Production Method 1

75-31-0

105780-38-9

81024-42-2

Reaction Conditions

1.1 Solvents: Isopropanol ;  12 h, rt

Reference

Asymmetric hydrolytic kinetic resolution with recyclable polymeric Co(III)-salen complexes: a practical strategy in the preparation of (S)-metoprolol, (S)-toliprolol and (S)-alprenolol: computational rationale for enantioselectivity

Roy, Tamal; et al, Catalysis Science & Technology, 2014, 4(11), 3899-3908

Production Method 2

95586-81-5

81024-42-2

Reaction Conditions

1.1 Reagents: Potassium carbonate Solvents: Acetone ;  6 h, 50 °C

Reference

Application of kinetic resolution using HCS as chiral auxiliary: Novel synthesis of β-blockers (S)-betaxolol and (S)-metoprolol

Zhang, Jing-Yu; et al, Chirality, 2009, 21(8), 745-750

Production Method 3

104450-91-1

81024-42-2

Reaction Conditions

1.1 Reagents: Sulfuric acid Solvents: Methanol

Reference

A new route from D-mannitol to enantiomerically pure (S)-1-(alkylamino)-3-(aryloxy)-2-propanols

Lamm, Bo; et al, Acta Chemica Scandinavica, 1987, 41(3), 202-7

Production Method 4

75-31-0

81024-42-2

Reaction Conditions

1.1 2 h, reflux

Reference

Asymmetric synthesis of (S)-Metoprolol

Song, Guang-Wei; et al, Yingyong Huaxue, 2010, 27(11), 1286-1290

Production Method 5

114218-34-7

75-31-0

81024-42-2

Reaction Conditions

1.1 Solvents: Isopropylamine
1.2 Reagents: Sulfuric acid

Reference

A new route from D-mannitol to enantiomerically pure (S)-1-(alkylamino)-3-(aryloxy)-2-propanols

Lamm, Bo; et al, Acta Chemica Scandinavica, 1987, 41(3), 202-7

Production Method 6

75-31-0

113798-78-0

81024-42-2

Reaction Conditions

1.1 Reagents: Trimethyl orthoacetate Catalysts: Pyridinium p-toluenesulfonate Solvents: Dichloromethane ;  20 min, rt
1.2 Reagents: Acetyl bromide Solvents: Dichloromethane ;  6 min, rt; 30 min, rt
1.3 Reagents: Potassium carbonate Solvents: Methanol ;  1.5 h, rt
1.4 Solvents: Water ;  1.5 h, reflux

Reference

Asymmetric synthesis of (S)-metoprolol via Sharpless asymmetric dihydroxylation induced by a recoverable polymer ligand QN-AQN-OPEG-OMe

Cheng, Sikun; et al, Letters in Organic Chemistry, 2012, 9(7), 516-519

Production Method 7

56718-70-8

75-31-0

81024-42-2

Reaction Conditions

1.1 Catalysts: β-Cyclodextrin Solvents: Ethanol ,  Water
1.2 -

Reference

Enantioselective ring opening of epoxides with trimethylsilyl azide (TMSN3) in the presence of β-cyclodextrin: an efficient route to 1,2-azido alcohols

Kamal, Ahmed; et al, Tetrahedron: Asymmetry, 1999, 10(22), 4261-4264

Production Method 8

104450-90-0

75-31-0

81024-42-2

Reaction Conditions

1.1 Solvents: Isopropylamine
2.1 Reagents: Sulfuric acid Solvents: Methanol

Reference

A new route from D-mannitol to enantiomerically pure (S)-1-(alkylamino)-3-(aryloxy)-2-propanols

Lamm, Bo; et al, Acta Chemica Scandinavica, 1987, 41(3), 202-7

Production Method 9

113798-78-0

81024-42-2

Reaction Conditions

1.1 Reagents: Trimethyl orthoacetate Catalysts: Pyridinium p-toluenesulfonate Solvents: Dichloromethane ;  20 min, rt
1.2 Reagents: Acetyl bromide ;  rt; 30 min, rt
1.3 Reagents: Potassium carbonate Solvents: Methanol ;  1.5 h, rt
1.4 Reagents: Ammonium chloride Solvents: Water
2.1 Solvents: Water ;  1.5 h, reflux

