Facile synthesis of 2-alkylthio-5,6,7,8-tetrahydrobenzothieno[2,3-d]- Pyrimidin-4(3H)-ones

Article abstract of DOI:10.1080/00397910903097294

Isothiocyanate 2, obtained from aza-Wittig reaction of iminophosphorane 1 with CS2, reacted with amine to give 2-thioxo-2,3,5,6,7,8- hexahydrobenzothieno[2,3-d]pyrimidin-4(1H)-ones 4 in the presence of sodium ethoxide. S-Alkylation of 4 produced 2-alkylth

Full text of DOI:10.1080/00397910903097294

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Facile Synthesis of 2-Alkylthio-5,6,7,8-
tetrahydrobenzothieno[2,3-
d]pyrimidin-4(3H)-ones
Xiao-Hua Zeng a b , Min Liu a , Ming-Wu Ding a & Hong-Wu He a
a Key Laboratory of Pesticide and Chemical Biology of Ministry of
Education, Central China Normal University, Wuhan, China
b Department of Medicinal Chemistry, Yunyang Medical College,
Shiyan, China
Published online: 23 Apr 2010.
To cite this article: Xiao-Hua Zeng , Min Liu , Ming-Wu Ding & Hong-Wu He (2010): Facile Synthesis of
2-Alkylthio-5,6,7,8-tetrahydrobenzothieno[2,3-d]pyrimidin-4(3H)-ones, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 40:10, 1453-1460
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Synthetic Communications1, 40: 1453–1460, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903097294
FACILE SYNTHESIS OF 2-ALKYLTHIO-5,6,7,8-
TETRAHYDROBENZOTHIENO[2,3-d]-
PYRIMIDIN-4(3H)-ONES
Xiao-Hua Zeng,1,2 Min Liu,1 Ming-Wu Ding,1 and
Hong-Wu He1
1Key Laboratory of Pesticide and Chemical Biology of Ministry of
Education, Central China Normal University, Wuhan, China
2Department of Medicinal Chemistry, Yunyang Medical College,
Shiyan, China
Isothiocyanate 2, obtained from aza-Wittig reaction of iminophosphorane 1 with CS2, reacted
with amine to give 2-thioxo-2,3,5,6,7,8-hexahydrobenzothieno[2,3-d]pyrimidin-4(1H)-ones
4 in the presence of sodium ethoxide. S-Alkylation of 4 produced 2-alkylthio-5,6,7,8-
tetrahydrobenzothieno[2,3-d]pyrimidin-4(3H)-ones 5 in good yields.
Keywords: Aza-Wittig reaction; carbon disulfide; iminophosphorane; isothiocyanate; thieno[2,3-d]-
pyrimidin-4(3H)-one
Thienopyrimidines, which are well-known bioisosteres of quinazolines, are of great
importance because of their remarkable biological properties. They show significant
antifungal, antibacterial, antimalarial, and antiallergic activities.[1–5] Also 2-alkylthio-
substituted thienopyrimidinones show significant angiotensin II receptor blocker or
5-HT1A receptor activities.[6,7] 2-Alkylthio-substituted thienopyrimidinones are gen-
erally synthesized from corresponding isothiocyanates (Scheme 1); however, the
highly toxic thiophosgene was used to transfer 2-amino-thiophene-3-carboxylates
into isothiocyanates in the synthetic route.[8–11]
The aza-Wittig reactions of functionalized iminophosphoranes with isocyanates
or carbon disulfide were applied to produce carbodiimides or isothiocyanate able to
undergo a plethora of heterocyclization reactions.[12–14] Recently, we have become
interested in the preparation of N-heteroaryliminophosphoranes because these spe-
cies are promising building blocks for the synthesis of nitrogen heterocycles.[15–20]
As a continuation of our research for new biologically active heterocycles, we herein
report a facile synthesis of 2-alkylthio-5,6,7,8-tetrahydrobenzothieno[2,3-d]pyrimi-
din-4(3H)-ones without using the highly toxic thiophosgene.
Received April 1, 2009.
Address correspondence to Ming-Wu Ding or Hong-Wu He, Key Laboratory of Pesticide and
Chemical Biology of Ministry of Education, Central China Normal University, Wuhan, 430079,
P. R. China. E-mail: mwding@mail.ccnu.edu.cn
1453

1454
X.-H. ZENG ET AL.
