Facile methods for preparation of thiazolopyridine and tetrahydrothiazolopyridine derivatives

Article abstract of DOI:10.3987/COM-04-10071

The improved routes to prepare tetrahydrothiazolo[5,4-c]-pyridine-2- carboxylic acid lithium salts (2 and 3) were developed. Route A is consisted of the improved preparation of thiazolopyridine intermediates, and Route B is applicable for a large scale synthesis of tetrahydrothiazolo[5,4-c]pyridine-2- carboxylic acid derivatives. The methods we developed may serve as facile means for preparing thiazolopyridine and tetrahydrothiazolopyridine derivatives.

Full text of DOI:10.3987/COM-04-10071

HETEROCYCLES, Vol. 63, No. 7, 2004, pp. 1555 - 1561
Received, 12th March, 2004, Accepted, 13th May, 2004, Published online, 14th May, 2004
FACILE METHODS FOR PREPARATION OF THIAZOLOPYRIDINE
AND TETRAHYDROTHIAZOLOPYRIDINE DERIVATIVES
Noriyasu Haginoya,* Satoshi Komoriya, Ken Osanai, Toshiharu Yoshino,
Tsutomu Nagata, Masatoshi Nagamochi, Ryo Muto, Mitsuhiro Yamaguchi,
Takayasu Nagahara, and Hideyuki Kanno
Medicinal Chemistry Reseach Laboratoty, Daiichi Pharmaceutical Co., Ltd,
1
-16-13,
Kita-Kasai,
Edogawa-ku,
Tokyo
134-8630,
Japan;
hagin9kg@daiichipharm.co.jp
Abstract –The improved routes to prepare tetrahydrothiazolo[5,4-c]-
pyridine-2-carboxylic acid lithium salts (2 and 3) were developed. Route A is
consisted of the improved preparation of thiazolopyridine intermediates, and
Route
B
is
applicable
for
a
large
scale
synthesis
of
tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid derivatives. The methods we
developed may serve as facile means for preparing thiazolopyridine and
tetrahydrothiazolopyridine derivatives.
INTRODUCTION
Recently we reported a potent factor Xa (fXa) inhibitor (1), which is expected to function as an orally
1
effective anticoagulant having a tetrahydrothiazolo[5,4-c]pyridine ring. In the X-Ray crystal analysis of
the complex of 1 and des-Gla fXa, we confirmed the existence of an intramolecular S-O close contact in
2
the 2-carbamoylthiazole moiety of 1. It is known that an intramolecular S-O close contact plays an
3
important role on the mechanism of several biological effects. The intermediates (2) and (3) of 1 are
interesting building blocks, because not only do they have a bifunctional group, an aliphatic amine and a
O
S-O close contact
O
CONH2
S
S
Cl
OLi
N
N
R N
N
N
S
N
O O
2
3
: R = Me
: R = Boc
1
Figure 1: Structures of 1 containing an S-O close contact and key intermediates (2) and (3).

carboxylic acid, which are applicable for synthesis of various compounds, but they also contain an
intramolecular S-O close contact unit, which restricts the conformation of a compound. In this paper, we
report the efficient methods for preparing 2 and 3.
RESULTS AND DISCUSSION
In our early research on fXa inhibitors, we had used a general route illustrated in Scheme 1 to prepare 2
2
, 3
4
and 3. This consisted of the cyclization of α-chloro-ketone (5) with thioformamide to construct the
fused thiazole ring, followed by the exchange of protecting groups and the introduction of a carboxyl
2
group by lithiation and bubbling of CO . This route has some drawbacks, however, against its practical
use for the large scale production. Firstly, in the purification of α-chloro-ketone (5), it is difficult to
separate 5 from the starting material (4) by either distillation or silica gel column chromatography.
Secondly, in the preparation of thioformamide from formamide with either P S or Lawsson’s reagent,
2
5
2
there are respective problems exemplified by the dangerous formation of H S or the cost performance for
the expensive reagent. Thirdly, a number of steps are required for the exchange of protecting groups. To
solve these problems, we explored a new synthetic route for 2 and 3.
1
2
) LDA, TMSCl
/ THF
) NCS, NaOAc
nBuLi
O
O
thioformamide
EtOH refluxed
3.5 N NaOH
refluxed
/
Ether -78℃
/
S
Cl
S
then CO2
/
Acetone
then Boc O
2
3
N
EtO CN
2
BocN
N
N
N
CO Et
CO Et
7
2
2
6
4
5
LAH / THF
nBuLi
/
Ether -78℃
then CO2
S
2
N
N
8
Scheme 1: Previous synthetic route for the preparation of 2 and 3.
One synthetic route (Route A), which involves N-methylation and reduction of a quaternary pyridinium
2
salt, is shown in Scheme 2. Route A has some advantages for the preparation of both
thiazolo[5,4-c]pyridine and thiazolo[4,5-c]pyridine, in which the protecting group is not needed for an
5
amino moiety of the tetrahydrothiazolopyridine ring. However, the methods reported for the preparation
of thiazolo[4,5-c]pyridine (13) and thiazolo[5,4-c]pyridine (14) have some problems, the requirements of
a number of steps and low yields in cyclizations to obtain thiazolopyridines, especially in the [5,4-c] type
(
9-25%). To prepare these thiazolopyridines more conveniently, we selected 3- or
4
-tert-butoxycarbonylaminopyridine (9 or 10) as the starting material because the aminopyridines that are
6
protected by appropriate acyl groups are easily prepared and used for introduction of a functional group

