Synthetic studies on a nonsteroidal progesterone metabolite: Regioselective N-alkylation of an activated pyrazole

Synlett

Volumn , Issue 6, 2010, Pages 873-876

  Bradley, Paul A ^a   De Koning, Pieter D ^a   Gibson, Karl R ^a   Lecouturier, Yann C ^a   MacKenny, Malcolm C ^a   Morao, Inaki ^a   Poinsard, Cedric ^a   Underwood, Toby J ^a  

^a PFIZER GLOBAL RESEARCH AND DEVELOPMENT   (United Kingdom)

Author keywords

Carbonylation; Iodination; Regioselective pyrazole alkylation

Indexed keywords

PROGESTERONE DERIVATIVE; PROGESTERONE RECEPTOR; PYRAZOLE DERIVATIVE;

ALKYLATION; ARTICLE; CHEMICAL MODIFICATION; CHEMICAL REACTION; PROGESTERONE SYNTHESIS; STEREOCHEMISTRY;

EID: 77949900541     PISSN: 09365214     EISSN: 14372096     Source Type: Journal    
DOI: 10.1055/s-0029-1219535     Document Type: Article

References (12)

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7. Tong Y, Claiborne A, Pyzytulinska M, Tao Z, Stewart K D., Kovar P, Chen Z, Credo R B., Guan R, Merta [nl]P J., Zhang H, Bouska J, Everitt E A., Murry B P., Hickman D, Stratton T J., Wu J, Rosenberg S H., Sham H L., Sowin T J., Lin N, Bioorg. Med. Chem. Lett. 2007 17 3618
8. 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 N2H tautomer). On the other hand, in the case of compound 20, the stabilizing electrostatic interaction between N2H and lone pair of the carbonyl group involves a preferential stability of N2H tautomer in the gas phase (5.9 kcal/mol). In solution, however, the most polar N1H tautomer becomes nearly isoenergetic (only 0.3 kcal/mol differences).
9. Tong, Y.; Claiborne, A.; Pyzytulinska, M.; Tao, Z.; Stewart, K. D.; Kovar, P.; Chen, Z.; Credo, R. B.; Guan, R.; Merta, P. J.; Zhang, H.; Bouska, J.; Everitt, E. A.; Murry, B. P.; Hickman, D.; Stratton, T. J.; Wu, J.; Rosenberg, S. H.; Sham, H. L.; Sowin, T. J.; Lin, N. Bioorg. Med. Chem. Lett. 2007, 17, 3618.
10. 4-(5-Cyclopropyl-1-methanesulfonylmethyl-1H-pyrazol-4-yloxy)-2, 6-dimethylbenzonitrile (15a) 1H NMR (400 MHz, CDCl3): d = 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-1H-pyrazol-4-yloxy) -2,6-dimethylbenzonitrile (15b) 1H NMR (400 MHz, CDCl3): d = 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).
11. 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 6-31Gbasis 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 PoissonBoltzmann continuum solvation model, where he solvent is represented as a polarizable continuum (with dielectric e) 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.
12. 4-(3-Cyclopropyl-5-hydroxymethyl-1-methanesulfonylmethyl- 1H-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): d = 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 C18H21N3O4S0.66H2O: C, 55.82; H, 5.81; N, 10.85. Found: C, 55.80; H, 5.76; N, 10.87