A convenient new and efficient commercial synthetic route for dasatinib (Sprycel)

Article abstract of DOI:10.1080/00397911.2017.1337150

A new and efficient synthetic route for dual-Src/Abl kinase inhibitor dasatinib (Sprycel), an anticancer drug, is described. This commercially viable process yields dasatinib monohydrate free of potential impurities with consistent yield of 68% in route A and 61% in route B with HPLC purity >99.80% over four stages.

Full text of DOI:10.1080/00397911.2017.1337150

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
A Convenient New and Efficient Commercial
Synthetic Route for Dasatinib (Sprycel®)
Garbapu Suresh, Ratnakaram Venkata Nadh, Navuluri Srinivasu &
Durgaprasad Yennity
To cite this article: Garbapu Suresh, Ratnakaram Venkata Nadh, Navuluri Srinivasu &
Durgaprasad Yennity (2017): A Convenient New and Efficient Commercial Synthetic Route for
Dasatinib (Sprycel®), Synthetic Communications
To link to this article: http://dx.doi.org/10.1080/00397911.2017.1337150
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Date: 09 June 2017, At: 08:05

A Convenient new and Efficient Commercial Synthetic Route for Dasatinib
(Sprycel®)
1
2
1
Garbapu Suresh , Ratnakaram Venkata Nadh , Navuluri Srinivasu and Durgaprasad
3
Yennity
1
Division of Chemistry, Department of Science and Humanities, Vignan’s Foundation for
Science Technology and Research University, Guntur, India
2
GITAM University – Bengaluru Campus, Karnataka , India
3
Division of Organic Chemistry, CSIR-National Chemical Laboratory, , Pune, India
Address Correspondence to: G. Suresh Email: garbapusuresh@gmail.com
Abstract
A new and efficient synthetic route for dual Src/Abl kinase inhibitor Dasatinib
(Sprycel®), an anticancer drug, is described. This commercially viable process yields
Dasatinib monohydrate free of potential impurities with consistent yield of 68% in route
A and 61% in route B with HPLC purity >99.80% over 4 stages.
GRAPHICAL ABSTRACT
KEYWORDS: chronic myeloid leukemia, Dasatinib monohydrate, des-hydroxy ethyl
Dasatinib, 2-bromoethanol, alkylation.
INTRODUCTION
Cancer is a genetic disease characterized by an uncontrolled cell division. As per the
st
World Health Organization (WHO) reports Cancer is a fast growing disease in 21
1

[
1]
century with an estimation of 13.1 million deaths in 2030 . Chronic myeloid leukemia
(CML) is a hematopoietic stem cell cancer that affects the blood and bone marrow. CML
is a type of myeloproliferative disease resulting in the Philadelphia (Ph) chromosomal
translocation, carrying the Bcr-Abl (Breakpoint cluster region-Abelson leukemia)
[
2]
oncogene . In view of the increased demand and seriousness of the deadly cancer
disease various tyrosine kinase inhibitors (TKIs), Imatinib, Sunitinib, Nilotinib, Dasatinib
and Lapatinib (Figure 2) are developed and are used to treat Chronic myeloid leukemia
(CML). Among these clinical agents, Dasatinib is chemically described as N-(2-chloro-6-
methylphenyl)-2-((6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-
yl)amino)thiazole-5-carboxamide.
Crystalline monohydrate form of Dasatinib 1 (Figure 1) is approved by the FDA in 2006
®
and sold under the brand name SPRYCEL , had 2015 sales of US$ 1.6 billion with
[
3]
®
projected sales of US$ 1.917 billion by 2018 . SPRYCEL is the leading kinase
inhibitor used for the treatment of chronic, accelerated, or myeloid or lymphoid blast
[4]
phase Ph+ CML with resistance or intolerance to prior therapy including Imatinib . In
addition, Dasatinib has potent activity against members of the SRC family (Src, Lck,
Fyn, Yes, Fgr, Hck, Blk, Frk) and double-digit nanomolar activity against PDGFR, c-Kit,
[
5,6]
and other members of the Ephrin and Tec kinase families, amongst others
. It is being
evaluated for use in several other cancers, including advanced prostate cancer.
In view of the significance of Dasatinib several routes were developed to make Dasatinib
monohydrate. Following are some important synthetic routes which are practiced to make
2

