7754 J . Org. Chem., Vol. 64, No. 21, 1999
Hartner et al.
through the filter cake to give 2.72 kg of 5a (92%). The solid
can be recrystallized from MeOH: mp 185-186.5 °C; 1H NMR
(DMSO-d6) δ 2.08 (m, 2H), 2.93 (t, J ) 7.3, 2H), 3.34 (t, J )
6.4, 2H), 3.75 (t, J ) 7.3, 2H), 3.80 (s, 3H), 4.31 (t, J ) 6.9,
2H), 7.04 (s, 1H), 7.32 (m, 2H), 8.48 (m, 2H); 13C NMR (DMSO-
d6) δ 28.2, 32.9, 45.5, 47.4, 48.9, 51.7, 110.9, 124.2 (2 C), 139.4,
141.0, 147.8, 149.5 (2 C), 160.4, 161.5. Anal. Calcd for
C16H18N4O3: C, 61.13; H, 5.77; N, 17.82. Found: C, 61.07; H,
5.54; N, 17.67.
2-(S)-p-Tolu en esu lfon yla sp a r a gin e (14). To a slurry of
L-asparagine monohydrate (3.9 kg, 26.0 mol) in H2O (57 L)
was added 50% NaOH dropwise to adjust the pH to 10. A
solution of p-TsCl (6.0 kg, 31.5 mol) in acetone (13 L) was
added dropwise simultaneously with 50% NaOH to maintain
a pH of 10 and temperatures of 30-50 °C. When the reaction
was complete and excess p-TsCl had been consumed, the pH
was adjusted to 2-3 with concd HCl (4.5 L) at 15-20 °C. The
mixture was stirred for 1 h, and the solid was filtered and
washed with H2O (32 L). The solid was dried by passing dry
N2 through the filter cake to give 5.5 kg of 14 (74%). An
analytical sample was crystallized from MeOH: mp 184-185
°C (lit.13 mp 185-188 °C); 1H NMR (DMSO-d6) δ 2.25 (dd, J )
6.1, 15.5, 1H), 2.36 (s, 3H), 2.47 (dd, J ) 7.0, 15.5, 1H), 4.08
(ddd, J ) 6.1, 7.0, 8.7, 1H), 6.89 (s, 1H), 7.34 (d, J ) 8.2, 2H),
7.36 (s, 1H), 7.67 (d, J ) 8.2, 2H), 7.95 (d, J ) 8.7, 1H); 13C
NMR (DMSO-d6) δ 20.9, 37.9, 52.3, 126.5 (2 C), 129.3 (2 C),
138.4, 142.4, 170.5, 171.9.
tion reaction with bromopropylamine, a Michael addition
of a lactam to 4-vinylpyridine, and a controlled Hofmann
reaction of N-tosylasparagine.
Exp er im en ta l Section
Gen er a l Meth od s. All reactions were carried out in Pyrex
glass vessels under an atmosphere of N2, and solvents and
reagents were dried where appropriate over molecular sieves
prior to use. Other solvents and reagents were used as
1
received. H and 13C NMR spectra were collected at 250 and
63 MHz, respectively. Coupling constants (J ) are reported in
Hz. A Haake Buchler melting point apparatus was employed.
Melting points are uncorrected. Karl Fisher water analyses
were determined on a Metrohm 684 KF coulometer.
1H-P yr a zole-3,5-d ica r boxylic Acid Dim eth yl Ester (2).
To pyrazole-3,5-dicarboxylic acid (1.67 kg, 9.59 mol) in MeOH
(48 L) at 4 °C was added SOCl2 (1.75 L, 24.0 mol) over 1 h. At
the end of the addition, the solution was heated to 50-55 °C
for 3 h and then cooled to 3 °C. The pH of the solution was
adjusted to 7.5 with a cold aqueous solution of NaOH, and
diester 2 crystallized. The mixture was concentrated under
vacuum with an internal batch temperature of e26 °C until
31 L of distillate was collected. Water was added (8 L), another
7 L of distillate was collected, and additional H2O (8 L) was
added. The mixture was cooled to 4 °C and filtered, and the
cake was washed with cold H2O. The cake was slurried for
1.5 h at 0-5 °C in H2O (8 L) and filtered, and the cake was
washed with cold H2O (2.5 L). The cake was dried at 40-50
°C at reduced pressure to give diester 2 (1.65 kg, 93% yield).
