C. Trécant et al. / Tetrahedron Letters 52 (2011) 4753–4755
4755
1
6
2
), 6.67 (d, 2H, J 8.0 Hz, H-2), 5.83 (m, 2H, H-8), 5.32 (m, 2H, H-7), 4.95 (d, 2H, J
.0 Hz, H-5), 4.20 (m, 2H, H-6), 3.40 (m, 2H, H-9), 3.10 (m, 2H, H-10a), 2.74 (m,
Conclusion
We have thus achieved an efficient process using a non pat-
H, H-14), 2.67–2.61 (m, 2H, H-16a), 2.47 (s, 6H, NCH ), 2.42–2.31 (m, 4H, H-
3
13
10b, H-16b), 2.13–2.05 (m, 2H, H-15a), 1.96–1.92 (m, 2H, H-15b). C NMR
(75 MHz, CDCl d: 163.3 (C@O), 148.8 (C-ipso), 134.3 (C-8), 130.5 (CH-
terephthalate), 129.7, 128.6 (C-ipso), 127.8 (C-7), 126.4 (C-ipso), 121.1 (C-1),
1
1
ented starting material to produce M6G. This methodology could
be applied on multigram scale starting from readily available com-
pounds. The salient advantages described here were the use of a
known glycosyl donor and the experimental procedure which does
not require anhydrous conditions and low temperature. Moreover
this method which allows the synthesis of M6G in good yield and
high purity led also to morphine as the by-product, which could be
recycled.
3
)
20.0 (C-2), 92.5 (C-5), 65.9 (C-6), 58.9 (C-9), 46.4 (C-16), 43.1 (NCH
3
), 42.7 (C-
3), 40.5 (C-14) 35.3 (C-15), 20.9 (C-10). HRMS (ES): calc for C42H N O
42 2 8
2+
2
[M+H ] : 351.1471, found: 351.1467.
1
9. For experimental procedures and spectral data for compounds 2b–2k see:
Dlubala, A.; Ripoche, I.; Trécant, C. PCT WO2010067007, 2010.
0. Nakajima, R.; Ono, M.; Aiso, S.; Akita, H. Chem. Pharm. Bull. 2005, 53, 684–687.
21. Treatment of glycosyl donor with methyl orthoformate did not lead to an
improvement of the yield.
2. (a) Veeneman, G. H. Carbohydr. Chem. 1998, 98–174; (b) Jacquinet, J. C.; Sinaÿ,
P. J. Chem. Soc., Perkin Trans. 1 1979, 314–318; (c) Nukada, T.; Berces, A.;
Whitfield, D. M. J. Org. Chem. 1999, 64, 9030–9045.
2
2
Acknowledgments
2
3. Schmidt, R. R. Angew. Chem., Int. Ed. Engl. 1986, 25, 212–235.
2
4. Experimental procedure: To a solution of dimorphin-3-yl terephthalate 2a
C.T. is thankful to Sanofi-Aventis and Francopia for the award of
a fellowship.
(
50 mg, 0.071 mmol) in chlorobenzene (4 mL) at room temperature was added
TMSOTf (27 L, 0.15 mmol). The mixture was stirred at room temperature for
min then trichloroacetimidate methyl 2,3,4-tri-O-acetyl-1-O-
trichloroacetimidoyl- -D-glucopyranuronate (171 mg, 0.36 mmol) and
L, 0.071 mmol). The reaction mixture was stirred for
(100 mg) was added followed by CH Cl (5 mL) and water
l
3
a
3
References and notes
then TMSOTf (13
l
30 min and NaHCO
3
2
2
1
.
(a) Lotsch, J.; Stockmann, A.; Kobal, G.; Brune, K.; Waibel, R.; Schmidt, N.;
Geisslinger, G. Clin. Pharmacol. Ther. 1996, 60, 316–325; (b) Hasselstrom, J.;
Sawe, J. Pharmacokinet. 1993, 24, 344–354; (c) Osborne, R.; Joel, S.; Trew, D.;
Slevin, M. Clin. Pharmacol. Ther. 1990, 47, 12–19.
