An improved synthesis of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine

Article abstract of DOI:10.1007/s10593-018-2320-0

[Figure not available: see fulltext.] An improved seven-step synthesis of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine from dimethyl malonate with 31% overall yield is described. The procedure is operationally simple and practical for the synthesis of the 4-chloro-7H-pyrrolo[2,3-d]pyrimidine building block.

Full text of DOI:10.1007/s10593-018-2320-0

DOI 10.1007/s10593-018-2320-0
Chemistry of Heterocyclic Compounds 2018, 54(6), 638–642
An improved synthesis of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine
Yu-Liu Zhang1, Cheng-Tao Xu1, Ting Liu1, Yong Zhu2, Yu Luo1*
1 Shanghai Engineering Research Center of Molecular Therapeutics
and New Drug Development, School of Chemistry and Molecular Engineering,
East China Normal University,
Shanghai 200241, P. R. China; е-mail: yluo@chem.ecnu.edu.cn
2 Suzhou Highfine Biotech Co., Ltd.,
Suzhou 215129, P. R. China; e-mail: yluo@chem.ecnu.edu.cn
Published in Khimiya Geterotsiklicheskikh Soedinenii,
2018, 54(6), 638–642
Submitted April 4, 2018
Accepted May 17, 2018
OEt
OEt
OEt
OEt
CHO
Cl
N
O
O
Cl
Cl
Cl
Cl
Cl
NH2
MeO
OMe
N
H
N
N
N
N
N
N
N
seven-step synthesis
31% overall yield
An improved seven-step synthesis of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine from dimethyl malonate with 31% overall yield is described.
The procedure is operationally simple and practical for the synthesis of the 4-chloro-7H-pyrrolo[2,3-d]pyrimidine building block.
Keywords: pyrimidine, Janus kinase inhibitor, ozonolysis, synthesis.
Janus kinase (JAK) inhibitors are a type of compounds
that inhibit the activity of one or more of the JAK family of
enzymes, thereby interfering with JAK – signal transducer
and activator of transcription protein (STAT) signal
pathway, which is a chain of interactions between proteins
in the cell and is involved in cell division and death and in
tumor formation processes. The pathway involves a
chemical signal transfer from the outside into the cell
nucleus, resulting in the activation of genes through a
transcription process. Disrupted JAK-STAT signaling may
lead to a variety of diseases affecting the immune system.1
JAK inhibitors have therapeutic applications in the
treatment of cancer and inflammatory diseases, such as
rheumatoid arthritis, psoriasis, myelofibrosis, polycythemia
vera, dermatitis, and others.2 So far, three JAK inhibitors
have been approved by FDA, including ruxolitinib,3
tofacitinib,4 and oclacitinib5 (Fig. 1). In addition, a number
of JAK inhibitors are in clinical trials, such as baricitinib,6
filgotinib,7 gandotinib8 (Fig. 1). Several JAK inhibitors
have a common pyrrolo[2,3-d]pyrimidine core. Thus, 4-chloro-
7H-pyrrolo[2,3-d]pyrimidine (1) might be a practical
building block in the synthesis of many JAK inhibitors.
Up to now, a considerable number of synthetic routes
for this heterocyclic compound have been reported, as
summarized in Figure 2.9–15 In few synthetic methods, ethyl
cyanoacetate or isoxazole is employed as starting materials.
Figure 1. Chemical structures of representative JAK inhibitors.
0009-3122/18/54(6)-0638©2018 Springer Science+Business Media, LLC
638

Chemistry of Heterocyclic Compounds 2018, 54(6), 638–642
target molecule in a different way.14 In this method, an
OH
N
ref. 10
O
ref. 12
O
aldehyde is produced as an intermediate, which is directly
cyclized to afford the desired compound. However, we
have found that the yield of this direct cyclization is poor,
probably due to the aldehyde enolization. To develop an
efficient and practical synthetic protocol, we improved
N
N
N
NC
OEt
N
H
CHO
Cl
OMe
NH2
Zhang's method and disclosed
a concise synthetic
Cl
procedure in a Chinese patent.16 Herein, we report a more
detailed investigation on the synthesis of the 4-chloro-7H-
pyrrolo[2,3-d]pyrimidine building block.
Cl
Cl
N
N
N
N
N
H
N
1
Our synthesis of building block 1 is depicted in Scheme 1.
