Synthesis of 7-alkyl-4-amino-7H-pyrrolo-[2,3-d]pyrimidine-6-carboxylic acids

Article abstract of DOI:10.1007/s10593-013-1218-0

Two variants are discussed for the synthesis of ethyl N-alkyl-N-(6-amino-5- formylpyrimidin-4-yl)-glycinate derivatives, which are converted by intramolecular cyclization under the influence of sodium methoxide to give methyl 7H-pyrrolo[2,3-d]pyrimidine-6

Full text of DOI:10.1007/s10593-013-1218-0

Chemistry of Heterocyclic Compounds, Vol. 48, No. 12, March, 2013 (Russian Original Vol. 48, No. 12, December, 2012)
SYNTHESIS OF 7-ALKYL-4-AMINO-7H-PYRROLO-
[2,3-d]PYRIMIDINE-6-CARBOXYLIC ACIDS
E. V. Verves1, A. V. Kucher1, L. V. Muzychka1, and O. B. Smolii1*
Two variants are discussed for the synthesis of ethyl N-alkyl-N-(6-amino-5-formylpyrimidin-4-yl)-
glycinate derivatives, which are converted by intramolecular cyclization under the influence of sodium
methoxide to give methyl 7H-pyrrolo[2,3-d]pyrimidine-6-carboxylates. New derivatives of pyrimido-
[5',4':4,5]pyrrolo[2,1-c][1,4]oxazines containing 3-chloropropyl groups at position 8 have been
prepared.
Keywords: ethyl N-alkylglycinate, pyrimido[5',4':4,5]pyrrolo[2,1-c][1,4]oxazine, 7H-pyrrolo[2,3-d]-
pyrimidine, cyclization.
In recent years, pyrrolo[2,3-d]pyrimidine derivatives have been intensively studied and used
successfully for the solution of real problems of medicinal chemistry and molecular biology. The increasing
number of publications with the description of biological properties of compounds of this class indicates their
considerable potential. Recently obtained derivatives of pyrrolo[2,3-d]pyrimidines have anticancer and
antiproliferative activities, and are also antagonists of the CRF1 receptor [1-3]. However the principal stimulus
for the discovery of new substances in the 7H-pyrrolo[2,3-d]pyrimidine series has been the discovery of the
strongly selective inhibitors of the kinases JAK3 (CP-690,550) and Akt (CCT128930), which are effective in
therapy of autoimmune and oncological diseases [4-7].
N
C
NH2
Me
N
Cl
NR1R2
Me
N
N
N
OH
O
O
N
N
N
N
N
N
N
N
H
H
R
CP-690,550
CCT128930
A
_______
*To whom correspondence should be addressed, e-mail: smolii@bpci.kiev.ua.
1Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine, 1
Murmanska St., Kyiv 02660, Ukraine.
________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, 1968-1976. December, 2013.
Original article submitted December 21, 2011.
1844
0009-3122/13/4812-1844©2013 Springer Science+Business Media New York

Despite the fact that the synthesis of pyrrolo[2,3-d]pyrimidine derivatives has been well studied, some
representatives could not be readily obtained. One example of this is the synthesis of compound A, which was
not achieved using the previously described method [8, 9]. Starting from 4,6-dichloropyrimidine-5-carb-
aldehyde, we obtained compounds 1a-d. Treatment of these with bases caused intramolecular cyclization with
participation of the aldehyde and methylene groups, which was accompanied by pronounced resinification of
the reaction mixture, apparently connected with nucleophilic attack at position 2 of the pyrimidine ring and the
subsequent ring opening.
NR1R2
NR1R2
Cl
H
CHO
CHO
CHO
Cl
N
CO2Et
NHR1R2
K2CO3
MeCN
N
N
N
R
K2CO3
MeCN
N
N
R
CO2Et
2a–l
N
N
R
CO2Et
N
3a–d
1a–d
Et3N
MeOH
MeONa MeOH
(from 1а)
Cl
N
NR1R2
NR1R2
NHR1R2
PhMe
N
N
NaOH
CO2H
CO2Me
CO2Me
EtOH
H2O
N
R
N
N
N
N
N
R
6a–l
5a–l
Ph
4
1a, 5a–d, 6a–d R = benzyl, 1b, 5e, 6e R = allyl, 1c, 5f,i,k, 6f,i,k R = 2-methoxyethyl,
1d, 5g,h,j,l, 6g,h,j,l R = (tetrahydrofuran-2-yl)methyl; 3a, 5a,e,f,g, 6a,e,f,g NR1R2 = NMe2,
3b, 5b,h, 6b,h NR1R2 = pyrrolidin-2-yl, 3c, 5c,i,j, 6c,i,j NR1R2 = piperidin-1-yl,
3d, 5d,k,l, 6d,k,l NR1R2 = morpholin-4-yl
Compound 4 was obtained in a sole example in 30% yield. Hence use of the sequence 1 → 4 → 5 for
the synthesis of target compounds 6a-l seemed unpromising. It should be noted that the chloroaldehydes 1a-d
were nevertheless successfully converted into the pyrrolo[2,3-d]pyrimidine derivatives 5a-l in sufficiently high
yields. This was facilitated by introduction of electron-donor substituents at position 4 of the pyrimidine ring,
which decreased the electrophilicity of the carbon atom at position 2 of the heterocyclic ring. The most successful
substitution of the labile chlorine atom by secondary amines in aldehydes 1a-d was carried out in anhydrous
acetonitrile in the presence of potassium carbonate. Compounds 2a-l were also obtained by treatment of the
aldehydes 3a-d with N-acylglycinates. Monitoring of the conversions 1 → 2 and 3 → 2 was carried out by TLC. It
should be noted that by-products were practically absent in these reactions. Aldehydes 2a-l were oily substances
which rapidly darkened in the air so they were used for further conversions without additional purification.
