Synthetic Studies on a Nonsteroidal Progesterone Metabolite: Regioselective N-Alkylation of an Activated Pyrazole

Abstract

This paper describes the large-scale synthesis of a progesterone receptor metabolite. The key step in this sequence was the regioselective pyrazole N-alkylation.

Key words

regioselective pyrazole alkylation - iodination - carbonylation

References and Notes

• 1 Bradley PA. De Koning PD. Johnson PS. Lecouturier YC. McManus DJ. Robin A. Underwood TJ. Org. Process Res. Dev.  2009,  13:  848 
• 2 Narsaiah AV. Synlett  2002,  1178 
• 3 Shinkre BA. Velu SS. Synth. Commun.  2007,  37:  2399 
• 4 Calverley MJ. Tetrahedron  1987,  43:  4609 
• 5 Del Carmen Cruz M. Tamariaz J. Tetrahedron  2005,  61:  10061 
• 6 Lebedev AV. Lebedeva AB. Sheludyakov VD. Kovaleva EA. Ustinova OL. Kozhevnikov IB. Russ. J. Org. Chem.  2005,  75:  412 
• 8 Tong Y. Claiborne A. Pyzytulinska M. Tao Z. Stewart KD. Kovar P. Chen Z. Credo RB. Guan R. Merta PJ. Zhang H. Bouska J. Everitt EA. Murry BP. Hickman D. Stratton TJ. Wu J. Rosenberg SH. Sham HL. Sowin TJ. Lin N. Bioorg. Med. Chem. Lett.  2007,  17:  3618 

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The pyrazoles can exit in two tautomeric forms, that is, the hydrogen atom may be bound to either the N1 or N2 atom. This tautomeric equilibrium has not been experimentally studied in this manuscript, and the corresponding schemes herein only show an arbitrary tautomer. The stability of both pyrazole tautomers was computational analyzed for compounds 12 and 20 in both gas phase and water solution as the extreme media in terms of dielectric constant. In the unsubstituted case 12, the tautomers are almost equally stable in both media (0.7 and 0.0 kcal/mol, respectively, in favor of N2-H tautomer). On the other hand, in the case of compound 20, the stabilizing electrostatic interaction between N2-H and lone pair of the carbonyl group involves a preferential stability of N2-H tautomer in the gas phase (5.9 kcal/mol). In solution, however, the most polar N1-H tautomer becomes nearly isoenergetic (only 0.3 kcal/mol differences).

9

4-(5-Cyclopropyl-1-methanesulfonylmethyl-1 H -pyrazol-4-yloxy)-2,6-dimethylbenzonitrile (15a)
^¹H NMR (400 MHz, CDCl₃): δ = 0.75 (m, 2 H), 0.90 (m, 2 H), 1.80 (m, 1 H), 2.45 (s, 6 H), 3.05 (s, 3 H), 5.35 (s, 2 H), 6.65 (s, 2 H), 7.40 (s, 1 H).
4-(3-Cyclopropyl-1-methanesulfonylmethyl-1 H -pyrazol-4-yloxy)-2,6-dimethylbenzonitrile (15b)
^¹H NMR (400 MHz, CDCl₃): δ = 0.85 (m, 4 H), 1.65 (m, 1 H), 2.45 (s, 6 H), 2.90 (s, 3 H), 5.10 (s, 2 H), 6.70 (s, 2 H), 7.45 (s, 1 H).

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All the calculations reported in this paper have been performed within density functional theory, using the hybrid three-parameter functional customarily denoted as B3LYP. In all cases the standard 6-31G** basis set was used as implemented in Jaguar package (Schrodinger, LLC, Portland, Oregon). This level (B3LYP/6-31G**) has been shown to be a convenient method for the computational study of these types of reactions in terms of computational cost and accuracy. Reactants and intermediates were characterized by frequency calculations and have positive definite Hessian matrixes. Transition structures (TS) show only one negative eigenvalue in their diagonalized force constant matrixes, and their associated eigenvectors were confirmed to correspond to the motion along the reaction coordinate under consideration. Nonspecific solvent effects were partially taken into account by means of the standard Poisson-Boltzmann continuum solvation model, where he solvent is represented as a polarizable continuum (with dielectric ε) surrounding the molecular complex at an interface constructed by combining atomic van der Waal radii with the effective probe radius of the solvent. In several cases molecular mechanics computations were performed on several stationary points in order to determine the minimum energy conformations. These calculations were performed using the AMBER* force field as implemented in the MacroModel package (Schrodinger, LLC, Portland, Oregon). The different possible conformers were optimized and then Monte Carlo simulations were performed on 1000 structures. All geometries are available on request to the authors.

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4-(3-Cyclopropyl-5-hydroxymethyl-1-methanesulfonyl-methyl-1 H -pyrazol-4-yloxy)-2,6-dimethylbenzonitrile (6)
Lithium borohydride (0.66 mL, 2 M in THF, 1.32 mmol) was added dropwise to a solution of compound 24 (250 mg, 0.6 mmol) in THF (6 mL), under nitrogen, and the resulting mixture was stirred for 30 min. The solvent was removed in vacuo, and the residue was azeotroped with MeOH (25 mL). The resulting solid was purified by flash chromatography (silica gel) eluting with 70% EtOAc in pentane to afford compound 6 as a white foam (180 mg, 80%). ^¹H NMR (400 MHz, CDCl₃): δ = 0.80 (m, 4 H), 1.60 (m, 1 H), 2.40 (t, 1 H), 2.45 (s, 6 H), 3.00 (s, 3 H), 4.60 (d, 2 H), 5.35 (s, 2 H), 6.65 (s, 2 H). Anal. Calcd for C₁₈H₂₁N₃O₄S˙0.66H₂O: C, 55.82; H, 5.81; N, 10.85. Found: C, 55.80; H, 5.76; N, 10.87.