Table 2 Composition of products obtained from the two-stage,
continuous-flow reaction
8 M. Katoh, T. Mikami and H. Watanabe, JP, 72994, 1994.
9 N. Kubodera, H. Watanabe and K. Miyamoto, JP, 80626,
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1
e
Yield (%)
Flow rate/
mL min
À1
d
7
Entry
Conc./mM
1
3
4
5
6
1
1 M. P. Rappoldt and E. Havinga, Recl. Trav. Chim. Pays-Bas, 1960,
79, 369–381.
a
1
2
3
4
5
6
20
20
20
30
30
30
5
10
38
46
38
60
49
40
4
4
4
9
5
4
12
17
15
12
14
12
33
7
6
8
6
12
22
36
6
24
36
1
4
1
5
2
1
b
12 D. R. Rafael and P. Andreas, WO, 2008128783, 2008.
13 K. Geyer, J. D. C. Codee and P. H. Seeberger, Chem.–Eur. J.,
2006, 12, 8434–8442.
14 J. Kobayashi, Y. Mori and S. Kobayashi, Chem.–Asian J., 2006, 1,
22–35.
c
25a
5b
10
25
c
7
1
5 M. Brivio, W. Verboom and D. N. Reinhoudt, Lab Chip, 2006, 6,
329–344.
a
RT in the photo-microreactor: 10 min. RT in the photo- and
b
thermal-microreactor: 20 min. RT in the photo-microreactor:
16 B. P. Mason, K. E. Price, J. L. Steinbacher, A. R. Bogdan and
D. T. McQuade, Chem. Rev., 2007, 107, 2300–2318.
c
min. RT in the photo- and thermal-microreactor: 10 min. RT in
5
the photo-microreactor: 2 min. RT in the photo- and thermal-
1
7 I. R. Baxendale, J. J. Hayward and S. V. Ley, Comb. Chem. High
Throughput Screening, 2007, 10, 802–836.
18 P. Watts and C. Wiles, Chem. Commun., 2007, 443–467.
d
3
microreactor: 4 min. Undesired trans-vitamin D (7) was generated
e
3
from the photo-isomerization of vitamin D (1). The yields were
1
9 (a) J. Yoshida, A. Nagaki and T. Yamada, Chem.–Eur. J., 2008,
4, 7450–7459; (b) S. Suga, D. Yamada and J. Yoshida, Chem.
Lett., 2010, 39, 404–406.
calculated based on the relative UV absorption after allowance was
made for the extinction coefficient at 282 nm.
1
2
2
0 C. Wiles and P. Watts, Eur. J. Org. Chem., 2008, 1655–1671.
1 T. Fukuyama, T. Rahman, M. Sato and I. Ryu, Synlett, 2008,
151–163.
2 M. Okamoto and J. Oshida, JP, 163856, 2001.
3 3
previtamin D (4). Finally, the desired vitamin D (1) was
2
23 B. D. A. Hook, W. Dohle, P. R. Hirst, M. Pickworth, M. B. Berry
obtained in excellent yield (HPLC-UV: 60%, isolated: 32%).
To the best of our knowledge, this is the highest yield ever
achieved without the use of a laser, a sensitizer or a filter
compound. One of the advantages of using microreactors is
the ease of scaling up. It should be possible to scale up our
developed process by either continuous running or by the
numbering up of the microreactors. It should be noted that the
continuous micro-flow synthesis of vitamin D3 (1) did not
require the purification of intermediates or high-dilution
conditions, thereby reducing waste.
and K. I. Booker-Milburn, J. Org. Chem., 2005, 70, 7558–7564.
4 Y. Matsushita, T. Ichimura, N. Ohba, S. Kumada, K. Sakeda,
2
T. Suzuki, H. Tanibata and T. Murata, Pure Appl. Chem., 2007,
7
9, 1959–1968.
25 We have examined one-stage irradiation method in a single photo-
and thermal-microreactor by using the 400 W high-pressure
mercury lamp with a Vycor filter (313–578 nm, 100 1C). As a
3
result, an undesired photo-isomerization of vitamin D (1) to
3
trans-vitamin D (7) was observed (ref. 33).
26 V. Malatesta, C. Willis and P. A. Hackett, J. Am. Chem. Soc.,
981, 103, 6781–6783.
7 W. G. Dauben and R. B. Phillips, J. Am. Chem. Soc., 1982, 104,
55–356.
1
2
This work was supported by the Project of Micro Chemical
Technology for Production, Analysis, and Measurement
Systems of NEDO, Japan.
3
28 M. Okabe, R. C. Sun, M. Scalone, C. H. Jibilian and
S. D. Hutchings, J. Org. Chem., 1995, 60, 767–771.
2
3
9 Custom-made microreactors, a syringe pump and its regulating
system were purchased from Senshu Scientific Co. Ltd.
Notes and references
0 The photo-isomerization of provitamin D
batch reactor (concentration of provitamin D
reaction time 150 min) afforded the desired mixture of previtamin
(4) and tachysterol (6) in 23% combined yield. A large
amount of provitamin D (3) was recovered (50%) and undesired
3
(3) using conventional
1
R. Bouillon, W. H. Okamura and A. W. Norman, Endocr. Rev.,
995, 16, 200–257.
R. H. Ettinger and H. F. DeLuca, Adv. Drug Res., 1996, 28,
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3
(3): 20 mM,
1
2
D
3
2
3
3
4
G. D. Zhu and W. H. Okamura, Chem. Rev., 1995, 95, 1877–1952.
G. H. Posner and M. Kahraman, Eur. J. Org. Chem., 2003,
lumisterol (5) was generated (25%). This result clearly shows the
advantages of the flow condition over the batch condition.
3
889–3895.
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I. Hijikuro, T. Doi and T. Takahashi, J. Am. Chem. Soc., 2001,
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N. Kubodera and H. Watanabe, JP, 188061, 1991.
31 W. G. Dauben and R. B. Phillips, J. Am. Chem. Soc., 1982, 104,
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32 S. C. Eyley and D. H. Williams, J. Chem. Soc., Chem. Commun.,
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33 H. J. C. Jacobs, J. W. J. Gielen and E. Havinga, Tetrahedron Lett.,
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5
6
7
1
1
8
724 Chem. Commun., 2010, 46, 8722–8724
This journal is c The Royal Society of Chemistry 2010