Intramolecular cyclizations of aldehydes 2a-l were carried out in absolute methanol with an equimolar quantity of
sodium methoxide and were accompanied by transesterification. The required compounds – 7H-pyrrolo-
[2,3-d]pyrimidine-6-carboxylic acids 6a-l (Table 1) – were obtained by alkaline hydrolysis of the esters 5a-l.
The introduction of the carboxylic group into the pyrrolo[2,3-d]pyrimidine nucleus opens the possibility
for the creation of diverse chemical libraries, especially those of amides. Compounds with a (tetrahydrofuran-
2-yl)methyl group at the nitrogen atom of the pyrrole ring are an exception. Treatment of compounds 6g,j,l with
thionyl chloride gave rise to opening of the tetrahydrofuran ring with subsequent transformation into tricyclic
derivatives of pyrimido[5',4':4,5]pyrrolo[2,1-c][1,4]oxazines 7a-c. We had previously observed this
recyclization in a similar example [10].
1845

TABLE 1. Characteristics of the Compounds Synthesized
Found, %
——————
Calculated, %
H
Com-
pound
Empirical
formula
Yield, %
(Method)
Mp*, °С
C
3
Cl
N
6
1
2
4
5
7
8
C16H16ClN3O 57.62
57.58
4.80
4.83
10.65
10.62
12.56
12.59
121-122
59
1a
3
3
4
4
2
C12H14ClN3O 50.81
50.80
4.95
4.97
12.59
12.50
14.85
14.81
81-82
75-76
58
55
50
55
1b
1c
1d
4
C12H16ClN3O 47.85
47.77
5.39
5.34
11.79
11.75
13.95
13.93
C14H18ClN3O 51.34
51.30
5.59
5.54
10.85
10.82
12.79
12.82
73-74
C15H12ClN3O 59.69
59.71
4.00
4.01
11.78
11.75
13.95
13.93
124-125
C17H18N4O2
C19H20N4O2
C20H22N4O2
C19H20N4O3
C13H16N4O2
C13H18N4O3
C15H20N4O3
C17H22N4O3
C16H22N4O3
C18H24N4O3
C15H20N4O4
C17H22N4O4
C16H16N4O2
C18H18N4O2
C19H20N4O2
C18H18N4O3
C12H14N4O2
C12H16N4O3
C14H18N4O3
C16H20N4O3
65.76
65.79
5.82
5.85
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
18.02
18.05
135-136
165-166
158-160
159-160
109-110
105-106
94-95
68 (A)
70 (B)
5a
5b
5c
5d
5e
5f
67.80
67.84
5.93
5.99
16.69
16.65
65 (A)
54 (B)
68.52
68.55
6.30
6.33
15.91
15.99
70 (A)
73 (B)
64.70
64.76
5.76
5.72
15.98
15.90
76 (A)
68 (B)
59.90
59.99
6.31
6.20
21.58
21.52
70
68
63
73
70
62
68
59
91
81
75
82
93
90
75
70
73
71
56.21
56.10
6.59
6.52
20.18
20.13
59.27
59.20
6.67
6.62
18.50
18.41
5g
5h
5i
61.89
61.80
6.65
6.71
16.85
16.96
93-94
60.30
60.36
6.90
6.97
17.65
17.60
124-125
95-97
62.71
62.77
7.15
7.02
16.25
16.27
5j
56.19
56.24
6.35
6.29
17.56
17.49
143-144
130-131
>270
5k
5l
58.90
58.95
6.51
6.40
16.25
16.17
64.94
64.85
5.49
5.44
18.80
6a
6b
6c
6d
6e
6f
18.91 (decomp.)
17.49 >300
17.38 (decomp.)
67.15
67.07
5.68
5.63
67.93
67.84
5.90
5.99
16.72
16.65
221-222
63.98
63.89
5.39
5.36
16.63
>280
16.56 (decomp.)
22.84 >240
22.75 (decomp.)
21.17 >260
21.20 (decomp.)