(5 mL). The organic layer was dried over Na SO4 and concentrated. A mixture
2
of three compounds containing di 6-O-acétylmorphin-3-yl terephthalate, 6-O-
acétylmorphin-3-yl
terephthalate
and
6-O-(2,3,4-tri-O-acétyl-b-D-
glucopyranosylmethyluronate)-morphin-3-yl and di 6-O-(2,3,4-tri-O-acétyl-
b-D-glucopyranosylmethyluronate)-morphin-3-yl-terephthalate in a 7:30:63
ratio was obtained. Purification on reverse phase chromatography (gradient
(H O+0.1%TFA)-CH CN 95:5–20:80) furnished the three compounds: di 6-O-
2
3
.
.
Barlett, S. E.; Smith, M. T. Life Sci. 1995, 57, 609–615.
Penson, R. T.; Joel, S. P.; Clark, S.; Gloyne, A.; Slevin, M. L. J. Pharm. Sci. 2001, 90,
1
810–1816.
2
3
4.
5.
6.
7.
Kilpatrick, G. J.; Smith, T. W. Med. Res. Rev. 2005, 25, 521–544.
1
3
acetylmorphin-3-yl terephthalate 4a: H NMR (300 MHz, CDCl ) d 8.30 (s, 4H,
Lotsch, J.; Geisslinger, G. Clin. Pharmacokinet. 2001, 40, 485–499.
Cann, C.; Curran, J.; Milner, T.; HO, B. Anaesthesia 2002, 57, 1200–1203.
Romberg, R.; Olofsen, E.; Sarton, E.; Teppema, L.; Dahan, A. Anaesthesiology
CH-terephthalate), 6.91 (d, 2H, J 8.0 Hz, H-1), 6.66 (d, 2H, J 8.0 Hz, H-2), 5.67 (m,
2H, H-8), 5.46 (m, 2H, H-7), 5.15 (m, 4H, H-5, H-6), 3.43 (m, 2H, H-9), 3.10 (m,
2H, H-10a), 2.81 (m, 2H, H-14), 2.67 (m, 2H, H-16a), 2.47 (s, 6H, NCH ), 2.43–
3
2
003, 99, 788–798.
2.34 (m, 4H, H-10b, H-16b), 2.14–1.91 (m, 10H, CH CO, H-15). 13C NMR
3
8
.
.
Okura, T.; Saito, M.; Nakanishi, M.; Komiyama, N.; Fujii, A.; Yamada, S.; Kimura,
R. Br. J. Pharmacol. 2003, 140, 211–217.
(a) Yoshimura, H.; Oguri, K.; Tsukamoto, H. Chem. Pharm. Bull. 1968, 16, 2114–
(75 MHz, CDCl ) d 170.4, 163.2 (C@O), 149.5, 133.6, 132.5, 131.8, 131.6 (C-
3
ipso), 130.3 (CH-terephthalate), 129.2 (C-7), 128.7 (C-8), 121.9 (C-1), 119.5 (C-
9
2), 88.7 (C-5), 68.0 (C-6), 58.9 (C-9), 46.5 (C-16), 42.8 (NCH ), 42.7 (C-13), 40.3
3
2
119; (b) Yoshimura, H.; Oguri, K.; Tsukamoto, H. Tetrahedron Lett. 1968, 16,
2 10
(C-14) 35.0 (C-15), 20.8 (C-10), 20.6 (CH CO). HRMS (ES): calc for C46H46N O
3
4
83–486.
