Reactions of 1,4-Benzodiazepinic N-Nitrosoamidines with Tosylmethyl Isocyanide: A Novel Synthesis of Midazolam

Abstract

Reaction of 1,4-benzodiazepinic N-nitrosoamidines, used as synthetic equivalents of imidoyl chlorides, with the mono-anion of tosylmethyl isocyanide is described. The process gives entry to 3-(4-tosyl)imidazo[1,5-a][1,4]benzodiazepines, compounds which have not been described yet in the literature. These systems can be derivatized to the corresponding trisubstituted 1,4-benzodiazepines by alkylation or acylation of the imidazole ring. These new heterocyclic derivatives are potentially useful in the field of medicinal chemistry. In addition, midazolam 3, the anesthetic properties of which are well established, can be easily prepared in one step by desulfonylation of compound 7a.

heterocycles - cyclizations - reductions - benzodiazepines - isocyanides

References.

<A NAME="RF03204SS-40-1A">40-1a</A> Benzodiazepines Divided: A Multidisciplinary Review   Wiley; New York: 1983. 

<A NAME="RF03204SS-40-1B">40-1b</A> Bock MG. DiPardo RM. Evans BE. Rittle KE. Whitter WL. Veber DF. Anderson PS. Freidinger RM. J. Med. Chem.  1989,  32:  13 

<A NAME="RF03204SS-40-2">40-2</A> Sneader W. In Comprehensive Medicinal Chemistry   Vol. 1:  Hansch C. Sammes PG. Taylor JB. Pergamon; London: 1990.  p.65 

<A NAME="RF03204SS-40-3A">40-3a</A> Archer GA. Sternbach LH. Chem. Rev.  1968,  68:  747 

<A NAME="RF03204SS-40-3B">40-3b</A> Sharp JT. In Comprehensive Heterocyclic Chemistry II   Vol 7:  Katritzky AR. Rees CW. Pergamon; Amsterdam: 1984.  p.593 

<A NAME="RF03204SS-40-3C">40-3c</A> Tucker H. Le Count DJ. In Comprehensive Heterocyclic Chemistry II   Vol 9:  Katritzky AR. Rees CW. Scriven EFV. Elsevier; Amsterdam: 1996.  p.151 

For 1,4-benzodizazepines as inhibitors of reverse transcriptase, see:

<A NAME="RF03204SS-40-4A">40-4a</A> Robl JA. Cimarusti MP. Simpkins LM. Brown B. Ryono DE. Bird JE. Asaad MM. Schaeffer TR. Trippodo NC. J. Med. Chem.  1996,  39:  494 

<A NAME="RF03204SS-40-4B">40-4b</A> Merluzzi VJ. Hargrave KD. Labadia M. Grozinger K. Skoog M. Wu JC. Shih C.-K. Eckner K. Hattox S. Adams J. Rosenthal AS. Faanes R. Eckner RJ. Koup RA. Sullivan JL. Science  1990,  250:  1411 

For 1,4-benzodiazepines as antitumor and gene targeted drugs, see:

<A NAME="RF03204SS-40-5A">40-5a</A> Wang T. Lui AS. Cloudsdale IS. Org. Lett.  1999,  1:  1835 

<A NAME="RF03204SS-40-5B">40-5b</A> Novelli F. Sparatore A. Tasso B. Sparatore F. Bioorg. Med. Chem. Lett.  1999,  9:  3031 

<A NAME="RF03204SS-40-5C">40-5c</A> Wilson SC. Howard PW. Forrow SM. Hartley JA. Adams LJ. Jenkins TC. Kelland LR. Thurston DE. J. Med. Chem.  1999,  42:  4028 

<A NAME="RF03204SS-40-6">40-6</A> For 1,4-benzodiazepines as inhibitors of phosphodiesterases PDE4, see: Pascal Y. Andrianjara CR. Auclair E. Avenel N. Bertin B. Calvet A. Féru F. Lardon S. Moodley I. Ouagued M. Payne A. Pruniaux M.-P. Szilagyi C. Bioorg. Med. Chem. Lett.  2000,  10:  35 

For 1,4-benzodiazepines as potent and selective oxytocin antagonist, see:

<A NAME="RF03204SS-40-7A">40-7a</A> Evans B. Pipe A. Clark L. Banks M. Bioorg. Med. Chem. Lett.  2001,  11:  1297 

<A NAME="RF03204SS-40-7B">40-7b</A> Wyatt PG. Allen MJ. Chilcott J. Hickin G. Miller ND. Woollard PM. Bioorg. Med. Chem. Lett.  2001,  11:  1301 

