent / pyridine / 6.5 h / 60 °C 3: H2 / 10 percentPd/C / ethanol / 20 °C View Scheme

[(R)-2-(4-Benzyloxy-3-nitro-phenyl)-2-trimethylsilanyloxy-ethyl]-[(R)-2-(4-methoxy-phenyl)-1-methyl-ethyl]-amine → (R,R)-formoterol (73573-87-2)

Conditions	Yield
Multi-step reaction with 4 steps 1: neutral Al2O3 (activity III) 2: 67 percent / Fe turnings; 1M aq. HCl / methanol / 0.75 h / Heating 3: 69 percent / pyridine / 6.5 h / 60 °C 4: H2 / 10 percentPd/C / ethanol / 20 °C View Scheme

4-methoxybenzyl methyl ketone (122-84-9) + 1-<4-methoxy-phenyl>-propanol-(2) → (R,R)-formoterol (73573-87-2)

Conditions	Yield
Multi-step reaction with 5 steps 1: H2 / Pt-C / ethanol 2: 90 °C 3: H2 / PtO2 5: H2 / Pd-C / ethanol View Scheme

(R)-(-)-1-(4'-methoxyphenyl)-2-benzylaminopropane (67346-60-5) → (R,R)-formoterol (73573-87-2)

Conditions	Yield
Multi-step reaction with 4 steps 1: 90 °C 2: H2 / PtO2 4: H2 / Pd-C / ethanol View Scheme
Multi-step reaction with 4 steps 1.1: 10 h / 20 - 110 °C 2.1: water; sodium dithionite / di-isopropyl ether; acetone; methanol / 20 - 60 °C 2.2: 25 - 60 °C / pH 9 - 9.5 3.1: polyethylene glycol-400 / 20 - 65 °C 3.2: pH 7 - 7.5 4.1: hydrogen / palladium 10% on activated carbon / methanol View Scheme
Multi-step reaction with 2 steps 1: 12 h / 90 - 110 °C 2: palladium 10% on activated carbon; hydrogen / isopropyl alcohol / 35 - 36 °C / Autoclave View Scheme
Multi-step reaction with 5 steps 1: potassium carbonate; potassium iodide / acetone / 3 h / 25 - 30 °C 2: dimethylsulfide borane complex; (3aR)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole / tetrahydrofuran / -10 - -5 °C 3: ammonium formate / palladium 10% on activated carbon / N,N-dimethyl-formamide / 2 h / 40 - 75 °C 4: acetic anhydride / tetrahydrofuran; toluene / 15 - 30 °C 5: hydrogen / palladium 10% on activated carbon / ethanol / 3 h / 25 - 30 °C / 2942.29 Torr View Scheme

(R,R)-3-amino-α-[[[2-(4-methoxyphenyl)-1-methylethyl](phenyl methyl)amino]methyl]-4-(phenylmethoxy)-benzenemethanol (289657-26-7) → (R,R)-formoterol (73573-87-2)

Conditions	Yield
Multi-step reaction with 2 steps 2: H2 / Pd-C / ethanol View Scheme
Multi-step reaction with 2 steps 1.1: polyethylene glycol-400 / 20 - 65 °C 1.2: pH 7 - 7.5 2.1: hydrogen / palladium 10% on activated carbon / methanol View Scheme
Multi-step reaction with 2 steps 1: acetic anhydride / tetrahydrofuran; toluene / 15 - 30 °C 2: hydrogen / palladium 10% on activated carbon / ethanol / 3 h / 25 - 30 °C / 2942.29 Torr View Scheme

(R,R)-3-nitro-α-[[[2-(4-methoxyphenyl)-1-methylethyl](phenylmethyl)amino]methyl]-4-(phenylmethoxy)-benzenemethanol (245759-65-3) → (R,R)-formoterol (73573-87-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: H2 / PtO2 3: H2 / Pd-C / ethanol View Scheme
Multi-step reaction with 3 steps 1.1: water; sodium dithionite / di-isopropyl ether; acetone; methanol / 20 - 60 °C 1.2: 25 - 60 °C / pH 9 - 9.5 2.1: polyethylene glycol-400 / 20 - 65 °C 2.2: pH 7 - 7.5 3.1: hydrogen / palladium 10% on activated carbon / methanol View Scheme
Multi-step reaction with 3 steps 1: ammonium formate / palladium 10% on activated carbon / N,N-dimethyl-formamide / 2 h / 40 - 75 °C 2: acetic anhydride / tetrahydrofuran; toluene / 15 - 30 °C 3: hydrogen / palladium 10% on activated carbon / ethanol / 3 h / 25 - 30 °C / 2942.29 Torr View Scheme