Dasatinib monohydrate. The Scheme 1 denotes the first and initial synthesis of Dasatinib
[
5]
.
The first step of the synthesis in Scheme 1 involves the sulphur directed ortho-lithation of
- chlorothiazole 10 followed by subsequent nucleophilic reaction with 1-chloro-2-
2
isocyanato-3-methylbenzene 11 to give the compound 2-chloro-N-(2-chloro-6-
methylphenyl)thiazole-5-carboxamide 12. Protection of amide nitrogen in 12 with 4-
methoxybenzyl chloride followed by coupling with 6-chloro-2-methylpyrimidin-4-amine
1
3a under basic medium gave an intermediate compound, 2-((6-chloro-2-
methylpyrimidin-4-yl)amino)-N-(2-chloro-6-methylphenyl)-N-(4-
methoxybenzyl)thiazole-5-carboxamide 14. Further deprotection of the para methoxy
benzyl group (PMB) of 14 afforded the penultimate intermediate, 2-((6-chloro-2-
methylpyrimidin-4-yl) amino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide 5,
which on coupling with 2-(piperazin-1-yl)ethan-1-ol (HEP) 15, gave Dasatinib free base
1
a. 1a in 2NHCl, ether/methanol medium converted into hydrochloride salt 1b. The
overall yield of this route is 61% for hydrochloride salt over six stages.
Jagabandhu Das and his co-workers reported the synthesis of Dasatinib monohydrate as
[
7]
shown in Scheme 2 . The initial step of synthesis involves the nucleophilic coupling of
amino thiazole carboxamide 9 with 4,6-dichloro-2-methylpyrimidine 8 to give
penultimate intermediate 5 in 61% yield which was coupled with 2-(piperazin-1-yl)ethan-
1
-ol (HEP) 15 and subsequent water addition to give final product Dasatinib
monohydrate 1.
3

Chen, Bang-Chi et.al reported the synthesis of Dasatinib monohydrate as depicted in
[
8]
Scheme 3 . The first step of the synthesis involves the α-bromination of β-
ethoxyacrylamide 16 followed by coupling with thiourea compound 17 to give compound
5
which was condensed with HEP 15 in n-butanol gives a pseudo polymorph crystalline
Dasatinib n-butanol solvate 1c. Further compound 1c on treatment with 80% aqueous
ethanol at 75°C yielded compound 1. The overall yield of this route is 59% over 3 stages.
Chen, Bang-Chi et.al also reported the another route of synthesis of Dasatinib, as shown
[
8]
in Scheme 4 . The first stage of synthesis involves the coupling of 8 with HEP 15 in
DCM, TEA at rt. for 2h to give intermediate, 2-(4-(6-chloro-2-methylpyrimidin-4-
yl)piperazin-1-yl)ethan-1-ol 18 which was under taken for Buchwald–Hartwig amination
with amino thiazole carboxamide 9 in the presence of K CO , Pd(OAc) and BINAP
2
3
2
yielded the crude product which on further column purification yielded 1.
These synthetic methods involve huge quantities of HEP 15 to make compound 1, which
accounts costing and generates a potential impurity called Des-hydroxy ethyl Dasatinib 2
(
DHED- Impurity) which is a tough task to remove form the final compound. Also
synthesis of 1 involves Palladium catalyst and column purification to get the compound
. As per the ICH (Q3A, R2) regulatory amendments for a new drug substance (API)
having maximum daily dose ≤ 2 g per day, the reporting identification thresholds for a
1
[
9]
known and an unspecified impurity are 0.15% and 0.10% respectively . Further, as per
the International Conference on Harmonization (ICH) guideline (ICH Q3D) for a drug
4

