A. Leyva-Pérez et al. / Tetrahedron 66 (2010) 8203e8209
8209
4. Experimental
include MOL files and InChiKeys of the most important compounds
described in this article.
4.1. Typical reaction procedure for olanzapine 1 (entry 8,
Table 1)
References and notes
PtIV/ITQ-2 (0.4 wt %, 105 mg, 4 mol %) and 2-(2-nitroanilino)-5-
methylthiophene-3-carbonitrile 5 (25.9 mg, 0.1 mmol) were placed
in a hydrogenator reactor. Mesitylene (1 ml) and N-methylpiper-
1. (a) Nicolaou, K. C.; Snyder, S. A. Classics in Total Synthesis II: More Targets,
strategies, Methods; Wiley-VCH: Weinheim: 2003; Vol. 2, pp 560; (b) Nicolaou,
K. C.; Sorensen, E. J. Classics in Total Synthesis II: Targets, Strategies, Methods;
Wiley-VCH: Weinheim: 1996; pp 798.
azine (110 ml, 1 mmol, 10 equiv) were added and the reactor was
sealed, purged three times with H2 and finally loaded with with H2
(8e10 atm, w1.0e1.3 mmol, 10e13 equiv). The reaction mixture
was placed in a pre-heated oil bath at 160 ꢀC and magnetically
stirred for 16 h. After cooling, the hydrogen gas was removed and
the mixture was magnetically stirred for additional 32 h at 160 ꢀC.
After cooling, the catalyst was filtered off and washed with DCM.
The resulting combined filtrates were concentrated under reduced
pressure and analysed by NMR. The crude was purified by pre-
parative TLC on silica (10% MeOH in DCM) to afford olanzapine 1 (16
2. (a) Baxendale, I. R.; Hayward, J. J.; Lanners, S.; Ley, S. V.; Smith, C. D. In
Microreactors in Organic Synthesis and Catalysis; Wirth, T., Ed.; Wiley-VCH:
Weinheim: 2008; pp 84e122; (b) Baxendale, I. R.; Ley, S. V. Ernst Schering
Foundation Symposium Proceedings 2006-3; Springer: Berlin, Heidelberg:
2007; 151e185; See also: Thomas, J. M.; Raja, R. Stud. Surf. Sci. Catal. 2007,
170A, 19e40; (c) Ruiz, V. R.; Corma, A.; Sabater, M. J. Tetrahedron 2010, 66,
730e735; (d) Climent, M. J.; Corma, A.; Iborra, S.; Santos, L. L. Chem.dEur. J.
2009, 15, 8834e8841; (e) Corma, A.; Renz, M. Angew. Chem., Int. Ed. 2007, 46,
298e300.
3. (a) For examples on solid-phase synthesis of natural products see Ley, S. V.;
Baxendale, I. R.; Bream, R. N.; Jackson, P. S.; Leach, A. G.; Longbottom, D. A.;
Nesi, M.; Scott, J. S.; Storer, R. I.; Taylor, S. J. J. Chem. Soc., Perkin Trans. 1 2000,
3815e4195; (b) Nielsen, J. Curr. Op. Chem. Biol. 2002, 6, 297e305.
4. Beller, M. Ernst Schering Foundation Symposium Proceedings 2006-3; Springer:
Berlin, Heidelberg: 2007; pp 99e116.
5. (a) Corma, A. Catal. Rev. Sci. Eng. 2004, 46, 369e417; (b) Copéret, C. New J. Chem.
2004, 28, 1e10.
6. (a) Boronat, M.; Climent, M. J.; Corma, A.; Iborra, S.; Monton, R.; Sabater, M. J.
Chem.dEur. J. 2010, 16, 1221e1231; (b) Corma, A.; Serna, P. Science 2006, 313,
332e334.
7. (a) Juárez, R.; Concepción, P.; Corma, A.; Fornés, V.; García, H. Angew. Chem., Int.
Ed. 2010, 49, 1286e1290; (b) Corma, A.; Serna, P.; Concepcion, P.; Calvino, J. J.
