Synthesis of 2,3-disubstituted derivatives of pyrano-, thiopyrano-, and benzoannelated pyrido[2,3-b]thieno[3,2-d]pyrimidines

Article abstract of DOI:10.1007/s10593-008-0145-y

A new methods have been developed for the synthesis of condensed pyrido[2,3-b]thieno[3,2-d]pyrimidines based on cyclic derivatives of 4-cyanopyridine-3-thiones. The presence of two different reactive functional groups NH₂ and CONH gives the possibility of carrying out different conversions of thieno[2,3-b]pyridines.

Full text of DOI:10.1007/s10593-008-0145-y

Chemistry of Heterocyclic Compounds, Vol. 44, No. 8, 2008
SYNTHESIS OF 2,3-DISUBSTITUTED
DERIVATIVES OF PYRANO-, THIO-
PYRANO-, AND BENZOANNELATED
PYRIDO[2,3-b]THIENO-
[3,2-d]PYRIMIDINES
E. G. Paronikian, Sh. F. Akopian, and A. S. Noravian
A new methods have been developed for the synthesis of condensed pyrido[2,3-b]thieno[3,2-d]pyrimi-
dines based on cyclic derivatives of 4-cyanopyridine-3-thiones. The presence of two different reactive
functional groups NH2 and CONH gives the possibility of carrying out different conversions of
thieno[2,3-b]pyridines.
Keywords: N-alkyl-4-oxothieno[3,2-d]pyrimidine-2-thiones, pyrano(thiopyrano)(4',3':4,5]pyrido[2,3-b]-
thieno[3,2-d]pyrimidines, pyridothieno[3,2-d]pyrimidines, pyrimido[5',4':2,3]thieno[2,3-c]isoquino-
lines, 4-cyanopyridin-3-thiones.
Pyridothieno[3,2-d]pyrimidines are one of the interesting classes of heterocycles. Many of them are of
interest as biologically active compounds [1-3]. In the present paper we describe methods for the synthesis of
new tetracyclic heterocyclic systems – pyrano(thiopyrano)[4',3':4,5]-pyrido[2,3-b]thieno[3,2-d]pyrimidines and
pyrimido[5',4':2,3]thieno[2,3-c]isoquinolines.
4-Cyanopyridine-3-thiones 1a-e, condensed with cyclohexane or tetrahydropyrane (thiopyrane) ring [4],
were used as starting materials to obtain the 2,3-substituted derivatives. Reaction of compounds 1 with
chloroacetamides in basic media gave the corresponding 1-amino-2-carbamoylpyrano[4,3-d]thieno[2,3-b]pyri-
dines and -thieno[2,3-b]isoquinolines 3a-h. In some cases we isolated intermediate compounds – condensed
3-aminoacylthio(N-alkylaminoacyl)-4-cyanopyridines 2a-d (Table 1). The structures of products 3 were
1
confirmed by IR and H NMR spectra (Table 2). For examples, in the IR spectra of compounds there are
absorption bands of the nitrile groups in the 2220 cm-1 region. After closure of the thiophene ring and formation
of products 3 this band disappears and some absorption bands appear in the 3160-3420 cm-1 region,
characteristic of NH2 and NH groups.
The presence of NH2 and CONH groups permitted further reactions of compounds 3. For example,
condensation with tri-methyl esters of orthoacids gave the corresponding thieno[3,2-d]pyrimidin-4-(3H)ones
4a-i, and treatment with hydrogen sulfide gave N-alkyl-4-oxothieno[3,2-d]pyrimidine-2-thiones 5a-d. The
corresponding S-substituted derivatives 6a-f were obtained by alkylation of compounds 5 with alkyl halides.
__________________________________________________________________________________________
A. L. Mndzhoyan Institute of Fine Organic Chemistry, National Academy of Sciences, Republic of
Armenia, Erevan 375091; e-mail: shogikakopyan@rambler.ru. Translated from Khimiya Geterotsiklicheskikh
Soedinenii, No. 8, 1245-1252, August, 2008. Original article submitted June 7, 2007. Revised version submitted
October 2, 2007.