The product can be recrystallized from acetone: mp 156.5-
2-(S)-p-Tolu en esu lfon yla m in o-â-a la n in e (15). See ref 13
for the procedure: 1H NMR (DMSO-d6) δ 2.37 (s, 3H), 2.86
(dd, J ) 9.1, 12.0, 1H), 3.02 (dd, J ) 4.5, 12.0, 1H), 3.21 (dd,
J ) 4.5, 9.1, 1H), 7.38 (d, J ) 8.3, 2H), 7.72 (d, J ) 8.3, 2H),
7.82 (br, 4H); 13C NMR (DMSO-d6) δ 20.9, 41.5, 52.7, 126.9 (2
C), 129.6 (2 C), 136.2, 143.0, 169.5.
1
158.5 °C; H NMR (CDCl3) δ 3.83 (s, 6H), 7.20 (s, 1H), 12.95
(br, 1H); 13C NMR (DMSO-d6) δ 52.0 (2 C), 110.8, 139.1 (br, 2
C), 160.2 (2 C).
2-(S)-(p-Tolu en esu lfon yla m in o)-â-a la n in e Ben zyl Es-
ter Tosyla te (16). A mixture of aminoalanate 15 (4.1 kg, 15.9
mol), benzyl alcohol (3.4 L, 32.9 mol), and p-toluenesulfonic
acid monohydrate (3.18 kg, 16.7 mol) in toluene (30 L) was
refluxed for 6 h while H2O (620 mL) was collected with a
Dean-Stark trap. The thick slurry was diluted with toluene
(30 L), cooled to 20-23 °C, and stirred for 18 h. The solid was
filtered, washed with 1:1 THF/toluene (10 L) and then toluene
(20 L), and dried by passing dry N2 through the filter cake to
afford 7.73 kg of 16 (94%). The product can be recrystallized
from MeOH: mp 170.3-172.8 °C; 1H NMR (DMSO-d6) δ 2.29
(s, 3H), 2.34 (s, 3H), 2.92 (dd, J ) 7.9, 13.0, 1H), 3.16 (dd, J )
5.9, 13.0, 1H), 4.24 (m, 1H), 4.85 (s, 2H), 7.12 (d, J ) 8.0, 2H),
7.20 (m, 2H), 7.29 (d, J ) 8.2, 2H), 7.35 (m, 3H), 7.50 (d, J )
8.0, 2H), 7.64 (d, J ) 8.2, 2H), 8.02 (br s, 3H), 8.58 (br m, 1H);
13C NMR (DMSO-d6) δ 20.7, 20.9, 40.2, 53.4, 66.8, 125.4 (2 C),
126.6 (2 C), 127.9 (2 C), 128.1 (3 C), 128.3 (2 C), 129.5 (2 C),
134.9, 137.3, 137.9, 143.0, 145.2, 168.0.
Meth yl [5,6,7,8-Tetr a h yd r o-4-oxo-4H-p yr a zolo[1,5-a ]-
[1,4]d ia zep in -2-yl]ca r boxyla te (4a ). A mixture of 2 (2.40 kg,
13 mol) and bromopropylamine hydrobromide (5.71 kg, 26 mol)
