Preparation of a clinically investigated ras farnesyl transferase inhibitor

Journal of Heterocyclic Chemistry

Volumn 40, Issue 2, 2003, Pages 229-241

  Maligres, Peter E ^a   Waters, Marjorie S ^a   Weissman, Steven A ^a   McWilliams, J Christopher ^a   Lewis, Stephanie ^a   Cowen, Jennifer ^a   Reamer, Robert A ^a   Volante, R P ^a   Reider, Paul J ^a   Askin, David ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

(1 BENZYL 1H IMIDAZOL 5 YL)METHANOL; 4 [(1 BENZYL 1H IMIDAZOL 5 YL)METHYL]BENZONITRILE; 4 [(5 BENZYL 1H IMIDAZOL 1 YL)METHYL]BENZONITRILE; 4 [[1 (4 FLUOROBENZYL) 1H IMIDAZOL 5 YL]METHYL]BENZONITRILE; 4 [[5 (4 FLUOROBENZYL) 1H IMIDAZOL 1 YL]METHYL]BENZONITRILE; 4 [[5 (HYDROXYMETHYL) 1H IMIDAZOL 1 YL]METHYL]BENZONITRILE; 5 BENZYL 1 (4 FLUOROBENZYL 1H IMIDAZOLE); CHLOROMETHYLIMIDAZOLE; IMIDAZOLE DERIVATIVE; PIPERAZINONE; PROTEIN FARNESYLTRANSFERASE INHIBITOR; RAS PROTEIN; UNCLASSIFIED DRUG; [1 (4 BROMOBENZYL) 1H IMIDAZOL 5 YL]METHANOL; [1 (4 METHOXYBENZYL) 1H IMIDAZOL 5 YL]METHANOL; [1 (4 NITROBENZYL) 1H IMIDAZOL 5 YL]METHANOL;

ARTICLE; ARYLATION; CHEMICAL REACTION; CYCLIZATION; DEPROTECTION REACTION; DRUG SYNTHESIS; MITSUNOBU REACTION; STEREOCHEMISTRY; TECHNIQUE;

EID: 0037696559     PISSN: 0022152X     EISSN: None     Source Type: Journal    
DOI: 10.1002/jhet.5570400206     Document Type: Article

References (90)

