An efficient amination method for manufacturing cytidines

Article abstract of DOI:10.1021/op0499371

A novel method for amination of uridine derivatives was developed and applied to the syntheses of cytidines. The method consists of an activation step with 1-methylpiperidine at the C⁴-position of a uracil base. Large-scale preparation of 2′-deoxycytidine was performed using this method.

Full text of DOI:10.1021/op0499371

Organic Process Research & Development 2004, 8, 564−567
Articles
An Efficient Amination Method for Manufacturing Cytidines
Hironori Komatsu,* Kunihiko Morizane,† Toshiyuki Kohno,† and Hiroharu Tanikawa†
Catalysis Science Laboratory, Mitsui Chemicals, Inc., 580-32 Nagaura, Sodegaura-shi, Chiba 299-0265, Japan
Scheme 1
Abstract:
A novel method for amination of uridine derivatives was
developed and applied to the syntheses of cytidines. The method
consists of an activation step with 1-methylpiperidine at the C4-
position of a uracil base. Large-scale preparation of 2′-
deoxycytidine was performed using this method.
Introduction
Cytidine structures are frequently found in pharmaceuti-
cally useful drugs.1 They are difficult to synthesize due to
the low stereoselectivity of glycosylation with cytosine. In
addition to the synthesis of 2′-deoxycytidine, aminations of
the corresponding uridine derivatives also have practical
applications. Among the number of amination methods
reported over a few decades, reactions with POCl3/triazoles,2
4-chlorophenyl phosphorodichloridate/1,2,4-triazole,3 and
2,4,6-triisopropylsulfonyl chloride (TPS-Cl),4 followed by
ammonolysis, are currently the best protocols so far. In some
cases, however, manufacturing cost and scalability of
purification limit their applicability to large-scale production.
Toluenesulfonyl chloride (TsCl) is an alternative inexpensive
and industrially available reagent for activating the C4-
carbonyl group of uridines. Unlike TPS-Cl, ammonolysis at
the C4-position competes with an attack at a sulfonyl group
(path B and path A in Scheme 1). Bulky isopropyl groups
of TPS-Cl are indispensable for suppressing this undesirable
side reaction (path A in Scheme 1). A transient substitution
with 1,2,4-triazole avoids this pathway, but a large excess
amount of 1,2,4-triazole and a long reaction time are required
to complete the reaction. We report an efficient amination
that selectively proceeds, even with TsCl, in the presence
of 1-methylpiperidine and its application to the large-scale
preparation of 2′-deoxycytidine-HCl (1).
Table 1. Results of the amination of
3′,5′-bis(4-chlorobenzoyl)-2′-deoxyuridinea
reaction
yield of
4c,g
amount
(equiv)
time
(h)
ratio of
entry
additives
4:2b
(%)
1
2
1-methyl-piperidine
DABCO
1.2
1.2
2.0
2.1
1.2
0.5
0.5d
0.1d
2.2e
2.2e
1
0.5
4
22
30
30
40
47
22
22
99.7:0.3
99.8:0.2f
93:6
80
81
ND
60
ND
ND
ND
ND
ND
ND
3
DABCO
4
4-DMAP
4-DMAP
4-DMAP
4-DMAP
4-DMAP
K2CO3
99:1
5
89:11
86:14
92:8
6
7
8
84:16f
72:28
91:9f
9
10
K2CO3
a Reaction conditions: TsCl (1.2 equiv), Et3N (2 equiv), CH3CN, rt, then
NH4OH. b The ratios were monitored by HPLC. c Isolated yields were shown.
d TsCl (2 equiv) was used. e TsCl (3.2 equiv) was used. f NH3 was used instead
of NH4OH. g ND: not determined because of the low selectivity between 4 and
2.
* Corresponding author. Telephone: +81-438-64-2313. Fax: +81-438-64-
2371. E-mail: hironori.komatsu@mitsui-chem.co.jp.
Results and Discussion
† Present address: Functional Chemicals Laboratory, Mitsui Chemicals, Inc.,
1144 Togo, Mobara-shi, Chiba 297-0017, Japan.
As a substrate for amination, 3′,5′-O-bis(4-chlorobenzoyl)-
2′-deoxyuridine (2)5 was used to investigate appropriate
reaction conditions. Initially, 2 was reacted with TsCl in the
presence of Et3N in CH3CN. The reaction was monitored
by HPLC and completed in 1 h to give an intermediate
tosylate (3b). Activators that could be replaced with the TsO
group of 3b were selected from nucleophilic tertiary amines
(1) Huryn, D. M.; Okabe, M. Chem. ReV. 1992, 92, 1745.