Scheme 1. Literature preparative route of 2-alkylthiothienopyrimidinones.
The tetrahydrobenzo[b]thiophene, easily obtained by the Gewald method from
cyclohexanone, ethyl cyanoacetate, and sulfur, was converted to iminophosphorane
1 via reaction with triphenylphosphine, hexachloroethane, and triethylamine
(Scheme 2).[21]
The iminophosphorane 1 reacted with excess carbon disulfide to give isothio-
cyanate 2. However, the reaction was very slow at room temperature as determined
by thin-layer chromatography (TLC). Good results were obtained when the reaction
mixture was refluxed in a mixed solvent CH2Cl2=CH3CN (1:1) for 24 h under dry N2
protection. Addition of the primary amines to the reaction mixture gave the thiourea
intermediates 3, which were further treated with sodium ethoxide to provide 2-
thioxo-2,3,5,6,7,8-hexahydrobenzothieno[2,3-d]pyrimidin-4(1H)-ones 4 in 60–68%
yields (Table 1). S-Alkylation of 4 with alkyl halides in the presence of potassium
Scheme 2. Preparation of iminophosphorane 1.
Table 1. Preparation of compounds 4 and 5
No.
R1
R2X
Conditions
Yield (%)
4a
4b
4c
5a
5b
5c
5d
5e
5f
Pr
rt, 2 h
60
65
68
75
65
78
67
92
80
78
74
73
85
83
90
79
93
78
2-NH2C6H4
4-ClC6H4
Pr
40 ꢀC, 6 h
50 ꢀC, 6 h
rt, 2 h
MeI
PrBr
Pr
Pr
40 ꢀC, 2 h
50 ꢀC, 2 h
50 ꢀC, 2 h
50 ꢀC, 2 h
rt, 1 h
40 ꢀC, 1 h
40 ꢀC, 1 h
50 ꢀC, 1 h
rt, 1 h
40 ꢀC, 1 h
40 ꢀC, 1 h
50 ꢀC, 1 h
50 ꢀC, 1 h
50 ꢀC, 1 h
BuBr
Pr
Pr
ClCH2CN
ClCH2COOEt
MeI
2-NH2C6H4
2-NH2C6H4
2-NH2C6H4
2-NH2C6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
5g
5h
5i
EtBr
PrBr
BuBr
MeI
5j
5k
5l
EtBr
PrBr
5m
5n
5o
BuBr
PhCH2Cl
ClCH2COOEt

2-ALKYLTHIO THIENO[2,3-d]PYRIMIDIN-4(3H)-ONES
1455
Scheme 3. Preparation of 2-alkylthiothienopyrimidinones.
carbonate provided 2-alkylthio-5,6,7,8-tetrahydrobenzothieno[2,3-d]pyrimidin-
4(3H)-ones 5 in 65–93% yields. With an alkylation reagent such as R2I, the alky-
lation could be carried out at room temperature. With other alkylation reagents,
the alkylation had to be carried out at 40–50 ꢀC (Scheme 3).
The structure of the synthesized compound 5 was confirmed by spectral data
1
and elemental analyses. For example, the H NMR spectral data of 5a show the
signals of –NCH2 at 4.02 ppm as triplets, signals of SCH3 at 2.60 ppm as singlets,
and the signals of CH2CH3 at 1.81–1.74 ppm and 0.99 ppm as multiplets and triplets
respectively. The cyclohexnyl ring’s signals appeared at 2.99–2.71 ppm and
1.88–1.82 ppm as multiplets. The MS spectrum of 5a shows a molecule ion peak
(Mþ) at m=z 294 with 100% abundance.
In conclusion, we have developed a facile synthesis of 2-alkylthio-5,6,7,8-tetra-
hydrobenzothieno[2,3-d]pyrimidin-4(3H)-ones starting from easily accessible materi-
als without using the highly toxic thiophosgene.
EXPERIMENTAL
Melting points were determined using an X-4 model apparatus and are uncor-
rected. Mass spectra (MS) were measured on a Finnigan Trace MS spectrometer. 1H
NMR spectra were recorded in CDCl3 on a Varian Mercury 400 spectrometer, and
resonances are given in ppm (d) relative to tetramethylsilane (TMS). Elemental
analyses were performed on a Vario EL III elementary analysis instrument.
