title: An enantioselective formal synthesis of montelukast sodium.
abstract: A formal synthesis of the antiasthma drug montelukast sodium is described, wherein the key chiral diol intermediate was accessed with greater convergence of the C-C bond-forming steps as compared to previous routes. Improved synthetic efficiency was achieved by deploying homogeneous metal-based catalysis in two pivotal steps. In the first, a tandem Mizoroki-Heck reaction and double-bond isomerization between a previously known allyl alcohol intermediate and a hindered 2-(2-halophenyl)propan-2-ol secured direct access to the 3-(2-(2-hydroxypropan-2-yl)phenyl)-1-phenylpropan-1-one moiety in the product. In the second step, asymmetric hydrogenation of the ketone functionality in the Mizoroki-Heck reaction product provided a convenient method to introduce the benzylic alcohol chiral center and obtain the desired chiral diol precursor of montelukast sodium. A detailed catalyst screening led to the identification of ((R)-Xyl-BINAP)((R,R)-DPEN)RuCl2 as a catalyst that afforded an enantioselectivity of 99% ee in the hydrogenation step on a multigram lab scale at a molar substrate:catalyst loading of 5000:1.
authors: †Integrated Product Development Organization, Dr. Reddy's Laboratories Ltd., Bachupally, Qutabullapur, Hyderabad 500 072, Telangana, India.
authors: Satyanarayana
authors: S
authors: Bollikonda
authors: †Integrated Product Development Organization, Dr. Reddy's Laboratories Ltd., Bachupally, Qutabullapur, Hyderabad 500 072, Telangana, India.
authors: Saravanan
authors: S
authors: Mohanarangam
authors: †Integrated Product Development Organization, Dr. Reddy's Laboratories Ltd., Bachupally, Qutabullapur, Hyderabad 500 072, Telangana, India.
authors: Rajender Reddy
authors: RR
authors: Jinna
authors: †Integrated Product Development Organization, Dr. Reddy's Laboratories Ltd., Bachupally, Qutabullapur, Hyderabad 500 072, Telangana, India.
authors: Venkata Kiran Kumar
authors: VK
authors: Kandirelli
authors: Laxman
authors: L
authors: Makthala
authors: Saikat
authors: S
authors: Sen
authors: §Chirotech Technology Centre, Dr. Reddy's Laboratories (EU) Limited, 410 Cambridge Science Park, Cambridge, CB4 0PE, United Kingdom.
authors: David A
authors: DA
authors: Chaplin
authors: §Chirotech Technology Centre, Dr. Reddy's Laboratories (EU) Limited, 410 Cambridge Science Park, Cambridge, CB4 0PE, United Kingdom.
authors: Richard C
authors: RC
authors: Lloyd
authors: §Chirotech Technology Centre, Dr. Reddy's Laboratories (EU) Limited, 410 Cambridge Science Park, Cambridge, CB4 0PE, United Kingdom.
authors: Thomas
authors: T
authors: Mahoney
authors: †Integrated Product Development Organization, Dr. Reddy's Laboratories Ltd., Bachupally, Qutabullapur, Hyderabad 500 072, Telangana, India.
authors: Vilas Hareshwar
authors: VH
authors: Dahanukar
authors: Srinivas
authors: S
authors: Oruganti
authors: §Chirotech Technology Centre, Dr. Reddy's Laboratories (EU) Limited, 410 Cambridge Science Park, Cambridge, CB4 0PE, United Kingdom.
authors: Martin E
authors: ME
authors: Fox
mesh_terms: D000085:Acetates / Q000138:chemical synthesis* / Q000737:chemistry; D018927:Anti-Asthmatic Agents / Q000138:chemical synthesis* / Q000737:chemistry; D002384:Catalysis; D056831:Coordination Complexes / Q000737:chemistry*; D003521:Cyclopropanes; D006865:Hydrogenation; D015394:Molecular Structure; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry; D012428:Ruthenium / Q000737:chemistry; D012964:Sodium / Q000737:chemistry; D013237:Stereoisomerism; D013440:Sulfides
chemical_list: D000085:Acetates; D018927:Anti-Asthmatic Agents; D056831:Coordination Complexes; D003521:Cyclopropanes; D011804:Quinolines; D013440:Sulfides; D012428:Ruthenium; D012964:Sodium; C093875:montelukast