(R,R)-N-(2-benzyloxy-5-{1-hydroxy-2-[[2-(4-methoxy-phenyl)-1-methyl-ethyl]-(1-phenyl-ethyl)-amino]-ethyl}-phenyl)-formamide (1316100-17-0) → (R,R)-formoterol (73573-87-2)

Conditions	Yield
With 5% Pd(II)/C(eggshell); hydrogen In methanol under 2327.23 Torr; for 12h;	5.57 g
With hydrogen; 5% Pd(II)/C(eggshell) In ethanol at 40℃; under 7600.51 Torr; for 20h; Product distribution / selectivity;	n/a

4-methoxybenzyl methyl ketone (122-84-9) → (R,R)-formoterol (73573-87-2)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: hydrogen / platinum on carbon / methanol / 20 h / 30 °C / 7600.51 Torr 2.1: hydrogenchloride / water; acetone / 1 h / 0 - 23 °C 3.1: 20 h / 140 °C / Inert atmosphere 4.1: hydrogen / Ni-Raney / isopropyl alcohol; toluene / 20 h / 40 °C / 13680.9 Torr 5.1: acetic anhydride / 2 h / 50 °C / Inert atmosphere 5.2: 1 h / 0 °C 5.3: 0.25 h / 0 °C 6.1: hydrogen / 5% Pd(II)/C(eggshell) / ethanol / 20 h / 40 °C / 7600.51 Torr View Scheme
Multi-step reaction with 7 steps 1.1: 1,2-dichloro-ethane / 2 h / 20 - 40 °C 2.1: sodium tris(acetoxy)borohydride / 1,2-dichloro-ethane / 3 h / 5 - 25 °C 3.1: tetrahydrofuran / 50 - 55 °C / Resolution of racemate 4.1: 10 h / 20 - 110 °C 5.1: water; sodium dithionite / di-isopropyl ether; acetone; methanol / 20 - 60 °C 5.2: 25 - 60 °C / pH 9 - 9.5 6.1: polyethylene glycol-400 / 20 - 65 °C 6.2: pH 7 - 7.5 7.1: hydrogen / palladium 10% on activated carbon / methanol View Scheme
Multi-step reaction with 6 steps 1.1: tetrahydrofuran / 2 h / 20 - 40 °C / Autoclave 1.2: 20 - 30 °C 2.1: tetrahydrofuran / 50 - 55 °C / Resolution of racemate 3.1: 10 h / 20 - 110 °C 4.1: water; sodium dithionite / di-isopropyl ether; acetone; methanol / 20 - 60 °C 4.2: 25 - 60 °C / pH 9 - 9.5 5.1: polyethylene glycol-400 / 20 - 65 °C 5.2: pH 7 - 7.5 6.1: hydrogen / palladium 10% on activated carbon / methanol View Scheme

(R)-1-(4-methoxyphenyl)-N-((R)-1-phenylethyl)propan-2-amine (140173-30-4) → (R,R)-formoterol (73573-87-2)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: 20 h / 140 °C / Inert atmosphere 2.1: hydrogen / Ni-Raney / isopropyl alcohol; toluene / 20 h / 40 °C / 13680.9 Torr 3.1: acetic anhydride / 2 h / 50 °C / Inert atmosphere 3.2: 1 h / 0 °C 3.3: 0.25 h / 0 °C 4.1: hydrogen / 5% Pd(II)/C(eggshell) / ethanol / 20 h / 40 °C / 7600.51 Torr View Scheme

[2-(4-methoxy-phenyl)-1-methyl-ethyl]-(1-phenyl-ethyl)-amine → (R,R)-formoterol (73573-87-2)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: hydrogenchloride / water; acetone / 1 h / 0 - 23 °C 2.1: 20 h / 140 °C / Inert atmosphere 3.1: hydrogen / Ni-Raney / isopropyl alcohol; toluene / 20 h / 40 °C / 13680.9 Torr 4.1: acetic anhydride / 2 h / 50 °C / Inert atmosphere 4.2: 1 h / 0 °C 4.3: 0.25 h / 0 °C 5.1: hydrogen / 5% Pd(II)/C(eggshell) / ethanol / 20 h / 40 °C / 7600.51 Torr View Scheme