7
at the adjoining position with lithiation and electrophilic substitution . Reaction of Boc-protected
aminopyridines (9) and (10), via their lithiated pyridines, with S as an electrophile reagent and afforded
mercapto compounds (11) and (12). The mercapto compounds (11) and (12) were respectively cyclized to
3 and 14 in HCO H with moderate yields (45-72%). N-Methylation and reduction of the resultant
quaternary pyridinium salt, followed by introduction of the carboxy group gave the desired
8
1
2
5
-methyltetrahydropyridine-2-carboxylic acid lithium salts (2) and (16) respectively. Each total yield of
6 or 2 from 9 or 10 to was 19% or 14 %.
1
O
O
HN
O
S
S
S
(b)
(c)
(d)
OLi
R
V
W
N
X
N
N
X
W
Y
Y
V
1
3 : V = CH, W = N
15 : X = CH
8: X = NMe, Y = CH 2
2
, Y = NMe
16 : X = CH , Y = NMe
2
2: X = NMe, Y = CH 2
9
: V = CH, W = N, R = H
1
4 : V = N, W = CH
1
0 : V = N, W = CH, R = H
(a)
(a)
1
1
1 : V = CH, W = N, R = SH
2 : V = N, W = CH, R = SH
Scheme 2: Improved route for the preparations of tetrahydrothiazolopyridine-2-carboxylic acids (Route
A).
Reagents and Conditions: (a) n-BuLi, S
8
2
/ THF, -78 ~ 0 °C, 34 - 46%; (b) HCO H, refluxed, 45 - 72%; (c)
i) MeI / DMF, 80 °C, ii) NaBH / H O, 2 steps 70 - 78%; (d) n-BuLi, CO
4
2
2
/ THF, -78 ~ 0 °C, quant.
On the other hand, we conceived of another alternative strategy for the synthesis of 2 and 3. Because
Route A involves a few problems, such as the inadequacy for the Boc derivative (3) and the use of
HCO
2
H, which has a stimulative smell, as the solvent. Alternative improved synthesis (Route B) of 2 and
8
3
is outlined in Scheme 3. Kozikowski’s method has been applied to the conversions of 17 to19. The
enamine formation of 17 followed by the reaction with elemental sulfur and subsequent addition of
cyanamide constructed the tetrahydrothiazolo[5,4-c]pyridine ring to give 18, which was easily purified by
9
crystallization to obtain the solid in 63% yield. A substitutive deamination reaction with t-BuONO and
2
CuBr afforded the 2-bromoderivatives (19) in 49% yield, when DMF was employed as the solvent
because of the insolubility of 18 against some solvents such as MeCN and THF. Reductive amination
after deprotection of the Boc group of 19 gave compound (20) in 90% yield. The desired compounds (2)
and (3) were obtained by the halogen-metal exchange reaction and the introduction of carboxylate. In the
large scale synthesis of 2, purification on a silica gel column needed only two steps, deamination and
reductive amination, and the total yield was 28%.
In conclusion, we have established improved routes to prepare lithium tetrahydrothiazolo[5,4-c]-
pyridine-2-carboxylates (2) and (3) by developing Route A, which consisted of the preparation of
thiazolopyridine intermediates, and Route B, which is applicable for a large scale synthesis of

tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid derivatives. The methods we developed may serve as
the facile means for preparing thiazolopyridine and tetrahydrothiazolopyridine derivatives.
S
NH2
S
Br
S
Br
(a)
(b)
(c)
BocN
O
BocN
N
BocN
N
N
N
1
7
18
19
20
(e)
(d)
O
O
S
S
OLi
OLi
BocN
N
N
N
3
2
Scheme 3: Improved route for the preparations of tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acids
Route B).
(
Reagents and Conditions: (a) i) pyrrolidine, TsOH·H O / cyclohexane refluxed, ii) S , cyanamide / MeOH,
2
8
6
3%; (b) t-BuONO, CuBr
aq. HCHO / CH Cl
C, 66%, .
2
/ DMF, 50 °C, 49%; (c) i) TFA / CH
2
Cl
2
, ii) NaBH(OAc)
3
, Et
3
N, AcOH, 36%
/ ether, -78
2
2
, 2 steps 90%; (d) n-BuLi, CO
2
/ ether, -78 ~ 0 °C, 99%, (e) n-BuLi, CO
2
°
EXPERIMENTAL
General. All solvents and reagents were used as acquired from commercial sources without purification.
Melting points were determined on a Yanagimoto apparatus and are uncorrected. Column
chromatography was performed on Merck silica gel 60 (0.063-0.200 mm). Thin layer chromatography
1
13
(
TLC) was performed on Merck TLC plates pre-coated with silicagel 60 F254. H-NMR and C-NMR
spectra were recorded on a JEOL JNM-EX400 spectrometer, and chemical shifts are given in ppm (δ)
from tetramethylsilane, which was used as the internal standard. Mass spectra were performed using a
JEOL JMS-AX505W (EI) or a JEOL JMS-HX110 (FD, FAB) spectrometer.
3
-(tert-Butoxycarbonyl)amino-4-mercaptopyridine (11)
To a stirred solution of 9 (2.00 g, 10.3 mmol) in dry THF (200 mL) was added n-BuLi (1.54 M in
hexanes; 16.7 mL, 25.8 mmol) at -78 °C under an argon atmosphere. The reaction temperature was
warmed up to 0 °C, stirred for 2 h and recooled to -78 °C. To the mixture was added S
mmol) in one portion. After the reaction temperature was increased to rt, the reaction mixture was stirred
for 1 h. To the mixture was added H O (100 mL) and the organic layer was discarded. To the aqueous
layer was added 3 N HCl until the aqueous solution was pH 3 ~ 4. This solution was extracted with
CH Cl and the organic layer was dried over Na SO and concentrated in vacuo. Purification of the
8
(400 mg, 1.57
2
2
2
2
4
residue by column chromatography (hexane/AcOEt, 2/1) and crystallization from AcOEt- hexane gave 11
1
(
783 mg, 34%) as a colorless solid: mp 176-178 °C. H NMR (400 MHz, DMSO-d
6
) δ 1.48 (9H, s), 7.41

