A Machine-Assisted Flow Synthesis of SR48692
FULL PAPER
(C), 143.3 (C), 138.9 (C), 134.7 (C), 131.8 (CH), 128.0 (CH), 127.7 (CH),
125.9 (CH), 122.1 (C), 118.1 (CH), 111.7 (CH), 105.6 (C), 104.0 (CH),
55.3 ppm (CH3); FT-IR (neat): 1687, 1575, 1479, 1456, 1434 cmÀ1; LC-
MS: tR =4.35 min, m/z [M+H]+: 410.25; HRMS (ESI): m/z calcd for
C21H17N3O4Cl+: 410.0908; found 410.0904; microanalysis calculated
(found) for C12H16N3O4Cl: C 61.54 (61.30%), H 3.94% (4.00%), N
10.25% (10.17%).
crystallisation from dichloromethane/hexane (yield 47 mg, 0.07 mmol,
73%). M.p. 230–2348C; 1H NMR (400 MHz, CDCl3, 258C): d=8.76 (d,
1H, J=4.6 Hz), 8.13 (d, 1H, J=2.1 Hz), 7.95 (d, 1H, J=9.0 Hz), 7.48
(dd, 1H, J=9.1, 2.2 Hz), 7.21 (t, 1H, J=8.4 Hz), 7.10 (s, br, 1H), 7.07 (s,
1H), 7.04 (d, 1H, J=4.6 Hz), 6.39 (d, 2H, J=8.4 Hz), 3.38 (s, 6H), 2.66
(m, 2H), 2.20–2.09 (m, 2H), 2.09–2.00 (m, 2H), 1.84–1.61 (m, 8H),
1.51 ppm (s, 9H); 13C NMR (100 MHz, CDCl3, 258C): d=171.63 (C),
160.55 (C), 158.00 (C), 151.01 (CH), 150.16 (C), 148.59 (C), 144.48 (C),
139.40 (C), 135.96 (C), 131.58 (CH), 128.44 (CH), 128.09 (CH), 126.34
(CH), 122.89 (C), 117.52 (CH), 110.66 (CH), 106.85 (C), 103.79 (CH),
80.87 (C), 64.06 (C), 55.41 (CH3), 38.03 (CH2), 34.17 (CH2), 33.39 (CH2),
32.95 (CH), 28.20 (CH), 27.13 (CH), 26.84 ppm (CH3); FT-IR (neat):
2914, 1731, 1685, 1589, 1532, 1473, 1430, 1364.9 (w), 1290, 1252, 115,
tert-Butyl 2-aminoadamantane-2-carboxylate (12): Batch reaction: HClO4
(0.09 mL, 70% aqueous solution) was added dropwise to a sealed solu-
tion of (2; 0.150 g, 0.65 mmol) in tert-butyl acetate (5.4 mL) cooled to
08C. The reaction was stirred at RT for 6 h and then quenched slowly at
08C with NaOH solution (1N) until the pH reached 9–10. The mixture
was extracted with EtOAc (4ꢄ50 mL) and washed with brine. After
being dried with sodium sulfate, the solution was filtered and concentrat-
ed to give the product as an off-white solid (yield 0.090 g, 0.36 mmol,
55%). M.p. 101–1038C; 1H NMR (500 MHz, [D6]DMSO, 258C): d=3.32
(s, 2H), 2.40 (d, 2H, J=12.1 Hz), 1.91 (s, 2H), 1.72 (m, 2H), 1.67 (m,
4H), 1.60 (m, 2H), 1.40–1.42 ppm (m, 11H); 13C NMR (125 MHz,
[D6]DMSO, 258C): d=176.1 (C), 78.8 (C), 61.0 (C), 37.3 (CH2), 34.6
(CH2), 33.5 (CH), 31.4 (CH2), 27.5 (CH), 26.7 (CH), 26.3 ppm (CH3);
1H NMR (400 MHz, CDCl3, 258C): d=2.22 (2H, d, J=12.4 Hz), 2.03
(2H, s), 1.71–1.78 (6H, m), 1.66 (2H, m) 1.54 (2H, d, J=12.4 Hz), 1.46
(9H, s), 1.43 ppm (2H, s); 13C NMR (100 MHz, CDCl3, 258C): d=176.1
(C), 80.1 (C), 62.0 (C), 37.9 (CH2), 35.3 (CH2), 34.3 (CH), 32.1 (CH2),
28.1 (CH), 27.3 (CH), 27.0 ppm (CH3); FT-IR (neat): 2901, 2851, 1710,
1450, 1365 cmÀ1; LC-MS: tR =3.44 min, [M+Na]+: 252.36; HRMS (ESI):
m/z calcd for C15H26O2N+: 252.1964; found 252.1952; microanalysis: cal-
1101, 1057, 1006, 951, 908, 881, 851, 835, 818, 781.9, 731.0, 682.0 cmÀ1
;
LC-MS: tR =5.96 min, m/z [M+H]+: 644.08; HRMS (ESI): m/z calcd for
C36H40N4O5Cl+: 643.2687; found 643.2693; the structure was unambigu-
ously confirmed by single X-ray crystallography; space group P21/n: a=
10.541, b=19.462, c=15.486 ꢅ; a=90.0, b=90.5, g=90.0o.
