1. Single Step80%OverviewSteps/Stages Notes1.1R:AlCl3, S:CH2Cl2, 15 h, refluxReactants: 2, Reagents: 1, Solvents: 1, Steps:1, Stages: 1, Most stages in any one step: 1ReferencesHybrids consisting of the pharmacophores ofsalmeterol and roflumilast or phthalazinone:Dual β2-adrenoceptor agonists-PDE4inhibitors for the treatment of COPDBy Liu, Anqiu et alFrom Bioorganic & Medicinal ChemistryLetters, 23(5), 1548-1552; 2013CASREACT ®: Copyright © 2015 American Chemical Society. All Rights Reserved. CASREACT contains reactions from CAS and from: ZIC/VINITI database (1974-1999) provided by InfoChem; INPI data prior to 1986; Biotransformations database compiled under the direction of Professor Dr. Klaus Kieslich; organic reactions, portions copyright 1996-2006 John Wiley & Sons, Ltd., John Wiley and Sons, Inc., Organic Reactions Inc., and Organic Syntheses Inc. Reproduced under license. All Rights Reserved.2. Single Step71%OverviewSteps/Stages Notes1.1R:AlCl3, S:CH2Cl2, rt → reflux 1.2reflux; 14 h, reflux; reflux → rt Reactants: 2, Reagents: 1, Solvents: 1, Steps: 1, Stages: 2, Most stages in any one step: 2ReferencesProcess for preparation of α-(aminomethyl)-4-hydroxy-1,3-benzenedimethanol and intermediatesBy Xiao, Xuhua et alFrom Faming Zhuanli Shenqing, 102584608, 18 Jul 2012CASREACT ®: Copyright © 2015 American Chemical Society. All Rights Reserved. CASREACT contains reactions from CAS and from: ZIC/VINITI database (1974-1999) provided by InfoChem; INPI data prior to 1986; Biotransformations database compiled under the direction of Professor Dr. Klaus Kieslich; organic reactions, portions copyright 1996-2006 John Wiley & Sons, Ltd., John Wiley and Sons, Inc., Organic Reactions Inc., and Organic Syntheses Inc. Reproduced under license. All Rights Reserved.3. Single StepOverviewSteps/Stages Notes1.1R:AlCl3, S:CH2Cl2, 10 h, rt1.2S:CH2Cl2, rt; 2 h, rt; 4 h, rt → reflux1.3R:H2O, cooledReactants: 2, Reagents: 2, Solvents: 1, Steps:1, Stages: 3, Most stages in any one step: 3ReferencesA new route for synthesis of salmeterolxinafoateBy Wu, XiaochunFrom Xinan Shifan Daxue Xuebao, ZiranKexueban, 34(4), 85-88; 2009CASREACT ®: Copyright © 2015 American Chemical Society. All Rights Reserved. CASREACT contains reactions from CAS and from: ZIC/VINITI database (1974-1999) provided by InfoChem; INPI data prior to 1986; Biotransformations database compiled under the direction of Professor Dr. Klaus Kieslich; organic reactions, portions copyright 1996-2006 John Wiley & Sons, Ltd., John Wiley and Sons, Inc., Organic Reactions Inc., and Organic Syntheses Inc. Reproduced under license. All Rights Reserved.4. Single Step82%OverviewSteps/Stages Notes1.1R:AlCl3, S:CH2Cl2, 30 min, 0°C; 0°C → 10°C 1.210°C → 30°C; 1 h, 30°C1.330°C → 40°C; 15 h, 40°C1.4R:H2O Reactants: 2, Reagents: 2, Solvents: 1, Steps: 1, Stages: 4, Most stages in any one step: 4 ReferencesMethod for synthesis of (R)-Salmeterol by asymmetrical hydrogen transfer reactionBy Li, Xingshu et alFrom Faming Zhuanli Shenqing Gongkai Shuomingshu, 101684074, 31 Mar 2010CASREACT ®: Copyright © 2015 American Chemical Society. All Rights Reserved. CASREACT contains reactions from CAS and from: ZIC/VINITI database (1974-1999) provided by InfoChem; INPI data prior to 1986; Biotransformations database compiled under the direction of Professor Dr. Klaus Kieslich; organic reactions, portions copyright 1996-2006 John Wiley & Sons, Ltd., John Wiley and Sons, Inc., Organic Reactions Inc., and Organic Syntheses Inc. Reproduced under license. All Rights