Preparation of 2-Thioxo-2,3,5,6,7,8-hexahydrobenzothieno-
[2,3-d]pyrimidin-4(1H)-one 4
Excess carbon disulfide (15 mL) was added to a solution of iminophosphorane
1 (9.70 g, 20 mmol) in anhydrous methylene chloride and acetonitrile (20 mL, v=v ¼
1:1). After the reaction mixture was refluxed for 24 h under dry N2 protection, the
solvent was condensed under reduced pressure, and ether (10 mL) was added to pre-
cipitate triphenylphosphine sulfide. The precipitate was removed by filtration, and
the filtrate was evaporated to give isothiocyanate 2, which was used directly without
further purification. Amine (20 mmol) was added to a solution of the crude 2 in

1456
X.-H. ZENG ET AL.
CH3CN (20 mL), and the mixture was stirred for 0.5–1 h at room temperature. After
a catalytic amount of sodium ethoxide was added, the reaction mixture was stirred
for 2–6 h at room temperature to 50 ꢀC. The precipitated solid was collected, washed
with ethanol, and recrystallized from methylene chloride=petroleum ether to give
2-thioxo-2,3,5,6,7,8-hexahydrobenzothieno[2,3-d]pyrimidin-4(1H)-ones 4.
1
Previously unreported 4b. White solid, mp 250–252 ꢀC, H NMR (CDCl3,
400 MHz) d 8.6 (s, 1H, NH), 7.32–6.84 (m, 4H, Ar-H), 3.05 (br, 2H, NH2),
2.94–2.65 (m, 4H, 2CH2), 1.85–1.77 (m, 4H, 2CH2); MS m=z (%), 329 (Mþ, 24),
315 (4), 267 (6), 174 (14), 149 (100), 132 (45), 117 (72). Elemental anal. calcd. for
C16H15N3OS2: C, 58.33; H, 4.59; N, 12.76. Found: C, 58.54; H, 4.63; N, 12.59.
Preparation of 2-Alkylthio-5,6,7,8-tetrahydrobenzothieno-
[2,3-d]pyrimidin-4(3H)-ones 5
Alkyl halide (1 mmol) and solid potassium carbonate (0.28 g, 2 mmol) were
added to a solution of 2-thioxo-2,3,5,6,7,8-hexahydrobenzothieno[2,3-d]pyrimidin-
4(1H)-one 4 (1 mmol) in dry CH3CN (5 mL). The mixture was stirred for 1–2 h at
room temperature or 40–50 ꢀC and filtered. The filtrates was condensed, and the
residue was recrystallized from methylene chloride=petroleum ether to give
2-alkylthio-5,6,7,8-tetrahydrobenzothieno[2,3-d]pyrimidin-4(3H)-ones 5a–5o.
2-Methylthio-3-propyl-5,6,7,8-tetrahydrobenzothieno[2,3-d]pyrimidin-
1
4(3H)-one (5a). White solid, mp 121–123 ꢀC. H NMR (CDCl3, 400 MHz): d 4.02
(t, J ¼ 7.8 Hz, 2H, NCH2), 2.99–2.71 (m, 4H, 2CH2), 2.60 (s, 3H, SCH3),
1.88–1.82 (m, 4H, 2CH2), 1.81–1.74 (m, 2H, CH2), 0.99 (t, J ¼ 7.2 Hz, 3H, CH3).
MS (m=z, %): 294 (Mþ, 100), 279 (51), 252 (90), 224 (37), 205 (22), 179 (11), 133
(13). Elemental anal. calcd. for C14H18N2OS2: C, 57.11; H, 6.16; N, 9.51. Found:
C, 57.34; H, 6.31; N, 9.59.