substance the permitted daily exposure (PDE) limit for Palladium (Pd) is 100 µg/day or
00 ppm or 0.01% for an oral exposure. It is a tough task to achieve the desired yield and
1
purity by avoiding impurities, especially impurity 2 & 5. Also It is challenging task to
achieve the acceptable limits of Palladium (Pd) (limit < 100 ppm) as per the ICH
[10]
guidelines to meet the pharmaceutical compositions , which required a series of
purifications, resulting in low yield.
Considering the lacunas of the prior art synthetic routes, we became intrigued by the
possibility of streamlining the synthesis of 1 and designed an alternative synthetic route
by considering the following points.
a)
By avoiding the use of highly reactive premade organometallic species and
hazardous chemicals.
b)
c)
To make high purity Dasatinib monohydrate.
To develop a robust process with consistent yield and quality.
As a part of our research for developing an alternative synthetic route for Dasatinib
monohydrate 1, we designed our synthetic route as depicted in Scheme 6.
The requisite key starting material for this study, 2-amino-N-(2-chloro-6-
methylphenyl)thiazole-5-carboxamide 9 is made accordingly as shown in Scheme 5
The first step of the synthesis involves the Boc protection of amine 19 with Boc
anhydride to give compound 20 in 68% yield, which was hydrolyzed by NaOH in
[
11]
.
5

THF/MeOH to give 21 in 94% yield. Compound 21 was treated with oxalyl chloride and
coupling with amine 22, yielded compound 23 in 51% yield. Deprotection of Boc
functional in compound 23 with Trifluoroacetic acid (TFA) in DCM yields the key
intermediate amino thiazole carboxamide 9 in 89% yield as off white solid.
RESULTS AND DISCUSSION
Present synthetic route deals with the synthesis of crystalline Dasatinib monohydrate 1
via two synthetic paths, route A and route B as shown in Scheme 6. The developed four
stages process yielded compound 1 with an overall yield of 68% in route A and 61% in
route B. The first step of synthesis in route A and B deals with the nucleophilic
displacement of the chlorine in 4,6-dichloro-2-methylpyrimidine 8 with 2-amino-N-(2-
chloro-6-methylphenyl)thiazole-5-carboxamide 9 in presence of base, Sodium tert-
[
12]
butoxide (STB-Solid) yielded intermediate 5 about 76% . In view of the costing and
safe industrial operations, attempts have made to optimize the reaction conditions to get
the optimum yield of compound 5 (94%) with 98.3% HPLC purity. Optimization was
done using various reaction media, inorganic bases NaH, NaNH , Solid KOtBu, KOtBu
2
in THF (25%), NaOtBu in THF (~30%) to obtain the better yield and quality. Finally,
obtained 94% yield with 98% HPLC purity by carrying out the reaction in 28-30%
NaOtBu in THF solution at 10-20°C for 1h. Experimental results are tabulated in Table-
1
.
In route A second step deals with coupling of compound 5 with Boc-piperazine 6 in n-
pentanol, yielded the intermediate, tert-butyl 4-(6-((5-((2-chloro-6-
6

