Synthesis of 3-Substituted 1 , 4-Benzodiazepin-2-ones

Benzodiazepines are one of the most important classes of therapeutic agents. For example, different benzodiazepines have anxiolytic, anticonvulsant and antihypnotic activities, serve as cholecystokinin A and B antagonists, opioid receptor ligands, platelet-activating factor antagonists, HIV trans-activator Tat antagonists, HIV reverse transcriptase inhibitors and ras farnesyltransferase inhibitors. Due to the biological importance of benzodiazepines, we have carried out the solid-phase synthesis of libraries of over 10,000 unique 1,4-benzodiazepines derivatives. These libraries have been assayed against a number of receptor and enzyme targets. In one study, benzodiazepine 1 was identified as the first small molecule inhibitor of autoantibody•DNA interactions in lupus-prone mice. Related autoantibody•DNA interactions have been implicated in the autoimmune disease systemic lupus erythematosus (SLE). Blocking this interaction could potentially provide the first effective treatment of SLE. In order to perform animal studies to evaluate this potential strategy for treatment, large quantities of benzodiazepine 1 were required. Herein, we report an efficient synthesis route to multigram quantities of 1 and further describe the scope and limitations of this approach for the preparation of other 3-substituted benzodiazepine derivatives.


Introduction
Benzodiazepines are one of the most important classes of therapeutic agents.For example, different benzodiazepines have anxiolytic, anticonvulsant and antihypnotic activities 1 , serve as cholecystokinin A and B antagonists 2 , opioid receptor ligands 3 , platelet-activating factor antagonists 4 , HIV trans-activator Tat antagonists 5 , HIV reverse transcriptase inhibitors 6 and ras farnesyltransferase inhibitors 7 .Due to the biological importance of benzodiazepines, we have carried out the solid-phase synthesis of libraries of over 10,000 unique 1,4-benzodiazepines derivatives [8][9][10][11][12] .These libraries have been assayed against a number of receptor and enzyme targets.In one study, benzodiazepine 1 was identified as the first small molecule inhibitor of autoantibody•DNA interactions in lupus-prone mice 13 .Related autoantibody•DNA interactions have been implicated in the autoimmune disease systemic lupus erythematosus (SLE) 14 .Blocking this interaction could potentially provide the first effective treatment of SLE.In order to perform animal studies to evaluate this potential strategy for treatment, large quantities of benzodiazepine 1 were required.Herein, we report an efficient synthesis route to multigram quantities of 1 and further describe the scope and limitations of this approach for the preparation of other 3-substituted benzodiazepine derivatives.

Results and Discussion
Most synthesis routes to 3-substituted benzodiazepin-2-ones rely on the incorporation of amino acids into the benzodiazepine structure 1,15 .Accordingly, benzodiazepine 1 can be prepared from the nonproteinogenic amino acid β-naphthylalanine.However, due to the high cost of βnaphthylalanine, an alternative route was prefered for the preparation of large quantities of 1. Alkylation of the enolate of benzodiazepine 4 (Scheme 1) with 2-naphthylmethyl bromide could potentially provide a cost effective route to 1.Although Sternbach has documented the propensity for 1,4-benzodiazepines enolates to rearrange to isoindols 16 , other researchers in limited reports have described successful benzodiazepine enolate alkylations. 17,18In order to explore this approach, benzodiazepine 4 was prepared in three steps from aminobenzophenone 2 19 .Treatment of 2 with bromoacetyl bromide in diethyl ether followed by amination and cyclization under acidic conditions provided 3 in 73% overall yield (Scheme 1). 1,20N-Methylation with methyl iodide using potassium carbonate as a base then provided benzodiazepine 4 in 90% yield.
Next, we turned our attention to enolate alkylation of 4. Reaction conditions were optimized by evaluating a number of bases, reaction temperatures, and reagent stoichiometries.Benzodiazepine 5a (Table 1) was obtained in good yield (78%) using potassium tert-butoxide as base with THF as solvent at -78 °C (Method A).In order to evaluate the generality of these reaction conditions, several other benzodiazepine derivatives were also prepared (Table 1).Notably, with less reactive alkylating agents (entries 5d-5g), potassium bis(trimethylsilyl)amide should be used as the base (Method B).Under these conditions, moderate yields of the benzodiazepine products are observed.
Demethylation of 5a using aluminum tribromide in ethanethiol 21 proceeded in 86% yield, thereby providing benzodiazepine 1. Greater than 50 g of benzodiazepine 1 has been prepared by this synthesis sequence.

Conclusion
Multigram quantities of benzodiazepine 1 have efficiently been prepared with the key step being enolate alkylation of benzodiazepine 4. The scope and generality of preparing substituted benzodiazepines by enolate alkylation has also been established.All products were fully characterized by 1 H-NMR, 13 C-NMR, and HRMS analysis.b Yields of pure compounds after chromatography.c See experimental section for reaction procedures. (

General
Unless otherwise noted, materials were obtained from commercial suppliers and used without further purification.Tetrahydrofuran and diethyl ether were distilled under N2 from sodium/benzophenone immediately prior to use.Flash column chromatography was carried out using Merck 60 230-400 mesh silica gel. 1 H-NMR spectra were obtained with a University of California at Berkeley Bruker AM-400 or AM-500 FT spectrometer.Proton-decoupled 13 C-spectra were obtained at 100 or 125 MHz with the same instruments.Chemical shifts are reported in ppm.High resolution mass spectra were obtained at the University of California at Berkeley mass spectrometry laboratory using fast atom bombardment (FAB) with 3-nitrobenzyl alcohol as matrix solvent.

Method A
To a solution of 4 (15 g, 48 mmol) in 200 mL of THF at -78 °C was added 122 mL of 0.59 M potassium tert-butoxide in THF.After 10 min, a solution of 2-(bromomethyl)naphthalene (13.7 g, 62 mmol) in THF (20 mL) was added by cannula.The solution was stirred for 1 h and quenched with 100 mL of saturated NH4Cl solution.The aqueous layer was extracted with ethyl acetate (3 x 150 mL), and the combined organic layer was washed with water, brine, dried over sodium sulfate, and concentrated in vacuo.The residue was recrystallized from methanol to provide 16.8 g of 5a (78%) as a white solid.

Method B
To a solution of 4 (100 mg, 0.32 mmol) in 2.0 mL of THF at -20 °C was added 0.83 mL of 0.5 M potassium hexamethyldisilazide (KHMDS) in toluene.The solution was allowed to warm to --5 °C and a solution of alkyl bromide (0.42 mmol) in THF (1 mL) was added by cannula.After stirring overnight, the solution was quenched with saturated NH4Cl solution and then the work-up procedure described for Method A was followed.