3-Propyl-2-propylthio-5,6,7,8-tetrahydrobenzothieno[2,3-d]pyrimidin-
1
4(3H)-one (5b). White solid, mp 78–79 ꢀC. H NMR (CDCl3, 400 MHz): d 4.03 (t,
J ¼ 7.8 Hz, 2H, NCH2), 3.20 (t, J ¼ 7.2 Hz, 2H, SCH2), 2.97–2.74 (m, 4H, 2CH2),
1.86–1.74 (m, 8H, 4CH2), 1.06 (t, J ¼ 7.2 Hz, 3H, CH3), 1.00 (t, J ¼ 7.2 Hz, 3H,
CH3). MS (m=z, %): 322 (Mþ, 100), 280 (46), 239 (7). Elemental anal. calcd. for
C16H22N2OS2: C, 59.59; H, 6.88; N, 8.69. Found: C, 59.44; H, 6.64; N, 8.86.
2-Butylthio-3-propyl-5,6,7,8-tetrahydrobenzothieno[2,3-d]pyrimidin-
1
4(3H)-one (5c). White solid, mp 68–70 ꢀC. H NMR (CDCl3, 400 MHz): d 4.03 (t,
J ¼ 7.6 Hz, 2H, NCH2), 3.22 (t, J ¼ 7.2 Hz, 2H, SCH2), 2.99–2.72 (m, 4H, 2CH2),
1.87–1.48 (m, 10H, 5CH2), 1.02–0.95 (m, 6H, 2CH3). MS (m=z, %): 336 (Mþ,
100), 279 (49), 238 (79), 178 (53), 150 (12). Elemental anal. calcd. for C17H24N2OS2:
C, 60.68; H, 7.19; N, 8.32. Found: C, 60.72; H, 7.32; N, 8.26.
2-(Cyanomethylene)thio-3-propyl-5,6,7,8-tetrahydrobenzothieno[2,3-
d]pyrimidin-4(3H)-one (5d). White solid, mp 189–190 ꢀC. 1H NMR (CDCl3,
400 MHz): d 4.05 (s, 2H, SCH2), 3.98 (t, J ¼ 7.6 Hz, 2H, NCH2), 2.99–2.74 (m, 4H,
2CH2), 1.89–1.77 (m, 6H, 3CH2), 1.01 (t, J ¼ 7.2 Hz, 3H, CH3). MS (m=z, %): 319

2-ALKYLTHIO THIENO[2,3-d]PYRIMIDIN-4(3H)-ONES
1457
(Mþ, 100), 280 (77), 244 (22), 223 (13). Elemental anal. calcd. for C15H17N3OS2: C,
56.40; H, 5.36; N, 13.15. Found: C, 56.12; H, 5.48; N, 13.26.
2-(Ethoxycarbonylmethylene)thio-3-propyl-5,6,7,8-tetrahydrobenzothieno-
1
[2,3-d]pyrimidin-4(3H)-one (5e). White solid, mp 94–95 ꢀC. H NMR (CDCl3,
400 MHz): d 4.23 (q, J ¼ 7.2 Hz, 2H, OCH2), 4.04 (t, J ¼ 7.6 Hz, 2H, NCH2), 3.96
(s, 2H, SCH2), 2.99–2.74 (m, 4H, 2CH2), 1.85–1.79 (m, 6H, 3CH2), 1.31 (t,
J ¼ 7.2 Hz, 3H, CH3), 1.01 (t, J ¼ 7.2 Hz, 3H, CH3). MS (m=z, %): 366 (Mþ, 100),
321 (14), 279 (59), 42 (11). Elemental anal. calcd. for C17H22N2O3S2: C, 55.71; H,
6.05; N, 7.64. Found: C, 55.53; H, 6.21; N, 7.56.
3-(2-Aminophenyl)-2-methylthio-5,6,7,8-tetrahydrobenzothieno[2,3-d]-
pyrimidin-4(3H)-one (5f). White solid, mp 234–235 ꢀC. 1H NMR (CDCl3,
400 MHz): d 7.33–6.89 (m, 4H, Ar-H), 3.34 (br, 2H, NH2), 2.96–2.75 (m, 4H,
2CH2), 2.48 (s, 3H, SCH3), 1.91–1.80 (m, 4H, 2CH2). MS (m=z, %): 343 (Mþ,
100), 326 (18), 295 (65), 267 (27), 254 (7), 117 (6). Elemental anal. calcd. for
C17H17N3OS2: C, 59.45; H, 4.99; N, 12.23. Found: C, 59.68; H, 4.92; N, 12.35.
