Kapa Prasad et al.
COMMUNICATIONS
chemical shifts are expressed in ppm relative to internal tetra-
methylsilane; coupling constants (J) are expressed in Hertz.
Melting points were measured on a Büchi 535 melting point ap-
paratus.
tion of the reaction, the mixture was cooled to 208C, the sus-
pension filtered through Celite, and the Celite washed with
95% ethanol. The filtrate was concentrated, treated with 2 N
HCl (8 mL), and washed with TBME (25 mL). 6 N NaOH
(3.6 mL) was added to the aqueous layer, the solids were col-
lected and dried at 408C for 16 h to give of the desired product;
yield: 1.67 g (80%); mp 67–688C. 1H NMR (CDCl3): d¼1.72–
1.81 (m, 2H), 1.97–2.01 (m, 1H), 2.16–2.26 (m, 2H), 2.97–3.12
(m, 2H), 3.87–3.90 (m, 1H), 7.39–7.46 (m, 1H), 8.13 (s, 1H),
8.26–8.31 (m, 1H), 10.24 (br s, 1H); 13C NMR(CDCl3): d¼
26.61, 31.21, 47.69, 61.26, 114.59, 114.65, 125.29, 125.55,
135.54, 135.88, 147.83, 147.86, 154.98, 158.31, 174.48; MS:
m/z¼210 (MþHþ).
2-Methoxy-4-morpholinoaniline Dihydrochloride (2)
A 250-mL, round-bottomed flask was charged with 10% Pd/C
(50% water, 1.77 g), 1 (8.86 g, 37.2 mmol), triethylamine
(0.379 g, 3.75 mmol), and 95% ethanol (54.7 g). The resulting
suspension was heated to 53Æ58C and formic acid (6.25 g,
135.8 mmol) added slowly while maintaining the temperature
at 53Æ58C. The suspension was held at 53Æ58C for 1 h after
the addition. The reaction with was monitored by HPLC. After
completion of the reaction, the mixture was cooled to 20Æ58C,
the suspension filtered through Celite, and the Celite washed
with 95% ethanol. The filtrate was concentrated under vacuum
at 508C until the volume of the residue was about 27.9 mL. The
suspension was cooled to 20Æ58C and HCl (concentrated,
7.44 g) slowly added. The suspension to was heated 608C and
held at this temperature for 45 min. Then it was cooled to
20Æ58C and acetonitrile (41.4 g) added. After stirring at this
temperature for 1 h, the solids were filtered, and washed with
acetonitrile (11.7 g). The solid was dried in the oven at 708C
trans-(R)-{[N-(4-Ethoxyphenylsulfonyl)-N-(4-
pyridinylmethyl)]amino}-4-propoxycyclohexaneacetic
Acid (8)
The benzyl ester 7 (54.75 g, 94.3 mmol) was dissolved in abso-
lute ethanol(1.1 L) at408C, allowed to cool to 308C, and added
to 10% Pd/C, (50% water, 11.0 g). Triethylamine (2.88 g,
28.5 mmol) was added followed by the dropwise addition of
96% formic acid (22.76 g, 471.5 mmol) over 5 min. The dark
suspension was heated at 608C for 1.5 h and filtered while
hot through Celite. The filtrate was allowed to cool slowly to
room temperature, and the resulting solid was filtered with suc-
tion, washed with absolute ethanol(100 mL), and dried at508C
under reduced pressure to give 8 as a white solid; yield: 27.9 g
(60%); mp 206–2088C. 1H NMR (DMSO-d6): d¼12.91 (br s,
1H), 8.48 and 7.37 (d of d, J¼5.0 Hz, 4H), 7.78 and 7.03 (d of
d, J¼10.0 Hz, 4H), 4.62 (m, 2H), 4.10 (q, J¼6.2 Hz, 2H),
3.96 (d, J¼11.2 Hz, 1H), 3.25 (t, J¼7.50, 2H), 3.02 (m, 1H),
1.88 (m, 1H), 1.72 (m, 1H), 1.54 (m, 1H), 1.37 (m, 7H), 0.93
(m, 2H), 0.78 (t, J¼7.50, 3H), 0.75 (m, 1H), 0.52 (m, 1H);
MS: m/z¼491 (Mþ); anal. calcd. for C25H34N2O6S: C 61.20, H
6.98, N 5.71, S 6.54; found: C 61.19, H 6.92, N 5.69, S 6.48.