(R,R)-1-(4-benzyloxy-3-nitro-phenyl)-2-[[2-(4-methoxy-phenyl)-1-methyl-ethyl]-(1-phenyl-ethyl)-amino]-ethanol (1262020-50-7) → (R,R)-formoterol (73573-87-2)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: hydrogen / Ni-Raney / isopropyl alcohol; toluene / 20 h / 40 °C / 13680.9 Torr 2.1: acetic anhydride / 2 h / 50 °C / Inert atmosphere 2.2: 1 h / 0 °C 2.3: 0.25 h / 0 °C 3.1: hydrogen / 5% Pd(II)/C(eggshell) / ethanol / 20 h / 40 °C / 7600.51 Torr View Scheme

[2-(4-methoxyphenyl)-1-methylethyl](phenylmethyl)amine (43229-65-8) → (R,R)-formoterol (73573-87-2)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: tetrahydrofuran / 50 - 55 °C / Resolution of racemate 2.1: 10 h / 20 - 110 °C 3.1: water; sodium dithionite / di-isopropyl ether; acetone; methanol / 20 - 60 °C 3.2: 25 - 60 °C / pH 9 - 9.5 4.1: polyethylene glycol-400 / 20 - 65 °C 4.2: pH 7 - 7.5 5.1: hydrogen / palladium 10% on activated carbon / methanol View Scheme
Multi-step reaction with 2 steps 1.1: methanol / 20 °C / Inert atmosphere; Reflux 2.1: potassium carbonate / methanol; tetrahydrofuran / 25 °C / Inert atmosphere 2.2: 255 / 24 h / 120 °C / Inert atmosphere 2.3: 25 °C / 2327.23 Torr / Inert atmosphere View Scheme

C17H19NO (1096141-37-5) → (R,R)-formoterol (73573-87-2)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: sodium tris(acetoxy)borohydride / 1,2-dichloro-ethane / 3 h / 5 - 25 °C 2.1: tetrahydrofuran / 50 - 55 °C / Resolution of racemate 3.1: 10 h / 20 - 110 °C 4.1: water; sodium dithionite / di-isopropyl ether; acetone; methanol / 20 - 60 °C 4.2: 25 - 60 °C / pH 9 - 9.5 5.1: polyethylene glycol-400 / 20 - 65 °C 5.2: pH 7 - 7.5 6.1: hydrogen / palladium 10% on activated carbon / methanol View Scheme

N-[5-((1R)-2-bromo-1-hydroxyethyl)-2-(phenylmethoxy)phenyl]carboxamide (201677-59-0) + (R)-N-benzyl-N-(1-methyl-2-p-methoxyphenylethyl)amine L-mandelate → (R,R)-formoterol (73573-87-2)

Conditions	Yield
Stage #1: N-[5-((1R)-2-bromo-1-hydroxyethyl)-2-(phenylmethoxy)phenyl]carboxamide; (R)-N-benzyl-N-(1-methyl-2-p-methoxyphenylethyl)amine L-mandelate With potassium carbonate In tetrahydrofuran; methanol at 25℃; Inert atmosphere; Stage #2: at 120℃; for 24h; Inert atmosphere; Stage #3: With palladium 10% on activated carbon; hydrogen In ethanol at 25℃; under 2327.23 Torr; Inert atmosphere;	n/a

(1R)-1-[3-amino-4-(phenylmethoxy)phenyl]-2-bromoethan-1-ol (333796-54-6) → (R,R)-formoterol (73573-87-2)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: acetic anhydride / 0 - 5 °C / Inert atmosphere 1.2: 1 h / 0 - 5 °C / Inert atmosphere 2.1: 12 h / 90 - 110 °C 3.1: palladium 10% on activated carbon; hydrogen / isopropyl alcohol / 35 - 36 °C / Autoclave View Scheme
Multi-step reaction with 4 steps 1.1: acetic anhydride / 0 - 5 °C 1.2: 1 h / 0 - 5 °C / Inert atmosphere 2.1: potassium carbonate / tetrahydrofuran; methanol / 2 h / 25 - 30 °C / Inert atmosphere; Large scale 3.1: 12 h / 90 - 110 °C 4.1: palladium 10% on activated carbon; hydrogen / isopropyl alcohol / 35 - 36 °C / Autoclave View Scheme

L-Tartaric acid (87-69-4) + (R,R)-formoterol (73573-87-2) → (R,R)-formoterol L-tartrate

Conditions	Yield
In methanol; acetonitrile at 23℃; for 1h; Solvent; Temperature; Time;	91%
In water; isopropyl alcohol; toluene at 20 - 45℃; for 5.5h;	70%
In water; isopropyl alcohol; toluene
In water; toluene at 25 - 30℃; for 3h; Inert atmosphere;	68 g