[M+H2]2+
:
393.1576, found: 393.1560; 6-O-(2,3,4-tri-O-acétyl-b-D-methyl
glucopyranosyluronate) morphin-3-yl terephthalate 4b: NMR (300 MHz,
CDCl ) d 8.31 (m, 4H, CH-terephthalate), 6.89 (m, 2H, H-1, H-1 ), 6.65 (m, 2H,
), 5.68 (m, 1H, H-8), 5.46 (m, 1H, H-7), 5.33 (m, 1H,
), 5.19 (m, 2H, H-300, H-400), 5.15 (m, 1H, H-6), 4.96 (m, 3H, H-200, H-5, H-5
),
4.86 (d, 1H, J 7.5 Hz, H-100), 4.31 (m, 1H, H-6 ), 4.05 (m, 1H, H-500), 3.72 (s, 3H,
OCH ), 3.48 (m, 2H, H-9, H-9 ), 3.11 (m, 2H, H-10a, H-10a ), 2.85-2.65 (m, 4H,
), 2.52–2.37 (m, 10H, NCH , H-10b, H-10b , H-16b,
1
1
0. (a) Bugge, A.; Aasmundstad, T.; Aasen, A. J.; Christophersen, A. S.; Morgenlie, S.;
Morland, J. Acta Chem. Scand. 1995, 49, 380–384; (b) Mertz, A. A. H. Int. Patent
WO 93/05057, 1993.; (c) Carrupt, P. A.; Testa, B.; Bechalany, A.; Tayar, N. E.;
Descas, P.; Perrissoud, D. J. Med. Chem. 1991, 34, 1272–1275.
1. (a) Berrang, B. D.; Berrangyrick, C. D.; Yvy-Carroll, F.; Seltzman, H. H. J. Labelled
Compd. Radiopharm. 1999, 42, 851–857; (b) Berrang, B.; Brine, G. A.; Yvy-
Carroll, F. Synthesis 1997, 1165–1168; (c) Lacy, C.; Sainsbury, M. Tetrahedron
Lett. 1995, 36, 3949–3950.
1
H
0
3
0
0
), 5.77 (m, 1H, H-8
H-2, H-2
H-7
0
0
0
0
0
3
0
0
0
H-14, H-14
0
, CH CO), 1.73 (s, 3H, CH CO); 13C NMR
H-16b ), 2.15–1.85 (m, 13H, H-15, H-15
3 3
, H-16a, H-16a
3
0
1
2. Rukhman, I.; Yudovich, L.; Nisnevich, G.; Gutman, A. L. Tetrahedron 2001, 57,
(75 MHz, CDCl ) d 170.4, 170.1, 169.4, 169.0, 167.3, 163.6, 163.3 (C@O), 150.4,
3
1
083–1092.
149.5 133.7, 133.6 (C-ipso), 132.0, 131.6, 130.8, 130.6, 130.3 129.0, 128.9 (CH-
1
3. Bickley, J.; Cottrell, J. A.; Ferguson, J. R.; Field, R. A.; Harding, J. R.; Hughes, D. L.;
terephthalate, C-8, C-8
(C-2, C-2
0
, C-7, C-7
0
, C-ipso), 122.2, 122.0 (C-1, C-1
0
), 119.6, 119.3
Kartha, K. P. R.; Law, J. L.; Scheinmann, F.; Stachulski, A. V. Chem. Commun.
0
), 99.3 (C-100), 89.8, 88.7 (C-5, C-5
0
), 73.7 (C-6
), 46.6,
),
0
), 72.7 (C-500), 71.8 (C-300
2
003, 1266–1267.
4. Rukhman, I.; Yudovich, L.; Nisnevich, G.; Gutman, A. L. Synthesis 2000, 9, 1241–
246.