58.62
58.53
5.75
5.73
54.61
54.54
6.15
6.10
57.86
57.92
6.29
6.25
19.23
19.30
238-239
245-246
184-185
203-204
6g
6h
60.72
60.75
6.31
6.37
17.78
17.71
C15H20N4O3
C17H22N4O3
59.27
59.20
6.57
6.62
18.47
18.41
6i
6j
61.72
61.80
6.76
6.71
16.90
16.96
1846

TABLE 1 (continued)
1
2
3
4
5
6
7
8
C14H18N4O4
C16H20N4O4
54.93
54.89
57.89
57.82
5.90
5.92
6.16
6.07
—
—
18.36
18.29
16.92
16.86
212-213
194-195
75
68
6k
6l
C14H17ClN4O2
C17H21ClN4O2
C16H19ClN4O3
54.52
54.46
5.61
5.55
11.59
11.48
18.26
18.15
>255
(decomp.)
70
66
65
7a
7b
7c
58.60
58.53
6.12
6.07
10.23
10.16
16.15
16.06
>256
(decomp.)
54.70
54.78
5.50
5.46
10.04
10.11
16.03
15.97
192-193
_______
*Solvents for recrystallization: EtOH (compounds 5a-l), 2-PrOH (compound 4),
DMF–EtOH (compounds 6a-l), DMF (compounds 7a-c).
NR1R2
NR1R2
OH
N
O
N
SOCl2
N
O
O
N
N
N
O
Cl
6g,j,l
7a,b,c
6g, 7a NR1R2 = NMe2, 6j, 7b NR1R2 = piperidin-1-yl, 6l, 7c NR1R2 = morpholin-4-yl
The composition and structures of the compounds synthesized were confirmed by elemental analysis
and the data of IR spectra, chromato-mass spectroscopy, as well as 1H and 13C NMR spectra. The appearance of
1
proton singlets in the region of 7.32-7.47 ppm in the H NMR spectra of compounds 5a-l indicates closure of
the pyrrole ring. Characteristic of the pyrimido[5',4':4,5]pyrrolo[2,1-c][1,4]oxazines 7a-c is the presence of NCH2
group signals in the form of two one-proton double doublets at 4.05-4.71 ppm. The 13C NMR signal of the C-8
carbon in compounds 7a-c was observed at 81.8-82.0 ppm (Tables 2-4).
So, in this work, we have found a method for the synthesis of 7H-pyrrolo[2,3-d]pyrimidine-
6-carboxylic acid derivatives, which are potential intermediates for the preparation of protein kinase inhibitors.
It has been shown that some of the derivatives containing a (tetrahydrofuran-2-yl)methyl substituent at the
nitrogen atom of the pyrrole ring on treatment with thionyl chloride underwent recyclization with the formation
of pyrimido[5',4':4,5]pyrrolo[2,1-c][1,4]oxazine derivatives.
EXPERIMENTAL
1
IR spectra of KBr pellets were recorded with a Bruker Vertex 70 FTIR spectrometer. H and 13C NMR
spectra were recorded with a Varian Mercury 400 spectrometer (400 MHz for 1H nuclei, compounds 1b, 5e,h, 7a),
1
and a Bruker Avance DRX-500 spectrometer (500 and 125 MHz for H and 13C nuclei, respectively) in CDCl3
(compounds 1a-d, 4, 5a-l), DMSO-d6 (compounds 6a-l, 7a-c), CF3COOD (for 13C spectra of compounds 6d, 7a-c)
with TMS as internal standard. Chromato-mass spectrometry was performed on an Agilent 1100 Series HPLC,
equipped with a diode matrix with an Agilent LC/MSD SL mass sensitive detector, chemical ionization at
atmospheric pressure, and a scanning range of 80-1000 m/z. Elemental analysis was carried out by combustion
using Pregl–Dumas method, analysis for chlorine content by chloride anion titration after combustion in oxygen.
1847

TABLE 2. 1H NMR Spectra of the Compounds Synthesized.