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52. The filtration of the phthalazine byproduct from the reaction mixture resulting from the deprotection of 10 with hydrazine was very slow and required prolonged washing of the filter cake to recover all of 8a. Attempted phthalimide deprotection with borohydride followed by acid catalyzed hydrolysis resulted in complex mixtures. [a] F. Dasgupta and P. J. Garegg, J. Carbohydrate Chem., 7, 701 (1988); [b] J. O. Osby, M. G. Martin and B. Ganem, Tetrahedron Lett., 25, 2093 (1984); Cleavage of the phthalimide from 10 with methylamine or aqueous NaOH gave complex mixtures; [c] M. S. Motawia, J. Wengel, A. E.-S. Abdel-Megid and E. B. Pedersen, Synthesis, 384 (1989).
53. The filtration of the phthalazine byproduct from the reaction mixture resulting from the deprotection of 10 with hydrazine was very slow and required prolonged washing of the filter cake to recover all of 8a. Attempted phthalimide deprotection with borohydride followed by acid catalyzed hydrolysis resulted in complex mixtures. [a] F. Dasgupta and P. J. Garegg, J. Carbohydrate Chem., 7, 701 (1988); [b] J. O. Osby, M. G. Martin and B. Ganem, Tetrahedron Lett., 25, 2093 (1984); Cleavage of the phthalimide from 10 with methylamine or aqueous NaOH gave complex mixtures; [c] M. S. Motawia, J. Wengel, A. E.-S. Abdel-Megid and E. B. Pedersen, Synthesis, 384 (1989).
54. The filtration of the phthalazine byproduct from the reaction mixture resulting from the deprotection of 10 with hydrazine was very slow and required prolonged washing of the filter cake to recover all of 8a. Attempted phthalimide deprotection with borohydride followed by acid catalyzed hydrolysis resulted in complex mixtures. [a] F. Dasgupta and P. J. Garegg, J. Carbohydrate Chem., 7, 701 (1988); [b] J. O. Osby, M. G. Martin and B. Ganem, Tetrahedron Lett., 25, 2093 (1984); Cleavage of the phthalimide from 10 with methylamine or aqueous NaOH gave complex mixtures; [c] M. S. Motawia, J. Wengel, A. E.-S. Abdel-Megid and E. B. Pedersen, Synthesis, 384 (1989).
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72. 4) did not affect the yield or purity of the imidazole formation.
73. 4.
74. Several solvents were examined as mediums for the Marckwald reaction to prepare 7a. The use of water, methanol, ethanol, isopropanol and acetic acid as solvents for the preparation of 7a resulted in lower yields. The amounts of acetic acid and water employed in the Marckwald reaction were found to have a considerable effect on the yield.
75. A copious quantity of a colorless gas is evolved during the addition of sodium nitrite (presumably nitric oxide), which is converted to brown nitrogen dioxide gas upon contact with air.
76. It is important to maintain a temperature above 35°C during the addition of peroxide to avoid the buildup of peroxide in the reaction mixture. The peroxide reacts more slowly with the mercaptoimidazole below 35°C allowing peroxide to build up during the addition leading to a less controlled reaction later. No reaction takes place in the absence of acetic acid or in more dilute aqueous solutions of acid.
77. 2.
78. [a] M. S. Waters, J. A. Cowen, J. C. McWilliams, P. E. Maligres, and D. Askin, Tetrahedron Lett., 41, 141 (1999);
79. [b] D. Askin, J. A. Cowen, P. E. Maligres, J. C. McWilliams, and M. S. Waters, U. S. Patent 6239280 (2001); Chem. Abstr., 134, 366876n (2001).
80. 6-DMSO.
81. M. M. Paz, J. F. Correa, M. I. Cabeza, and F. J. Sardina, Tetrahedron Lett., 37, 9259 (1996).
82. The imidate ester A was observed to be formed rapidly at -20°C (React-IR) and is not converted to 2 until the mixture is heated to -5°C. Conducting the reaction in pure DMF (5 mL/g 12a) renders A completely soluble at - 10°C. Upon warming, A is converted to 2, which crystallizes from solution.
83. D. Askin, J. A. Cowen, P. E. Maligres, J. C. McWilliams, and M. S. Waters, PCT International Patent 0001674 (2000); Chem. Abstr., 132, 93318s (2000).
84. G. S. Poindexter, D. A. Owens, P. L. Dolan, and E. Woo, J. Org. Chem., 57, 6257 (1992). The use of sulfolane as a solvent for the condensation of 3-chloroaniline·HCl with oxazolidone allowed the reaction to be more conveniently performed.
85. S. A. Weissman, S. Lewis, D. Askin, R. P. Volante, and P. J. Reider, Tetrahedron Lett., 39, 7459 (1998).
86. 3B). Activation of 12a as its acetate, pivaloate, phenyl and 4-nitrophenyl derivatives followed by reaction with 3 began forming product 1 only at temperatures above 120°C. Similarly reaction of 2 with 1,4-diazabicyclo[2.2.2]octane and 4-dimethylaminopyridine to form the corresponding quaternary salt derivatives in situ followed by reaction with 3 gave 1 only at elevated temperatures.
87. D. Askin, J. A. Cowen, P. E. Maligres, J. C. McWilliams, and J. A. McCauley, PCT International Patent 0001691 (2000); Chem. Abstr., 132, 93336w (2000).
88. 13C satellites of chloromethylene protons signal at 4.65 ppm with the hydroxymethylene protons signal integral at 4.4 ppm. Hplc analysis of a reaction mixture aliquot quenched with DABCO (1,4-diazabicyclo[2.2.2]octane) indicated ≥99.5% conversion to 2. DABCO reacts with 2 forming a quaternary ammonium salt DABCO adduct. Hplc conditions: Zorbax Eclipse XDB-C18 4.6 ? 75 mm column, gradient elution over 7 min with 10/90 → 70/30 acetonitrile/0.01 M aqueous phosphate buffer (pH = 6.3), 2.0 mL/min flow at 40°C with detection at 210 nm. Hplc retention times: DABCO-2 adduct = 0.7 min, 12a = 1.8 min.
89. Progress of the reaction was monitored by quantitative hplc analysis, analyzing for the mg/mL of remaining 2. The analysis distinguishes 2 from 12a by comparing a sample quenched with DABCO versus a sample quenched with an aqueous phosphate buffer (pH = 6.33). The reaction usually proceeds so that ≤ 4-6% 2 remains unreacted after 24 h, but requires much longer (typically 38-45 h) so that ≤ 2% 2 remains. The reaction can be crystallized at 24 h, with only a slight decrease in assay/isolated yields (2-4%). Hplc conditions: Eclipse-XDB 0.46 ? 7.5 cm column, gradient elution over 10 min with 10:90 → 80:20 acetonitrile/10 mM aqueous phosphate buffer (pH = 6.33), 2.0 mL/min flow at 25°C with detection at 210 nm. Retention times: DABCO-chloromethylimidazole adduct = 0.9 min, 2 = 2.0 min, 3 = 2.6 min, Quaternary ammonium salt (double alkylation product in ref 25) = 4.8 min, 1 = 5.2 min.
90. 2NEt prior to crystallization has been found to reduce the amount of a trace phenolic impurity in the final crystalline product. The formation of a solid is often observed during the course of the reaction. This precipitate is crystalline 1 in its anhydrous form.