2-[1-(7-Chloroquinolin-4-yl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-car-
boxamido]adamantane-2-carboxylic acid (1): Polymer-supported sulfonic
acid (QP-SA; 0.6 g, 2.4 mmol) was added to a solution of tert-butyl 2-[1-
(7-chloroquinolin-4-yl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxa-
mido]adamantane-2-carboxylate (13; 30 mg, 0.05 mmol) in dichlorome-
thane and the reaction was stirred at RT for 18 h. The QP-SA was fil-
tered off and the filtrate concentrated in vacuo to provide the title com-
pound as white crystals (yield 25 mg, 0.04 mmol, 86%). M.p. 219–2228C;
1H NMR (400 MHz, CDCl3, 258C): d=8.91 (d, 1H, J=4.6 Hz), 8.15 (d,
1H, J=2.1 Hz), 7.78 (d, 1H, J=9.1 Hz), 7.68 (dd, 1H, J=2.1, 9.1 Hz),
7.28 (d, 1H, J=4.7 Hz), 7.24 (t, 1H, J=8.5 Hz), 7.91 (s, 1H), 6.52 (d, 2H,
J=8.5 Hz), 3.42 (s, 6H), 2.64–2.56 (m, 2H), 2.17–2.05 (m, 2H), 2.04–1.92
(m, 2H), 1.82–1.71 (m, 2H), 1.71–1.61 (m, 4H), 1.61–1.50 ppm (m, 2H);
13C NMR (100 MHz, CDCl3, 258C): d=173.3(C), 159.9 (C), 157.5 (C),
157.5 (C), 151.8 (CH), 149.1 (C), 143.4 (C), 139.2 (C), 134.8 (C), 131.9
(CH), 128.0 (CH), 127.7 (CH), 125.9 (CH), 122.2 (C), 118.6 (CH), 109.6
(CH), 105.8 (C), 104.0 (CH), 55.4 (CH3), 55.3 (C), 37.4 (CH2), 33.6
(CH2), 32.8 (CH2), 31.9 (CH), 26.5 (CH), 26.2 ppm (CH); FT-IR (neat):
3405, 2922, 1728, 1674, 1591, 1527, 1474, 1433, 1379, 1357, 1288, 1251,
1206, 1101, 1077, 1031, 1006, 957, 882, 865, 823, 779, 725, 682 cmÀ1; LC-
MS: tR =5.29 min, m/z [M+H]+: 587.46; HRMS (ESI): m/z calcd for
C32H32N4O5Cl+: 587.2061, found 587.2053; the structure was unambigu-
culated (found) for C15H25O2N:
C 71.37% (71.67%), H 10.05%
(10.02%), N 5.69% (5.57%); the structure was unambiguously con-
firmed by single X-ray crystallography; space group P21/c: a=10.501,
b=10.882, c=12.101 ꢅ; a=90.0, b=92.0, g=90.0o.