In the first step, dimethyl malonate was treated with allyl
bromide under basic conditions to afford dimethyl 2-allyl-
malonate 2 in 68% yield. We have found that dimethyl
malonate is a more convenient starting compound than
diethyl malonate. The boiling point of dimethyl ester 2 is
lower than that of the corresponding diethyl ester, resulting
in an easier purification via vacuum distillation. Although
the condensation of ester 2 with formamidine acetate
proceeded smoothly to produce 5-allylpyrimidine-4,6-diol
3 in good yield, we found that formamide could also be
used to effect this condensation and produce the desired
compound in 92% yield. Since formamide is much cheaper
than formamidine acetate, our protocol is more cost-
efficient and convenient. Thereafter, pyrimidine 3 was
Zhang's
Xia's
method14
method13
O
O
EtO
OEt
Figure 2. Literature reported routes toward building block 1.
Although the reported methods are quite different, 4-hydroxy-
pyrrolo[2,3-d]pyrimidine is used as a common intermediate
in all of them, which is further converted into the target
molecule. Xia and coworkers reported a synthetic route via
vinyl ether intermediate using diethyl malonate as the
starting compound.13 Recently, Zhang and coworkers
described another synthetic route, employing diethyl
malonate as the starting material too, but constructing the
Scheme 1
CH2
O
O
MeO
HCONH2
NaOMe
POCl3
CH2=CHCH2Br
NaOMe
O
O
N,N-dimethylaniline
MeO
OMe
HO
OH
MeOH, 60°C, 1 h
92%
MeCN, 80°C, 3 h
85%
MeOH
0–5°C then rt, 5 h
68%
MeO
N
N
CH2
CH2
2
3
CHO
NH4OH
O3, Et3N
Cl
NH2
Cl
NH2
DMSO, MeOH
–5–0°C, 2 h
EtOH, 70°C, 24 h
90%
N
N
N
N
6
5
AcOH
43% in 2 steps
Route 1
CH2
Cl
Route 2
CHO
Cl
N
O3
NH4OH
Cl
Cl
Cl
N
H
MeOH, CH2Cl2
–40°C, 2 h
76%
60–70°C, 24 h
34%
N
N
N
N
N
1
4
7
aq HCl
HC(OEt)3
TsOH, EtOH
40°C, 2 h
90%
petroleum ether
50°C, 4 h
91%
Route 3
OEt
OEt
NH4OH
OEt
NH2
OEt
Cl
Cl
N
Cl
EtOH, 70°C, 20 h
94%
N
N
N
8
9
639

Chemistry of Heterocyclic Compounds 2018, 54(6), 638–642
treated with phosphorus oxychloride to give 5-allyl-4,6-
Dimethyl prop-2-en-1-ylpropanedioate (2). To a
solution of NaOMe (122 g, 2.27 mol) in MeOH (400 ml) in
a three-necked flask at 0–5°C, dimethyl malonate (300 g,
2.27 mol) was added, and the mixture was stirred for 1 h.
Then allyl bromide (174 g, 2.27 mol) was added dropwise
at room temperature and stirring continued for 5 h. Water
(150 ml) was added to quench the reaction. The reaction
mixture was evaporated to dryness under reduced pressure
to give a residue that was extracted with EtOAc (500 ml),
washed with water (2×200 ml) and brine (200 ml). The
organic layer was dried over anhydrous Na2SO4 and
concentrated under reduced pressure to give the crude
product that was purified by vacuum distillation (85–90°C,
dichloropyrimidine (4) in 85% yield.
With dichloride 4 in hand, three synthetic routes were
investigated. First, dichloride
4
was treated with
ammonium hydroxide to produce the monosubstituted
amine 5 in 90% yield. Then, amine 5 was subjected to
ozonolysis to afford intermediate 6, which immediately
cyclized under acidic conditions to produce the target
molecule in 43% two-step yield. To dissolve compound 5,
a mixture of DMSO and MeOH was used. Even so, the
temperature should not be below –10°C. Otherwise,
compound 5 would precipitate from the solvent. Since the
active intermediates during ozonolysis were very unstable,
they might partially decompose at this temperature,
resulting in low yields. Another reason for the low yield
might be the deactivation of amino group, since the amino
group might be protonated under the acidic conditions.
Thus, more efficient synthetic routes were desired.
1
10 mmHg). Yield 266 g (68%), colorless oil. H NMR
spectrum (CDCl3), δ, ppm (J, Hz): 5.82–5.72 (1H, m,
=CH); 5.14–5.05 (2H, m, =CH2); 3.73 (6H, s, OCH3); 3.47
(1H, t, J = 7.6, CH); 2.65 (2H, t, J = 7.1, CH2).