Com-
pound
Chemical shifts, δ, ppm (J, Hz)
1
2
1.29 (3H, t, 3J = 7.0, OCH2CH3); 4.19 (2H, s, CH2Ph); 4.24 (2H, q, 3J = 7.0, OCH2CH3);
1а
4.88 (2H, s, CH2CO); 7.31-7.37 (5H, m, H Ph); 8.45 (1H, s, H-2); 10.27 (1H, s, CHO)
1.28 (3H, t, 3J = 7.0, OCH2CH3); 4.08 (2H, d, 3J = 5.5, NCH2);
4.22-4.26 (4H, m, CH2COOCH2CH3); 5.23 (1H, d, 3J = 17.2) and
5.32 (1H, d, 3J = 10.4, NCH2CH=CH2); 5.82-5.91 (1H, m, CH=CH2);
8.37 (1H, s, H-2); 10.33 (1H, s, CHO)
1b
1.30 (3H, t, 3J = 7.0, OCH2CH3); 3.34 (3H, s, OCH3); 3.76-3.78 (4H, m, (CH2)2OCH3);
4.24 (2H, q, 3J = 7.0, OCH2CH3); 4.41 (2H, s, CH2CO); 8.37 (1H, s, H-2);
10.38 (1H, s, CHO)
1c
1.30 (3H, t, 3J = 7.0, OCH2CH3); 1.45-1.48 (1H, m) and 2.10-2.12 (1H, m, CH2);
1.63-1.66 (2H, m, CH2); 3.46-3.49 (1H, m) and 3.74-3.77 (1H, m, CH2);
1d
3.84-3.86 (2H, m, CH2); 4.24 (2H, q, 3J = 7.0, OCH2CH3); 4.28-4.32 (1H, m, CH);
4.32-4.35 (1H, m) and 4.64-4.66 (1H, m, CH2); 8.36 (1H, s, H-2); 10.38 (1H, s, CHO)
3.93 (3H, s, OCH3); 5.97 (2H, s, CH2Ph); 7.24-7.28 (5H, m, H Ph); 7.41 (1H, s, H-5);
8.81 (1H, s, H-2)
4
3.44 (6H, s, N(CH3)2); 3.85 (3H, s, OCH3); 5.89 (2H, s, CH2Ph); 7.18-7.22 (3H, m, H Ph);
7.24-7.28 (2H, m, H Ph); 7.44 (1H, s, H-5); 8.44 (1H, s, H-2)
5a
5b
5c
2.05-2.14 (4H, m, (CH2)2 pyrrolidine); 3.82-3.85 (7H, m, N(CH2)2 pyrrolidine, OCH3);
5.88 (2H, s, CH2Ph); 7.18-7.28 (5H, m, H Ph); 7.41 (1H, s, H-5); 8.44 (1H, s, H-2)
1.74-1.77 (6H, m, (CH2)3 piperidine); 3.86 (3H, s, OCH3);
3.96-4.00 (4H, m, N(CH2)2 piperidine); 5.89 (2H, s, CH2Ph); 7.19-7.22 (3H, m, H Ph);
7.25-7.28 (2H, m, H Ph); 7.38 (1H, s, H-5); 8.43 (1H, s, H-2)
3.86-3.88 (7H, m, OCH3, N(CH2)2 morpholine); 4.01-4.05 (4H, m, O(CH2)2 morpholine);
5.90 (2H, s, CH2Ph); 7.19-7.22 (3H, m, H Ph); 7.25-7.28 (2H, m, H Ph);
7.37 (1H, s, H-5); 8.46 (1H, s, H-2)
5d
5e
3.40 (6H, s, N(CH3)2); 3.87 (3H, s, OCH3); 4.84 (1H, d, 3J = 16.8) and
5.07 (1H, d, 3J = 10.4, NCH2CH=CH2); 5.22-5.25 (2H, m, NCH2);
5.92-6.00 (1H, m, CH=CH2); 7.39 (1H, s, H-5); 8.38 (1H, s, H-2)
3.31 (3H, s, CH2CH2OCH3); 3.42 (6H, s, N(CH3)2); 3.73 (2H, t, 3J = 5.5, CH2OCH3);
5f
3.92 (3H, s, OCH3); 4.86 (2H, t, 3J = 5.5, NCH2); 7.40 (1H, s, H-5); 8.41 (1H, s, H-2)
1.68-1.72 (1H, m) and 1.84-1.86 (1H, m, CH2); 1.95-1.98 (2H, m, CH2);
3.42 (6H, s, N(CH3)2); 3.67-3.72 (1H, m) and 3.86-3.90 (1H, m, CH2); 3.91 (3H, s, OCH3);
4.30-4.34 (1H, m, CH); 4.63 (1H, dd, 3J = 5.0, 2J = 13.0) and
5g
4.81 (1H, dd, 3J = 8.5, 2J = 13.0, NCH2); 7.39 (1H, s, H-5); 8.40 (1H, s, H-2)
1.67-1.72 (1H, m) and 1.82-1.86 (1H, m, CH2); 1.94-1.98 (2H, m, CH2);
2.05-2.20 (4H, m, (CH2)2 pyrrolidine); 3.67-3.72 (1H, m) and 3.76-3.79 (1H, m, CH2);