L-Tartaric acid (87-69-4) + (R,R)-formoterol (73573-87-2) → (R,R)-formoterol-L-tartrate

Conditions	Yield
In ethanol; water; isopropyl alcohol at 20 - 80℃; Product distribution / selectivity;

Upstream product

• 43229-65-8 [2-(4-methoxyphenyl)-1-methylethyl](phenylmethyl)amine 
• 1096141-37-5 C₁₇H₁₉NO 
• 1049695-95-5 benzyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amine; hydrochloride 
• 1198769-18-4 (R)-4-benzyloxy-3-nitro-α-(N-benzyl-N-(1-methyl-2-p-methoxyphenylethyl)amino)acetophenone 
• 245759-64-2 (R)-N-benzyl-N-(1-methyl-2-p-methoxyphenylethyl)amine L-mandelate 
• 201677-57-8 N-[2-(benzyloxy)-5-[(2R)-oxiran-2-yl]phenyl]formamide 
• 245759-64-2 N-benzyl-1-(4-methoxyphenyl)propan-2-amine mandalate salt 
• 201677-59-0 N-[5-((1R)-2-bromo-1-hydroxyethyl)-2-(phenylmethoxy)phenyl]carboxamide 
• 333796-54-6 (1R)-1-[3-amino-4-(phenylmethoxy)phenyl]-2-bromoethan-1-ol 
• 1262020-50-7 (R,R)-1-(4-benzyloxy-3-nitro-phenyl)-2-[[2-(4-methoxy-phenyl)-1-methyl-ethyl]-(1-phenyl-ethyl)-amino]-ethanol 
• 140173-30-4 (R)-1-(4-methoxyphenyl)-N-((R)-1-phenylethyl)propan-2-amine 
• 122-84-9 4-methoxybenzyl methyl ketone 
• 1316100-17-0 (R,R)-N-(2-benzyloxy-5-{1-hydroxy-2-[[2-(4-methoxy-phenyl)-1-methyl-ethyl]-(1-phenyl-ethyl)-amino]-ethyl}-phenyl)-formamide 
• 245759-65-3 (R,R)-3-nitro-α-[[[2-(4-methoxyphenyl)-1-methylethyl](phenylmethyl)amino]methyl]-4-(phenylmethoxy)-benzenemethanol 

Downstream Products

• 87833-61-2 formoterol hemifumarate 
• 43229-80-7 N-[2-hydroxy-5-[(1R)-1-hydroxy-2-[[(1R)-(4-methoxyphenyl)-1-methylethyl]-amino]ethyl]phenyl]formamide 

Relevant academic research and scientific papers

PROCESS FOR THE PREPARATION OF ARFORMOTEROL OR SALT THEREOF

Provided is an improved process for the preparation of arformoterol L-(+)-tartrate, and more specifically provided is a novel process for the preparation of arformoterol L-(+)-tartrate via arformoterol D-(?)-tartrate.

PROCESSES FOR PREPARING SUBSTANTIALLY PURE ARFORMOTEROL AND ITS INTERMEDIATES

Provided herein are improved, convenient and industrially advantageous processes for the preparation of N-[2-hydroxy-5-[(1R)-1-hydroxy-2-[[(1R)-2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]phenyl]formamide (Arformoterol) or a pharmaceutically acceptable salt thereof, in high yield and purity. Provided further herein is an improved and industrially advantageous process for the preparation of a substantially enantiomerically pure arformoterol intermediate, (R)-4-methoxy-α-methyl-N-(phenylmethyl)benzeneethanamine.

Process for preparation of intermediates of arformoterol

An improved method for the preparation of optically pure isomers of Formoterol is disclosed, particularly the (R,R)-isomer.A method of preparation of substantially enantiomerically pure (R,R)-1-(4-Benzyloxy-3-nitro-phenyl)-2-[[2-(4-methoxy-phenyl)-1-methyl-ethyl]-(1-phenyl-ethyl)-amino]-ethanol to use in the production of (R,R)-Formoterol is also disclosedAn improved method for the preparation of optically pure isomers of Formoterol is disclosed, particularly the (R,R)-isomer. A method of preparation of substantially enantiomerically pure (R,R)-1-(4-Benzyloxy-3-nitro-phenyl)-2-[[2-(4-methoxy-phenyl)-1-methyl-ethyl]-(1-phenyl-ethyl)-amino]-ethanol to use in the production of (R,R)-Formoterol is also disclosed

The asymmetric synthesis of (R,R)-formoterol via transfer hydrogenation with polyethylene glycol bound Rh catalyst in PEG2000 and water

(R,R)-formoterol was synthesized in seven steps with 4-hydroxyl-3-nitro- acetophenone as the starting material. The key intermediate, the chiral secondary alcohol 4, was prepared via Rh-catalyzed asymmetric transfer hydrogenation with (S,S)-PEGBsDPEN as the ligand and sodium formate as the hydrogen donor under mild conditions. With a mixture of PEG 2000 and water as the reaction media, the catalyst system could be recycled four times.