5-(Prop-2-en-1-yl)pyrimidine-4,6-diol (3). A solution
of NaOMe (220 g, 4.07 mol) in dry methanol (500 ml) in a
three-necked flask was cooled to 0–5°C, and HCONH2
(157 g, 3.49 mol) was added. The mixture was stirred at
60°C for 1 h. Compound 2 (200 g, 1.16 mol) was added to
the mixture and stirring at 60°C continued for 4 h. After
completion of the reaction, the solvent was removed under
reduced pressure. Ice-water (400 ml) and concentrated
hydrochloric acid (120 ml) were added to the residue to
adjust pH to 2. The precipitate was collected and washed
by ice-water to give the crude product, which was triturated
with EtOAc (500 ml). Yield 162.6 g (92%), white solid,
mp 238–241°C (mp 240°C18). 1H NMR spectrum (DMSO-d6),
δ, ppm (J, Hz): 11.30 (2H, br. s, OH); 7.94 (1H, s, H-2);
5.85–5.76 (1H, m, =CH); 4.97–4.87 (2H, m, =CH2); 3.01
(2H, d, J = 6.0, CH2). 13C NMR spectrum (DMSO-d6),
δ, ppm: 164.3; 147.1; 135.8; 114.3; 100.1; 26.6.
4,6-Dichloro-5-(prop-2-en-1-yl)pyrimidine (4). To a
solution of compound 3 (290 g, 1.91 mol) in MeCN
(600 ml), N,N-dimethylaniline (60 ml) was added, then the
mixture was warmed to 80°C and POCl3 (822 g, 5.36 mol)
was added dropwise. The reaction mixture was refluxed for
3 h under nitrogen atmosphere. Then it was quenched with
ice-water (500 ml) and concentrated to dryness under
reduced pressure. The residue was extracted with 1,2-di-
chloroethane (500 ml), washed with water (3×100 ml) and
aqueous Na2CO3 (200 ml). The organic phase was dried
over anhydrous Na2SO4 and concentrated under reduced
pressure to give the crude, that was purified by vacuum
distillation (94–96°C, 8 mmHg). Yield 306 g (85%), light-
yellow oil. 1H NMR spectrum (CDCl3), δ, ppm (J, Hz):
8.64 (1H, s, H-2); 5.89–5.82 (1H, m, =CH); 5.17–5.09 (2H,
m, =CH2); 3.64 (2H, d, J = 6.2, CH2). 13C NMR spectrum
(CDCl3), δ, ppm: 162.0; 155.8; 131.0; 130.6; 118.2; 34.0.
Mass spectrum, m/z (Irel, %): 191 [M(35Cl,37Cl)+H]+ (61),
189 [M(35Cl)+H]+ (100),
The second route was similar to Zhang's work, while we
used ozonolysis to produce the desired aldehyde 7, instead
of oxidation by NaIO4/K2OsO4. Since ozone is inexpen-
sive, this protocol would be more practical.17 Thus,
dichloride 4 was treated with ozone at low temperature to
produce aldehyde 7 in 76% yield. However, it was found
that the direct cyclization of aldehyde 7 in concentrated
ammonium hydroxide produced the target compound 1 in
only 34% yield. Indeed, several conditions were screened,
but the yields were still quite low. These unsatisfactory
results led us to devise new strategies.
The low yield might be ascribed to the aldehyde
enolization. Thus, aldehyde 7 was protected with ethanol to
give acetal 8 in excellent yield. Treatment of compound 8
with ammonium hydroxide proceeded smoothly to give the
monosubstituted amine 9 in 94% yield. At last, the
hydrolysis and cyclization occured successively under
acidic conditions to produce the desired compound 1 in
91% yield. Although the synthetic route was prolonged, the
yields of the last three steps were nearly quantitative. Thus,
this seven-step synthesis was more valuable and attractive.
In conclusion, we have developed a convenient seven-
step synthetic approach toward 4-chloro-7H-pyrrolo[2,3-d]-
pyrimidine in 31% overall yield from commercially
available dimethyl malonate.