Reference

Synthesis of (S)-metoprolol by by asymmetric dihydroxylation

Xiang, Shun; et al, Hecheng Huaxue, 2011, 19(1), 127-129

Production Method 10

51384-51-1

81024-42-2

81024-43-3

Reaction Conditions

1.1 Reagents: β-Cyclodextrin, 6A,6B,6C,6D,6E,6F,6G-heptakis-O-(carboxymethyl)-2A,2B,2C,2D,2E,2… ;  20 °C

Reference

Characterization of a single-isomer carboxymethyl-beta-cyclodextrin in chiral capillary electrophoresis

Fejos, Ida; et al, Electrophoresis, 2017, 38(15), 1869-1877

Production Method 11

87-69-4

51384-51-1

81024-42-2

81024-43-3

Reaction Conditions

Reference

Enantioseparations of 11 Amino Alcohols Using Di-n-amyl L-Tartrate-Boric Acid Complex as Chiral Mobile Phase Additive by RP-HPLC

Zou, Yanan; et al, Chromatographia, 2015, 78(11-12), 753-761

Production Method 12

929205-75-4

75-31-0

81024-42-2

Reaction Conditions

1.1 5 h, rt

Reference

Asymmetric synthesis of (2S)-1-[4-(2-methoxyethyl)phenoxy]-3-[(1-methylethyl)amino]-2-propanol [(S)-metoprolol]

Ji, Dehua; et al, Xiandai Huagong, 2008, 28(11), 58-59

Production Method 13

929205-75-4

75-31-0

81024-42-2

Reaction Conditions

1.1 Solvents: Isopropylamine ,  Water ;  2 h, reflux
1.2 Reagents: Ammonia Solvents: Water

Reference

Concise synthesis of β-blockers (S)-metoprolol and (S)-betaxolol using hydrolytic kinetic resolution

Muthukrishnan, M.; et al, Tetrahedron, 2007, 63(8), 1872-1876

Production Method 14

133397-54-3

75-31-0

81024-42-2

Reaction Conditions

1.1 Catalysts: Borate(1-), tetrafluoro-, zinc (2:1), hydrate ;  2 h, rt

Reference

Zinc Tetrafluoroborate Hydrate as a Mild Catalyst for Epoxide Ring Opening with Amines: Scope and Limitations of Metal Tetrafluoroborates and Applications in the Synthesis of Antihypertensive Drugs (RS)/(R)/(S)-Metoprolols

Pujala, Brahmam; et al, Journal of Organic Chemistry, 2011, 76(21), 8768-8780

Production Method 15

91678-97-6

81024-42-2

Reaction Conditions

1.1 Reagents: Potassium hydroxide Solvents: Ethanol ,  Water ;  8 - 10 h, reflux
1.2 Reagents: Acetic acid ;  neutralized

Reference

Concise Synthesis of Two β-Adrenergic Blocking Agents in High Stereoselectivity Using the Readily Available Chiral Building Block (2S,2'S,2''S)-Tris-(2,3-epoxypropyl)-isocyanurate

Sonawane, Swapnil P.; et al, Organic Process Research & Development, 2011, 15(6), 1365-1370

Production Method 16

149380-56-3

81024-42-2

Reaction Conditions

1.1 Reagents: Hydrogen Catalysts: Platinum dioxide Solvents: Methanol

Reference

Catalysts for asymmetric synthesis and preparation of (S)-metoprolol

, Japan, , ,

Production Method 17

134582-18-6

81024-42-2

Reaction Conditions

1.1 24 h, 70 °C
1.2 Reagents: Hydrochloric acid Solvents: Water ;  pH 3

Reference

Synthesis technique and control of impurities of (S)-succinate metoprolol

Di, Pan-pan; et al, Anhui Yiyao, 2015, 19(3), 427-430

Production Method 18

105780-38-9

81024-42-2

Reaction Conditions

Reference

Kinetic resolution of aryl glycidyl ethers: a practical synthesis of the optically pure β-blocker S-metoprolol

Gurjar, Mukund K.; et al, Heterocycles, 1998, 48(7), 1471-1476

Production Method 19

56392-18-8

81024-42-2

Reaction Conditions

Reference

Immobilized cellulase (CBH I) as a chiral stationary phase for direct resolution of enantiomers

Erlandsson, Per; et al, Journal of the American Chemical Society, 1990, 112(11), 4573-4