PROCESS FOR THE SYNTHESIS OF ARFORMOTEROL

The present invention provides a process for preparing a compound of formula (Vl) or a salt thereof, the process comprising: (i) reacting 4-methoxyphenyl acetone with an amine of formula (VIII) under conditions of reductive amination to produce a compound of formula (II) or a salt thereof, wherein there is no isolation of an imine intermediate formed during the reductive amination; (ii) condensing the compound (II) or the acid addition salt thereof with an α-haloketone of formula (III) to produce the compound of formula (IV); (iii) reducing the compound (IV) to a compound of formula (V); and (iv) reducing the compound (V) to the compound of formula (Vl), wherein the reduction is carried out in the presence of either (1 ) a hydrogen donating compound in the presence of a hydrogen transfer catalyst; or (2) ammonium formate using a hydrogenation catalyst, wherein: R1 and R2 are independently optionally substituted arylalkyl, and Hal is selected from chloro or bromo.

AN IMPROVED PROCESS FOR THE PREPARATION OF HIGH PURITY FORMOTEROL AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS

The present invention relates to an improved process for the preparation of high purity formoterol and its pharmaceutically acceptable salts of Formula-I(C).

Compositions and methods for inducing adipose tissue cell death

Pharmaceutical compositions, methods for increasing the rate of apoptosis in adipose tissue cells, and methods of reducing adipose tissue mass in a host, are described. One exemplary pharmaceutical composition, among others, includes at least one catecholamine in combination with a pharmaceutically acceptable carrier. The catecholamine is present in a dosage level effective to increase the rate of apoptosis in adipose tissue cells in a host.

Administration of medicinal dry powders

A method as well as a therapeutic metered combined dose are disclosed for a combined administration of medicinal dry powders. A metered medicinal dry powder combined dosage comprising at least two medicaments of separate dry powder formulations is prepared, whereby the metered powder quantity per medicament is deposited in a dose forming step creating the medicinal combined dose. The deposits of the at least two medicaments are suitably kept separated from each other, such that the medicaments cannot detrimentally interact after forming of the combined dose, and the medicinal combined dose is introduced into an inhaler device for a delivery of the powder dose during the course of a single inhalation. The therapeutic metered medicinal, combined dosage of finely divided dry medication powders disclosed comprises metered quantities of at least two medicaments, separately deposited and the medicinal combined dosage is adapted for a user initiated delivery of the dosage during a single inhalation through an inhaler device. The at least two medicaments of the medicinal combined dosage will generally be aerosolized simultaneously or sequentially during the inhalation such that a large proportion of each medicament will settle in the intended target area of the airways and lungs of a user.

Combined doses

The present invention discloses a method and a pharmaceutical dry powder combined dose for the prophylaxis or treatment of a respiratory disorder in a mammalian host by inhalation of a metered dry powder combined dose of finely divided dry medication powders. At least one dry powder medicament is selected from a first group of bronchodilating medicaments and at least one dry powder medicament from a second group of anti-inflammatory medicaments. A metered dry powder medicinal combined dose comprising separately metered deposits of medicinally suitable quantities of each of the selected medicaments is prepared, in which the sum of the metered deposits constitutes the metered quantities of powder of the combined dose and the medicinal combined dose is introduced into an adapted inhaler device for a generally simultaneous delivery of the medicinal combined dose during the course of a single inhalation by a user, such that the delivered medicinal combined dose is composed of a high proportion of mixed de-aggregated fine particles of the selected medicaments, whereby an desired therapeutic or treating effect to the user is achieved.

Bronchodilating compositions and methods

Bronchodilating compositions and methods are provided. The compositions are intended for administration as a nebulized aerosol. In certain embodiments, the compositions contain formoterol, or a derivative thereof. Methods for treatment, prevention, or amelioration of one or more symptoms of bronchoconstrictive disorders using the compositions provided herein are also provided.