1
for 16 h to give 2; yield: 9.4 g (90%); mp 2008C (dec.). H
NMR (D2O): d¼3.63–3.66 (m, 2H), 3.91 (s, 3H), 4.02–4.04
(m, 4H), 7.17 (d, J¼8.64 Hz, 1H), 7.24 (s, 1H), 7.48 (d, J¼
8.64 Hz, 1H); 13C NMR (D2O): d¼54.71, 56.99, 64.68, 105.62,
113.27, 120.27, 125.66, 125.76, 143.60, 154.20; MS (Mþ): m/
z¼208; anal. calcd. for C11H18N2Cl2O2 ·H2O: C44.16, H 6.74,
N 9.36, Cl 23.70; found: C 43.98, H 6.54, N 9.32, Cl 23.50.
2-Methoxy-4-(4-methyl-1-piperazinyl)aniline
Dihydrochloride (4)
A solution of 3 (9.80 g, 39 mmol) in absolute ethanol (60 mL)
was added to 0.98 g of 10% Pd/C (50% water). To this mixture
was added 96% formic acid (9.35 g, 195 mmol) dropwise over
30 min. The reaction mixture was then heated at 708C for 2 h
and allowed to cool to 208C. The catalyst was removed by suc-
tion filtration through Celite, and the solids were washed with
absolute ethanol (25 mL). The combined filtrate and wash was
added to a mixture of 2-propanol/12 N HCl (120 mL/6.5 mL)
dropwise. The resulting solution was treated with ethyl acetate
(30 mL), and the suspension thus obtained was left at 48C over-
night. The solid was filtered with suction, washed with ethyl
acetate (10 mL), and dried at 508C under reduced pressure
to give 4; yield: 8.8 g (77%); mp 150–1518C;.
cis-3-Aminocyclobutanemethyl Benzoate
Butanedioate (1:1 salt) (10)
The substrate 9 (free base) (18.4 g, 47.7 mmol) was dissolved in
n-pentanol (87 mL) and added to 10% Pd/C (50% water,
4.03 g). Triethylamine (0.48 g, 4.77 mmol) was added followed
by 96% formic acid (11.48 g) added dropwise. After the addi-
tion was complete, the reaction mixture was stirred at 608C
for 2 h. The catalyst was removed by filtration through Celite,
and the solids were rinsed with n-pentanol (20 mL). The solu-
tion was washed with water (2ꢁ15 mL) and warmed to 508C at
which time an additional amount of water separated and was
removed. Succinic acid (5.65 g, 47.8 mmol) was added and
the mixture was heated at 958C to dissolve the solids and
then allowed to cool to room temperature over several hours.
The solution was seeded, and heptane (90 mL) was added. Af-
ter stirring for 18 h at room temperature, the solids were re-
moved by filtration, washed with 1:1 n-pentanol and heptane
(30 mL), and dried in a vacuum oven at 508C/40 mbar to afford
10; yield: 80%; mp 165–1708C. 1H NMR (DMSO-d6): d¼9.8
(br s, 4H), 7.95 (d, 2H), 7.60 (m, 3), 4.25 (d, 2H), 3.55 (m,
1H), 2.4 (m, 7H), 1.90 (m, 2H).
(2S)-2-{[(5-Fluoro-2-pyridinyl)amino]carbonyl}-1-
pyrrolidine (6)
A 100-mL, round-bottomed flask was charged with 10% Pd/C
(50% water, 0.34 g), 5 (3.43 g, 10 mmol), triethylamine
(0.14 mL, 0.99 mmol), and 95% ethanol (18 mL). The resulting
suspension was heated to 538C and formic acid (0.46 mL,
12.2 mmol) slowly added while maintaining the temperature
at 538C. The suspension was kept at 538C for 1 h after the ad-
dition. The reaction was monitored with HPLC. After comple-
1772
asc.wiley-vch.de
ꢁ 2005 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim
Adv. Synth. Catal. 2005, 347, 1769 – 1773