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Karsten Menzel,
Fouzia Machrouhi,
Matthew Bodenstein,
Anthony Alorati,
Cameron Cowden,
Andrew W. Gibson,
Brian Bishop,
Norihiro Ikemoto,
Todd D. Nelson, Michael H. Kress,
Doug E. Frantz
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ABSTRACT: As part of Merck’s continued research effort on inflammation and pain, a safe synthesis of an orally bioavailable and CNS penetrant bradykinin 1 antagonist was developed and demonstrated on kilogram scale. The key step included a novel regioselective metal−halogen exchange reaction on 1,2-dibromo-5-chloro-3-fluorobenzene using isopropyl magnesium chloride to install the 1,2,4-oxadiazole ring structure. Suzuki cross-coupling reaction between a highly functionalized and sterically hindered electrophile and boronic ester generated the biaryl ring system, which was converted to the target molecule (1) using standard chemistry. The safe installation of a 1,2,4-oxadiazole ring proved to be challenging since the original synthetic route relied on the preparation of a highly functionalized benzonitrile using potassium cyanide and resulted in low yields and large amounts of potentially hazardous waste. Overall, a safe and robust synthesis was developed, which occurred in eight linear steps with an overall yield of 28%.
05/2009;
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ABSTRACT: A facile protocol for the synthesis of 1,2-dibromoarenes is described. A standard ortho-lithiation/bromination procedure, when applied to bromoarenes, resulted in poor yields of the corresponding 1,2-dibromoarenes (13-62% yield). However, transmetalation of the transient aryllithium intermediate to an arylzinc species with ZnCl2, followed by bromination, resulted in dramatically improved yields of the synthetically useful 1,2-dibromoarenes (68-95% yield).
The Journal of Organic Chemistry 04/2006; 71(5):2188-91. · 4.45 Impact Factor
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ABSTRACT: A practical synthesis of benzisoxazole 1 and its conversion to alpha-aryloxyisobutyric acid 2 using 1,1,1-trichloro-2-methyl-2-propanol (chloretone) was developed. Benzisoxazole 1 was formed in high yields by the action of either methanesulfonyl chloride/base upon intermediate oxime 8 or with thionyl chloride/base, which initially forms cyclic sulfite 10. A highly reactive, short-lived intermediate derived from chloretone was detected by ReacIR and its half-life determined to be approximately 5 min. Reaction conditions for the Bargellini reaction were developed that resulted in a 95% yield of 2 from the reaction of highly hindered phenol 1 with chloretone hemihydrate and powdered NaOH in acetone. Thus highly hindered alpha-aryloxyisobutyric acids can be made in a single step in high yield.
The Journal of Organic Chemistry 11/2005; 70(21):8560-3. · 4.45 Impact Factor
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ABSTRACT: A practical synthesis of benzisoxazole 1 and its conversion to α-aryloxyisobutyric acid 2 using 1,1,1-trichloro-2-methyl-2-propanol (chloretone) was developed. Benzisoxazole 1 was formed in high yields by the action of either methanesulfonyl chloride/base upon intermediate oxime 8 or with thionyl chloride/base, which initially forms cyclic sulfite 10. A highly reactive, short-lived intermediate derived from chloretone was detected by ReacIR and its half-life determined to be 5 min. Reaction conditions for the Bargellini reaction were developed that resulted in a 95% yield of 2 from the reaction of highly hindered phenol 1 with chloretone hemihydrate and powdered NaOH in acetone. Thus highly hindered α-aryloxyisobutyric acids can be made in a single step in high yield.
09/2005;
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ABSTRACT: An efficient synthesis of the potent KDR inhibitor 3-[5-[[4-(methylsulfonyl)-1-piperazinyl]methyl]-1H-indole-2-yl]quinolin-2(1H)-one (1) is described. The process features a noncryogenic indole boronation and a dicyclohexylamine-mediated Suzuki coupling.
The Journal of Organic Chemistry 02/2005; 70(1):175-8. · 4.45 Impact Factor
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Todd D Nelson,
Carl R LeBlond,
Doug E Frantz,
Louis Matty,
Jeffrey V Mitten,
Damian G Weaver,
Jeffrey C Moore,
Jaehon M Kim,
Russell Boyd,
Pei-Yi Kim,
Kodzo Gbewonyo,
Mark Brower,
Michael Sturr,
Kathleen McLaughlin,
Daniel R McMasters, Michael H Kress,
James M McNamara,
Ulf H Dolling
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ABSTRACT: The concise synthesis of a potent thrombin inhibitor was accomplished by a mild lactone aminolysis between an orthogonally protected bis-benzylic amine and a diastereomerically pure lactone. The lactone was synthesized by the condensation of l-proline methyl ester with an enantiomerically pure hydroxy acid, which in turn was synthesized by a highly stereoselective (>500:1 er) and productive (100,000:1, S/C) enzymatic reduction of an alpha-ketoester. In addition, a second route to the enantiomerically pure lactone was accomplished by a diastereoselective ketoamide reduction.
The Journal of Organic Chemistry 06/2004; 69(11):3620-7. · 4.45 Impact Factor
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ABSTRACT: The enantiomers of the stereolabile peroxisome proliferator-activated receptor (PPAR) agonist, 1, were isolated by preparative chiral chromatography and their absolute configuration established using a combination of chromatographic and NMR methods. Enantiomer interconversion was investigated under a variety of conditions, with rapid racemization being observed in most solvents, including all aqueous systems studied, irrespective of pH. Rapid racemization in both dog and human plasma was confirmed by chiral HPLC with MS detection.
Chirality 03/2003; 15(2):143-7. · 2.35 Impact Factor
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ABSTRACT: [reaction: see text] A practical and efficient synthesis of aryl triflates under biphasic basic aqueous conditions is described. The current methodology provides entry into these valuable substrates that omits the use of amine bases and allows facile isolation by simple solvent evaporation after phase separation. Good yields can also be obtained without the use of organic solvent.
Organic Letters 01/2003; 4(26):4717-8. · 5.86 Impact Factor
