Journal of Medicinal Chemistry
ARTICLE
85/15 heptane/EtOH with 0.1% diethylamine modifier) to afford the
following compounds.
were added methylamine (2.0 M in THF, 167 mL, 334 mmol) and T3P
(50 wt % solution in EtOAc, 128 mL, 201 mmol). The resulting reaction
mixture was stirred at room temperature for 1 h. Then 1 N aqueous
NaOH (575 mL) and EtOAc (400 mL) were added and the layers were
separated. The aqueous layer was subjected to EtOAc extraction (2 ꢁ
500 mL), and the combined organic layers were dried over MgSO4,
filtered, and concentrated. Chromatography with a gradient of 5ꢀ15%
MeOH in CH2Cl2 containing 0.25% NH4OH provided the title
12a (cis isomer): colorless gum. 1H NMR (CDCl3, 400 MHz) δ 7.79
(d, J = 8.3, 2H), 7.32 (d, J = 7.9, 2H), 7.24 (d, J = 7.9, 2H), 7.08 (d, J = 7.9,
2H), 3.99 (d, J = 6.2, 2H), 3.57 (s, 2H), 3.31ꢀ3.40 (m, 1H), 2.53ꢀ2.63
(m, 1H), 2.46ꢀ2.50 (m, 4H), 2.42 (s, 3H), 2.36ꢀ2.41 (m, 2H),
1.78ꢀ1.87 (m, 2H), 1.72ꢀ1.77 (m, 4H). 13C NMR (CDCl3, 100 MHz)
δ 144.4, 143.1, 136.9, 132.8, 129.6, 128.5, 127.5, 125.8, 73.6, 60.0, 53.8,
35.3, 31.9, 29.7, 23.1, 21.3. MS (APCI) m/z = 400.3 (M + 1).
12b (trans isomer): colorless gum. 1H NMR (CDCl3, 400 MHz) δ
7.84 (d, J = 8.1, 2H), 7.37 (d, J = 7.8, 2H), 7.26 (d, J = 8.2, 2H), 7.13
(d, J = 8.2, 2H), 4.19 (d, J = 7.4, 2H), 3.59 (s, 2H), 3.49ꢀ3.57 (m, 1H),
2.57ꢀ2.65 (m, 1H), 2.49ꢀ2.52 (m, 4H), 2.47 (s, 3H), 2.23ꢀ2.31 (m,
2H), 2.14ꢀ2.21 (m, 2H), 1.76ꢀ1.80 (m, 4H). 13C NMR (CDCl3, 100
MHz) δ 144.7, 143.9, 137.0, 133.2, 129.8, 128.9, 127.9, 126.1, 73.6, 60.3,
54.1, 35.9, 30.6, 29.9, 23.4, 21.6. MS (APCI) m/z = 400.3 (M + 1).
{trans-3-[4-(Pyrrolidin-1-ylmethyl)phenyl]cyclobutyl}-
methanol (13). Magnesium turnings (4.87 g, 201 mmol) and 12b (8.0 g,
20 mmol) in MeOH (160 mL) were stirred for 4 h to give a milky mixture.
Aqueous NaOH (15%) was added, and the mixture was extracted with 3:1
CHCl3/i-PrOH. The organic phase was dried over MgSO4, filtered, and
concentrated to yield the title compound (3.6 g, 73%) as a colorless oil. This
1
compound (25.9 g, 48%). H NMR (CDCl3, 400 MHz) δ 7.46ꢀ7.48
(m, 2H), 7.34 (dd, J = 7.9, 1.7, 1H), 6.03ꢀ6.11 (br m, 1H), 5.77 (br s,
1H), 3.76 (s, 2H), 2.85 (d, J = 4.9, 3H), 2.73ꢀ2.86 (m, 3H), 2.56ꢀ2.63
(m, 4H), 2.47ꢀ2.54 (m, 2H), 1.76ꢀ1.84 (m, 4H). 13C NMR (CDCl3,
100 MHz) δ 177.3, 145.8, 135.1, 133.8, 130.6, 126.1, 123.3, 74.1, 56.5,
54.1, 40.8, 33.1, 26.6, 23.5. MS (APCI) m/z = 323.1 (M + 1).
trans-3-[3-Chloro-4-(pyrrolidin-1-ylmethyl)phenyl]-N-
methylcyclobutanecarboxamide (18). TFA (48 mL) was added
to a solution of 16 (10.0 g, 31.4 mmol) in DCE (202 mL), and the re-
sulting mixture was heated at 75 °C for 18 h and concentrated. The
crude TFA salt of 3-[3-chloro-4-(pyrrolidin-1-ylmethyl)phenyl]-N-
methylcyclobut-2-ene-1-carboxamide (17) thus obtained was redis-
solved in EtOH (130 mL) and hydrogenated (45 psi) at 60 °C in the
presence of chlorotris(triphenylphosphine)rhodium(I) (Wilkinson’s
catalyst, 1.5 g). After 2 h, the mixture was cooled and concentrated.