5. Pougny, J. R.; Jacquinet, J. C.; Nassr, M.; Milat, M. L.; Sinaÿ, P. J. Am. Chem. Soc.
977, 99, 6762–6763.
or C-400), 71.0 (C-200), 69.4 (C-300 ou C-400), 67.9 (C-6), 59.0, 58.8 (C-9, C-90
1
1
46.3 (C-16, C-16 ), 42.8 (NCH ), 40.6, 40.2 (C-14, C-14 ) 35.2, 34.9 (C-15, C-15
21.2, 21.0, 20.7, 20.6, 20.5, 20.4 (C-10, C-10 CH CO); HRMS (ES): calc. for
0
0
0
3
1
0
3
C57H60N O [M+H2]2+: 530.1921, found: 530.1918; di 6-O-(2,3,4-tri-O-acetyl-
2
18
1
b-D-methyl glucopyranosyluronate)morphin-3-yl terephthalate 4c:
1
H NMR
1
1
6. Schmidt, R. R.; Michel, J. Angew. Chem., Int. Ed. Engl. 1980, 19, 731–732.
7. (a) Brown, R. T.; Carter, N. E.; Mayalarp, S. P.; Scheinmann, F. Tetrahedron 2000,
(300 MHz, CDCl ) d 8.34 (s, 4H, CH-terephthalate), 6.90 (d, 2H, J 8.0 Hz, H-1),
3
6.63 (d, 2H, J 8.0 Hz, H-2), 5.77 (m, 2H, H-8), 5.34 (m, 2H, H-7), 5.23 (m, 4H, H-
56, 7591–7598; (b) Brown, R. T.; Carter, N. E.; Lumbard, K. W.; Scheinmann, F.
3
0
, H-4
0
), 5.02–4.94 (m, 4H, H-2
), 3.72 (s, 6H, OCH ), 3.48 (m, 2H, H-9), 3.11 (m,
0 0
, H-5), 4.86 (d, 2H, J 7.5 Hz, H-1 ), 4.32 (m, 2H,
Tetrahedron Lett. 1995, 36, 8661–8664; (c) Scheinmann, F.; Lumbard, K. W.;
Brown, R. T.; Mayalarp, S. P.; Carter, N. E. Int. Patent WO 93/03051, 1993.
8. Typical procedure: To a solution of morphine monohydrate (40.0 g, 0.132 mol)
in aqueous NaOH 0.66 N (300 mL, 0.198 mol) and chlorobenzene (300 mL) was
added, in small quantities on a period of 2.5 h, terephthaloyl chloride (12.0 g,
H-6), 4.06 (d, 2H, J 9.5 Hz, H-5
0
3
2H, H-10a), 2.75–2.2.60 (m, 4H, H-14, H-16a), 2.51–2.25 (m, 10H, NCH3, H-10b,
1
H-16b), 2.16–1.90 (m, 16H, H-15, CH CO), 1.75 (s, 6H, CH CO); 13C NMR
3
3
(75 MHz, CDCl ) d 170.0, 169.4, 169.3, 167.4, 163.9 (C@O), 150.4, 133.7, 132.5,
3
131.7, 131.4 (C-ipso), 130.6 (CH-terephthalate, C-8), 128.9 (C-7), 122.0 (C-1),
0
.0594 mol). The mixture was then stirred for 15 min and the precipitate was
119.3 (C-2), 99.2 (C-1
0
70.9 (C-2 ), 69.4 (C-3 ou C-4
0
), 88.7 (C-5), 73.6 (C-6), 72.9 (C-5
0 0 0
), 71.7 (C-3 ou C-4 ),
filtered. The solid was triturated with a mixture of chlorobenzene and aqueous
0
0
), 58.8 (C-9), 52.9 (OCH ), 46.2 (C-16), 43.1 (NCH ),
3
3
NaOH (0.66 N) (300 mL/300 mL) then washed with water (3 ꢀ 250 mL) to
41.1 (C-14), 35.7 (C-15), 21.0 (C-10), 20.6, 20.5, 20.4 (CH CO); HRMS (ES):
3
afford the dimorphin-3-yl terephthalate 2a as a white solid (38.2 g, 92%). 1
H
2+
calc.for C68H74N O [M+H2] : 667.2265, found: 667.2253.
2 26
3
NMR (300 MHz, CDCl ) d: 8.30 (s, 4H, CH-terephthalate), 6.87 (d, 2H, J 8.0 Hz, H-