Production Method 20

104450-90-0

81024-42-2

Reaction Conditions

1.1 Reagents: Sulfuric acid Solvents: Methanol
2.1 Solvents: Isopropylamine
2.2 Reagents: Sulfuric acid

Reference

A new route from D-mannitol to enantiomerically pure (S)-1-(alkylamino)-3-(aryloxy)-2-propanols

Lamm, Bo; et al, Acta Chemica Scandinavica, 1987, 41(3), 202-7

Production Method 21

113798-78-0

81024-42-2

Reaction Conditions

1.1 Reagents: Triethylamine Solvents: Dichloromethane ;  rt → -10 °C
1.2 Reagents: Thionyl chloride Solvents: Dichloromethane ;  -10 °C; 4 h, -10 °C
2.1 2 h, reflux

Reference

Asymmetric synthesis of (S)-Metoprolol

Song, Guang-Wei; et al, Yingyong Huaxue, 2010, 27(11), 1286-1290

Production Method 22

81024-42-2

Reaction Conditions

1.1 Reagents: Sodium hydride Solvents: N-Methyl-2-pyrrolidone ;  20 min, 0 - 5 °C; 5 - 6 h, 5 °C → 65 °C
2.1 Reagents: Potassium hydroxide Solvents: Ethanol ,  Water ;  8 - 10 h, reflux
2.2 Reagents: Acetic acid ;  neutralized

Reference

Concise Synthesis of Two β-Adrenergic Blocking Agents in High Stereoselectivity Using the Readily Available Chiral Building Block (2S,2'S,2''S)-Tris-(2,3-epoxypropyl)-isocyanurate

Sonawane, Swapnil P.; et al, Organic Process Research & Development, 2011, 15(6), 1365-1370

(S)-Metoprolol Raw materials

• L(+)-Tartaric acid
• 2-Propanol, 1-iodo-3-[4-(2-methoxyethyl)phenoxy]-, (2R)-
• Metoprolol
• 3-4-(2-Methoxyethyl)phenoxy-1,2-epoxypropane
• (R)-3-4-(2-Methoxyethyl)phenoxy-1,2-epoxypropane
• 1-Propanamine, 2,2'-[methylenebis(oxy)]bis[3-[4-(2-methoxyethyl)phenoxy]-N-(1-methylethyl)-, [S-(R*,R*)]- (9CI)
• 1-Propanol, 2,2'-[methylenebis(oxy)]bis[3-[4-(2-methoxyethyl)phenoxy]-, dimethanesulfonate, [R-(R*,R*)]- (9CI)
• 1,2-Propanediol, 3-[4-(2-methoxyethyl)phenoxy]-, 1-methanesulfonate, (R)- (9CI)
• 2-Propanol, 1-amino-3-[4-(2-methoxyethyl)phenoxy]-, (S)-
• 2-Propanol, 1-[4-(2-methoxyethyl)phenoxy]-3-nitro-, (2S)-
• 1-[4-(2-methoxyethyl)phenoxy]-3-[(1-methylethyl)amino]propan-2-ol hydrochloride
• propan-2-amine
• (2S)-3-(4-(2-Methoxyethyl)phenoxy)propane-1,2-diol
• (S)-3-4-(2-Methoxyethyl)phenoxy-1,2-epoxypropane
• 2-Oxazolidinone, 5-[[4-(2-methoxyethyl)phenoxy]methyl]-3-(1-methylethyl)-, (5S)-
• 1-Chloro-2-hydroxy-3-(4-(2-methoxyethyl)phenoxy)-propane, (R)-

(S)-Metoprolol Preparation Products

• (S)-Metoprolol (81024-42-2)
• (R)-Metoprolol (81024-43-3)

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• 62572-90-1(3-4-(2-Methoxyethyl)phenoxy-1,2-propanediol)
• 98418-47-4(Metoprolol succinate)
• 81024-43-3((R)-Metoprolol)
• 51384-51-1(Metoprolol)
• 56392-16-6(a-Hydroxy Metoprolol (Mixture of Diastereomers))
• 93379-54-5((S)-Atenolol)
• 29122-68-7(Atenolol)
• 56392-17-7(Metoprolol Tartrate (mixture of isomers))
• 37350-58-6(Metoprolol)
• 56392-14-4(Metoprolol Acid)