(2) (a) Matsuda, A.; Obi, K.; Miyasaka, T. Chem. Pharm. Bull. 1985, 33, 2575.
(b) Hodge, R. P.; Brush, C. K.; Harris, C. M.; Harris, T. M J. Org. Chem.
1991, 56, 1553.
(3) Sung, W. L. J. Org. Chem. 1982, 47, 3623.
(4) (a) Reese, C. B.; Ubasawa, A. Tetrahedron Lett. 1980, 21, 2265. (b) Sekine,
M. J. Org. Chem. 1989, 54, 2321. (c) Matsuda, A.; Yasuoka, J.; Sasaki, T.;
Ueda, T. J. Med. Chem. 1991, 34, 999. (d) Awano, H.; Shuto, S.; Miyashita,
T.; Ashida, N.; Machida, H.; Kira, T.; Shigeta, S.; Matsuda, A. Arch. Pharm.
Pharm. Med. Chem. 1996, 329, 66.
(5) Aoyama, H. Bull. Chem. Soc. Jpn. 1987, 60, 2073.
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10.1021/op0499371 CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/20/2004

Scheme 2
Figure 1. Presumed structures of byproducts observed in the
amination.
such as 4-DMAP,4d 1-methylpiperidine, and DABCO. The
results were monitored by HPLC after ammonolysis con-
ducted with NH4OH (Table 1). The selectivity between path
B and path A was determined as the ratio of 4 and 2. The
isolated yields were determined when the reaction proceeded
selectively. 1-Methylpiperidine demonstrated rapid conver-
sion and high selectivity, even when 1.2 equiv was used [4:2
) 99.7:0.3 (entry 1)]. The resulting product (4) was
crystallized directly from the reaction solution, thus simple
filtration was sufficient to isolate 4 (80% of isolated yield).
The reaction with DABCO was fast, but gaseous NH3 was
required for ammonolysis to obtain high selectivity and high
isolated yield (compare entries 2 and 3; 4:2 ) 99.8:0.2 and
93:6, respectively). When NH4OH was used for the am-
monolysis, competitive hydrolysis occurred and there was
no crystallization of 4. The reaction with 4-DMAP was rather
slow, and 1.2 equiv was insufficient to complete the reaction
(entries 4-8). Use of 2.1 equiv of 4-DMAP, however,
resulted in moderate selectivity [4:2 ) 99:1 (entry 4)] and
in a low isolated yield (60%). The high basicity of 4-DMAP
compared with 1-methylpiperidine or DABCO contributed
to these results, because 4-DMAP rather than Et3N would
favorably capture HCl and a substitution with 4-DMAP
would likely be inhibited. The reaction proceeded with K2-
CO3, but with low selectivity [4:2 ) 72:28 (entry 9)].
Selectivity was slightly improved when ammonolysis was
performed with gaseous NH3 [4:2 ) 91:9 (entry 10)]. This
result reflected substantial selectivity between path B and
path A, because the intermediate was apparently 3b and no
other activator was involved in this reaction.
There were two major byproducts observed in the reaction
solution of entry 1 in Table 1. Their molecular weights were
determined by LC-MS analyses, and the chemical structures
were presumed as depicted in Figure 1. The samples of 5
and 6 were alternatively synthesized and were identical to
the compounds observed in the reaction solution of entry 1
by HPLC analyses. The results supported the reaction
mechanism described in Scheme 2. 1-Methylpiperidine was
replaced with the TsO group, and a quaternary ammonium
salt (7) was produced as an intermediate. Demethylation of
7 gave 6, and this side reaction was suppressed by conducting
the reaction at a low reaction temperature (0 °C). Even if
path B competed with path A, a presumable product (8) is
likely to reproduce 3b without consuming the reagents.6
Ammonolysis by nucleophilic NH3 rather than hydrolysis
selectively occurred at the C4-position of 7, and 4 was
Scheme 3
obtained in high yield. A small amount of byproduct (5) was
produced by reacting with residual TsCl.