0009-3122/08/4408-1003©2008 Springer Science+Business Media, Inc.
1003

CN
R2
R1
CN
R2
R1
SCH2CONHR3
ClCH2CONHR 3
S
R
R
X
N
X
NH
2a–d
1a–e
R1
R
R1
R
X
X
N
O
R4
R3
NH2
CONHR3
R4C(OEt)3
N
R2
N
S
R2
N
S
4a–i
3a–h
CS2
R
R1
R
R1
X
5 Hal
N
SR5
R3
X
R
H
N
S
N
R2
N
S
N
R2
R3
N
S
O
6a–f
O
5a–d
1 a X = O, R = R1 = Me; b X = O, R = R1 = Me; c X = CH2, R = R1 = H; d X = O, R = H,
R1 = i-Pr; e X = S, R = R1 = Me; a, c–e R2 = morpholino, b R2 = pyrrolidino; 2, 3 a X = O,
R = R1 = Me, R3 = H; b X = O, R = R1 = Me, R3 = Ph; c X = CH2, R = R1 = Me, R3 = Ph;
d X = CH2, R = R1 = R3 = H; 3 e X = CH2, R = R1 = H, R3 = o-MeOC6H4; f X = O, R = H,
R1 = i-Pr, R3 = 2,4-(MeO)2C6H3; g X = S, R = R1 = Me, R3 = H; h X = S, R = R1 = Me,
R3 = o-ClC6H4; 2 a,d, 3 a,d–h R2 = morpholino, 2, 3 b, c R2 = pyrrolidino; 4 a–d X = O,
R = R1 = Me; a R3 = R4 = H; b R3 = H, R4 = Me; c R3 = Ph, R4 = H; d R3 = Ph, R4 = H;
e X = O, R = H, R1 = i-Pr, R3 = 2,4-(MeO)2C6H3, R4 = H; f X = S, R = R1 = Me, R3 = R4 = H;
g X = S, R = R1 = Me, R3 = o-ClC6H4, R4 = H; h X = CH2, R = R1 = R3 = R4 = H; i X = CH2,
R = R1 = R3 = H, R4 = Me; a–c, e–i R2 = morpholino, b R2 = pyrrolidino; 5 a X = O,
R = R1 = Me, R3 = H; b X = O, R = R1 = Me, R3 = Ph; c X = O, R = H, R1 = i-Pr, R3 = H;
d X = CH2, R = R1 = R3 = H; a–d R2 = morpholino; 6 a–d X = O, a R = R1 = R5 = Me,
R3 = H; b R = R1 = Me, R3 = Ph, R5 = Et; c R = R1 = Me, R3 = H, R5 = Et; d R = H,
R1 = i-Pr, R3 = H, R5 = Et; e, f X = CH2, R = R1 = R3 = H, f R5 = Me;
f R5 = Et; a–f R2 = morpholino
EXPERIMENTAL
1
IR spectra of nujol mulls were recorded with a UR-20 spectrometer. H NMR spectra of DMSO-d6
solutions with TMS as internal standard were recorded on a Mercury 300 (300 MHz) instrument. Mass spectra
were recorded on an MX-1320 instrument with direct insertion into the ion source. Purity of compounds was
monitored by TLC on Silufol UV-254 plates.