methylphenyl)carbamoyl)thiazol-2-yl)amino)-2-methylpyrimidin-4-yl)piperazine-1-
[5]
carboxylate 3 in 84% yield . The structure of the intermediate 3 was established on the
basis of its spectral data.
Thus compound 3 was obtained as off white solid. Its positive quasi molecular ion peak
+
+
at m/z 544.1 [M + H] along with Boc eradicated fragment m/z 444.1 [M + H] in mass
spectrum is compatible with the molecular formulae C H ClN O S Presence of sharp
2
5
30
7
3 .
1
singlet at δ 1.40 along with other thiazole protons in H NMR spectrum confirms the
1
3
existence of Boc functional in compound 3. In C NMR of 3 Boc carbons appeared at δ
9.13 and 80.21. Intermediate 3 on Boc deprotection in dilute hydrochloric acid afforded
the penultimate intermediate, N-(2-chloro-6-methylphenyl)-2-((2-methyl-6-(piperazin-1-
2
[
13]
yl)pyrimidin-4-yl)amino)thiazole-5-carboxamide (DHED) 2 in 93.5% yield
.
In route B second step deals with the coupling of compound 5 with N-formyl piperazine
, in DMF gave novel intermediate, N-(2-chloro-6-methylphenyl)-2-((6-(4-
formylpiperazin-1-yl)-2-methylpyrimidin-4-yl) amino) thiazole-5-carboxamide 4 in 79%
7
[
5]
yield .
The structure of the novel intermediate 4 was confirmed on the basis of its spectral data.
Thus compound 4 was obtained as off white solid. Its negative quasi molecular ion peak
-
at m/z 470.3 [M - H] in mass spectrum is compatible with the molecular formulae
C H ClN O S Presence of sharp singlet at δ 8.10 along with other thiazole protons in
21
22
7
2 .
1
H NMR spectrum confirms the presence of formyl (CHO) functional in compound 4. In
7

1
3
C NMR of compound 4 formyl carbon appeared at δ 160.91. Deformylation of
compound 4 in presence of H SO , methanol yielded the penultimate intermediate,
2
4
DHED 2 in 91% yield.
The, Synthesized Des-hydroxy ethyl Dasatinib (DHED) intermediate 2 is fully
1
13
characterized by UV, IR, H NMR, C NMR and mass spectral data.
Finally, alkylation of 2 with 2-bromoethanol in the presence of K CO , NaI, in
2
3
Acetonitrile followed by the water addition at 70-75°C, yielded the targeted compound 1
[
14]
.
Efforts have been made to optimize the base and solvent to get the optimum yield and
quality of the compound 1. Based on the experimental results, refluxing acetonitrile for
h in basic Cs CO resulted the optimum yield and quality. Experimental results are
6
2
3
tabulated in Table-2.
Ultimately, we made the target compound 1 with consistent yield of 68% in route A and
6
1% in route B with 99.91% and 99.89% HPLC purity respectively. Yields, % impurity
and purity levels of compound 1 by HPLC are tabulated in Table-3. The Desired
polymorph, crystalline Dasatinib monohydrate 1 was confirmed by p-XRD, DSC and
TGA spectral data. All the intermediates, novel compounds and final drug substance
1
13
described herein were fully characterized by IR, H NMR, C NMR, Mass and
Elemental analyses as listed in the experimental data.
CONCLUSION
8

In conclusion, we have successfully developed an alternative synthetic route to make
Dasatinib monohydrate with the following merits,
a)
b)
Practical and industrially viable process
Better yield. 68% in route-A, 61% in route B from compound 9 and an overall
yield of 20 % in route A, 18.2% in route B from commercially available thiazole amine
9.
c)
1
Pure Dasatinib monohydrate with total impurities < 0.10%.
The Desired polymorph, crystalline Dasatinib monohydrate 1 was confirmed by p-XRD,
DSC and TGA spectral data.
EXPERIMENTAL
All of the chemicals were obtained from commercial sources and used without further
purification. Melting points were determined in open glass capillaries on a Fisher–Johns
1
13
melting point apparatus and are uncorrected. NMR ( H 400 MHz; C 100 MHz) were
recorded at room temperature in DMSO as solvent and TMS as an internal standard (δ =
0
ppm), and the values were reported in the following order: chemical shift (δ in ppm),
multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet
of doublet), coupling constants (J in Hz), and integration. p-XRD was recorded on Bruker
D8 Focus Powder X-ray Diffractometer. DSC and TGA were done on PerkinElmer
instruments Q2000, Q50 respectively. All the reactions were monitored by thin layer
9