For 1,4-benzodiazepines as antagonists of the GPllb/llla receptor, see:

<A NAME="RF03204SS-40-8A">40-8a</A> Hayes JF. Synlett  1999,  865 

<A NAME="RF03204SS-40-8B">40-8b</A> Andrews IP. Atkins RJ. Badham RF. Bellingham RK. Breen GF. Carey JS. Etridge SK. Hayes JF. Hussain N. Morgan DO. Share AC. Smith SAC. Walsgrove TC. Wells AS. Tetrahedron Lett.  2001,  42:  4915 

<A NAME="RF03204SS-40-9">40-9</A> For 1,4-benzodiazepines as cholecystokinin (CCK-A) receptor antagonists, see: Sherrill RG. Berman JM. Birkemo L. Croom DK. Dezube L. Ervin GN. Grizzle MK. James MK. Johnson MF. Queen KL. Rimele TJ. Vanmiddlesworth F. Sugg EE. Bioorg. Med. Chem. Lett.  2001,  11:  1145 

For 1,4-benzodiazepines as herbicides, see:

<A NAME="RF03204SS-40-10A">40-10a</A> Karp GM. Manfredi MC. Guaciaro MA. Ortlip CL. Marc P. Szamosi IT. J. Agric. Food Chem.  1997,  45:  493 

<A NAME="RF03204SS-40-10B">40-10b</A> Karp GM. J. Org. Chem.  1999,  64:  8156 

<A NAME="RF03204SS-40-11A">40-11a</A> Vida JA. In Medicinal Chemistry   Wolf MW. Burger A. Wiley; New York: 1981.  p.787 

<A NAME="RF03204SS-40-11B">40-11b</A> Fryer RI. In Comprehensive Heterocyclic Chemistry   Vol 3:  Hansch C. Pergamon Press; New York: 1990.  p.539 

<A NAME="RF03204SS-40-12A">40-12a</A> Hester JB. Rudzik AB. Kamdar BV. J. Med. Chem.  1971,  14:  1078 

<A NAME="RF03204SS-40-12B">40-12b</A> Schulte E. Dtsch. Apoth.-Ztg.  1975,  115:  1243 

<A NAME="RF03204SS-40-12C">40-12c</A> Gilman NW. Holland BC. Fryer RI. J. Heterocycl. Chem.  19 77,  14:  1163 

<A NAME="RF03204SS-40-12D">40-12d</A> Walser A. Benjamin LE. Flynn T. Mason C. Schwartz R. Fryer RI. J. Org. Chem.  1978,  43:  936 

<A NAME="RF03204SS-40-13A">40-13a</A> Hester JB. Duchamp D. Chidester CG. Tetrahedron Lett.  1971,  1609 

<A NAME="RF03204SS-40-13B">40-13b</A> Coffen DL. DeNoble JP. Evans EL. Field GF. Fryer RI. Katonak DA. Mandel BJ. Sternbach LH. Zally WJ. J. Org. Chem.  1974,  39:  167 

<A NAME="RF03204SS-40-13C">40-13c</A> Gall M. Hester JB. Rudzik AD. Lahti RA. J. Med. Chem.  1976,  19:  1057 

<A NAME="RF03204SS-40-13D">40-13d</A> Hester JB. J. Heterocycl. Chem.  1980,  17:  575 

<A NAME="RF03204SS-40-13E">40-13e</A> Hester JB. Rudzik AD. Voigtlander PFV. J. Med. Chem.  1980,  23:  392 

<A NAME="RF03204SS-40-13F">40-13f</A> Hester JB. Rudzik AD. Voigtlander PFV. J. Med. Chem.  1980,  23:  402 

<A NAME="RF03204SS-40-13G">40-13g</A> Hester HB. Rudzik AD. Voigtlander PFV. J. Med. Chem.  1980,  23:  643 

<A NAME="RF03204SS-40-13H">40-13h</A> Gall M. Kamdar BV. J. Med. Chem.  1981,  24:  1575 

<A NAME="RF03204SS-40-13I">40-13i</A> Walser A. Fryer RI. J. Heterocycl. Chem.  1983,  20:  551 

<A NAME="RF03204SS-40-13J">40-13j</A> Gall M. Kamdar BV. J. Heterocycl. Chem.  1988,  25:  1649 

<A NAME="RF03204SS-40-13K">40-13k</A> Banks WL. Digenis GA. Tetrahedron Lett.  1989,  6473 

<A NAME="RF03204SS-40-13L">40-13l</A> Hester JB. Ludens JH. Emmert DE. West BE. J. Med. Chem.  1989,  32:  1157 

