3.72-3.81 (m, 1 H) 3.94 (br s, 1 H) 4.50 (t, J ) 5.31 Hz, 1 H).
13C NMR (100 MHz, DMSO-d6) δ 27.4, 28.7, 39.2, 64.2, 78.9,
154.5. MS (ES+): 115.9 (M + H - 100 (Boc group))+. Chiral
HPLC: >99.5% ee. Anal. Calcd for C11H21NO3: C: 61.37; H:
9.83; N: 6.51. Found: C: 61.41; H: 9.93; N: 6.53.
was slowly added while the internal temperature was held
below 15 °C. The resulting HCl solution in ethanol was
stirred at 0-5 °C for 1 h.
To the above HCl solution in ethanol was added a
solution of N-Boc-piperidine 13 (737 g, 1.66 mol) in ethyl
acetate (1.5 L) as a small stream over 15 min. The mixture
was warmed to 15 °C over 1 h. The solvent was removed
under reduced pressure, and to the oily residue was added
ethyl acetate (2 L). The solvent was removed under
reduced pressure, and this same procedure was repeated
once more to remove any residual ethanol. To the resulting
foamy solid was added MTBE (14 L), and the mixture
was stirred at 20 °C for 18 h. The suspension was filtered,
and the solid was washed with MTBE (1 L) and dried
under vacuum (17 Torr) at 50 °C for 24 h to give 593 g
(94%) of HCl salt 14 as a white solid. Mp: 94-103 °C.
Synthesis of Mesylate 12. To a solution of alcohol 11 (408
g, 1.89 mol) in dry CH2Cl2 (3 L) under nitrogen at 5 °C was
added triethylamine (396 mL, 2.84 mol) as a small stream over
5 min. The mixture was stirred for 10 min, and methanesulfonyl
chloride (177 mL, 2.27 mol) was slowly added while the internal
temperature was held below 12 °C. The mixture was warmed
to 20 °C and stirred for 16 h. The suspension was filtered, and
the solid (triethylamine hydrochloride) was washed with CH2Cl2
(500 mL) and discarded. The combined filtrates were washed
with water (3 × 500 mL), and the solution was concentrated at
reduced pressure to give 567 g (100%) of mesylate 12 as an
oil that slowly crystallized into a white solid. Crude 12 was
used in the next step without further purification. An analytical
sample was purified by flash chromatography (CH2Cl2/EtOAc,
9:1). Mp: 72-74 °C. HPLC retention time: 4.93 min. 1H NMR
(400 MHz, CDCl3) δ 1.21-1.35 (m, 1 H) 1.36-1.53 (m, 10
H) 1.58-1.69 (m, 1 H) 1.74-1.85 (m, 1 H) 1.85-1.99 (m, 1
H) 2.73 (br s, 1 H) 2.84-2.94 (m, 1 H) 3.00 (s, 3 H) 3.71-3.83
(m, 1 H) 3.92 (br s, 1 H) 4.00-4.13 (m, 2 H). 13C NMR (100
MHz, CDCl3) δ 24.10, 26.8, 28.6, 35.5, 37.5, 71.3, 79.9, 154.9.
MS (ES+): 294.2 (M + H)+. Anal. Calcd for C12H23NO5S: C:
49.13; H: 7.90; N: 4.77; S, 10.93. Found: C: 49.23; H: 8.14;
N: 4.99; S, 10.96.
1
HPLC retention time: 4.94 min. H NMR (400 MHz,
DMSO-d6) δ 1.30-1.47 (m, 1 H) 1.66-1.93 (m, 3 H)
2.34-2.46 (m, 1 H) 2.68-2.89 (m, 2 H) 3.20 (d, J )
12.09 Hz, 1 H) 3.33-3.45 (m, 1 H) 4.19 -4.39 (m, 2 H)
7.24-7.43 (m, 3 H) 7.43-7.53 (m, 2 H) 7.56 (dd, J )
8.33, 2.29 Hz, 1 H) 7.62 (t, J ) 7.87 Hz, 1 H) 9.36 (br s,
2 H). 13C NMR (100 MHz, DMSO-d6) δ 21.8, 25.2, 33.6,
43.8, 45.7, 71.2, 104.7, 105.0, 113.6, 113.7, 117.6, 117.7,
118.4, 118.6, 126.0, 126.1, 127.3, 127.4, 128.3, 129.8,
129.9, 138.9, 154.6, 156.5, 157.1, 157.6, 157.7, 158.8.