1004

Table 1. Physicochemical Characteristics of Compounds 2-6
Found, %
Calculated, %
——————
Com-
pound
Empirical
formula
mp,°C
Yield, %
C
3
H
4
N
5
S
6
1
2
7
8
2a
C17H22N4O3S
56.47
56.33
6.31
6.11
15.22
15.46
8.78
8.84
226-229
74
2b
2c
2d
3a
3b
3c
3d
3e
3f
C23H26N4O3S
C23H26N4O2S
C16H20N4O2S
C17H22N4O3S
C23H26N4O3S
C23H26N4O2S
C16H20N4O2S
C23H26N4O3S
C26H32N4O5S
C17H22N4O2S2
C23H25ClN4O2S2
C18H20N4O3S
C19H22N4O3S
C24H24N4O3S
C24H24N4O2S
C27H30N4O5S
C18H20N4O2S2
C24H23ClN4O2S2
C17H18N4O2S
C18H20N4O2S
C18H20N4O3S2
C24H24N4O3S2
C19H22N4O3S2
C17H18N4O2S2
C19H22N4O3S2
C26H28N4O3S2
C20H24N4O3S2
C21H26N4O3S2
C18H20N4O2S2
C19H22N4O2S2
63.24
62.99
65.54
65.37
57.78
57.81
56.52
56.33
63.27
62.99
65.58
65.37
57.68
57.81
63.17
62.99
60.84
60.92
53.71
53.94
56.67
56.48
58.22
58.05
59.27
59.05
64.14
64.26
66.85
66.64
62.25
62.05
55.84
55.65
57.54
57.76
59.84
59.63
60.79
60.65
53.64
53.45
59.84
59.98
54.64
54.53
54.67
54.52
54.65
54.53
61.21
61.39
55.44
55.53
56.34
56.48
55.41
55.65
56.85
56.69
5.84
5.98
6.32
6.20
6.24
6.06
6.31
6.12
5.78
5.98
6.31
6.20
6.21
6.06
5.72
5.98
6.41
6.29
5.69
5.86
5.36
5.15
5.12
5.41
5.58
5.74
5.11
5.39
5.32
5.59
5.56
5.79
5.38
5.19
4.74
4.64
5.54
5.29
5.45
5.65
4.85
4.98
5.25
5.03
5.41
5.29
4.94
4.84
5.44
5.29
5.67
5.55
5.34
5.59
5.76
5.87
5.34
5.19
5.31
5.51
12.65
12.77
13.44
13.25
16.74
16.85
15.24
15.46
12.98
12.77
13.45
13.26
16.98
16.85
12.95
12.77
10.78
10.93
14.68
14.80
11.62
11.46
15.24
15.04
14.62
14.49
12.64
12.49
12.84
12.95
10.84
10.72
14.57
14.42
11.35
11.23
16.58
16.36
15.52
15.72
13.67
13.85
11.47
11.66
13.14
13.39
14.78
14.96
13.54
13.39
11.15
11.01
12.84
12.95
12.69
12.54
14.54
14.42
13.72
13.92
7.24
7.31
7.39
7.58
9.48
9.65
8.98
8.85
7.49
7.31
7.36
7.59
9.41
9.65
7.57
7.31
6.35
6.25
16.74
16.94
13.34
13.11
8.88
8.61
8.43
8.29
7.32
7.15
7.68
7.41
6.28
6.14
16.62
16.51
12.94
12.85
9.11
9.36
8.72
8.99
15.64
15.85
13.46
13.34
15.54
15.32
17.33
17.12
15.47
15.32
12.75
12.61
14.65
14.82
14.21
14.36
16.68
16.51
15.78
15.93
246-250
203-205
194-196
308-309
259-261
234-235
255-256
221-222
218-220
264-266
226-227
371-372
>360
77
73
64
80
79
83
80
60
67
64
80
75
64
87
88
98
98