3-(2-Aminophenyl)-2-ethylthio-5,6,7,8-tetrahydrobenzothieno[2,3-d]-
pyrimidin-4(3H)-one (5g). White solid, mp 159–160 ꢀC. 1H NMR (CDCl3,
400 MHz): d 7.30–6.87 (m, 4H, Ar-H), 3.22 (br, 2H, NH2), 3.11–3.08 (m, 2H,
SCH2), 2.97–2.75 (m, 4H, 2CH2), 1.89–1.80 (m, 4H, 2CH2), 1.31 (t, J ¼ 7.2 Hz,
3H, CH3). MS (m=z, %): 357 (Mþ, 100), 341 (32), 295 (98), 267 (77), 254 (21), 118
(18). Elemental anal. calcd. for C18H19N3OS2: C, 60.47; H, 5.36; N, 11.75. Found:
C, 60.59; H, 5.16; N, 11.84.
3-(2-Aminophenyl)-2-propylthio-5,6,7,8-tetrahydrobenzothieno[2,3-d]-
pyrimidin-4(3H)-one (5h). White solid, mp 175–176 ꢀC. 1H NMR (CDCl3,
400 MHz): d 7.33–6.88 (m, 4H, Ar-H), 3.20 (br, 2H, NH2), 3.12–3.02 (m, 2H,
SCH2), 2.95–2.76 (m, 4H, 2CH2), 1.89–1.80 (m, 4H, 2CH2), 1.71–1.66 (m, 2H,
CH2), 0.99 (t, J ¼ 7.2 Hz, 3H, CH3). MS (m=z, %): 371 (Mþ, 100), 354 (13), 296
(97), 267 (46), 90 (19). Elemental anal. calcd. for C19H21N3OS2: C, 61.42; H, 5.70;
N, 11.31. Found: C, 61.59; H, 5.76; N, 11.24.
3-(2-Aminophenyl)-2-butylthio-5,6,7,8-tetrahydrobenzothieno[2,3-d]-
pyrimidin-4(3H)-one (5i). White solid, mp 159–160 ꢀC. 1H NMR (CDCl3,
400 MHz): d 7.33–6.88 (m, 4H, Ar-H), 3.20 (br, 2H, NH2), 3.12–3.02 (m, 2H,
SCH2), 2.95–2.76 (m, 4H, 2CH2), 1.89–1.80 (m, 4H, 2CH2), 1.65–1.40 (m, 4H,
2CH2), 0.91 (t, J ¼ 7.2 Hz, 3H, CH3). MS (m=z, %): 385 (Mþ, 100), 368 (11), 312
(22), 295 (85), 267 (27), 222 (20). Elemental anal. calcd. for C20H23N3OS2: C,
62.30; H, 6.01; N, 10.90. Found: C, 62.53; H, 5.83; N, 10.96.
3-(4-Chlorophenyl)-2-methylthio-5,6,7,8-tetrahydrobenzothieno[2,3-d]-
pyrimidin-4(3H)-one (5j). White solid, mp > 300 ꢀC. 1H NMR (CDCl3, 400 MHz):
d 7.52–7.21 (m, 4H, Ar-H), 2.94–2.77 (m, 4H, 2CH2), 2.49 (s, 3H, SCH3), 1.89–1.80
(m, 4H, 2CH2). MS (m=z, %): 362 (Mþ, 100), 329 (21), 314 (31), 277 (93), 234 (12), 76
(13). Elemental anal. calcd. for C17H15ClN2OS2: C, 56.26; H, 4.17; N, 7.72. Found:
C, 56.38; H, 4.24; N, 7.43.

1458
X.-H. ZENG ET AL.
3-(4-Chlorophenyl)-2-ethylthio-5,6,7,8-tetrahydrobenzothieno[2,3-d]-
pyrimidin-4(3H)-one (5k). White solid, mp 211–212 ꢀC. 1H NMR (CDCl3,
400 MHz): d 7.51–7.20 (m, 4H, Ar-H), 3.11 (q, J ¼ 7.2 Hz, 2H, SCH2), 2.94–2.75
(m, 4H, 2CH2), 1.89–1.80 (m, 4H, 2CH2), 1.31 (t, J ¼ 7.2 Hz, 3H, CH3). MS (m=z,
%): 376 (Mþ, 100), 347 (32), 295 (98), 267 (77), 254 (21), 149 (11), 90 (19). Elemental
anal. calcd. for C18H17ClN2OS2: C, 57.36; H, 4.55; N, 7.43. Found: C, 57.23; H, 4.66;
N, 7.49.