3.88-3.91 (7H, m, OCH3, N(CH2)2 pyrrolidine); 4.30-4.33 (1H, m, CH);
4.62 (1H, dd, 3J = 3.5, 2J = 13.0) and 4.81 (1H, dd, 3J = 7.5, 2J = 13.0, NCH2);
7.36 (1H, s, H-5); 8.41 (1H, s, H-2)
5h
1.71-1.75 (6H, m, (CH2)3 piperidine); 3.32 (3H, s, CH2CH2OCH3);
3.73 (2H, t, 3J = 5.5, CH2OCH3); 3.92 (3H, s, OCH3);
3.94-3.98 (4H, m, N(CH2)2 piperidine); 4.86 (2H, t, 3J = 5.5, NCH2);
7.34 (1H, s, H-5); 8.41 (1H, s, H-2)
5i
1.72-1.76 (6H, m, (CH2)3 piperidine); 1.72-1.76 (1H, m) and 1.84-1.88 (1H, m, CH2);
1.94-1.99 (2H, m, CH2); 3.69-3.72 (1H, m) and 3.84-3.89 (1H, m, CH2);
3.91-3.95 (7H, m, N(CH2)2 piperidine, OCH3); 4.30-4.35 (1H, m) and
5j
5k
5l
4.60-4.65 (1H, m, CH2); 4.78-4.83 (1H, m, CH); 7.32 (1H, s, H-5); 8.39 (1H, s, H-2)
3.32 (3H, s, CH2CH2OCH3); 3.73 (2H, t, 3J = 5.5, CH2OCH3);
3.84-3.88 (4H, m, N(CH2)2 morpholine); 3.93 (3H, s, OCH3);
3.98-4.04 (4H, m, O(CH2)2 morpholine); 4.88 (2H, t, 3J = 5.5, NCH2); 7.33 (1H, s, H-5);
8.44 (1H, s, H-2)
1.59-1.63 (1H, m) and 1.74-1.77 (1H, m, CH2); 1.80-1.85 (2H, m, CH2); 3.55-3.58 (1H, m) and
3.60-3.65 (1H, m, CH2); 3.71-3.75 (4H, m, N(CH2)2 morpholine); 3.85 (3H, s, OCH3);
3.88-3.93 (4H, m, O(CH2)2 morpholine); 4.13-4.17 (1H, m, CH);
4.51 (1H, dd, 3J = 7.0, 2J = 13.5) and 4.80 (1H, dd, 3J = 10.0, 2J = 13.5, NCH2);
7.47 (1H, s, H-5); 8.30 (1H, s, H-2)
3.41 (6H, s, N(CH3)2); 5.82 (2H, s, CH2Ph); 7.06-7.07 (2H, m, H Ph);
6a
7.20-7.29 (3H, m, H Ph); 7.54 (1H, s, H-5); 8.32 (1H, s, H-2); 13.14 (1H, br. s, OH)
1848

TABLE 2 (continued)
1
2
1.95-2.06 (4H, m, (CH2)2 pyrrolidine); 3.65-3.69 (2H, m, NCH2 pyrrolidine);
3.86-3.90 (2H, m, NCH2 pyrrolidine); 5.78-5.82 (2H, m, CH2Ph);
7.04-7.05 (2H, m, H Ph); 7.20-7.26 (3H, m, H Ph); 7.43 (1H, s, H-5); 8.27 (1H, s, H-2)
6b
6c
6d
6e
1.70-1.74 (6H, m, (CH2)3 piperidine); 3.96-3.99 (4H, m, N(CH2)2 piperidine);
5.84 (2H, s, CH2Ph); 7.09-7.10 (2H, m, H Ph); 7.22-7.30 (3H, m, H Ph);
7.63 (1H, s, H-5); 8.39 (1H, s, H-2)
3.72-3.75 (4H, m, N(CH2)2 morpholine); 3.90-3.93 (4H, m, O(CH2)2 morpholine);
5.81 (2H, s, CH2Ph); 7.04-7.06 (2H, m, H Ph); 7.22-7.26 (3H, m, H Ph);
7.52 (1H, s, H-5); 8.31 (1H, s, H-2); 13.05 (1H, br. s, OH)
3.33 (6H, s, N(CH3)2); 4.70 (1H, d, 3J = 17.2) and 5.01 (1H, d, 3J = 10.0, NCH2CH=CH2);
5.13-5.16 (2H, m, NCH2); 5.93-5.97 (1H, m, NCH2CH=CH2); 7.40 (1H, s, H-5);
8.22 (1H, s, H-2); 12.93 (1H, br. s, OH)
3.21 (3H, s, CH2CH2OCH3); 3.34 (6H, s, N(CH3)2); 3.60 (2H, t, 3J = 5.5, CH2OCH3);
6f
4.72 (2H, t, 3J = 5.5, NCH2); 7.40 (1H, s, H-5); 8.25 (1H, s, H-2); 12.97 (1H, br. s, OH)
1.61-1.64 (1H, m) and 1.75-1.79 (1H, m, CH2); 1.85-1.87 (2H, m, CH2);
3.35 (6H, s, N(CH3)2); 3.56-3.59 (1H, m) and 3.74-3.78 (1H, m, CH2);