chromatography (TLC) on precoated silica gel 60 F254 (mesh); spots were visualized
under UV light at 254 nm.
Typical Experimental Procedure For The Key Compounds:Tert-Butyl 4-(6-((5-((2-
Chloro-6-Methylphenyl)Carbamoyl)Thiazol-2-Yl)Amino)-2-Methylpyrimidin-4-
Yl)Piperazine-1-Carboxylate (3)
To the stirred suspension of compound 5 (10.0 g, 0.03 mol), in n-pentanol (120.0 mL)
was added N-Boc piperazine (9.5g, 0.05 mol)) and N,N-diisopropylethylamine (DIPEA)
(6.6 g, 0.06 mol) and refluxed for 8h, cooled to 25-30°C and charged water (80.0 mL).
The precipitated solid was collected by vacuum filtration and washed the wet cake with
n-pentanol (15.0 mL) followed by water (30.0 mL), yielded the intermediate 3 (11.6 g,
8
4%) as off white solid.
1
MR: 293-295°C; IR (KBr, cm- ): 3397.4 (N-H), 3061.7 (Ar C-H), 1617.0 (amide C=O);
1
1
1
706.9 ( Boc C=O); H NMR spectrum (400 MHz, DMSO-d6), δ, ppm (J, Hz): 11.53 (bs,
H, thiazole-NH), 9.89 (s, 1H, amide-NH), 8.23 (s, 1H, thiazole-H), 7.40 (d, 1H, J =6.9,
Ar-H), 7.30-7.23 (m, 2H, Ar-H), 6.06 (s, 1H, pyrimidine-H), 3.53 (bs, 4H, piperazine-
CH ), 3.42 (bs, 4H, piperazine-CH ), 2.42 (s, 3H, Ar-CH ), 2.24 (s, 3H, pyrimidine-CH ),
2
2
3
3
1
3
1
.40 (s, 9H, Boc-CH ); C NMR spectrum (100 MHz, DMSO-d6), δ, ppm: 165.2
3
(
(
(
(
pyrimidine-C), 162.4 (pyrimidine-C), 161.9 (pyrimidine-C), 160.1 (amide-C), 156.9
thiazole-C), 151.4 (Boc-C), 140.5 (Ar-C), 139.1 (thiazole-C), 133.7 (thiazole-C), 132.0
Ar-C), 129.5 (Ar-C), 128.4 (Ar-C), 127.6 (Ar-C), 125.1 (pyrimidine-C), 81.6
pyrimidine-C), 80.2 (Boc-C), 50.2 (piperazine-2C), 49.9 (piperazine-2C), 29.1 (Boc-
10

CH ), 25.6 (Ar-CH ), 18.2 (pyrimidine-CH ); HPLC Purity 96.7%; MS (ESI) m/z 544.1
3
3
3
+
[
M + H] ; Anal. Calcd % for C H ClN O S: C 55.19; H 5.56; N 18.02. Found: C 55.07;
25 30 7 3
H 5.41; N 18.17.
N-(2-Chloro-6-Methylphenyl)-2-((6-(4-Formylpiperazin-1-Yl)-2-Methylpyrimidin-4-
Yl)Amino)Thiazole-5-Carboxamide (4)
To the stirred suspension of compound 5 (10.0 g, 0.03 mol), in N,N-dimethylformamide
(DMF) (10.0 ml) was added N-formyl piperazine (5.78, 0.05 mol), N,N-
diisopropylethylamine (DIPEA) (6.53 g, 0.05 mol) and heated for 5h at 80-85°C, cooled
to 25-30°C. The precipitated solid was collected by vacuum filtration and washed the wet
cake with water (30.0 mL) yielded the novel intermediate 4 (9.4 g, 79%) as off white
solid.
1
MR: 291-293°C; IR (KBr, cm- ): 3395.3 (N-H), 2923.7 (Ar C-H), 1660.5(amide C=O);
1
1
1
773.1 (aldehyde C=O); H NMR spectrum (400 MHz, DMSO-d6), δ, ppm (J, Hz):
1.54 (s, 1H, thiazole-NH, exchangeable with D O), 9.89 (s, 1H, amide-NH,
2
exchangeable with D O), 8.23 (s, 1H, thiazole-H), 8.10 (s, 1H, aldehyde-H), 7.40 (d, 1H,
2
J =7.3, Ar-H), 7.30-7.24 (m, 2H, Ar-H), 6.10 (s, 1H, pyrimidine-H), 3.59-3.55 (bs, 4H,
piperazine-CH ), 3.48 (bs, 4H, piperazine-CH ), 2.41 (s, 3H, Ar-CH ), 2.24 (s, 3H,
2
2
3
1
3
pyrimidine-CH ); C NMR spectrum (100 MHz, DMSO-d6), δ, ppm: 166.1 (pyrimidine-
3
C), 163.1 (pyrimidine-C), 162.6 (pyrimidine-C), 160.9 (aldehyde-C), 159.2 (amide-C),
1
1
57.5 (thiazole-C), 141.9 (Ar-C), 139.6 (thiazole-C), 132.9 (thiazole-C), 132.1 (Ar-C),
29.2 (Ar-C), 128.4 (Ar-C), 127.0 (Ar-C), 124.6 (pyrimidine-C), 81.6 (pyrimidine-C),
11