J. Am. Chem. Soc. 2008, 130, 8748e8753.
8. (a) For a very recent paper on the genetic component of schizophrenia, see
Citrome, L. Int. J. Clin. Pract. 2009, 63, 140e150; (b) Fazzari, O.; Paternain, A. V.;
Valiente, M.; Pla, R.; Luján, R.; Lloyd, K.; Lerma, J.; Marín, O.; Rico, B. Nature
2010. doi:10.1038/nature08928 published online 14 April.
mg, 0.054 mmol, 54%). The spectral data correlates those reported
previously.12 Rf (10% MeOH in DCM): 0.36. GCeMS (m/z): 312 (Mþ
,
ꢃ
30%), 311 (100%), 310 (70%), 283 (17%), 194 (100%), 103 (93%), 77
(64%). 1H NMR (
d
, ppm; J, Hz): 7.01 (1H, td, J¼7.9, 1.7), 6.95 (1H, dd,
J¼7.9, 1.5), 6.87 (1H, td, J¼7.9, 1.7), 6.60 (1H, dd, J¼7.8, 1.5), 6.30 (1H,
q, J¼1.3), 4.96 (1H, br s), 3.54 (4H, t, J¼5.0), 2.52 (4H, t, J¼5.0), 2.36
(3H, s), 2.31 (3H, d, J¼1.1). 13C NMR (
d, ppm): 160.7, 157.5, 142.7,
137.9, 139.4, 128.1, 126.9, 124.7, 124.3, 122.8, 119.1, 54.7 (2C), 46.6
(2C), 45.7, 15.5. HRMS (ESI) [MþHþ; calculated for C17H21N4S:
313.1487] found m/z 313.1485.
4.2. Typical reaction procedure for clozapine 2 (entry 10,
Table 3)
9. Chakrabarti, J.K.; Hotten, T.M.; Tupper, D.E.; Eli Lilly & Industries Limited: USA,
1993; Vol. US005229382A, p 6.
10. The patent for 1 expires in 2011 and no patent applies for 2 yet.
11. (a) For impurities and degradation products see Shastri, J.A.; Bhatnagar, A.;
Thaper, R.K.; Dubey, S.K.; Jubilant Organosys Limited: USA, 2006; Vol. WO 2006/
006180 A1, p 18. (b) Thatipalli, P.; Kumar, R.; Bulusu, C.; Chakka, R.; Padi, P. R.;
Yerra, A.; Bollikonda, S. ARKIVOC 2008, 11, 195e201; (c) Baertschi, S. W.;
Brunner, H.; Bunnell, C. A.; Cooke, G. G.; Diseroad, B.; Dorman, D. E.; Jansen, P. J.;
Kemp, C. A. J.; Maple, S. R.; Mccune, K. A.; Speakman, J. L. J. Pharm. Sci. 2008, 97,
883e892.
12. Shevchenko, V. P.; Nagaev, I. Y.; Kuznetsov, Y. V.; Polunin, E. V.; Zozulya, A. A.;
Myasoedov, N. F. Russ. J. Bioorg. Chem. 2005, 31, 378e382.
13. The use of stoichiometric SnCl2 is a standard method for reduction of nitro
compounds.
A similar procedure to that of olanzapine was employed but
using (4-chloro-2-nitrophenyl)-(2-cyanophenyl)-amine 15 (27.4
mg, 0.1 mmol) as substrate, the hydrogen gas was removed after 30
min and the mixture was left to react for 7 days. After filtration, the
crude was analysed by GC and purified by preparative TLC on silica
to achieve clozapine 2. The spectral data fits those of the com-
mercial pure compound. Rf (10% MeOH in AcOEt): 0.12. 1H NMR (
d,
ppm; J, Hz): 7.31 (1H, td, J¼7.6, 1.5), 7.25 (1H, dd, J¼7.5, 1.6), 7.06
(1H, d, J¼2.4), 7.02 (1H, td, J¼7.8, 1.1), 6.84 (1H, dd, J¼8.3, 2.5), 6.82
(1H, dd, J¼7.9, 0.8), 6.62 (1H, d, J¼8.3), 4.91 (1H, s), 3.60 (4H, br s),
14. For an example of an asymmetric hydrogenation over cinchona modified
€
€
€ €
2.68 (4H, br s), 2.46 (3H, s). 13C NMR (
d, ppm): 169.9 (C), 152.8 (C),
Pt/Al2O3 catalysts see: Balázsik, K.; Szori, K.; Felfoldi, K.; Torok, B.; Bartók, M.