97
73
65
80
85
98
85
88
94
42
83
86
58
3g
3h
4a
4b
4c
4d
4e
4f
205-208
210-213
257-260
>360
4g
4h
4i
210-212
>360
>360
5a
5b
5c
5d
6a
6b
6c
6d
6e
6f
>360
269-271
228-230
313-316
>360
233-235
324-326
283-286
>360
345-350
1005

Table 2. 1H NMR Spectra of Compounds 2-6
Com-
pound
Chemical shifts, δ, ppm (J, Hz)
1
2
2a
2b
1.30 (6H, s, 2CH3); 2.69 (2H, s, CH2); 3.33 (4H, m, N(CH2)2); 3.71 (4H, m, O(CH2)2);
3.76 (2H, s, SCH2); 4.47 (2H, s, OCH2); 6.90 (1H, br) and 7.16 (1H, br, NH2)
1.30 (6H, s, 2CH3); 2.70 (2H, s, CH2); 3.24 (4H, m, N(CH2)2); 3.59 (4H, m, O(CH2)2);
4.01 (2H, s, SCH2); 4.46 (2H, s, OCH2); 6.98 (1H, tt, 3J = 7.4, 4J = 1.2, HPh-4);
7.24 (2H, m, HPh-3,5); 7.57 (2H, m, HPh-2,6); 9.90 (1H, s, NH)
2c
1.28 (6H, s, 2CH3); 1.85 (4H, m, (CH2)2); 2.62 (2H, s, CH2); 3.62 (4H, m, N(CH2)2);
1
3.98 (2H, s, SCH2); 4.70 (2H, s, OCH2); 6.97 (1H, tt, J = 7.4, 2J = 1.2, HPh-4);
7.22 (2H, m, HPh-3,5); 7.56 (2H, m, HPh-2,6); 9.80 (1H, s, NH)
2d
1.70 (2H, m, CH2); 1.85 (2H, m, CH2); 2.51 (2H, t, J = 5.7, CH2);
2.82 (2H, t, J = 6.5, CH2); 3.31 (4H, m, N(CH2)2); 3.72 (4H, m, O(CH2)2);
3.76 (2H, s, SCH2); 6.87 (1H, br) and 7.10 (1H, br, NH2)
3a
3b
1.29 (6H, s, 2CH3); 3.08 (4H, m, N(CH2)2); 3.20 (2H, s, CH2); 3.73 (4H, m, O(CH2)2);
4.64 (2H, s, CH2); 6.81 (2H, s, NH2); 7.07 (2H, s, NH2)
1.33 (6H, s, 2CH3); 3.15 (4H, m) and 3.77 (4H, m, C4H8NO); 3.22 (2H, s, CH2);
4.65 (2H, s, OCH2); 6.81 (2H, s, NH2); 7.00 (1H, tt, 3J = 7.3, 4J = 1.2, HPh-4);
7.25 (2H, m, HPh-3,5); 7.69 (2H, m, HPh-2,6); 8.85 (1H, s, NH)
3c
1.34 (6H, s, 2CH3); 1.96 (4H, m, (CH2)2); 3.16 (2H, s, CH2); 3.56 (4H, m, N(CH2)2);
4.70 (2H, s, OCH2); 6.77 (2H, br, NH2); 6.97 (1H, tt, 3J = 7.3, 4J = 1.2, HPh-4);
7.23 (2H, m, HPh-3,5); 7.67 (2H, m, HPh-2,6); 8.62 (1H, s, NH)
3d
3e
1.71 (2H, m, CH2); 1.88 (2H, m, CH2); 2.65 (2H, m, CH2); 3.12 (2H, t, J = 6.5, CH2);
3.30 (4H, m, N(CH2)2); 3.74 (4H, m, O(CH2)2); 6.51 (2H, s, NH2); 6.63 (2H, s, NH2)
1.74 (2H, m, CH2); 1.91 (2H, m, CH2); 2.68 (2H, t, J = 5.9, CH2); 3.16 (4H, m, N(CH2)2);
3.33 (2H, t, J = 6.4, CH2); 3.76 (4H, m, O(CH2)2); 3.97 (3H, s, OCH3); 6.8 (2H, s, NH2);