Syntheses of 5 and 6 are shown in Scheme 3. Reaction
of 4 with TsCl/Et3N was performed to afford 5 in 53% yield.
The compound (6) was obtained by applying the newly
developed amination method by using piperidine instead of
NH4OH. Reaction of 2 with TsCl/Et3N/1-methylpiperidine
was followed by the addition of piperidine to obtain 6 in
69% yield. Additionally, deprotection of 6 by NH4OH/MeOH
afforded 9 in 87% yield. This result demonstrated the
applicability of this amination method to secondary amines
and preparations of cytidine derivatives such as 6 or 9.
The method was applied to a large-scale production of
2′-deoxycytidine-HCl (1) (Scheme 4). Uracil (10) was
silylated by using hexamethyldisilazane (HMDS) in the
presence of (NH4)2SO4. The resulting compound (11) was
condensed with a chloro sugar (12)7 in CHCl3 at 50 °C, and
2 was obtained in 95% yield. Stereoselectivity at an anomeric
position was 96:4 (â:R). The R-isomer was removed by
recrystallization in MeOH, and the ratio was improved to
99.3:0.7 (â:R). Amination of 2 was performed by TsCl/Et3N/
1-methylpiperidine followed by ammonolysis with NH4OH.
Selectivity, as determined by the ratio of 4:2, was 99.5:0.5
for the reaction solution and 99.1:0.9 for the isolated product
by HPLC analyses. The ratio of â:R increased to 99.9:0.01
after isolation. The resulting solid was further washed with
MeOH, and 4 was obtained in 75% yield. The ratios of 4:2
and â:R were 99.4:0.6 and 99.98:0.02, respectively, on
HPLC. This purification procedure was effective for remov-
(7) (a) Hoffer, M. Chem. Ber. 1960, 93, 2777. (b) Wang, Z.-X.; Duan, W.;
Wiebe, L. I.; Balzarini, J.; De Clercq, E.; Knaus, E. E. Nucleosides &
Nucleotides 2001, 20, 11.
(6) For sulfonylation with Me3N+-Ts, see: Yoshida, Y.; Sakakura, Y.; Aso,
N.; Okada, S.; Tanabe, Y. Tetrahedron 1999, 55, 2183.
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Scheme 4
was stirred at rt. The resulting crystals were collected by
filtration and dried in vacuo to give 2 (92.0 kg, 95%) as a
white powder: mp 206-8 °C; [R]25 -27.2° (c 0.372,
D
CHCl3); IR (KBr) 3440, 2360, 2340, 1720, 1700, 1680, 1270
cm-1; NMR δH (270 MHz, CDCl3) 8.58 (1H, s), 8.1-7.9
(4H, m), 7.6-7.4 (5H, m), 6.36 (1H, dd, J ) 2.7, 8.4 Hz),
5.67 (1H, d, J ) 8.4 Hz), 5.59 (1H, m), 4.70 (2H, m), 4.54
(1H, m), 2.75 (1H, ddd, J ) 2.7, 5.7, 14.6 Hz), 2.32 (1H,
ddd, J ) 7.6, 8.4, 14.6 Hz); NMR δC (67.8 MHz, CDCl3)
165.2, 165.1, 162.8, 150.1, 140.4, 140.2, 138.8, 131.2, 130.9,
129.1, 129.0, 127.7, 127.3, 103.0, 85.8, 82.6, 74.8, 64.2, 38.0;
MS (FD) m/z 504 (M - 1)-. HPLC tR 11.9 min (2), tR 10.8
min (R-2) [column, Inertsil ODS-2 (250 mm × 4.6 mm)
(from GL Sciences K. K.); mobile phase, CH3CN-H2O-
Et3N-AcOH (800:200:2:1); flow rate, 0.4 mL/min; UV
wavelength, 254 nm; column temperature, 30 °C], â-2:R-2
) 99.3:0.7.
3′,5′-O-Bis(4-chlorobenzoyl)-2′-deoxy-â-D-cytidine (4).
TsCl (72.5 kg, 380 mol) in CH3CN (181 kg) was added to
a mixture of 2 (91.9 kg, 182 mol), Et3N (38.5 kg, 380 mol),
and 1-methylpiperidine (21.7 kg, 219 mol) in CH3CN (361
kg) at 0 °C, and the reaction mixture was stirred for 3 h.