Reserved.5. Single Step81%OverviewSteps/Stages Notes1.1R:AlCl3, S:CH2Cl2, 10°C; 10°C → 30°C; 1 h, 30°C1.2S:CH2Cl2, 15 h, 30°CReactants: 2, Reagents: 1, Solvents: 1, Steps:1, Stages: 2, Most stages in any one step: 2ReferencesNew chiral ligand and its application insynthesis of a key intermediate of salmeterolBy Li, Lichan et alFrom Zhongguo Yaowu Huaxue Zazhi, 18(3),175-179; 2008CASREACT ®: Copyright © 2015 American Chemical Society. All Rights Reserved. CASREACT contains reactions from CAS and from: ZIC/VINITI database (1974-1999) provided by InfoChem; INPI data prior to 1986; Biotransformations database compiled under the direction of Professor Dr. Klaus Kieslich; organic reactions, portions copyright 1996-2006 John Wiley & Sons, Ltd., John Wiley and Sons, Inc., Organic Reactions Inc., and Organic Syntheses Inc. Reproduced under license. All Rights Reserved.6. Single StepOverviewSteps/Stages Notes1.1Go to Science of Synthesis, a criticallyreviewed reference work of syntheticmethodology, for more information.,Reactants: 2, Steps: 1, Stages: 1, Most stagesin any one step: 1ReferencesArenecarbaldehydes: synthesis by C-C bondformationBy Oestreich, M.From Science of Synthesis, 25, 667-688;2007CASREACT ®: Copyright © 2015 American Chemical Society. All Rights Reserved. CASREACT contains reactions from CAS and from: ZIC/VINITI database (1974-1999) provided by InfoChem; INPI data prior to 1986; Biotransformations database compiled under the direction of Professor Dr. Klaus Kieslich; organic reactions, portions copyright 1996-2006 John Wiley & Sons, Ltd., John Wiley and Sons, Inc., Organic Reactions Inc., and Organic Syntheses Inc. Reproduced under license. All Rights Reserved.7. Single Step80%OverviewSteps/Stages Notes1.1R:AlCl3, S:CH2Cl2, 10°C; 10°C → 30°C; 1 h, 30°C1.230°C; 15 h, 35°C1.3S:H2O, 0°CReactants: 2, Reagents: 1, Solvents: 2, Steps:1, Stages: 3, Most stages in any one step: 3ReferencesA convenient synthesis of (R)-salmeterol viaRh-catalyzed asymmetric transferhydrogenationBy Liu, Juntao et alFrom Tetrahedron: Asymmetry, 19(15), 1824-1828; 2008CASREACT ®: Copyright © 2015 American Chemical Society. All Rights Reserved. CASREACT contains reactions from CAS and from: ZIC/VINITI database (1974-1999) provided by InfoChem; INPI data prior to 1986; Biotransformations database compiled under the direction of Professor Dr. Klaus Kieslich; organic reactions, portions copyright 1996-2006 John Wiley & Sons, Ltd., John Wiley and Sons, Inc., Organic Reactions Inc., and Organic Syntheses Inc. Reproduced under license. All Rights Reserved.8. Single Step80%OverviewSteps/Stages Notes1.1R:AlCl3, S:CH2Cl2, rt → 50°C; 30 min, 50°C1.212 h, refluxReactants: 2, Reagents: 1, Solvents: 1, Steps:1, Stages: 2, Most stages in any one step: 2ReferencesSynthesis of levalbuterolBy He, Wei et alFrom Zhongguo Yaowu Huaxue Zazhi, 16(4),222-225; 2006CASREACT ®: Copyright © 2015 American Chemical Society. All Rights Reserved. CASREACT contains reactions from CAS and from: ZIC/VINITI database (1974-1999) provided by InfoChem; INPI data prior to 1986; Biotransformations database compiled under the direction of Professor Dr. Klaus Kieslich; organic reactions, portions copyright 1996-2006 John Wiley & Sons, Ltd., John Wiley and Sons, Inc., Organic Reactions Inc., and Organic Syntheses Inc. Reproduced under license. All Rights Reserved.9. Single StepOverviewSteps/Stages Notes1.1R:AlCl3, S:CH2Cl2, 10°C; 10°C → 30°C; 1 h, 30°C 1.2S:CH2Cl2, 30°C; 12-15 h, 35-40°C1.3R:H2O, 0-5°C Reactants: 2, Reagents: 