<A NAME="RF03204SS-40-13M">40-13m</A> Walser A. Flynn T. Mason C. Crowley H. Maresca C. Yaremko B. O’Donnel M. J. Med. Chem.  1991,  34:  1209 

<A NAME="RF03204SS-40-14">40-14</A> Ning RY. Fryer RI. Madan PB. Sluboski BC. J. Org. Chem.  1976,  41:  2724 

<A NAME="RF03204SS-40-15">40-15</A> Walser A. Fryer RI. J. Org. Chem.  1975,  40:  153 

<A NAME="RF03204SS-40-16">40-16</A> van Leusen AM. Lect. Heterocycl. Chem.  1980,  5:  S-111  

<A NAME="RF03204SS-40-17A">40-17a</A> van Nispen SPJM. Mensink C. van Leusen AM. Tetrahedron Lett.  1980,  3723 

<A NAME="RF03204SS-40-176B">40-176b</A> Massa S. Di Santo R. Costi R. Mai A. Artico M. Med. Chem. Res.  1993,  3:  192 

<A NAME="RF03204SS-40-17C">40-17c</A> Di Santo R. Massa S. Artico M. Il Farmaco  1993,  48:  209 

<A NAME="RF03204SS-40-17D">40-17d</A> Sisko J.; J. Org. Chem.; 1998, 63: 4529

<A NAME="RF03204SS-40-17E">40-17e</A> Mendiola J. Minguez JM. Alvarez-Buylla J. Vaquero JJ. Org. Lett.  2000,  2:  3253 

<A NAME="RF03204SS-40-17F">40-17f</A> Sisko J. Kassick AJ. Mellinger M. Filan JJ. Allen A. Olsen MA. J. Org. Chem.  2000,  65:  1516 

<A NAME="RF03204SS-40-17G">40-17g</A> Chen P. Barrish JC. Iwanowicz E. Lin J. Bernarz MS. Chen B.-C. Tetrahedron Lett.  2001,  4293 

<A NAME="RF03204SS-40-17H">40-17h</A> Barret AGM. Cramp SM. Hennessy A. Procopiou PA. Roberts RS. Org. Lett.  2001,  3:  271 

<A NAME="RF03204SS-40-17I">40-17i</A> Kobayashi K. Matsumoto T. Irisawa S. Yoneda K. Morikawa O. Konishi H. Heterocycles  2001,  55:  973 

<A NAME="RF03204SS-40-17J">40-17j</A> Nair V. Vinod AU. Rajesh C. J. Org. Chem.  2001,  66:  4427 

<A NAME="RF03204SS-40-18">40-18</A> van Leusen AM. Wildeman J. Oldenziel OH. J. Org. Chem.  1977,  42:  1153 

<A NAME="RF03204SS-40-19A">40-19a</A> Walser A. Fryer RI. Sternbach LM. J. Heterocycl. Chem.  1974,  11:  619 

<A NAME="RF03204SS-40-19B">40-19b</A> Walser A. Benjamin L. Flynn T. Mason C. Schwartz R. Fryer R. J. Org. Chem.  1978,  43:  936 

<A NAME="RF03204SS-40-20">40-20</A> Bock MG. Di Pardo RM. Evans BE. Rittle KE. Veber DF. Freidinger RM. Hirshfield J. Springer JP. J. Org. Chem.  1987,  52:  3232 

<A NAME="RF03204SS-40-21">40-21</A> Bakhtiar C. Smith EH. J. Chem. Soc., Perkin Trans. 1  1994,  243 

<A NAME="RF03204SS-40-22">40-22</A> Nájera C. Yus M. Tetrahedron  1999,  55:  10547 

<A NAME="RF03204SS-40-23">40-23</A> Addie MS. Taylor RJV. J. Chem. Soc., Perkin Trans. 1  2000,  527 

<A NAME="RF03204SS-40-24A">40-24a</A> Holton RA. Crouse DJ. Williams AD. Kennedy RM. J. Org. Chem.  1987,  52:  2317 

<A NAME="RF03204SS-40-24B">40-24b</A> Adrio J. Rivero MR. Carretero JC. Angew. Chem. Int. Ed.  2000,  39:  2906 

<A NAME="RF03204SS-40-24C">40-24c</A> Adrio J. Rivero MR. Carretero JC. Chem.-Eur. J.  2001,  7:  2435 

<A NAME="RF03204SS-40-25">40-25</A>

For a slightly different reduction process using Zn-AcOH and leading to a similar product see earlier reference.^13m