25% NH4OH was added, and the reaction solution was stirred
at rt overnight. The resulting precipitates were filtered,
washed with CH3CN, and stirred with MeOH at 0 °C for 2
h. The resulting crystals were collected by filtration and dried
in vacuo to give 4 (68.8 kg, 70%) as a white powder: mp
ing the byproducts, 5 and 6 (4.8% of 5 and 0.25% of 6
decreased to 1.4% and 0.14%, respectively). Finally, depro-
tection of 4 was performed by NaOH/MeOH, and 1 was
obtained as HCl salts by acidification with HCl/MeOH in
78% isolated yield. The comparatively low yield was due to
the isolation loss. The ratio of â:R was 99.99:0.01, and the
content of 2′-deoxyuridine was under the HPLC detection
limit (<0.01%). Consequently, 28.2 kg of 2′-deoxycytidine-
HCl (1) was synthesized from 95.0 kg (net 82.7 kg) of chloro
sugar (12), and we demonstrated the applicability of the
newly developed amination method to large-scale prepara-
tions.
237-8 °C; [R]25 -3.6° (c 0.162, CHCl3); IR (KBr) 3370,
D
3199, 2368, 2345, 1718, 1655, 1490, 1271, 1094 cm-1; NMR
δH (400 MHz, DMSO-d6) 8.04-7.96 (4H, m), 7.66-7.59
(5H, m), 7.21 (1H, s, D2O exchangeable), 7.17 (1H, s, D2O
exchangeable), 6.29 (1H, dd, J ) 6.95, 6.95 Hz), 5.70 (1H,
d, J ) 7.56 Hz), 5.61-5.59 (1H, m), 4.63-4.50 (3H, m),
2.55-2.47 (2H, m); NMR δH (270 MHz, CDCl3) 8.1-7.85
(4H, m), 7.61 (1H, d, J ) 7.3 Hz), 7.6-7.35 (4H, m), 6.8-
5.2 (2H, br), 6.37 (1H, dd, J ) 5.7, 7.8 Hz), 5.65 (1H, d, J
) 7.3 Hz), 5.56 (1H, m), 4.67 (2H, m), 4.55 (1H, m), 2.94
(1H, ddd, J ) 1.7, 5.7, 14.6 Hz), 2.23 (1H, ddd, J ) 6.8,
7.8, 14.6 Hz); NMR δC (100 MHz, DMSO-d6) 165.6, 164.6,
164.4, 154.8, 140.8, 138.5, 138.4, 131.2, 131.0, 128.9, 128.9,
128.1, 128.05, 94.4, 85.6, 80.9, 75.2, 64.6, 36.7; MS (FD)
m/z 504 (M+). HPLC 1 tR 9.8 min (4); tR 9.1 min (R-4), tR
11.8 min (2) [column, Inertsil ODS-2 (250 mm × 4.6 mm)
(from GL Sciences K. K.); mobile phase, CH3CN-H2O-
Et3N-AcOH (800:200:2:1); flow rate, 0.4 mL/min; UV
wavelength, 254 nm; column temperature, 30 °C], 4:2) 99.4:
0.6, â-4:R-2) 99.98:0.02. HPLC 2 tR 8.5 min (7), 10.1 min
(4), 15.9 min (2), 28.0 min (6), tR 41.1 min (5) [column,
Inertsil ODS-2 (250 mm × 4.6 mm) (from GL Sciences K.
K.); mobile phase, CH3CN-10mM KH2PO4 (55:45); flow
rate, 1.0 mL/min; UV wavelength, 254 nm; column tem-
perature, 40 °C].
Experimental Section
Melting points were measured with a Buchi 535 melting
point apparatus and are uncorrected. IR spectra were obtained
1
on a JASCO FT/IR-300 spectrometer. H and 13C NMR
spectra were recorded on a JEOL GSX-270 spectrometer.
1
The H NMR chemical shifts are described as δ values in
ppm relative to TMS as an internal standard. The 13C NMR
chemical shifts are reported as δ values in ppm relative to
the used solvents. Mass spectra were obtained with a JEOL
SX-102A spectrometer. HPLC analyses were carried out
using a Shimadzu SCL-10A apparatus equipped with an
SPD-10AV UV detector.