6.86-7.00 (3H, m, HAr-3,4,5); 7.83 (1H, s, NH); 8.31 (2H, d. d, 3J = 7.8, 4J = 1.3, HAr-6)
3f
1.05 (6H, d, 3J = 6.7, CH3); 1.06 (3H, d, 3J = 6.7, CH3); 1.84 (1H, oct, 3J = 6.7, CH);
3.01-3.42 (7H, m, CH2, N(CH2)2 and OCH); 3.67-3.84 (4H, m, O(CH2)2);
3.79 (3H, s, OCH3); 3.93 (3H, s, OCH3); 4.59 (1H, d, 2J = 14.6)
and 4.76 (1H, d, 2J = 14.6, OCH2); 6.44 (1H, dd, 3J = 8.9, 4J = 2.7, HAr-5);
6.53 (1H, d, 4J = 2.7, HAr-3); 6.73 (2H, br, NH2); 7.70 (1H, s, NH);
8.08 (1H, d, 3J = 8.9, HAr-6)
3g
3h
1.35 (6H, s, 2CH3); 3.21 (4H, m, N(CH2)2); 3.55 (2H, s, CH2); 3.79 (4H, m, O(CH2)2);
3.81 (2H, s, CH2); 7.43 (2H, s, NH2); 7.21-7.41 (4H, m, C6H5); 8.26 (1H, s, NH)
1.42 (6H, s, 2CH3); 3.18 (4H, m) and 3.80 (4H, m, C4H8NO); 3.35 (2H, s, CH2);
3.79 (2H, s, SCH2); 6.97 (2H, s, NH2); 7.06 (1H, td, 3J = 7.7, 4J = 1.3)
and 7.28 (1H, td, 3J = 7.8, 4J = 1.3, HAr-4,5); 7.40 (1H, dd, 3J = 7.8, 4J = 1.3, HAr-3);
8.05 (1H, s, NH); 8.28 (1H, dd, 3J = 8.0, 4J = 1.3, HAr-6)
4a
4b
4c
4d
4e
1.35 (6H, s, 2CH3); 3.21 (4H, m) and 3.79 (4H, m, C4H8NO); 3.43 (2H, s, CH2);
4.68 (2H, s, OCH2); 8.06 (1H, s, N=CHN); 12.61 (1H, br, NH)
1.34 (6H, s, 2CH3); 2.48 (3H, m, CH3); 3.20 (4H, m, N(CH2)2); 3.43 (2H, s, CH2);
3.78 (4H, m, O(CH2)2); 4.67 (2H, s, ОCH2); 12.56 (1H, br, NH)
1.37 (6H, s, 2CH3); 3.26 (4H, m) and 3.81 (4H, m, C4H8NO); 3.44 (2H, s, CH2);
4.69 (2H, s, OCH2); 7.49-7.62 (5H, m, C6H5); 8.29 (1H, s, N=CHN)
1.36 (6H, s, 2CH3); 1.99 (4H, m, (CH2)2); 3.99 (2H, s, CH2); 3.66 (4H, m, N(CH2)2);
4.81 (2H, s, OCH2); 7.47-7.61 (5H, m, C6H5); 8.23 (1H, s, N=CH)
1.07 (6H, d, J =6.8, CH3); 1.86 (1H, oct, J = 6.8, CH); 3.11-3.21 (3H, m)
and 3.32 (2H, ddd, 2J = 12.9, 3J = 6.5, 3J = 3.0, N(CH2)2 and CH2);
3.46 (1H, ddd, 3J = 11.0, 3J = 6.8, 3J = 3.6, OCH); 3.67-3.88 (5H, m, O(CH2)2
and CH2); 3.84 (3H, s, OCH3); 3.89 (3H, s, OCH3); 4.68 (1H, d, 2J = 14.6 )
and 4.80 (1H, d, 2J = 14.6, OCH2); 6.64 (1H, dd, 3J = 8.7, 4J = 2.6, HAr-5);
6.71 (1H, d, 4J = 2.6, HAr-3); 7.26 (1H, d, 3J = 8.7, HAr-6); 8.05 (1H, s, N=CH)
4f
1.38 (6H, s, 2CH3); 3.24 (4H, m) and 3.81 (4H, m, C4H8NO); 3.75 (2H, s, CH2);
3.80 (2H, s, SCH2); 8.09 (1H, s, N=CHN); 12.65 (1H, br, NH)
4g