(1H, d, J = 6.3 Hz), 7.57 (1H, d, J = 6.3 Hz), 8.46 (1H, s), 8.93 (1H, s), 12.85 (1H, br s). MS (FAB) m/z
+
2
6
4
27 (M + H) . Anal. Calcd for C10
.02; N, 12.15; S, 13.88.
14 2 2
H N O S: C, 53.08; H, 6.24; N, 12.38; S, 14.17. Found: C, 53.14; H,
-(tert-Butoxycarbonyl)amino-3-mercaptopyridine (12)
Starting with 10 and following the procedure for the preparation of 11 gave 12 (46%) as a pale yellow
1
foam: H NMR (400 MHz, DMSO-d
6
) δ 1.52 (9H, s), 7.89 (1H, d, J = 6.4 Hz), 7.99 (1H, d, J = 6.4 Hz),
+
8
.20 (1H, s), 9.91 (1H, br s), 13.68 (1H, br s). MS (FAB) m/z 227 (M + H) . Anal. Calcd for
10 14 2 2 2
C H N O S·0.5H O: C, 51.04; H, 6.43; N, 11.91; S, 13.63. Found: C, 51.32; H, 6.35; N, 11.76; S,
1
3.69.
Thiazolo[4,5-c]pyridine (13)
2
A solution of 11 (9.20 g, 40.7 mmol) in HCO H (60 mL) was refluxed for 4 h. The reaction mixture was
concentrated. To the residue was added 5 N KOH (50 mL). The mixture was extracted with Et O and the
2
4 2
organic layer was dried over MgSO . Evaporation of the solvent and crystallization from Et O gave 13
5
a
1
(
3.97g, 72%) as a colorless solid: mp 103-105 °C (lit., mp 105-106 °C). H NMR (400 MHz, CDCl
3
) δ
+
7
.93 (1H, d, J = 5.4 Hz), 8.60 (1H, d, J = 5.4 Hz), 9.07 (1H, s), 9.46 (1H, s). MS (FAB) m/z 137 (M + H) .
6 4 2
Anal. Calcd for C H N S: C, 52.92; H, 2.96; N, 20.57; S, 23.55. Found: C, 52.98; H, 2.96; N, 20.65; S,
2
3.33.
Thiazolo[5,4-c]pyridine (14)
A solution of 12 (33.2 g, 147 mmol) in HCO
2
H (250 mL) was refluxed for 2 days. The reaction mixture
O and
and concentrated in vacuo. Purification of the residue by column
chromatography (CH Cl /MeOH, 50/1) and crystallization from Et O gave 14 (9.03 g, 45 %) as a
was concentrated. To the residue was added 5 N KOH (50 mL). The mixture was extracted with Et
the organic layer was dried over MgSO
2
4
2
2
2
5
b
5c
1
colorless solid: mp 105-108 °C (lit., mp 105-106 °C, lit.,. mp 102-105 °C). H NMR (400 MHz,
CDCl
3
) δ 8.05 (1H, d, J = 5.4 Hz), 8.70 (1H, d, J = 5.4 Hz), 9.23 (1H, s), 9.34 (1H, s). MS (FAB) m/z 137
+
(
M + H) . Anal. Calcd for C
6
H
4
N
2
S: C, 52.92; H, 2.96; N, 20.57; S, 23.55. Found: C, 52.80; H, 2.98; N,
2
2
0.40; S, 23.57.
-Amino-5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (18)
To a solution of 1-tert-butoxycarbonyl-4-piperidone (150 g, 752 mmol) in cyclohexane (500 mL) were
added pyrrolidine (66.0 mL, 790 mmol) and TsOH·H O (716 mg, 3.76 mmol). The reaction mixture was
refluxed for 2 h with Dean-Stark trap. After cooling, the mixture was filtered and the filtrate was
evaporated. To the solution of the residue in dry MeOH (200 mL) was added S (24.1 g, 94.1 mmol) in
2
8
one portion. To the stirred mixture was added dropwise the solution of cyanamide (31.7 g, 753 mmol) in
dry MeOH (25 mL) at 0 °C. The reaction mixture was stirred for 5 h and the solid was separated out.
1
Filteration and collection in the mixture gave 18 (122 g, 63%) as a pale yellow solid: mp 91-94 °C. H

NMR (400 MHz, DMSO-d
6
) δ 1.41 (9H, s), 2.40-2.46 (2H, m), 3.57 (2H, t, J = 5.6 Hz), 4.29 (2H, s), 6.79
+
(
2H, s). MS (EI) m/z 255 (M ). Anal. Calcd for C11
H
17
N O
3 2
S·0.1H
2
O: C, 51.38; H, 6.74; N, 16.34; S,
1
2.47. Found: C, 51.73; H, 6.96; N, 16.44; S, 12.14.
-Bromo-5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (19)
(181 g, 0.808 mol) in dry DMF (500 mL) was added tert-butyl nitrite
104 g, 1.01 mol). To the stirred mixture at 50 °C was added 18 (172 g, 0.674 mol) in portions. The
reaction mixture was stirred at 50-60 °C for 2 h and concentrated in vacuo. Purification of the residue by
2
To a stirred suspension of CuBr
2
(
2
column chromatography (hexane/AcOEt, 5/1) and crystallization from Et O gave 19 (105 g, 49%) as a
1
colorless solid: mp 42-44 °C. H NMR (400 MHz, CDCl
3
) δ 1.48 (9H, s), 2.85 (2H, br s), 3.72 (2H, t, J =
+
79
+
81
5
.6 Hz), 4.56 (2H, br s). MS (FAB) m/z 319 [(M + H) , Br ], 321 [(M + H) , Br ]. Anal. Calcd for
BrS: C, 41.39; H, 4.74; N, 8.78; Br, 25.03; S, 10.05. Found: C, 41.33; H, 4.68; N, 8.77; Br,
11 15 2
C H N
2
5.21; S, 10.15.
2
-Bromo-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (20)
To a stirred solution of 19 (74.7 g, 234 mmol) in CH Cl (160 mL) was added trifluoroacetic acid (500 g)
2
2
at 0 °C in an ice bath. The mixture was stirred at rt for 10 min and concentrated in vacuo. To the residue
was added Et O (300 mL) to obtain a colorless solid. To the suspension of this solid in CH Cl (150 mL)
was added Et N (63.7 mL, 460 mmol). To the stirred mixture at rt were added AcOH (39.4 mL, 689
2
2
2
3
mmol), 36 % aq. HCHO (39.4 mL), and sodium triacetoxyborohydride (80.3 g, 367 mmol). The mixture
was stirred for 1 h at rt under an argon atmosphere and poured into 1N NaOH (750 mL). The organic
layer was washed with brine, dried over Na
column chromatography (CH Cl
2
SO
4
and concentrated in vacuo. Purification of the residue by
1
2
2
/MeOH, 100/1) gave 20 (49.0 g, 90%) as a colorless oil: H NMR (400
1
3
MHz, CDCl ) δ 2.49 (3H, s), 2.79 (2H, t, J = 5.8 Hz), 2.88-2.93 (2H, m), 3.58 (2H, s). C NMR (400
3
+
79
+
81
MHz, CDCl
3
) δ 26.7, 45.0, 52.0, 52.2, 130.1, 133.3, 149.1. MS (EI) m/z 232 (M , Br ), 234 (M , Br ).
+
81
HR-MS (EI; M , Br ) Calcd for C
7
9 2
H N BrS 233.9649, Found 233.9652.
Lithium 5-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate (2)
To a stirred solution of 20 (48.9 g, 210 mmol) in dry Et O (500 mL) was added n-BuLi (1.53 M in
2
hexanes; 137 ml, 210 mmol) at -78 °C under an argon atmosphere. The reaction mixture was warmed
2
up to 0 °C, stirred for 20 min, and recooled to -78 °C. After the bubbling of CO gas for 5 min, the
reaction was warmed up to rt and concentrated in vacuo. Collection of the residue and washing with
1
hexane gave 2 (48.9 g, 99%) as a pale brown amorphous solid: H NMR (400 MHz, DMSO-d
6
) δ 2.37
+
(
3H, s), 2.64-2.77 (4H, m), 3.54 (2H, s). MS (FAB) m/z 199 (M + H) . Anal. Calcd for
C H N O LiS·1.6H O: C, 41.24; H, 5.28; N, 12.02. Found: C, 41.44; H, 4.89; N, 11.72.
8
9
2
2
2
Lithium 5-tert-Butoxycarbonyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate (3)