3′,5′-O-Bis(4-chlorobenzoyl)-2′-deoxy-â-D-uridine (2).
A mixture of uracil (10; 30 kg, 268 mol), (NH4)2SO4 (0.35
kg, 2.65 mol), and HMDS (129.6 kg, 803 mol) was heated
at reflux for 2 h. The resulting solution was concentrated,
and the residual liquid, 2,4-bis(trimethylsilyloxy)pyrimidine
(11), was dissolved in CHCl3 (1331 kg). To the solution 3′,5′-
O-bis(4-chlorobenzoyl)-2′-deoxy-R-D-ribosyl-1-chloride (12;
95.0 kg, 92 mol)7 was added, and the mixture was stirred at
50 °C for 3 h. Aqueous NaHCO3 solution was added to the
reaction mixture. The organic phase was separated and
evaporated. MeOH was added to the residue, and the mixture
2′-Deoxy-â-D-cytidine hydrochloride (1). A mixture of
4 (68.8 kg, 136 mol) and NaOH (0.56 kg, 3.07 mol) in
MeOH (392 L) was heated at 40 °C for 4.5 h. The reaction
mixture was neutralized with HCl-MeOH and diluted with
H2O. The solution was washed with CHCl3 and concentrated.
The resulting crystals were collected by filtration and dried
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in vacuo to give 1 (28.2 kg, 78%) as a white powder: mp
3-[3,5-O-Bis(4-chlorobenzoyl)-2-deoxy-â-D-ribofuranos-
1-yl]-4-(1-piperidino)pyrimidin-2-one (6). A mixture of 2
(10.0 g, 19.8 mmol), TsCl (7.55 g, 39.6 mmol), and Et3N
(4.01 g, 39.6 mmol) in CH3CN (39.0 g) was stirred at rt for
2 h. To the solution piperidine (2.87 mL, 23.7 mmol) was
added, and the mixture was stirred at rt for 72 h. The reaction
solution was concentrated. The residual solid was washed
with CH3CN and filtered. The resulting crude crystals were
recrystallized from MeOH to give 6 (3.23 g, 69%) as a white
powder: IR (KBr) 3450, 2959, 2677, 2492, 2364, 1725,
1656, 1626, 1490, 1278 cm-1; NMR δH (400 MHz, DMSO-
d6) 8.03 (2H, d, J ) 8.8 Hz), 7.96 (2H, d, J ) 8.4 Hz), 7.70
(1H, d, J ) 7.6 Hz), 7.63 (2H, d, J ) 8.4 Hz), 7.59 (2H, d,
J ) 8.4 Hz), 6.29 (1H, dd, J ) 6.8, 7.6 Hz), 6.16 (1H, d, J
) 7.6 Hz), 5.60 (1H, dd, J ) 3.2, 3.2 Hz), 4.60 (2H, m),
4.52 (1H, m), 3.70-3.50 (4H, m), 2.60 (2H, m), 1.62 (2H,
m), 1.49 (4H, m); MS [ESI (+)] m/z 572 (M+). HPLC tR
16.5 min (2), tR 29.0 min (6) [column, Inertsil ODS-2 (250
mm × 4.6 mm) (from GL Sciences K. K.); mobile phase,
CH3CN-10mM KH2PO4 (55:45); flow rate, 1.0 mL/min; UV
wavelength, 254 nm; column temperature, 40 °C].
3-(2-Deoxy-â-D-ribofuranos-1-yl)-4-(1-piperidino)pyri-
midin-2-one (9). A mixture of 6 (1.0 g, 1.75 mmol) and
25% NH4OH (8.98 g, 148 mmol) in MeOH (39.6 g) was
stirred at rt for 45 h, and the reaction solution was
concentrated. The residual solid was washed with AcOEt-
H2O and filtered. The resulting crude crystals were washed
with AcOEt to give 9 (447 mg, 87%) as a white powder:
NMR δH (400 MHz, DMSO-d6) 10.3 (1H, brs), 7.90 (1H, d,
J ) 8.0 Hz), 6.18 (1H, d, J ) 8.0 Hz), 6.15 (1H, dd, J )
6.4, 7.2 Hz), 5.22 (1H, s), 5.03 (1H, s), 4.21 (1H, m), 3.78
(1H, m), 3.8-3.3 (6H, m), 2.12 (1H, ddd, J ) 3.2, 6.4, 12.4
Hz), 1.98 (1H, ddd, J ) 5.6, 7.2, 12.4 Hz), 1.62 (2H, m),
1.49 (4H, m); MS [ESI (+)] m/z 296 (M+).