4
4.1 (piperazine-2C), 44.0 (piperazine-2C), 25.1 (Ar-CH ), 18.4 (pyrimidine-CH );
3 3
-
HPLC Purity 97.3%; MS (ESI) m/z 470.3 [M - H] ; Anal. Calcd % for C H ClN O S: C
2
1
22
7
2
5
3.44; H 4.70; N 20.77. Found: C 53.32; H 4.73; N 20.81.
N-(2-Chloro-6-Methylphenyl)-2-((2-Methyl-6-(Piperazin-1-Yl)Pyrimidin-4-
Yl)Amino)Thiazole-5-Carboxamide (2)
Con. sulfuric acid (9.36 g, 0.1 mol) was added to the stirred suspension of compound 4
9.0 g, 0.02 mol) in methanol (108.0 mL) at 5-10°C and heated for 5h at 60-65°C, cooled
(
to 25-30°C. Water (90.0 mL) was added, resulting suspension stirred for 3h at 25-30°C.
The precipitated solid was collected by vacuum filtration and washed the wet cake with
methanol (27.0 mL), water (36.0 mL) yielded the novel intermediate 2 (7.5 g, 91%,
HPLC purity 98.34%) as off white solid.
Similarly, the other Boc-protected compound 3 was deprotected to give compound 2, by
following the same procedure as depicted for compound 4.
1
MR: 298-301°C; IR (KBr, cm- ): 3435.8 (N-H), 2950.2 (Ar C-H), 1620.0 (C=O); UV
1
(
Methanol): ʎ max, 323.7 nm; H NMR spectrum (400 MHz, DMSO-d6), δ, ppm (J, Hz):
9
.88 (s, 1H, amide-NH), 8.23 (s, 1H, thiazole-H), 7.39 (d, 1H, J =5.9, Ar-H), 7.29-7.23
m, 2H, J =7.5, Ar-H), 6.04 (s, 1H, pyrimidine-H), 3.48 (t, 4H, piperazine-CH ), 2.79 (t,
(
2
13
4
H, J =4.8, piperazine-CH ), 2.40 (s, 3H, Ar-CH ), 2.23 (s, 3H, pyrimidine-CH ); C
2 3 3
NMR spectrum (100 MHz, DMSO-d6), δ, ppm: 165.1 (pyrimidine-C), 162.6
pyrimidine-C), 162.5 (pyrimidine-C), 160.0 (amide-C), 156.9 (thiazole-C), 140.9 (Ar-
(
12