1.41 (3H, s, CH3); 1.45 (3H, s, CH3); 3.29 (4H, m) and 3.84 (4H, m, C4H8NO);
3.72 (2H, d, 2J = 15.8, CH2); 3.84 (1H, d, 2J = 15.8) and 3.84 (1H, d, 2J = 15.8, CH2);
3.84 (2H, s, SCH2); 7.52-7.70 (4H, m, C6H4); 8.18 (1H, s, N=CHN)
4h
1.77 (2H, m) and 1.92 (2H, m, (CH2)2); 2.72 (2H, t, J = 5.8, CH2); 3.23 (4H, m, N(CH2)2);
3.53 (2H, t, J = 6.5, CH2); 3.78 (4H, m, O(CH2)2); 8.03 (1H, s, N=CH); 12.56 (1H, br, NH)
1006

Table 2 (continued)
1
2
4i
1.77 (2H, m, CH2); 1.91 (2H, m, CH2); 2.45 (3H, s, CH3); 2.71 (2H, t, J = 5.7, CH2);
3.21 (4H, m, N(CH2)2); 3.53 (2H, t, J = 6.5, CH2); 3.78 (4H, m, O(CH2)2);
12.50 (1H, s, NH)
5a
5b
1.35 (6H, s, 2CH3); 3.24 (4H, m) and 3.77 (4H, m, C4H8NO); 3.37 (2H, s, CH2);
4.64 (2H, s, OCH2); 11.24 (1H, br, NH); 12.59 (1H, s, NH)
1.38 (6H, s, 2CH3); 3.28 (4H, m) and 3.78 (4H, m, C4H8NO); 3.42 (2H, s, CH2);
4.66 (2H, s, OCH2); 7.23 (2H, m, HPh-2,6); 7.43 (1H, m, HPh-4); 7.50 (2H, m, HPh-3,5);
11.65 (1H, br, NH)
5c
1.07 (3H, d, 3J = 6.7, CH3); 1.09 (3H, d, 3J = 6.7, CH3); 1.86 (1H, oct, 3J = 6.7, CH);
3.14 (1H, dd, 2J = 17.3, 3J = 10.5) and 3.63 (1H, dd, 2J = 17.3, 3J = 3.9, CH2);
3.71 (2H, ddd, 2J = 11.4, 3J = 6.5, 3J = 2.9) and 3.81 (2H, ddd, 2J = 11.4, 3J = 6.5,
3J = 2.9, N(CH2)2); 3.44 (1H, ddd, 3J = 10.5, 3J = 6.6, 3J = 3.9, OCH);
3.70 (2H, ddd, 2J = 11.4, 3J = 6.5, 3J = 2.9) and 3.81 (2H, ddd, 2J = 11.4, 3J = 6.3,
3J = 2.9, O(CH2)2); 4.63 (1H, d, 2J = 14.5) and 4.72 (1H, d, 2J = 14.5, OCH2);
11.20 (1H, br, NH); 12.59 (1H, s, NH)
5d
6a
6b
1.75 (2H, m, CH2); 1.95 (2H, m, CH2); 2.68 (2H, t, J = 5.9, CH2); 3.26 (4H, m, N(CH2)2);
3.45 (2H, t, J = 6.7, CH2); 3.76 (4H, m, O(CH2)2); 10.70 (1H, br, NH); 12.59 (1H, s, NH)
1.33 (6H, s, 2CH3); 2.61 (3H, s, SCH3); 3.21 (4H, m) and 3.78 (4H, m, C4H8NO);
3.45 (2H, s, CH2); 4.67 (2H, s, OCH2); 12.85 (1H, br, NH)
1.35 (6H, s, 2CH3); 1.41 (3H, t, 3J = 7.3, CH2CH3); 3.15 (2H, q, 3J = 7.3, SCH2);
3.26 (4H, m) and 3.80 (4H, m, C4H8NO); 3.48 (2H, s, CH2); 4.70 (2H, s, OCH2);
7.30-7.36 (2H, m) and 7.55-7.61 (3H, m, C6H5)
6c
1.33 (6H, s, 2CH3); 1.47 (3H, t, 3J = 7.2, CH3); 3.21 (2H, q, 3J = 7.2, SCH2); 3.22 (4H, m)
and 3.78 (4H, m, C4H8NO); 3.44 (2H, s, CH2); 4.67 (2H, s, OCH2); 12.80 (1H, br, NH)