4.17-4.21 (1H, m, CH); 4.49 (1H, dd, 3J = 5.0, 2J = 13.5) and
4.66 (1H, dd, 3J = 8.5, 2J = 13.5, NCH2); 7.38 (1H, s, H-5); 8.24 (1H, s, H-2);
12.92 (1H, br. s, OH)
6g
1.61-1.64 (1H, m) and 1.77-1.81 (1H, m, CH2); 1.86-1.89 (2H, m, CH2);
2.05-2.09 (4H, m, (CH2)2 pyrrolidine); 3.56-3.59 (1H, m) and 3.70-3.75 (1H, m, CH2);
3.76-3.79 (2H, m, NCH2 pyrrolidine); 3.97-4.01 (2H, m, NCH2 pyrrolidine);
4.14-4.17 (1H, m, CH); 4.57 (1H, dd, 3J = 4.5, 2J = 13.5) and
4.69 (1H, dd, 3J = 8.5, 2J = 13.5, NCH2); 7.56 (1H, s, H-5); 8.38 (1H, s, H-2);
13.48 (1H, br. s, OH)
6h
1.59-1.63 (4H, m, (CH2)2 piperidine); 1.67-1.72 (2H, m, CH2 piperidine);
3.21 (3H, s, CH2CH2OCH3); 3.60 (2H, t, 3J = 5.5, CH2OCH3);
3.89-3.92 (4H, m, N(CH2)2 piperidine); 4.72 (2H, t, 3J = 5.5, NCH2); 7.35 (1H, s, H-5);
8.25 (1H, s, H-2); 13.03 (1H, br. s, OH)
6i
6j
1.58-1.61 (6H, m, (CH2)3 piperidine); 1.68-1.78 (4H, m, CH2CH2); 3.54-3.56 (1H, m) and
3.71-3.75 (1H, m, CH2); 3.89 (4H, m, N(CH2)2 piperidine); 4.15-4.21 (1H, m, CH);
4.48 (1H, dd, 3J = 5.5, 2J = 13.5) and 4.65 (1H, dd, 3J = 7.5, 2J = 13.5, NCH2);
7.33 (1H, s, H-5); 8.24 (1H, s, H-2); 12.98 (1H, br. s, OH)
3.19 (3H, s, CH2CH2OCH3); 3.60 (2H, t, 3J = 5.5, CH2OCH3);
6k
6l
3.70-3.76 (4H, m, N(CH2)2 morpholine); 3.87-3.93 (4H, m, O(CH2)2 morpholine);
4.73 (2H, t, 3J = 5.5, NCH2); 7.44 (1H, s, H-5); 8.29 (1H, s, H-2); 13.07 (1H, br. s, OH)
1.58-1.63 (1H, m) and 1.75-1.81 (3H, m, 2CH2); 3.53-3.59 (1H, m) and
3.57-3.62 (1H, m, CH2); 3.70-3.74 (4H, m, N(CH2)2 morpholine);
3.87-3.93 (4H, m, O(CH2)2 morpholine); 4.15-4.18 (1H, m, CH);
4.51 (1H, dd, 3J = 6.0, 2J = 13.5) and 4.67 (1H, dd, 3J = 8.0, 2J = 13.5, NCH2);
7.42 (1H, s, H-5); 8.29 (1H, s, H-2); 13.03 (1H, br. s, OH)
1.90-1.95 (4H, m, (CH2)2CH2Cl); 3.48 (6H, s, N(CH3)2); 3.70-3.76 (2H, m, CH2Cl);
4.14 (1H, dd, 3J = 11.2, 2J = 14.5) and 4.71 (1H, dd, 3J = 2.0, 2J = 14.5, NCH2);
4.95 (1H, m, CH); 7.75 (1H, s, H-5); 8.42 (1H, s, H-2)
7a
7b
1.68-1.73 (6H, m, (CH2)3 piperidine); 1.90-1.95 (4H, m, (CH2)2CH2Cl);
3.36-3.41 (2H, m, CH2Cl); 4.00 (4H, s, N(CH2)2 piperidine);
4.13 (1H, dd, 3J = 11.2, 2J = 14.5) and 4.71 (1H, dd, 3J = 2.0, 2J = 14.5, NCH2);
4.94 (1H, m, CH); 7.76 (1H, s, H-5); 8.42 (1H, s, H-2)
1.90-1.95 (4H, m, (CH2)2CH2Cl); 3.70-3.76 (6H, m, N(CH2)2 morpholine, CH2Cl);
3.91-3.96 (4H, m, O(CH2)2 morpholine); 4.05 (1H, dd, 3J = 11.2, 2J = 14.5) and
4.59 (1H, dd, 3J = 2.0, 2J = 14.5, NCH2); 4.87-4.90 (1H, m, CH); 7.63 (1H, s, H-5);
8.33 (1H, s, H-2)
7c
Melting points were determined on a Boetius hot stage apparatus. Reaction progress and the purity of obtained
compounds were controlled by TLC on Silufol UV-254 plates with 19:1 CHCl3–MeOH eluent.