MS (ES+): 344.1 (M + H, free base)+. Anal. Calcd for
C13H8F2N2O · 0.35H2O: C: 59.10; Cl, 9.18; F, 9.84; H:
5.40; N: 10.88. Found: C: 58.78; Cl, 9.10; F, 9.72; H:
5.43; N: 10.70.
Synthesis of Tartaric Acid Salt 1. (i) HCl salt 14 (22.79
g, 60 mmol) was suspended in ethyl acetate (200 mL). A 1 M
solution of K2CO3 in water (200 mL, 200 mmol) was added,
and the biphasic mixture was vigorously stirred. After 1 h, all
the solids had dissolved, and the two layers were separated.
The aqueous layer was extracted with ethyl acetate (2 × 100
mL), and the combined organic extracts were washed with
saturated brine (50 mL) and dried over MgSO4. The solution
was concentrated under reduced pressure to give free base 19
as a beige oil that was used in the next step without further
purification.
Synthesis of N-Boc-piperidine 13. To a solution of
indazolone 10 (475 g, 1.93 mol) in dry DMF (5.8 L) was
added K2CO3 (powder, 400 g, 2.89 mol) in one portion,
and the mixture was stirred at 20 °C for 10 min. A solution
of mesylate 12 (566 g, 1.93 mol) in dry DMF (1 L) was
added to the flask as a small stream over 5 min, and the
resulting mixture was heated to 85 °C and stirred for 18 h.
The reaction was cooled to 10 °C, and water (6 L) and
MTBE (2 L) were added. The layers were separated, and
the aqueous layer was extracted with MTBE (2 × 3 L).
The combined organic extracts were washed with water
(3 × 1 L), and the solvent was removed under reduced
pressure to give a pale-brown solid that was passed
through a plug of silica (hexanes/ethyl acetate, 3:1 as
mobile phase) to give 816 g (92%) of N-Boc-piperidine
13 as a yellow oil that partially solidified upon standing.
(ii) The free base from the previous step was dissolved in
absolute ethanol (200 mL) to give a hazy mixture. Solid
L-tartaric acid (9.00 g, 60 mmol) was added in one portion,
and the mixture was stirred at 22 °C for 1 h. A white solid
crystallized, and additional ethanol (600 mL) was added. The
slurry was heated to reflux, which resulted in the partial
dissolution of the solid. The suspension was cooled to 20 °C
over 4 h and stirred for 14 h. The solid was filtered, washed
with ethanol (50 mL), and dried under vacuum (17 Torr) at 50
°C for 24 h to give 18.91 g (83%) of tartaric acid salt 1 as a
white solid. Mp: 181-182 °C. HPLC chemical purity: 98.7%
1
HPLC retention time: 13.30 min. H NMR (400 MHz,
CDCl3) δ 1.21-1.62 (m, 13 H) 1.66-1.77 (m, 2 H) 1.88
-1.99 (m, 1 H) 2.06-2.20 (m, 1 H) 2.52-3.06 (m, 2 H)
3.83-4.18 (m, 3 H) 4.21-4.39 (m, 2 H) 7.12-7.22 (m,
2 H) 7.22-7.30 (m, 2 H) 7.30 -7.39 (m, 2 H) 7.51 -7.60
(m, 1 H). 13C NMR (100 MHz, CDCl3) δ 27.5, 28.6, 36.0,
79.6, 114.2, 117.0, 117.2, 117.5, 117.8, 125.1, 125.2,
127.7, 128.4, 128.5, 138.9, 154.7, 155.1, 156.5, 157.2,
158.9. Anal. Calcd for C25H31F2N3O3: C: 65.34; F, 8.27;
H: 6.80; N: 9.14. Found: C: 64.98; F, 8.57; H: 6.15; N:
9.45.
1
a/a. HPLC optical purity: 100% a/a. H NMR (400 MHz,
DMSO-d6) δ 1.28-1.46 (m, 1 H) 1.59-1.74 (m, 1 H)
1.75-1.93 (m, 2 H) 2.25-2.43 (m, 1 H) 2.69-2.87 (m, 2 H)
3.23 (d, J ) 12.09 Hz, 1 H) 3.35-3.48 (m, 1 H) 3.95 (s, 2 H)
4.19-4.38 (m, 2 H) 7.24-7.42 (m, 3 H) 7.43 -7.57 (m, 3 H)
7.62 (t, J ) 7.78 Hz, 1 H) 8.44 (br s, 3 H). 13C NMR (100
Synthesis of HCl Salt 14. Preparation of HCl solution
in ethanol: Absolute ethanol (4.7 L) under nitrogen was
cooled to 5 °C, and acetyl chloride (1.18 L, 16.6 mol)
882
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Vol. 12, No. 5, 2008 / Organic Process Research & Development