163 °C; [R]25 +56.5° (c 6, H2O); IR (KBr) 3363, 2921,
D
2366, 2344, 1714, 1670, 1541, 1270 cm-1; NMR δH (270
MHz, D2O) 7.98 (1H, d, J ) 8.1 Hz), 6.12 (1H, dd, J ) 6.2,
6.2 Hz), 6.11 (1H, d, J ) 8.1 Hz), 4.33 (1H, ddd, J ) 3.8,
3.8, 6.8 Hz), 3.98 (1H, ddd, J ) 3.8, 3.8, 4.8 Hz), 3.74 (1H,
dd, J ) 3.8, 12.7 Hz), 3.64 (1H, dd, J ) 4.8, 12.7 Hz), 2.39
(1H, ddd, J ) 4.6, 6.8, 14.6 Hz), 2.28 (1H, ddd, J ) 6.8,
7.8, 14.6 Hz); NMR δC (67.8 MHz, D2O) 160.0, 149.1, 145.4,
95.7, 88.1, 87.5, 71.1, 61.9, 40.0; MS (FD) m/z 228 (M +
1)+. HPLC 1 tR 6.0 min (1) [column, Inertsil ODS-2 (250
cm × 4.6 mm) (from GL Sciences K. K.); mobile phase,
CH3CN-H2O-Et3N-AcOH (800:200:2:1); flow rate, 0.4
mL/min; UV wavelength, 254 nm; column temperature, 30
°C]. HPLC 2 tR 15.0 min (1), tR 13.6 min (R-1) [column,
Inertsil ODS-2 (250 cm × 4.6 mm) (from GL Sciences K.
K.); mobile phase, CH3CN-H2O-Et3N-AcOH (10:990:3:
3); flow rate, 0.4 mL/min; UV wavelength, 254 nm; column
temperature, 35 °C], â-1:R-1) 99.99:0.01.
3′,5′-O-Bis(4-chlorobenzoyl)-N4-(4-toluenesulfonyl)-2′-
deoxy-â-D-cytidine (5). A mixture of 4 (2.0 g, 3.67 mmol),
TsCl (1.51 g, 7.93 mmol), and Et3N (803 mg, 7.93 mmol)
in CHCl3 (29.6 g) was heated at reflux for 15 h, and the
reaction solution was concentrated. The residual solid was
washed with AcOEt and filtered. The resulting crude crystals
were recrystallized from MeOH to give 5 (1.01 g, 39%) as
a white powder: IR (KBr) 3424, 2365, 2347, 1719, 1655,
1626, 1509, 1491 cm-1; NMR δH (400 MHz, DMSO-d6) 12.2
(1H, d, J ) 1.7 Hz), 8.01 (2H, d, J ) 8.8 Hz), 7.96 (2H, d,
J ) 8.8 Hz), 7.91 (1H, d, J ) 8.1 Hz), 7.69 (2H, d, J ) 8.5
Hz), 7.61 (2H, d, J ) 8.8 Hz), 7.57 (2H, d, J ) 8.8 Hz),
7.35 (2H, d, J ) 8.5 Hz), 6.51 (1H, dd, J ) 1.7, 8.1 Hz),
6.18 (1H, dd, J ) 6.8, 6.8 Hz), 5.59 (1H, m), 4.59-4.56
(3H, m), 2.64-2.63 (2H, m), 2.37 (3H, s); MS [ESI (+)]
m/z 658 (M+). HPLC tR 10.4 min (4), tR 46.5 min (5)
[column, Inertsil ODS-2 (250 mm × 4.6 mm) (from GL
Sciences K. K.); mobile phase, CH3CN-10mM KH2PO4 (55:
45); flow rate, 1.0 mL/min; UV wavelength, 254 nm; column
temperature, 40 °C].
Received for review March 28, 2004.
OP0499371
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