C), 138.8 (thiazole-C), 133.5 (thiazole-C), 132.5 (Ar-C), 129.0 (Ar-C), 128.2 (Ar-C),
27.0 (Ar-C), 125.7 (pyrimidine-C), 82.6 (pyrimidine-C), 45.3 (piperazine-2C), 44.8
1
+
(
piperazine-2C), 25.6 (Ar-CH ), 18.3 (pyrimidine-CH ); MS (ESI) m/z 444.1 [M + H] ;
3 3
Anal. Calcd % for C H ClN OS: C 54.11; H 4.99; N 22.08. Found: C 54.02; H 5.12; N
2
0
22
7
2
2.17; HPLC Purity 98.34%.
N-(2-Chloro-6-Methylphenyl)-2-((6-(4-(2-Hydroxyethyl)Piperazin-1-Yl)-2-
Methylpyrimidin-4-Yl)Amino)Thiazole-5-Carboxamide Monohydrate (1)
2
-bromoethanol (3.9 g, 0.03), Cs CO (10.2 g, 0.03 mol), KI (0.17g, 1 mmol) was added
2 3
to a stirred suspension of compound 2 (7.0 g, 0.02 mol), in acetonitrile (105.0 mL) and
refluxed for 6h. Water (280.0 mL) was added slowly at 75-80°C, cooled to 25-30°C and
stirred for 2h. The precipitated solid was collected by vacuum filtration, washed the wet
cake with Acetonitrile (28.0 mL), water (35.0 mL), yielded the final compound,
Dasatinib monohydrate 1 (7.4 g, 93%) as a white solid.
1
MR: 279-280 °C (free base); IR (KBr, cm- ): 3421.5 (N-H), 3250.58 (O-H), 1618.3
1
(
C=O); UV (Methanol): ʎ max, 322.16 nm; H NMR spectrum (400 MHz, DMSO-d6), δ,
ppm (J, Hz): 10.47 (bs, 1H, thiazole-NH), 9.88 (s, 1H, amide-NH), 8.22 (s, 1H, thiazole-
H), 7.40 (dd, 1H, J =6.1, 1.2, Ar-H), 7.30-7.23 (m, 2H, J =7.3, Ar-H), 6.04 (s, 1H,
pyrimidine-H), 4.46 (t, J = 4.8, -OH), 3.54-3.51 (m, 6H, -CH CH OH & piperazine-CH ),
2
2
2
2
.48-2.46 (m, 4H, piperazine-CH ), 2.44-2.42 (m, 2H, -CH CH OH), 2.40 (s, 3H, Ar-
2 2 2
1
3
CH ), 2.24 (s, 3H, pyrimidine-CH ); C NMR spectrum (100 MHz, DMSO-d6), δ, ppm:
3
3
1
65.2 (pyrimidine-C), 162.6 (pyrimidine-C), 162.4 (pyrimidine-C), 160.0 (amide-C),
13

1
1
6
56.9 (thiazole-C), 140.9 (Ar-C), 138.8 (thiazole-C), 133.5 (thiazole-C), 132.5 (Ar-C),
29.0 (Ar-C), 128.2 (Ar-C), 127.0 (Ar-C), 125.7 (pyrimidine-C), 82.6 (pyrimidine-C),
0.2 (piperazine-2C), 58.5 (piperazine-2C), 52.7 (CH ), 43.6 (CH ), 25.6 (Ar-CH ), 18.4
2
2
3
+
(
pyrimidine-CH ); MS (ESI) m/z 488.6 [M + H] ; Anal. Calcd % for C H ClN O S: C
3 22 28 7 3
5
2
4.15; H 5.37; N 20.09. Found: C 54.13; H 5.36; N 20.13; HPLC Purity: 99.91% (t =
R
7.4 min.); 2-brpmoethanol content by Headspace GC: 3 ppm; p-XRD: Observed 2ϴ
values at 18.0, 18.4, 19.2, 19.6, 21.2, 24.5, 25.9; 28.0; DSC (Differential scanning
calorimetry): Obtained endotherm at 287.23°C (92.05 J/g); TGA (Thermogravimetric
[
5,9]
analysis): weight (water) loss (%) = 3.488
.
SUPPORTING INFORMATION
1
13
Full experimental detail, elemental analysis, Mass, H NMR, C NMR Spectra and
characterization data for all synthesized compounds can be found via the “Supplementary
Content” section of this article’s webpage.
REFERENCES
[
1] (a) X Wu; HZeng; X Zhu; Q Ma; Y Hou; X Wu. Eur. J. Pharm. Sci. 2013, 50, 323-
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16