2, Solvents: 1, Steps: 1, Stages: 3, Most stages in any one step: 3ReferencesProcess for preparation of salmeterol xinafoateBy Gore, Vinayak G. et alFrom PCT Int. Appl., 2007045857, 26 Apr 2007Experimental ProcedureExample 1: Preparation of 5-(Bromoacetyl)-2-hydroxybenzaldehyde (2a) (Synthetic Communications,vol. 29(12a), pages 2155-2162, 1999; and US patent 5,011,993) To a suspension of aluminiumchloride (4 m/m) in dichloromethane (10 volumes), was added slowly bromoacetyl bromide (1.2 m/m)at 10°C and then the temperature was brought to 30°C. The reaction mass was stirred at thistemperature for an hour and to this was added a solution of 2-hydroxybenzaldehyde (1) indichloromethane at 30°C. The reaction mixture was stirred at 35-40°C for 12-15 hours and thenquenched in water at 0-5°C. The dichloromethane layer was separated and distilled off. To the slurryobtained, n-heptane was added and stirred for 15 minutes. This slurry was then filtered and the wetcake was washed with n-heptane (2 volumes). The wet cake was dried at 50°C to constant weight toobtain intermediate (2a). Yield: 55% w/w. HPLC purity: 97-99%CASREACT ®: Copyright © 2015 American Chemical Society. All Rights Reserved. CASREACT contains reactions from CAS and from: ZIC/VINITI database (1974-1999) provided by InfoChem; INPI data prior to 1986; Biotransformations database compiled under the direction of Professor Dr. Klaus Kieslich; organic reactions, portions copyright 1996-2006 John Wiley & Sons, Ltd., John Wiley and Sons, Inc., Organic Reactions Inc., and Organic Syntheses Inc. Reproduced under license. All Rights Reserved.10. Single Step66%OverviewSteps/Stages Notes1.1R:AlCl3, S:CH2Cl21.2S:CH2Cl21.3R:H2OReactants: 2, Reagents: 2, Solvents: 1, Steps:1, Stages: 3, Most stages in any one step: 3ReferencesA new synthetic approach to salmeterolBy Rong, Yajing and Ruoho, Amold E.From Synthetic Communications, 29(12),2155-2162; 1999Experimental Procedure5-(Bromoacetyl)-2-hydroxybenzaldehyde 3 To a stirred mixture of anhydrous AlCl3 (53.2 g, 0.4 mol)and CH2Cl2 (120 ml) was added a solution of bromoacetyl chloride (24.1 g, 0.12 mol) in CH2Cl2 (30 ml)at room temperature, and after 30 min salicyladehyde (12.2 g, 0.1 mol) in CH2Cl2 (30 ml) was addeddropwise. The mixture was refluxed for 14-18 hr, and then carefully poured into a mixture of ice andwater. The aqueous layer was extracted with CH2Cl2, the organic fractions were combined, washedwith water (50ml) and brine (50 ml). The organic phase was dried (MgSO4), and evaporated underreduced pressure to produce a residue which was recrystallized using CH2Cl2-hexane to give yellowneedles 16.0 g, yield 66%. 5-(Bromoacetyl)-2-hydroxybenzaldehyde 3, yield 16.0 g, 66%. mp:117.5-118°C (lit.10 117-118°C) IR(KBr): 1650 cm-11H NMR (CDCl3, 300HMz): 4.50 (s, 2H), 7.10 (d, 1H, J=9.0Hz), 8.18 (dd, 1H, J=3.0Hz, J=9.0Hz), 8.31 (d, 1H, J=3.0Hz), 10.0 (s, 1H), 11.50 (s, 1H)CASREACT ®: Copyright © 2015 American Chemical Society. All Rights Reserved. CASREACT contains reactions from CAS and from: ZIC/VINITI database (1974-1999) provided by InfoChem; INPI data prior to 1986; Biotransformations database compiled under the direction of Professor Dr. Klaus Kieslich; organic reactions, portions copyright 1996-2006 John Wiley & Sons, Ltd., John Wiley and Sons, Inc., Organic Reactions Inc., and Organic Syntheses Inc. Reproduced under license. All Rights Reserved.11. Single Step10%OverviewSteps/Stages Notes1.1C:AlBr3, S:CH2Br21.2Reactants: 2, Catalysts: 1, Solvents: 1, Steps:1, Stages: 2, Most