6d
1.04 (3H, d, 3J = 6.7, CH3); 1.06 (3H, d, 3J = 6.7, CH3); 1.43 (3H, t,3J = 7.3, CH3);
1.83 (1H, oct, 3J = 6.7, CH); 3.22 (2H, m, SCH2); 3.07-3.33 (5H, m, N(CH2)2 and CH2);
3.43 (1H, ddd, 3J = 10.9, 3J = 6.7, 3J = 3.6, OCH); 3.63-3.86 (5H, m, O(CH2)2
and CH2); 4.65 (1H, d, 2J = 14.7) and 4.77 (1H, d, 2J = 14.7, OCH2); 12.79 (1H, br, NH)
6e
6f
1.75 (2H, m) and 1.91 (2H, m, (CH2)2); 2.62 (3H, s, SCH3); 2.71 (2H, t, J = 5.8, CH2);
3.22 (4H, m, N(CH2)2); 3.54 (2H, t, J = 6.5, CH2); 3.77 (4H, m, O(CH2)2);
12.84 (1H, br, NH)
1.45 (3H, t, J = 7.3, CH3); 1.77 (2H, m, CH2); 1.92 (2H, m, CH2);
2.71 (2H, t, J = 5.8, CH2); 3.21 (2H, q, J = 7.3, SCH2); 3.22 (4H, m, N(CH2)2);
3.54 (2H, t, J = 6.5, CH2); 3.78 (4H, m, O(CH2)2); 12.74 (1H, br, NH)
2-(5-Cyano-3,3-dimethy-8-morpholino-2,4-dihydro-1H-pyrano[3,4-c]pyridin-6-sulfanyl)acetamide
(2a). Chloroacetamide (0.3 g, 3.3 mmol) was added to a solution of compound 1a (1g, 3.3 mmol) in 20 ml of an
aqueous solution of Na2CO3 (0.35 g, 3.3 mmol). The reaction mixture was stirred for 1h at room temperature.
The crystalline precipitate was filtered off, washed with water, and dried. The product was recrystallized from
ethanol.
Compounds 2b-d were prepared analogously.
1-Amino-8,8-dimethyl-5-morpholino-8,9-dihydro-6H-pyrano[4,3-d]thieno[2,3-b]pyridine-2-carbox-
amide (3a). Compound 2a (3.62 g, 10 mmol) was added to a solution of sodium ethoxide, prepared from
sodium (0.23 g, 10 mmol) in absolute ethanol (50 ml). The reaction mixture was heated for 2 h at 60°C. Water
was added after cooling. The precipitated crystals were filtered off, washed with ethanol, dried, and
recrystallized from 1:1 ethanol–chloroform.
Compounds 3b-d were prepared analogously.
1-Amino-5-morpholino-6,7,8,9-tetrahydrothieno[2,3-c]isoquinolino-2-(3-methoxyphenyl)carbox-
amide (3e). Compound 1c (2.75 g, 10 mmol) was added to a solution of sodium ethoxide, prepared from sodium
(0.46 g, 20 mmol) in absolute ethanol (55 ml). The mixture was stirred to complete solution and N-(2-
methoxyphenyl)-2-chloroacetamide (2.0 g, 10 mmol) was added. The reaction mixture was heated for 2 h at 60°.