The residue was redissolved in 1 N aqueous HCl (100 mL) and washed
twice with EtOAc (2 ꢁ 100 mL). The aqueous layer was then made basic
with 1 N aqueous NaOH (100 mL) and extracted with EtOAc (2 ꢁ
500 mL). The combined organic phases were dried over MgSO4,
filtered, and concentrated. Chromatography with a gradient of 5ꢀ15%
MeOH in CH2Cl2 containing 0.25% NH4OH gave a mixture of cis and
trans isomers of the title compound (4.6 g, 48% yield). These isomers
were separated by preparative chromatography on a Chiralcel OD
(10 cm ꢁ 50 cm) column using heptane/i-PrOH (90/10) to yield
the pure trans (3.6 g) and cis (0.52 g) isomers. trans-3-[3-Chloro-4-
(pyrrolidin-1-ylmethyl)phenyl]-N-methylcyclobutanecarboxamide (18):
1H NMR (CDCl3, 400 MHz) δ 7.39 (d, J = 7.8, 1H), 7.22 (d, J = 1.6, 1H),
7.09 (dd, J = 7.8, 1.2, 1H), 5.58 (br s, 1H), 3.69ꢀ3.77 (singlet at 3.72
(2H) overlapping multiplet (1H), 3H total), 2.94ꢀ3.00 (m, 1H), 2.86
(d, J = 5.1, 3H), 2.65ꢀ2.72 (m, 2H), 2.55ꢀ2.60 (m, 4H), 2.31ꢀ2.38
(m, 2H), 1.75ꢀ1.83 (m, 4H). 13C NMR (CDCl3, 100 MHz) δ 175.8,
145.7, 134.4, 133.8, 130.6, 127.1, 124.7, 56.7, 54.2, 36.2, 36.1, 31.9, 26.4,
23.5. MS (APCI) m/z = 307.4 (M + 1).
1
material was used without further purification. H NMR (CDCl3, 400
MHz) δ 7.28 (d, J = 8.0, 2H), 7.19 (d, J = 8.0, 2H), 3.73 (d, J = 7.4, 2H),
3.60 (s, 2H), 3.52ꢀ3.58 (m, 1H), 3.47 (br s, 1H), 2.49ꢀ2.56 (m, 4H),
2.41ꢀ2.49 (m, 1H), 2.16ꢀ2.29 (m, 4H), 1.70ꢀ1.81 (m, 4H). 13C NMR
(CDCl3, 100 MHz) δ 144.9, 136.2, 128.9, 126.1, 66.2, 60.2, 53.9, 36.3, 32.8,
31.0, 23.2. MS (APCI) m/z = 246.4 (M + 1).
(4-Bromo-2-chlorophenyl)(pyrrolidin-1-yl)methanone (14).
T3P (48.6 g, 153 mmol, 50 wt % in EtOAc) was added to a mixture of
4-bromo-2-chlorobenzoic acid (30 g, 130 mmol), triethylamine (25.8 g,
255 mmol), and pyrrolidine (18 g, 255 mmol) in EtOAc (1.5 L). After 1 h,
1 N aqueous NaOH (200 mL) was added and the mixture was stirred for
10 min. The layers were separated, and the aqueous phase was extracted
with EtOAc (2 ꢁ 500 mL). The combined organic extractswere driedover
MgSO4, filtered, and concentrated to provide a viscous oil. Chromatogra-
phy using a gradient of 50ꢀ80% EtOAc in hexanes yielded the title com-
pound as a light yellow, viscous oil (35.4 g, 96%). 1H NMR (CDCl3, 400
MHz) δ 7.56 (d, J = 1.7, 1H), 7.43 (dd, J = 8.3, 1.7, 1H), 7.17 (d, J = 8.3,
1H), 3.63 (br app t, J = 6.6, 2H), 3.17 (br app t, J = 6.6, 2H), 2.00ꢀ1.84 (m,
4H). 13C NMR (CDCl3, 100 MHz) δ 166.0, 136.6, 132.6, 131.3, 130.7,
128.9, 123.3, 48.0, 45.8, 26.1, 24.7. MS (APCI) m/z = 287.9 (M + 1).