Chem. Commun. 2000, 555e556.
143.5 (C), 140.3 (C), 132.1 (CH), 130.2 (CH), 129.1 (C), 126.8 (CH),
123.5 (C), 123.2 (CH), 123.0 (CH), 120.1 (CH), 120.0 (CH), 54.2
(CH2ꢁ2), 46.9 (CH2ꢁ2), 29.7 (CH3). HRMS (ESI) [MþHþ; calculated
for C18H20N4Cl: 327.1376] found m/z 327.1341.
15. (a) Corma, A.; Fornes, V.; Navarro, M. T.; Perez-Pariente, J. J. Catal. 1994, 148,
569e574; (b) Corma, A.; García, H.; Leyva, A. Tetrahedron 2004, 60, 8553e8560;
(c) Kosslick, H.; Lischke, G.; Parlitz, B.; Storek, W.; Fricke, R. Appl. Catal., A 1999,
184, 49e60.
16. For selected reports on the highly acidic ZrO2 see: (a) Chen, F. R.; Coudurier, G.;
Joly, J.-F.; Vedrine, J. C. J. Catal. 1993, 143, 616e626; (b) Reddy, B. M.; Sreekanth,
P. M.; Reddy, V. R. J. Mol. Cat. A 2005, 225, 71e78.
Acknowledgements
17. (a) Corma, A.; Fornes, V.; Guil, J. M.; Pergher, S.; Maesen, T. L. M.; Buglass, J. G.
Micropor. Mesopor. Mater. 2000, 38, 301e309; (b) Diaz, U.; Fornes, V.; Corma, A.
Micropor. Mesopor. Mater. 2006, 90, 73e80.
18. Metals (Pt, Pd or Au)-supported on TiO2 act as chemoselective hydrogenation
catalyst for nitrobenzenes, see Refs. 6 and 7 and also: (a) Boronat, M.; Con-
cepción, P.; Corma, A.; González, S.; Illas, F.; Serna, P. J. Am. Chem. Soc. 2007, 129,
16230e16237; (b) Corma, A.; Concepción, P.; Serna, P. Angew. Chem., Int. Ed.
2007, 46, 7266e7269; (c) Corma, A.; Serna, P.; García, H. J. Am. Chem. Soc. 2007,
129, 6358e6359.
19. (a) Sasikumar, T. K.; Burnett, D. A.; Zhang, H.; Smith-Torhan, A.; Fawzi, A.;
Lachowicz, J. E. Bioorg. Med. Chem. Lett. 2006, 16, 4543e4547; (b) Su, J.; Tang, H.;
McKittrick, B. A.; Burnett, D. A.; Zhang, H.; Smith-Torhan, A.; Fawzi, A.;
Lachowicz, J. Bioorg. Med. Chem. Lett. 2006, 16, 4548e4553; (c) de Paulis, T.;
Davis, D. A.; Smith, H. E.; Malarek, D. H.; Liebman, A. A. J. Labelled Compd.
Radiopharm. 1988, 25, 1027e1033.
We thank to Dr. Urbano Diaz for providing ITQ-2 samples, to
Dr. Maite Navarro for AleMCM-41 samples and to Dr. Pedro Serna
for metal-supported TiO2 samples. We also thank to Dr. Ana Primo
for HRMS measurements. J.R.C.-A. thanks MICINN for the conces-
sion of a FPU predoctoral fellowship. A.L.-P. thanks to CSIC for
a contract under the JAE-doctor program. Financial support by the
PLE2009 project from MCIINN is acknowledged.
Supplementary data
Additional schemes, general methods, reaction procedures,
compound characterisation, DRX data for compound 6 and NMR
spectra. Supplementary data associated with this article can be
20. Matloubi, H.; Ghandi, M.; Zarrindast, M.-R.; Saemian, N. Appl. Radiat. Isot. 2001,
55, 789e791.