Experimental
IR spectra were obtained on a FTIR Bruker Tensor 27
1
apparatus in KBr pellets. H NMR spectra were recorded
on a Bruker DRX-400 (400 MHz) spectrometer. 13C NMR
spectra were obtained on a JNM-EX400 (100 MHz) spectro-
meter, using TMS as internal standard. High-resolution
mass spectra (ESI) were recorded on a Bruker MicroTof II
mass spectrometer. Mass spectra (EI, 70 eV) were obtained
on an AGILENT 5975C mass spectrometer. Melting points
were measured on a SGW X-4 (INESA) temperature
apparatus and are uncorrected.
6-Chloro-5-(prop-2-en-1-yl)pyrimidin-4-amine (5).
A mixture of compound 4 (100.9 g, 0.53 mol) and NH4OH
(400 ml) in EtOH (300 ml) was stirred at 70°C for 24 h in a
sealed flask. The solvent was removed under reduced
pressure and EtOH (300 ml) was added to the residue. The
precipitated ammonium chloride was filtered off. The
Commercial reagents were used without further
purification. Petroleum ether fraction with boiling point in
the range from 60 to 90°C was used in the work-up of the
reaction mixtures.
640

Chemistry of Heterocyclic Compounds 2018, 54(6), 638–642
filtrate was concentrated under reduced pressure to give a
7.01 (2H, br. s, NH2); 4.67 (1H, t, J = 5.5, CH); 3.68–3.60
(2H, m, CH2CH3); 3.47–3.39 (2H, m, CH2CH3); 2.88 (2H,
d, J = 5.5, CH2); 1.06 (6H, t, J = 7.0, CH2CH3).13C NMR
spectrum (DMSO-d6), δ, ppm: 164.1; 158.4; 155.9; 109.5;
101.3; 62.3; 32.4; 15.2. Found, m/z: 268.0819 [M(35Cl2)+Na]+.
C10H16ClN3NaO2. Calculated, m/z: 268.0823. Found, m/z:
270.0793 [M(35Cl,37Cl)+Na]+. Calculated, m/z: 270.0796.
4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (1). Route 1.
A mixture of compound 5 (68 g, 0.41 mol), Et3N (60.9 g,
0.6 mol), and DMSO (47 g, 0.6 mol) in MeOH (320 ml)
was cooled to –5–0°C and ozone was bubbled through the
mixture for 2 h. After nitrogen was bubbled through the
mixture to remove the excess of ozone, thiocarbamide
(61.2 g, 0.81 mol) was added and mixture stirred for 1 h,
until the starch-KI paper did not turn blue. Then AcOH
(120 g, 2 mol) was added and stirring at room temperature
continued for 14 h. The solvent was removed under
reduced pressure. The residue was extracted with EtOAc
(500 ml), washed with brine (2×200 ml) and aqueous
NaHCO3 to neutralize the residual AcOH. The organic
phase was dried over anhydrous Na2SO4 and concentrated
under reduced pressure to give the crude, that was
recrystallized from a mixture of petroleum ether – EtOAc,
2:1. Yield 26.1 g (43%), white solid.
Route 2. A mixture of compound 7 (10.0 g, 50 mmol)
and NH4OH (40 ml) was stirred at 60–70°C for 24 h. Then
it was filtered to give the solid crude product, that was
purified by column chromatography on silica gel (eluent
petroleum ether – EtOAc, 5:1). Yield 2.7 g (34%), white
solid.
Route 3. A mixture of compound 9 (10.0 g, 41 mmol)
and 6 M HCl (30 ml) in petroleum ether (30 ml) was stirred
at 50°C for 4 h. The mixture was filtered to give the solid
crude, that was oven-dried and triturated with a mixture of
petroleum ether – EtOAc, 1:1. Yield 5.68 g (91%), white
solid, mp 189–190°C (mp 189–190°C12). 1H NMR
spectrum (DMSO-d6), δ, ppm (J, Hz): 12.59 (1H, s, NH);
8.58 (1H, s, H-2); 7.71 (1H, d, J = 3.4, H-6); 6.62 (1H, d,
J = 3.4, H-5). 13C NMR spectrum (DMSO-d6), δ, ppm:
151.8; 150.4; 150.3; 128.3; 116.5; 98.8. Found, m/z:
154.0164 [M+H]+. C6H5ClN3. Calculated, m/z: 154.0166.
solid product which was oven-dried and triturated with
EtOAc. Yield 81.1 g (90%), white solid, mp 150–152°C.
IR spectrum, ν, cm–1: 3411, 3376, 3181, 1653, 1546, 901.
1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 8.13 (1H,
s, H-2); 7.14 (2H, br. s, NH2); 5.89–5.79 (1H, m, =CH);
5.07 (2H, t, J = 8.9, =CH2); 3.36 (2H, d, J = 5.8, CH2).