Table-1. Optimization data of synthesized compound (5).
b
Base Mole DCMP Mole
a
c
Entry
Base
Temp (°C)
Yield (%)
Eq.
2.0
3.0
4.0
4.0
Eq.
1.1
1.1
1.1
1.1
1
2
3
4
Solid NaOtBu.
Solid NaOtBu.
Solid NaOtBu.
Sodium hydride
10-20
10-20
10-20
10-20
45
62
76
71
(NaH)
5
6
7
8
Sodamide (NaNH2)
Solid KOtBu.
25% KOtBu. in THF
28-30% NaOtBu. in
THF
4.0
4.0
4.0
3.0
1.1
1.1
1.1
1.1
10-20
10-20
10-20
10-20
73
68
69
71
9
1
1
1
28-30% NaOtBu. in
THF
4.0
4.0
4.0
4.0
1.1
1.2
1.2
1.0
10-20
10-20
0-5
84
94
88
0
1
2
28-30% NaOtBu. in
THF
28-30% NaOtBu. in
THF
28-30% NaOtBu. in
THF
10-20
~ 8%
unreacted
starting
material
17

a
b
c
All the reactions are carried out in THF solvent for 1 h
DCMP, 4,6-dichloro-2-methyl pyrimidine
Isolated yields of compound (5).
18

Table-2. Optimization data of synthesized compound (1).
a
Entry
Base
Solvent
Temp. (°C)
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
125
Yield (%)
1
2
3
4
5
6
7
8
9
K CO
2
Acetonitrile / H O
84
93
78
45
51
--
3
2
Cs CO
Acetonitrile / H O
2
3
2
Na CO
Acetonitrile / H O
2
3
2
DIPEA
DMAP
NaOH
Cs CO
Acetonitrile / H O
2
Acetonitrile / H O
2
Acetonitrile / H O
2
1,4-dioxane / H O
69
71
84
2
3
2
Cs CO
n-butanol / H O
2
3
2
Cs CO
DMF / H O
2
3
2
a
Isolated yields of compound (1).
19

Table-3. Yields and Quality of compound (1).
%
Impurity and purity levels of compound (1) by
HPLC
No of
Entry Scheme
Yield (%)
Imp
D
Stages
Imp A Imp B Imp C
Imp E
1
TI
(9)
(5)
(2)
(4)
(3)
6
from
1
2
3
4
1
2
3
4
compound 61
NA
1
0
2
from
compound 57
0.31
0.21
NA
0.42
0.29
0.21
0.16
NA NA
NA NA
98.91 1.09
99.23 0.44
9
3
from
compound 59
1
6
2
from
compound 61
8
6
8 (Route
4
from
0.02
0.01
0.01
0.02
0.02
0.03
ND NA
NA ND
99.91 0.04
99.89 0.06
A)
5
6
compound
6
1 (Route
9
B)
NA = Not applicable, ND = Not detected, Imp = Impurity. TI = Total impurities
20

[5]
Scheme 1. The first reported synthesis of Dasatinib and its hydrochloride salt .
21

[
7]
Scheme 2. Synthesis of Dasatinib monohydrate .
22

[
8]
Scheme 3. Synthesis of Dasatinib monohydrate .
23

[
8]
Scheme 4. Synthesis of Dasatinib .
24

[11]
Scheme 5. Synthetic route for key starting material 9
.
25

Scheme 6. Present synthetic route for Dasatinib monohydrate.
26

Figure 1. Structure of Dasatinib monohydrate
27

Figure 2. Chemical structures of Kinase inhibitors (tinibs)
28

Figure 3 Structures of novel intermediate (4) and (3).
29