S. J. Rozze and M. J. Fray
corresponding to [2H7]14 (Rt = 3.69 min) showed a range of sulfone-containing substituent by base-catalyzed exchange,
masses D3–D10; LRMS m/z (M–SCD3, relative abundance) 283 does not give a material that survived the clinical assay
(12%), 284 (47%), 285 (85%), 286 (87%), 287 (100%), 288 (86%), conditions without unacceptable loss of deuterium. This result
289 (45%), 290 (14%), 291 (2%); (M1H, relative abundance) 331 suggests that deuterium labelling of pharmaceutical drug
(7%), 332 (26%), 333 (51%), 334 (92%), 335 (100%), 336 (74%), candidates adjacent to a sulfonyl group should be avoided.
337 (45%), 338 (17%).
Labelling of the aromatic portion of 1 was readily achieved by
platinum-catalysis. However, the deuterium atoms on the
aromatic methyl groups were labile under the conditions of
the pyrazole alkylation step. To prevent loss of deuterium, all
sources of exchangeable hydrogen were removed. Once
satisfactory labelling had been achieved in the preparation of
16, selective exchange of the side chain deuterium atoms for
hydrogen was used to prepare 17, which possessed an
acceptable D0 /D8 ratio.
4-[3-Cyclopropyl-1-([2H5]methanethiomethyl)-5-methyl-1H-
pyrazol-4-yl]oxy-[2H6]2,6-dimethyl-[3,5-2H]benzonitrile (16)
A solution of [2H9]13 (1.77 g, 6.43mmol) in anhydrous DME (6 ml)
was added over 10min to potassium t-butoxide (1.44 g,
12.9mmol) in anhydrous DME (6ml) with cooling using an ice-
water bath. The mixture was stirred for 45min at room
temperature. A solution of [2H5]chloromethyl methylsulfide
(prepared from [2H5]dimethylsulfide, 1.31g, 12.9mmol as de-
scribed above) in anhydrous DME (6 ml) was added over 140 min,
and the mixture was stirred at 201C for 100 min. Deuterium oxide
(10 ml) was added, and the mixture was extracted with ethyl
acetate (2Â 30ml). The combined organic solutions were dried
(Na2SO4) and concentrated under reduced pressure. Purification
by flash column chromatography, eluting with ethyl acetate:
heptane= 10:90 then 25:75 gave [2H13]16 (900mg, 41%) and its
N-5 alkylated isomer (550mg, 25%). dH (400MHz, CDCl3) 6.65
(s, 0.017H, ArH), 5.01 (br s, 0.1H, NCDHS), 2.46 (m, 0.33H, ArCD2H),
2.13 (s, 3H), 1.61 (m, 1H), 0.79 (m, 4H). LRMS m/z (M–SCD3, relative
abundance) 287 (7%), 288 (41%), 289 (90%), 290 (100%), 291
(44%), 292 (6%); (M1H, relative abundance) 339 (16%), 340 (61%),
341 (100%), 342 (25%), 343 (7%).
Acknowledgements
I am indebted to Paul Macrae, Helen Westgate, Stephen Brooks
(Department of Pharmacokinetics, Dynamics and Metabolism)
and Sally-Ann Fancy for mass spectroscopic data, to Torren
Peakman for measuring 13C and 2H NMR spectra, to David
McManus for samples of intermediates and Olivier Thominet for
practical assistance.
References
[1] D. P. Richards, L. E. Sojo, B. O. Keller, J. Label. Compd. Radiopharm.
2007, 50, 1124–1136. DOI: 10.1002/jlcr.1392.
[2] W. A. Garland, M. P. Barbalas, J. Clin. Pharmacol. 1986, 26, 412–418.
4-[3-Cyclopropyl-1-(methanesulfonylmethyl)-5-methyl-1H-
pyrazol-4-yl]oxy-[2H6]2,6-dimethyl-[3,5-2H]benzonitrile (17)
[3] The steroid derivative asoprisnil is
a progesterone receptor
modulator currently in clinical trials for the treatment of uterine
fibroids, see P. Cole, J. Castaner, D. Fernandez-Fomer, Drugs Future
2005, 30, 985–991. DOI: 10.1358/dof.2005.030.10.945144.
[4] Secondary dysmenorrhea is a term that covers a number of
common conditions affecting women, including endometriosis
and uterine fibroids.
[5] For reviews, see E. Deligeoroglou, Ann. N.Y. Acad. Sci. 2000, 900,
237–244; M. Y. Dawood, Clin. Obstet. Gynecol. 1990, 33, 168–178.
[6] P. A. Bradley, K. N. Dack, P. S. Johnson, S. E. Skerratt, U.S. Pat. Appl.