tert-Butyl 2-[1-(7-chloroquinolin-4-yl)-5-(2,6-dimethoxyphenyl)-1H-pyra-
zole-3-carboxamido]adamantane-2-carboxylate (13): Batch reaction : 1-
(7-Chloroquinolin-4-yl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxyl-
ic acid (11; 22 mg, 54 mmol), DIPEA (49 mg, 0.38 mmol) and 2,6-lutidine
(58 mg, 5.4 mmol) were dissolved in dichloromethane (1 mL) and stirred
at RT. A solution of triphosgene (17 mg, 57 mmol) in dichloromethane
(1 mL) was added dropwise to the stirred reaction at RT. The reaction
was allowed to mature at RT for 10 min before adding tert-butyl 2-amino-
adamantane-2-carboxylate (12; 15 mg, 60 mmol) and stirring at RT for
18 h. Saturated ammonium chloride (2 mL) was added to quench the re-
action. The organic fraction was separated and the dichloromethane re-
moved, in vacuo. The residue obtained was suspended in EtOAc (5 mL)
and filtered through a pad of silica to provide the title compound as
yellow crystals (30 mg, 0.07 mmol, 86% yield). Flow Reaction: A solution
of DIPEA (13 mg, 9.9 mmol) in dichloromethane (10 mL, 0.2 mLminÀ1
pump A) was combined with a solution of triphosgene (16; 110 mg,
370 mmol) in dichloromethane (10 mL, 0.2 mLminÀ1 pump B) combined
at a T-piece mixer and flowed through a 500 mL stainless steel reactor at
1008C (1.25 min residence time) and then another 2.5 mL stainless steel
reactor at 258C (6.25 min residence time) before flowing into a Mettler-
Toledo FlowIRꢃ (50 mL flow cell). A 100 psi back pressure regulator
was placed after the reactor. 1-(7-Chloroquinolin-4-yl)-5-(2,6-dimethoxy-
phenyl)-1H-pyrazole-3-carboxylic acid (7; 41 mg, 0.10 mmol) was dis-
solved in a solution of DIPEA (0.2m) in dichloromethane (1 mL) and in-
troduced to flow stream A through a 1 mL injection loop. The flow reac-
tion was monitored at 803 cmÀ1 to observe the consumption of phosgene
by 7 and coordinate the introduction of the coupling partner. A solution
of tert-butyl-2-aminoadamantane-2-carboxylate (12; 30 mg, 0.12 mmol) in
dichloromethane (1 mL) was introduced into a flowing stream of di-
chloromethane (0.25 mLminÀ1, pump C) through a 1 mL injection loop
to coincide, at a T-piece mixer, with the plug of acid chloride from the re-
action of flow streams A and B. The combined reaction mixture then
flowed through a 14 mL PFA reactor at 1008C (23.33 min retention time)
before exiting the flow reactor through a 100 psi back pressure regulator
and into a flask of saturated ammonium chloride (20 mL). The organic
fraction was separated and the dichloromethane removed, in vacuo. The
residue obtained was suspended in EtOAc (5 mL) and filtered through a
pad of silica to provide the title compound (1) as yellow crystals after
¯
ously confirmed by single X-ray crystallography; space group P1: a=
10.249, b=11.718, c=12.634 ꢅ; a=76.6, b=72.9, g=76.4o.
CCDC-919687 (12), 919688 (13) and 919686 (1) contain the supplementa-
ry crystallographic data for this paper. These data can be obtained free
of charge from The Cambridge Crystallographic Data Centre via
Acknowledgements
We gratefully acknowledge funding from Pfizer (C.B.), Commonwealth
Scholarship Commission (B.J.D.), EPSRC (N.N.), the BP 1702 endow-
ment (S.V.L.) and the Royal Society (I.R.B.). We also wish to thank
Dr. J. E. Davies for crystal structure determination and the EPSRC for a
financial contribution toward the purchase of the X-ray diffractometer.
[1] I. R. Baxendale, J. J. Hayward, S. V. Ley, G. K. Tranmer, ChemMed-
[3] V. Hessel, H. Lowe, F. Schonfeld, Chem. Eng. Sci. 2005, 60, 2479–
2501.
Chem. Eur. J. 2013, 19, 7917 – 7930
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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