Ethyl N-Alkyl-N-(6-chloro-5-formylpyrimidin-4-yl)glycinates 1a-d (General Method). A solution of
NaHCO3 (0.57 g, 6.7 mmol) in H2O (20 ml) was added to a solution of 4,6-dichloropyrimidine-5-carbaldehyde
[11] (1.00 g, 5.6 mmol) in CH2Cl2 (10 ml). The mixture was cooled to 0°C, and the corresponding
1849

TABLE 3. 13C NMR Spectra of Compounds 6a-l, 7a-c
Com-
pound
Chemical shifts, δ, ppm
38.7 (N(CH3)2); 45.8 (CH2Ph); 101.3 (C-4a); 112.3 (C-5); 125.2, 126.8, 127.4, 128.6,
138.2 (6C Ph and C-6); 150.1, 151.0, 154.8 (C-2,4,7a); 161.9 (C=O)
6a
6b
25.2, 26.5 ((CH2)2 pyrrolidine); 49.4 (CH2Ph); 51.2, 53.1 (N(CH2)2 pyrrolidine);
103.8 (C-4a); 117.5 (C-5); 128.1, 128.4, 129.8, 130.8, 137.2 (6C Ph and C-6); 146.7,
149.9, 150.6 (C-2,4,7a); 166.8 (C=O)
23.0, 25.2 ((CH2)3 piperidine); 46.5, 48.7 (N(CH2)2 piperidine and CH2Ph); 101.5 (C-4a);
112.6 (C-5); 126.7, 127.4, 128.1, 129.2, 138.2 (6C Ph and C-6); 148.3, 151.0,
152.2 (C-2,4,7a); 162.3 (C=O)
6c
45.3, 45.6 (N(CH2)2 morpholine and CH2Ph); 66.1 (O(CH2)2 morpholine); 101.8 (C-4a);
110.9 (C-5); 124.9, 126.9, 127.3, 128.6, 139.0 (6C Ph and C-6); 153.8, 154.1,
158.0 (C-2,4,7a); 162.7 (C=O)
6d
38.8 (N(CH3)2); 44.6 (NCH2CH=CH2); 101.9 (C-4a); 111.4 (C-5); 115.8 (NCH2CH=CH2);
124.3 (C-6); 135.3 (NCH2CH=CH2); 153.1, 154.2, 158.3 (C-2,4,7a); 162.7 (C=O)
6e
6f
38.8 (N(CH3)2); 41.6 (NCH2); 57.8 (OCH3); 70.8 (CH2OCH3); 101.9 (C-4a); 111.2 (C-5);
124.5 (C-6); 153.3, 153.6, 158.1 (C-2, C-4, C-7a); 162.8 (C=O)
24.7, 28.2 ((CH2)2 tetrahydrofuran); 38.6 (N(CH3)2); 45.8 (NCH2);
67.1 (CH2 tetrahydrofuran); 77.0 (CH tetrahydrofuran); 101.9 (C-4a); 110.8 (C-5);
124.9 (C-6); 153.4, 153.8, 158.2 (C-2, C-4, C-7a); 163.0 (C=O)
6g
24.0 ((CH2)2 pyrrolidine); 24.8, 28.2 ((CH2)2 tetrahydrofuran); 46.7 (NCH2);
50.4 (N(CH2)2 pyrrolidine); 67.2 (CH2 tetrahydrofuran); 77.1 (CH tetrahydrofuran);
101.1 (C-4a); 112.0 (C-5); 127.6 (C-6); 145.7, 145.8, 149.2 (C-2,4,7a); 162.2 (C=O)
6h
6i
23.9, 25.3 ((CH2)3 piperidine); 41.7 (NCH2); 46.3 (N(CH2)2 piperidine); 57.9 (OCH3);
70.8 (CH2OCH3); 101.1 (C-4a); 110.2 (C-5); 124.8 (C-6); 153.7, 153.8, 157.5 (C-2,4,7a);
162.8 (C=O)
23.9 (CH2 piperidine); 24.7 (CH2 tetrahydrofuran); 25.4 ((CH2)2 piperidine);
28.2 (CH2 tetrahydrofuran), 45.9 (NCH2); 46.3 (N(CH2)2 piperidine);
67.1 (CH2 tetrahydrofuran); 77.1 (CH tetrahydrofuran); 101.4 (C-4a);
110.0 (C-5); 125.1 (C-6); 153.8, 153.9, 157.5 (C-2,4,7a); 163.0 (C=O)
6j
41.7 (NCH2); 45.3 (N(CH2)2 morpholine); 58.1 (OCH3); 66.1 (O(CH2)2 morpholine);
70.8 (CH2OCH3); 101.7 (C-4a); 110.1 (C-5); 125.2 (C-6); 153.7, 153.8, 158.0 (C-2,4,7a);
162.8 (C=O)
6k
6l
24.7, 28.2 (CH2 tetrahydrofuran); 45.3 (NCH2); 45.8 (N(CH2)2 morpholine);
66.1 (O(CH2)2 morpholine); 67.1 (CH2 tetrahydrofuran); 77.1 (CH tetrahydrofuran);
101.6 (C-4a); 109.8 (C-5); 125.6 (C-6); 153.6, 153.8, 157.9 (C-2,4,7a); 163.0 (C=O)
29.1, 30.9 (CH2CH2CH2Cl); 42.4, 44.0 (N(CH3)2); 44.9 (NCH2); 45.8 (CH2Cl); 82.0 (C-8);
105.5 (C-4a); 116.5 (C-5); 124.7 (C-5a); 148.2, 148.5, 153.9 (C-2,4,10a); 164.2 (C-6)
7a
7b
23.7, 26.4 ((CH2)3 piperidine); 28.7, 30.6 ((CH2)2CH2Cl); 44.6 (NCH2); 45.5 (CH2Cl);
50.5 (N(CH2)2 piperidine); 81.8 (C-8); 105.0 (C-4a); 115.7 (C-5); 124.2 (C-5a);
148.1, 148.8, 151.9 (C-2,4,10a); 164.2 (C-6)
29.0, 30.9 ((CH2)2CH2Cl); 44.9 (NCH2); 45.9 (CH2Cl); 49.6 (N(CH2)2 morpholine);
67.5 (O(CH2)2 morpholine); 82.0 (C-8); 105.2 (C-4a); 115.5 (C-5); 125.0 (C-5a);
147.8, 148.3, 154.9 (C-2,4,10a); 164.2 (C-6)
7c
ethyl N-alkyl glycinate (6.7 mmol) in CH2Cl2 (10 ml) was added dropwise with vigorous stirring. The reaction
mixture was stirred for 10 h at 20-25°C. The organic layer was separated, and the aqueous layer was extracted
with CH2Cl2 (210 ml). The combined organic extracts were dried over MgSO4 and evaporated in vacuum. The
residue was chromatographed on a column with CHCl3 as eluent. Compounds 1a-d were used for further
reactions without recrystallization.