After cooling, water was added, the mixture was filtered, the residue was washed with ethanol, dried, and
recrystallized from 1:1 ethanol–chloroform.
1007

Compounds 3f-h were prepared analogously.
2,2-Dimethyl-5-morpholino-1,4,8,9-tetrahydro-2H-pyrano[4",3":4',5']pyrido[3',2':4,5]thieno[3,2-d]-
pyrimidin-8-one (4a). A mixture of compound 3a (3.62 g, 10 mmol), acetic anhydride (25 ml), and ethyl
orthoformate (15 ml) was boiled under reflux for 3 h. The excess of solvent was boiled off and the residue was
dissolved in ethanol (10 ml). The precipitated crystals were filtered off, washed with ethanol, dried, and
recrystallized from DMSO. IR spectrum, νmax, cm-1: 3170 (NH), 1650 (C=O). Mass spectrum: m/z (Irel, %): 372
[M]+ (100), 357 (13), 341 (30), 329 (22), 302 (78).
Compound 4b. Mass spectrum: m/z (Irel, %): 386 [M]+ (100), 385 (32), 355 (20), 343 (10), 329 (19),
315 (16).
Compounds 4b-i were prepared analogously.
Compound 4a was also prepared by another method [1].
2,2-Dimethyl-5-morpholino-10-thioxo-1,4,8,9,10,11-hexahydro-2H-pyrano[4",3":4',5']pyrido[3',2':4,5]-
thieno[3,2-d]pyrimidin-8-one (5a). A mixture of compound 3a (2 g, 5.5 mmol), carbon disulfide (15 ml), and
pyridine (60 ml) was heated under reflux for 15 h. The solvent was distilled off and the residue was dissolved in
2 N aqueous potassium hydroxide solution. The mixture was filtered and the filtrate was acidified with 10%
hydrochloric acid. The precipitated crystals were filtered off, washed with water, dried, and recrystallized from
DMF. IR spectrum, ν, cm-1: 3440 (NH), 1680 (C=O).
Compounds 5b-d were prepared analogously.
2,2-Dimethyl-10-methylsulfanyl-5-morpholino-10-thioxo-1,4,8,9,10,11-hexahydro-2H-pyrano-
[4",3":4',5']pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-8-one (6a). DMF (50 ml) and compound 5a (4.04 g,
10 mmol) were added to a solution of KOH (0.56 g, 10 mmol) in water (5 ml). A solution of methyl iodide
(1.42 g, 10 mmol) in ethanol (30 ml) was added by degrees to the mixture, cooled to 10°C. The mixture was
stirred at room temperature for 5 h. Water (50 ml) and ethanol (50 ml) were then added to the reaction mixture.
The precipitated crystals were filtered off, dried, and recrystallized from 2:1 ethanol–DMF. IR spectrum, ν, cm-1:
1670 (C=O).
Compounds 6b-f were prepared analogously.
REFERENCES
1.
E. G. Paronikian, A. S. Noravyan, G. V. Mirzoyan, S. A. Vartanyan, Yu. Z. Ter-Zakharyan, and
Sh. G. Oganyan, USSR Inventor's Cert. 1282510; Byull. Izobret., No. 26, 290 (1995).
E. Bousquent, G. Romero, F. Guerrera, A. Caruso, and M. A. Roxas, Farmaco. Ed. Sci., 40, 869 (1985).
C. G. Dave, P. R. Shah, K. C. Dave, and V. J. Patee, J. Indian Chem. Soc., 66, 48 (1998).
E. G. Paronikian, G. V. Mirzoyan, A. S. Noravyan, D. A. Avakimyan, and Yu. Z. Ter-Zakharyan,
Khim.-farm. Zh., 27, No. 11, 29 (1993).
2.
3.
4.
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