3-(4-Chlorophenyl)-2-propylthio-5,6,7,8-tetrahydrobenzothieno[2,3-d]-
pyrimidin-4(3H)-one (5l). White solid, mp 204–205 ꢀC. 1H NMR (CDCl3,
400 MHz): d 7.51–7.20 (m, 4H, Ar-H), 3.09 (t, J ¼ 7.2 Hz, 2H, SCH2), 2.93–2.76
(m, 4H, 2CH2), 1.88–1.82 (m, 4H, 2CH2), 1.71–1.65 (m, 2H, CH2), 0.99 (t,
J ¼ 7.2 Hz, 3H, CH3). MS (m=z, %): 390 (Mþ, 100), 357 (32), 315 (19), 42 (19).
Elemental anal. calcd. for C19H19ClN2OS2: C, 58.37; H, 4.90; N, 7.17. Found: C,
58.13; H, 4.96; N, 7.24.
3-(4-Chlorophenyl)-2-butylthio-5,6,7,8-tetrahydrobenzothieno[2,3-d]-
pyrimidin-4(3H)-one (5m). White solid, mp 180–181 ꢀC. 1H NMR (CDCl3,
400 MHz): d 7.51–7.20 (m, 4H, Ar-H), 3.11 (t, J ¼ 7.2 Hz, 2H, SCH2), 2.94–2.75
(m, 4H, 2CH2), 1.89–1.80 (m, 4H, 2CH2), 1.64–1.37 (m, 4H, 2CH2), 0.92 (t,
J ¼ 7.2 Hz, 3H, CH3). MS (m=z, %): 404 (Mþ, 100), 348 (45), 315 (15), 56 (12).
Elemental anal. calcd. for C20H21ClN2OS2: C, 59.32; H, 5.23; N, 6.92. Found: C,
59.23; H, 5.26; N, 6.74.
3-(4-Chlorophenyl)-2-(phenylmethylene)thio-5,6,7,8-tetrahydroben-
zothieno[2,3-d]pyrimidin-4(3H)-one (5n). White solid, mp 201–202 ꢀC. 1H
NMR (CDCl3, 400 MHz): d 7.47–7.19 (m, 9H, Ar-H), 4.35 (s, 2H, SCH2),
2.94–2.76 (m, 4H, 2CH2), 1.89–1.80 (m, 4H, 2CH2). MS (m=z, %): 438 (Mþ, 100),
405 (52), 329 (11), 315 (19), 284 (29), 91 (27). Elemental anal. calcd. for
C22H17ClN2OS2: C, 62.93; H, 4.36; N, 6.38. Found: C, 62.77; H, 4.11; N, 6.42.
3-(4-Chlorophenyl)-2-(ethoxycarbonylmethylene)thio-5,6,7,8-tetrahy-
drobenzothieno[2,3-d]pyrimidin-4(3H)-one (5o). White solid, mp 211–213 ꢀC.
1H NMR (CDCl3, 400 MHz): d 7.53–7.25 (m, 4H, Ar-H), 4.21 (q, J ¼ 7.2 Hz, 2H,
OCH2), 3.85 (s, 2H, SCH2), 2.93–2.74 (m, 4H, 2CH2), 1.88–1.79 (m, 4H, 2CH2),
1.30 (t, J ¼ 7.2 Hz, 3H, CH3). MS (m=z, %): 434 (Mþ, 100), 388 (16), 361(31), 315
(16), 108 (72). Elemental anal. calcd. for C20H19ClN2O3S2: C, 55.23; H, 4.40; N,
6.44. Found: C, 55.37; H, 4.32; N, 6.32.
ACKNOWLEDGMENTS
We gratefully acknowledge financial support of this work by the National
Natural Science Foundation of China (Project No. 20772041), the Key Project of
Chinese Ministry of Education (No. 107082), and the Educational Commission of
Hubei Province of China (No. B20092412).

2-ALKYLTHIO THIENO[2,3-d]PYRIMIDIN-4(3H)-ONES
1459
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