13C NMR spectrum (DMSO-d6), δ, ppm: 163.1; 157.7;
156.0; 132.7; 115.5; 111.1; 29.7. Found, m/z: 169.0406
[M (35Cl)]+. C7H8ClN3. Calculated, m/z:169.0407.
(4,6-Dichloropyrimidin-5-yl)acetaldehyde (7). A solution
of compound 4 (100 g, 0.53 mol) in MeOH (400 ml) and
CH2Cl2 (150 ml) was cooled to –40°C, and ozone was
bubbled through the mixture for 2 h. Then the reaction
mixture was purged with nitrogen for 20 min to remove the
excessive ozone. Thiocarbamide (40 g, 0.53 mol) was
added to the mixture and stirred for 1 h until the starch-KI
paper did not turn blue. The solvent was distilled off, the
residue was extracted with CH2Cl2 (300 ml) and washed
with water (2×100 ml). The organic layer was dried over
anhydrous Na2SO4 and concentrated under reduced pressure
to give the residue that was triturated with petroleum ether
(200 ml). Yield 76.8 g (76%), white solid, mp 88–90°C
1
(mp 89–91°C19). H NMR spectrum (DMSO-d6), δ, ppm:
9.75 (1H, s, CHO); 8.89 (1H, s, H-2); 4.24 (2H, s, CH2).
13C NMR spectrum (DMSO-d6), δ, ppm: 196.9; 161.8;
157.0; 126.4; 44.5. Mass spectrum, m/z (Irel, %): 192
[M(35Cl,37Cl)]+(12), 190 [M(35Cl)]+ (20), 162 (100).
4,6-Dichloro-5-(2,2-diethoxyethyl)pyrimidine (8).
A mixture of compound 7 (20.0 g, 0.1 mol), triethyl ortho-
formate (18.6 g, 0.12 mol), and TsOH (1.0 g, 5.8 mmol) in
EtOH (100 ml) was stirred at 40°C for 2 h. After
completion of the reaction, aqueous Na2CO3 was added to
the mixture to adjust pH to 8. The solvent was removed
under reduced pressure and the residue extracted with
EtOAc (300 ml), washed with water (100 ml). The organic
layer was dried over anhydrous Na2SO4 and concentrated
under reduced pressure to give the residue that was purified
by column chromatography on silica gel (eluent petroleum
ether – EtOAc, 5:1). Yield 25.0 g (90%), colorless oil.
IR spectrum, ν, cm–1: 2987, 1546, 1518, 1123, 1068, 785.
1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 8.62 (1H, s,
H-2); 4.80 (1H, t, J = 5.8, CH); 3.74–3.66 (2H, m,
CH2CH3); 3.48–3.41 (2H, m, CH2CH3); 3.25 (2H, d, J = 5.7,
CH2); 1.13 (6H, t, J = 7.0, CH2CH3). 13C NMR spectrum
(CDCl3), δ, ppm: 162.7; 155.8; 132.5; 129.2; 100.9; 62.9;
35.4; 15.2. Found, m/z: 287.0323 [M(35Cl)+Na]+.
C10H14Cl2N2NaO2. Calculated, m/z: 287.0325. Found, m/z:
289.0295 [M(35Cl,37Cl)+Na]+. Calculated, m/z: 289.0296.
6-Chloro-5-(2,2-diethoxyethyl)pyrimidin-4-amine (9).
A mixture of compound 8 (20.0 g, 76 mmol) and NH4OH
(100 ml) in EtOH (120 ml) was stirred at 70°C for 20 h.
The solvent was removed under reduced pressure and the
residue extracted with EtOAc (200 ml), washed with water
(100 ml). The organic phase was dried over anhydrous
Na2SO4 and concentrated under reduced pressure. Yield
17.4 g (94%), yellow solid, mp 50–52°C. IR spectrum,
ν, cm–1: 3431, 3316, 2982, 1656, 1552, 1103, 788. 1H NMR
spectrum (DMSO-d6), δ, ppm (J, Hz): 8.09 (1H, s, H-2);
Supplementary information file containing IR, 1H and 13
C
NMR spectra of the synthesized compounds is available at
the journal website at http://link.springer.com/journal/10593.
This research was financially supported by The National
Key Technology R&D Program (No. 2015BAK45B00). We
also thank the Laboratory of Organic Functional
Molecules, the Sino-French Institute of ECNU for support.
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