stages in any one step: 2ReferencesA short synthesis of albuterolBy Babad, Esther et alFrom Synthesis, (12), 966-8; 1988 Experimental ProcedureB. Using AlBr3 as Lewis Acid, Preparation of a Homogeneous Sample of2: AlBr , (26.7 g, 0.1 mol) inCH2Br2 (100 mL) is treated with bromoacetyl bromide (5.1 g, 0.025 mol) with stirring and after 30 min,salicylaldehyde (1; 2.4g, 0.02 mol) is added. The mixture is heated at 80-90 °C for 18 h, and thencarefully poured onto ice (800 g) with stirring. The organic layer is separated, and the aqueous layer isextracted with CH2Cl2 (2x 100mL). The organic fractions are combined, washed with brine (2 x 250mL), dried (MgSO4), and evaporated under reduced pressure. The resulting brown oil is purified bychromatography on a silica gel column (15 x 2 cm; 230 -400 mesh) using hexane/EtOAc (6:1) aseluent to give 2. Light crystalline solid; yield 0.46 g, 10%. mp 117-118°C; C9H7BrO3 (243.1), calc. C44.24 H 2.90; found C 44.4 H 7 2.81; IR (KBr): v= 1650cm-1. UV (CH3CN): λmax = 243 nm (ε= 25082).1H-NMR (CDCl3): δ = 4.4 (s, 2H); 7.05 (d, 1 H, J= 10 Hz); 8.00-8.30 (m, 2 H):9.90 (s, 1 H); 11.40 (s, 1H).CASREACT ®: Copyright © 2015 American Chemical Society. All Rights Reserved. CASREACT contains reactions from CAS and from: ZIC/VINITI database (1974-1999) provided by InfoChem; INPI data prior to 1986; Biotransformations database compiled under the direction of Professor Dr. Klaus Kieslich; organic reactions, portions copyright 1996-2006 John Wiley & Sons, Ltd., John Wiley and Sons, Inc., Organic Reactions Inc., and Organic Syntheses Inc. Reproduced under license. All Rights Reserved.12. Single Step70% (86:14 )70% (86:14 )OverviewSteps/Stages Notes1.1C:AlCl3, S:CH2Cl2 1.2S:CH2Cl2Reactants: 2, Catalysts: 1, Solvents: 1, Steps: 1, Stages: 2, Most stages in any one step: 2 ReferencesA short synthesis of albuterolBy Babad, Esther et alFrom Synthesis, (12), 966-8; 1988Experimental Procedure5-(Bromoacetyl)-2-hydroxybenzaIdehyde (2): A. Using Alcl3 as Lewis Acid: To a suspension of AlCl3(333 g, 2.5 mol) in CH2Cl2 (350 mL) at reflux is added bromoacetyl chloride (99 g, 0.63 mol) in CH2Cl2(75 ML), and after 30 min salicylaldehyde (1; 61.1 g, 0.5 mol) in CH2Cl2 (75 ML) is added drop wise.The mixture is refluxed for 16 h, and then carefully poured into ice (3 kg), water (300 ML) and CH2Cl2(500 ML) with stirring. Once addition is complete, the mixture is stirred for 15 min, and the organiclayer separated. The aqueous layer is extracted with CH2Cl2 (3 x 250 ML), the organic fractions arecombined, washed with water (2 X 250ML) and brine (500 ML). The organic phase is dried (MgSO4),and evaporated under reduced pressure to give an oily solid (107 g). The solid is slurried with amixture of CH2Cl2 (20 ML) and ether (180 ML), and isolated by filtration. The residue is dried in vacuoat 50° to give a 6:1 mixture of 2 and 5-(chloroacetyl)-2-hydroxybenzaldehyde (3). Yield 83 g, 70 %. 1H-NMR (CDCl3): δ = 4.35, 4.65 (2 s, 2H); 7.05 (d, 1 H, J= 10 Hz); 8.00-8.30 (m, 2H); 9.90 (s, 1 H); 11.50(s, 1 H).CASREACT ®: Copyright © 2015 American Chemical Society. All Rights Reserved. CASREACT contains reactions from CAS and from: ZIC/VINITI database (1974-1999) provided by InfoChem; INPI data prior to 1986; Biotransformations database compiled under the direction of Professor Dr. Klaus Kieslich; organic reactions, portions copyright 1996-2006 John Wiley & Sons, Ltd., John Wiley and Sons, Inc., Organic Reactions Inc., and Organic Syntheses Inc. Reproduced under license. All Rights Reserved.。