The constants of 4-amino-6-chloropyrimidine-5-carbaldehydes 3a-d are cited elsewhere [12, 13].
Methyl 7-Benzyl-4-chloro-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate (4). Et3N (0.42 ml, 3.0 mmol)
was added to a solution of compound 1a (0.50 g, 1.5 mmol) in MeOH (15 ml). The mixture was refluxed for
20 h. The reaction mixture was evaporated in vacuum, and the residue was recrystallized from 2-PrOH.
Methyl 7-Alkyl-4-amino-7H-pyrrolo-[2,3-d]pyrimidine-6-carboxylates 5a-l (General Method). A.
(Compounds 5a-d). A mixture of compound 4 (0.50 g, 1.6 mmol) and secondary amine (4.8 mmol) was
refluxed in toluene for 12 h. The precipitate was cooled and filtered off. The filtrate was evaporated in vacuum,
and the residue was recrystallized from EtOH.
1850

TABLE 4. IR and Mass Spectra of Compounds 5a-l, 7a-c
Com-
IR spectrum,
ν (С=О), cm-1
Mass spectrum,
m/z [M+1]+
Com-
IR spectrum,
ν (С=О), cm-1
Mass spectrum,
m/z [M+1]+
pound
pound
1706
1700
1719
1704
1714
1697
1705
1697
311
337
351
353
261
279
305
331
1708
1711
1714
1704
1720
1727
1718
319
345
321
347
309
349
351
5a
5b
5c
5d
5e
5f
5i
5j
5k
5l
7a
7b
7c
5g
5h
B. (Compounds 5a-l). A mixture of chloroaldehyde 1a-d or 3a-d (5.0 mmol), secondary amine
(7.5 mmol), and K2CO3 (1.04 g, 7.5 mmol) in absolute MeCN was refluxed with stirring for 15-20 h. The
mixture was cooled, the precipitate was filtered off and washed with absolute MeCN. The filtrate was
evaporated in vacuum. The residue was dissolved in MeOH (5 ml), and a solution of MeONa (0.33 g, 6.0 mmol)
in MeOH (3 ml) was added. The reaction mixture was heated to reflux, cooled and kept at 0°C for 12 h. The
precipitate was filtered off, washed with H2O, and recrystallized from EtOH.
7-Alkyl-4-amino-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acids (6a-l) (General Method). NaOH
(0.072 g, 1.8 mmol) was added to a suspension of compound 5a-l (1.5 mmol) in 40% aqueous EtOH (10 ml),
and the mixture was refluxed for 2-3 h. The mixture was cooled and acidified with dilute HCl (1:1) to pH 5-6.
The reaction mixture was kept at 0°C for 12 h. The precipitate was filtered off, washed with water, and
recrystallized from DMF-EtOH.
8-(3-Chloropropyl)-4-dimethylamino-8,9-dihydro-6H-pyrimido[5',4':4,5]pyrrolo[2,1-c][1,4]oxazin-6-one
(7a). A suspension of acid 6g (0.50 g, 1.7 mmol) in SOCl2 (1 ml) was refluxed for 3 h. The reaction mixture was
cooled, the precipitate was filtered off, washed with PhH (10 ml) and EtOH (10 ml). The product was
recrystallized from DMF.
8-(3-Chloropropyl)-4-(piperidin-1-yl)-8,9-dihydro-6H-pyrimido[5',4':4,5]pyrrolo[2,1-c][1,4]oxazin-6-one
(7b) was obtained analogously from acid 6j.
8-(3-Chloropropyl)-4-(morpholin-4-yl)-8,9-dihydro-6H-pyrimido[5',4':4,5]pyrrolo[2,1-c][1,4]oxazin-
6-one (7c) was obtained analogously from acid 6l.
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