2007, US 2007105909; P. A. Bradley, P. D. de Koning, P. S. Johnson,
Y. C. Lecouturier, D. J. McManus, A. Robin, T. J. Underwood, Org.
Proc. Res. Dev. Submitted. K. R. Gibson, K. N. Dack, S. E. Skerratt,
P. S. Johnson, P. A. Bradley, T. Underwood, P. Bungay, N. Pullen,
A. de Giorgio-Miller, N. M. Mount, D. Howe, B. Wittke, Discovery of
PF-2413873: A nonsteroidal progesterone receptor antagonist for
the treatment of endometriosis. Abstracts of Papers, 237th ACS
National Meeting, Salt Lake City, UT, USA, 22–26 March 2009.
[7] A. W. Bridge, N. V. Harris, D. J. Lythgoe, C. Smith, PCT Int. Appl.
1991, WO 9110662.
A solution of compound 16 (900 mg, 2.64 mmol) in a mixture of
methanol (70 ml) and water (16 ml) was treated with Oxones
(3.40 gm) at 201C for 4 h. The mixture was filtered and the filter
cake was washed with methanol (2 Â 20 ml). The filtrate was
treated with aqueous sodium hydroxide (10 M, 27 ml) at 201C
for 21 h. The mixture was concentrated under reduced pressure.
Water (100 ml) was added and the mixture extracted with
dichloromethane (2 Â 100 ml). The organic solution was dried
(Na2SO4) and concentrated under reduced pressure. The crude
product was stirred with isopropanol (8 ml) for 1 h to produce a
solid, which was collected by filtration. This gave 17 (700 mg,
78%). dH (400 MHz, CDCl3) 6.64 (0.04H, s, Ar-H), 5.10 (s, 2H,
NCH2SO2), 2.96 (s, 3H, SO2CH3), 2.45 (0.07H, m, 2 Â ArCHD2), 2.17
(3H, s, 2-CH3), 1.62 (1H, m, cyclopropyl methine), 0.80 (4H, m,
cyclopropyl methylenes). dD (77 MHz, CHCl3) 6.69 (s, 2D), 2.46 (s,
6D). dC (125 MHz, CHCl3) 161.0 (C-O, Ar), 148.5 (C-C3H5), 144.5
(C-CD3), 134.6 (C-O, pyrazole), 133.1 (C-CH3), 117.3 (CN), 113.7
(t, J 25 Hz, C-D, Ar), 107.1 (C-CN), 67.7 (NCH2SO2), 40.1 (CH3SO2),
20.4 (pentet, J 20 Hz, ArCHD2), 20.1 (septet, J 19 Hz, ArCD3), 8.8
(CH3), 7.4 (CH2CH2), 6.8 (cyclopropyl CH). m/z (M1H, relative
abundance) 360 (0%), 361 (0.01%), 362 (0.01%), 363 (0.03%), 364
(0.13%), 365 (1.1%), 366 (9.4%), 367 (47%), 368 (100%), 369
(20%), 370 (2%). HRMS m/z Found: 368.1884, C18H13D8N3O3S
(M1H) requires 368.1892. Found: C, 58.72; H, 5.73; N, 11.38;
C18H13D8N3O3S requires C, 58.83; H, 5.76; N, 11.43%.
[8] A. Katsumata, Y. Tamada, T. Kudou, M. Saeki, T. Yano, PCT Int. Appl.
2005, WO 2005085205.
[9] S. J. Berthel, R. F. Kester, D. E. Murphy, T. J. Prins, F. Ruebsam,
R. Sarabu, C. V. Tran, D. Vourloumis, U.S. Pat. Appl. Publ. 2008, US
2008021032.
[10] J. E. Sheppeck, J. L. Gilmore, T. G. M. Dhar, H-Y. Xiao, PCT Int. Appl.
2008, WO 2008057856.
[11] For other methods of chlorinating b-diketones, see R. R. Fraser,
F. Kong, Synth. Commun. 1988, 18, 1071 (DMSO/Me3SiCl); R. Verhe,
L. De Buyck, N. De Kimpe, A. De Rooze, N. Schamp, Bull. Soc. Chim.
Belg. 1978, 87, 143 (SO2Cl2); R. G. Shepherd, A. C. White, J. Chem.
Soc. Perkin Trans. 1, 1987, 2153 (chloramine-T); M. A. Yawer,
I. Hussain, S. Reim, Z. Ahmed, E. Ullah, I. Iqbal, C. Fischer, H. Reinke,
H. Goerls, P. Langer, Tetrahedron 2007, 63, 12562 (NCS, CCl4, heat).
[12] F. Mohanazadeh, A. R. Momeni, Y. Ranjbar. Tetrahedron Lett. 1994,
35, 6127–6128. DOI: 10.1016/0040-4039(94)88094-8.
Conclusions
We have described two strategies for the preparation
of deuterated 1. The simpler method, labelling the
[13] D. H. Saunders, R. A. Barford, P. Magidman, L. T. Olszewski,
H. L. Rothbart. Anal. Chem. 1974, 46, 834–838.
J. Label Compd. Radiopharm 2009, 52 435–442
Copyright r 2009 John Wiley & Sons, Ltd.