1-(4-Bromo-2-chlorobenzyl)pyrrolidine (15). BoraneꢀTHF
complex (1.0 M in THF, 367 mL, 367 mmol) was added dropwise to a
solution of 14 (35.3 g, 122 mmol) in THF (120 mL), and the resulting
mixture was stirred at room temperature for 21 h. The reaction was
quenched with MeOH (120 mL), and the mixture was heated to 80 °C
for 18 h. The mixture was cooled to room temperature and concentrated
and the resulting residue was purified by chromatography using 50%
EtOAc in hexanes to yield the title compound as a colorless, viscous oil
(24.4 g, 74%). 1H NMR (CDCl3, 400 MHz) δ 7.47 (br s, 1H),
7.38ꢀ7.33 (m, 2H), 3.66 (s, 2H), 2.58ꢀ2.54 (m, 4H), 1.80ꢀ1.76 (m, 4H).
13C NMR (CDCl3,100 MHz) δ 136.4, 134.8, 132.0, 131.9, 130.0, 120.7,
56.6, 54.4, 23.8. MS (APCI) m/z = 275.8 (M + 1).
1-{trans-3-[3-Chloro-4-(pyrrolidin-1-ylmethyl)phenyl]-
cyclobutyl}-N-methylmethanamine (19). BH3ꢀTHF complex
(1.0 M inTHF, 319 mL, 319 mmol) was added to a solution of 18 (32.5 g,
106.2 mmol) in THF (516 mL), and the resulting solution was heated
at 70 °C for 16 h. MeOH was added to quench the excess borane, and the
heating was continued for another 16 h. The reaction mixture was cooled
to room temperature and concentrated to yield a viscous oil which was
redissolved in EtOAc (500 mL) and extracted into 6 N HCl (260 mL).
The acidic aqueous phase was basified with 15% aqueous NaOH (500 mL)
and extracted with EtOAc (2 ꢁ 750 mL). The extracts were dried over
MgSO4, filtered, and concentrated to yield 30.3 g of crude product.
Chromatography with a gradient of 5ꢀ100% MeOH in CH2Cl2
containing 0.25% NH4OH afforded the title compound (23.7 g, 77%
1
yield) as a colorless viscous oil. H NMR (CDCl3, 400 MHz) δ 7.39
3-[3-Chloro-4-(pyrrolidin-1-ylmethyl)phenyl]-3-hydroxy-
N-methylcyclobutanecarboxamide (16). n-Butyllithium (2.5 M
in hexanes, 135 mL, 0.335 mol) was added down the reaction flask walls
over 25 min to a ꢀ78 °C solution of 15 (92.0 g, 0.335 mol) in THF
(400 mL). After the mixturewasstirred atꢀ78 °C for 1 h, aꢀ78 °Csolution
of 3-oxocyclobutanecarboxylic acid (19.0 g, 167.5 mmol) in THF
(400 mL) was cannulated into the reaction mixture over 15 min. The
resulting dark orange solution was slowly warmed to room temperature
over 16 h. To the crude solution of the intermediate 3-[3-chloro-
4-(pyrrolidin-1-ylmethyl)phenyl]-3-hydroxycyclobutanecarboxylic acid
(d, J = 7.9, 1H), 7.23 (d, J = 1.7, 1H), 7.10 (dd, J = 7.9, 1.7, 1H), 3.73 (s, 2H),
3.55 (tt, J = 8.3, 8.2, 1H), 2.79 (d, J = 7.5, 2H), 2.56ꢀ2.61 (m, 4H), 2.48
(s, 3H) overlapping 2.44ꢀ2.51 (m, 1H), 2.21ꢀ2.31 (m, 2H), 2.12ꢀ2.18
(m, 2H), 1.76ꢀ1.83 (m, 4H). 13C NMR (CDCl3, 100 MHz) δ 146.5,
134.1, 133.7, 130.5, 127.2, 124.7, 57.3, 56.7, 54.2, 36.6, 36.2, 32.4, 30.9,
23.5. MS (APCI) m/z = 293.2 (M + 1).
N-({trans-3-[3-Chloro-4-(pyrrolidin-1-ylmethyl)phenyl]-
cyclobutyl}methyl)-N-methylacetamide (4). Acetic anhydride
(9.2 mL, 97 mmol) was added to a 0 °C solution of 19 (23.7 g, 81.2 mmol)
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dx.doi.org/10.1021/jm200939b |J. Med. Chem. 2011, 54, 7602–7620