To a stirred solution of 19 (1.28 g, 4.00 mmol) in dry Et
hexanes; 2.67 mL, 4.00 mmol) at -78 °C under an argon atmosphere. The reaction mixture was stirred
for 20 min at -78 °C. After the bubbling of CO gas for 5 min, the reaction was warmed up to rt and
2
O (150 ml) was added n-BuLi (1.50 M in
2
concentrated in vacuo. Collection of the residue and washing with AcOEt gave 3 (762 mg, 66%) as a pale
1
yellow amorphous solid: H NMR (400 MHz, DMSO-d
6
) δ 1.42 (9H, s), 2.71 (2H, br s), 3.60-3.66 (2H,
+
m), 4.55 (2H, s). MS (FD) m/z 285 (M + H) . Anal. Calcd for C12
H
15
N O
2 4
2
LiS·0.8H O: C, 47.31; H, 5.49;
N, 9.19. Found: C, 47.31; H, 5.18; N, 8.88.
ACKNOWLEDGEMENTS
The authors are grateful to the analytical group of research technology center in Daiichi Pharmaceutical
Co. Ltd. for characterizing the compounds reported here.
REFERENCES
1.
2.
3.
N. Haginoya, S. Kobayashi, S. Komoriya, Y. Hirokawa, T. Furugori, and T. Nagahara, Bioorg. Med.
Chem. Lett., 2004, in press.
N. Haginoya, S. Kobayashi, S. Komoriya, T. Yoshino, M. Suzuki, T. Shimada, K. Watanabe, Y.
Hirokawa, T. Furugori, and T. Nagahara, submitted for publication.
Y. Nagao, T. Hirata, S. Goto, S. Sano, A. Kakei, K. Iizuka, and M. Shiro, J. Am. Chem. Soc., 1998,
1
20, 3104.
4
.
.
P. A. Wonder and A. W. White, Tetrahedron, 1983, 39, 3767.
5
(a) T. Takahashi, K. Ueda, and T. Ichimoto, Pharm. Bull., 1954, 2, 196. (b) T. Takahashi and K.
Ueda, Pharm. Bull., 1956, 4, 216. (c) A. S. Katner and R. F. Brown, J. Heterocycl. Chem., 1990, 27,
5
63.
6.
7.
8.
9.
T. A. Kelly and D. W. McNeil, Tetrahedron Lett., 1994, 35, 9003.
J. A. Turner, J. Org. Chem., 1983, 48, 3401.
A. P. Kozikowski and W. Tückmantel, Helv. Chim. Acta, 1994, 77, 1256.
M. P. Doyle, B. Siegfried, and J. F. Dellaria, Jr., J. Org. Chem., 1977, 42, 2426.