in a mixture of CH3CN (3.6 L) and THF (20.5 L) was treated
with DBU (9.74 L, 65 mol) for 60-75 min with cooling to
maintain 20-25 °C. The reaction was stirred for an additional
18 h, cooled to 10 °C, and then added to a cold solution of 85%
H3PO4 (1.94 L) and NaCl (4.8 kg) in H2O (34 L). The mixture
was concentrated to 60 L, and the resulting solid was filtered
and washed with H2O. The solid was dried at 40-50 °C at
reduced pressure to give 2.2 kg of 4a (81%). The solid can be
recrystallized from 1:1 HOAc/H2O: mp 229-230 °C; 1H NMR
(DMSO-d6) δ 2.14 (m, 2H), 3.18 (q, J ) 5.4, 2H), 3.80 (s, 3H),
4.49 (t, J ) 6.6, 2H), 7.08 (s, 1H), 8.41 (t, J ) 5.1, 1H); 13C
NMR (DMSO-d6) δ 28.0, 38.7, 50.8, 51.7, 111.9, 139.7, 141.0,
161.3, 161.5. Anal. Calcd for C9H11N3O3: C, 51.67; H, 5.30; N,
20.09. Found: C, 51.53; H, 4.99; N, 19.78.
2(S)-[(p-Tolu en esu lfon yl)am in o]-3-[[[5,6,7,8-tetr ah ydr o-
4-oxo-5-[2-(4-p yr id in yl)eth yl]-4H-p yr a zolo[1,5-a ][1,4]d i-
a zep in -2-yl]ca r bon yl]a m in o]p r op ion ic Acid Ben zyl Es-
ter (17). To 5a (2.045 kg, 6.50 mol) in H2O (16 L) was added
a solution of NaOH (510 g of 50% NaOH in 2 L of H2O). A
water rinse (2 L) was added, and the mixture was warmed to
50 °C for 1 h. CH3CN (4 L) was added, and the solution was
aged for 30 min and then cooled to 25 °C. CH3CN (12 L) and
HOBT (86 g) were added, followed by 16 (3.38 kg, 6.50 mol).
EDC (1.53 kg, 8.0 mol) in H2O (16 L) was added dropwise over
2-3 h, and then additional H2O (6 L) was added. The mixture
was aged for 18 h and filtered, and the cake was washed with
H2O and dried by passing dry N2 through the filter cake, then
in vacuo at 60 °C to give 3.73 kg of 17 (91% yield, 98.7% ee).
The product can be recrystallized from CH3CN. Chiral SFC-
HPLC assay: Chiralpak AD, 250 × 4.6 mm, 32 vol % MeOH
containing 20 mmol TEA as modifier, 1.0 mL/min, 300 bar,
35 °C, 210 nm, tR (min) (R)-17, 26.2, (S)-17, 27.8: 1H NMR
(CDCl3) δ 2.05 (m, 2H), 2.32 (s, 3H), 2.95 (t, J ) 7.3, 2H), 3.23
(t, J ) 6.2, 2H), 3.66-3.87 (m, 4H), 4.10-4.21 (m, 3H), 4.94
(m, 2H), 6.56 (d, J ) 7.9, 1H), 7.12-7.35 (m, 11H), 7.64 (m,
2H), 8.50 (m, 2H); 13C NMR (CDCl3) δ 21.4, 28.6, 33.6, 41.5,
46.4, 48.5 (2 C), 55.7, 67.7, 109.9, 124.0 (2 C), 127.0 (2 C), 128.2
(2 C), 128.3, 128.4 (2 C), 129.5 (2 C), 134.7, 136.4, 139.4, 143.5,
Meth yl [5,6,7,8-Tetr ah ydr o-4-oxo-5-[2-(pyr idin -4-yl)eth -
yl]-4H-p yr a zolo[1,5-a ][1,4]d ia zep in -2-yl]ca r boxyla te (5a ).
A mixture of 4a (1.97 kg, 9.41 mol) and 4-vinylpyridine (1.97
L, 18.8 mol) in N-methylpyrrolidinone (9.84 L) was cooled to
8 °C and treated with a THF solution of t-BuOK (1.7M, 75
mL, 0.13 mol). The mixture was warmed to 20-25 °C, and
additional t-BuOK/THF (125 mL, 0.21 mol) was added in
portions over 2.5 h until the amount of 4a was e1.0 area %
compared to 5a . The reaction was monitored by HPLC. HPLC
conditions: Inertsil ODS-3, 250 × 4.6 mm, 5.0 µ, 210 nm, 30
°C, 0.7 mL/min; gradient, CH3CN/10 mM pH 6.5 potassium
phosphate buffer containing 10% CH3CN; t ) 0, 10% CH3CN,
t ) 2 min, 30% CH3CN, t ) 15 min, 50% CH3CN, t ) 18 min,
50% CH3CN; tR (min) 4a , 7.4, 5a , 8.8. The reaction mixture
was poured into a cold solution of KH2PO4 (1.6 kg) in H2O (40
L). The pH was adjusted to 7.5 with 50% NaOH. The solution
was extracted with CH2Cl2, and the combined extracts were
dried with Na2SO4. The solution was concentrated to a mixture
of solids and liquid (approximately 6 L). To the concentrate
was added a mixture of iPrOAc (5 L) and hexanes (10 L) over
1 h. The slurry was cooled to 0-5 °C, aged for 30 min, and
filtered. The solid was washed with cold 2:1 hexanes/iPrOAc
(3 L), followed by hexanes (6 L) and dried by passing dry N2