A new route for the synthesis of Palbociclib

Article abstract of DOI:10.1007/s11696-019-00841-7

Abstract: In this paper, a novel synthetic method for Palbociclib was reported. It was synthesized in eight steps from 2-(methylthio) pyrimidin-4-(3H)-one with approximately 10% overall yield. This protocol started material 2-(methylthio) pyrimidin-4-(3H)-one, involved nucleophilic substitution by thionyl chloride, bromination, nucleophilic substitution by cyclopentylamine, a one pot-two step method (Heck reaction, ring close sequence), oxidation and bromination, cross-coupling reaction, Heck reaction, aqueous workup to afford Palbociclib. This synthetic route used inexpensive raw material and reagents, involved readily controllable reaction conditions and reduced environmental hazards. Graphic abstract: Synthesis of Palbociclib, a small molecule CDK inhibitor, starting from 2-(methylthio) pyrimidin-4-(3H)-one by 8 steps reaction. This method afforded the Palbociclib in 10% yield. [Figure not available: see fulltext.].

Full text of DOI:10.1007/s11696-019-00841-7

Chemical Papers
https://doi.org/10.1007/s11696-019-00841-7
ORIGINAL PAPER
A new route for the synthesis of Palbociclib
Shu‑ting Li1 · Jun‑qing Chen1 · Cheng‑liang Feng2 · Wan‑feng Yang1 · Min Ji3
Received: 6 March 2019 / Accepted: 1 June 2019
© Institute of Chemistry, Slovak Academy of Sciences 2019
Abstract
In this paper, a novel synthetic method for Palbociclib was reported. It was synthesized in eight steps from 2-(methylthio)
pyrimidin-4-(3H)-one with approximately 10% overall yield. This protocol started material 2-(methylthio) pyrimidin-4-(3H)-
one, involved nucleophilic substitution by thionyl chloride, bromination, nucleophilic substitution by cyclopentylamine, a
one pot-two step method (Heck reaction, ring close sequence), oxidation and bromination, cross-coupling reaction, Heck
reaction, aqueous workup to aford Palbociclib. This synthetic route used inexpensive raw material and reagents, involved
readily controllable reaction conditions and reduced environmental hazards.
Graphic abstract
Synthesis of Palbociclib, a small molecule CDK inhibitor, starting from 2-(methylthio) pyrimidin-4-(3H)-one by 8 steps
reaction. This method aforded the Palbociclib in 10% yield.
Keywords CDK · CDK inhibitor · Palbociclib · Synthesis
Introduction
and Barbacid 2005; Harper and Adams 2001). Cyclin-
dependent kinases (CDKs) can regulate the cell cycle and
thus control transcriptional process, which is important
pathway for cell cycle regulatory machinery. CDKs 1, 2, 4,
6, and 7 are important drivers of the cell cycle, resulting in
division of a cell into two identical daughter cells by highly
orchestrated series of events (Malumbres et al. 2009; Diaz-
Moralli et al. 2013). Incorrect regulation of cyclin-dependent
kinases (CDKs) will lead to uncontrolled cell division and
Cyclin-dependent kinases (CDKs) are heterodimeric pro-
teins that comprise of a catalytic subunit (Cdk) and a mem-
ber of a family of regulatory subunits (cyclins). (Malumbres
* Jun-qing Chen
jqchen@seu.edu.cn
Extended author information available on the last page of the article
Vol.:(0123456789)
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metastasis, and then cause cancer. (Gupta et al. 2016; Bol-
lard et al. 2017). Palbociclib (1) (Fig. 1) (also IBRANCE)
is an efective anti-proliferative agent against Rb-positive
tumor cells in retinoblastoma, which inhibits Ser780/Ser795
phosphorylation on Rb protein to induce G1 arrest (Kim and
Scott 2017; Fry et al. 2004). In February 2015, the United
States Food and Drug Administration (FDA) approved
Palbociclib as a frst selective inhibitor of the CDK4/6 for
marketing. It was approved for using in combination with
letrozole as initial endocrine-based therapy for metastatic
disease in postmenopausal women with HR-positive, HER2-
negative breast cancer, and combination with fulvestrant in
women with HR-positive, HER2-negative advanced breast
cancer with disease progression following endocrine (Rocca
et al. 2017; Konecny 2016).
5-bromo-2,4-dichloropyrimidine (13) by six-step reaction
(Scheme 2) (Duan et al. 2016; Maloney et al. 2016; Chekal
et al. 2016). It also required the transformation of 5-bromo-
2,4-dichloropyrimidine (13) into intermediate 11. In displace-
ment of the chlorine of intermediate 13 to give intermediate
14, the presence of chlorine at the 2 and 4 positions selectively
afected the reaction yield and separation. The use of the high
boiling point solvent NMP in the Heck reaction increased the
difculty in post-reaction processing, resulting in difculty in
separating the purifed product. Overall, this procedure short-
ened the reaction step to six-step and achieved a relatively
high yield. However, the cost of this method was the higher,
not only used the palladium catalyst twice, but also used raw
materials expensive.
Another route investigated employed a convergent palla-
dium-catalyzed amination reaction (Scheme 3) (Nathel et al.
2014). Intermediate 18 was readily available by reaction
of intermediate 16 (Scheme 2) with a methanol solution of
ammonia. Hence, this method could share starting materials
with the Scheme 2 but involved diferent intermediates. While
the amino compound 18 readily underwent a Heck reaction to
produce intermediate 19 compared with intermediate 11, the
use of two palladium-catalyzed steps increased the accumu-
lation of palladium in the process, which increased the dif-
fculties to remove residual metals from the process (Carpino
2000). These problems also restricted large-scale synthesis of
Palbociclib and this procedure did not develop further.
Hence, we designed a novel route for the synthesis of Pal-
bociclib using an economic starting material 2-(methylthio)
pyrimidin-4-(3H)-one (20) and involving eight-step reaction
(Scheme 4). In the present procedure, it required the trans-
formation of 2-(methylthio) pyrimidin-4-(3H)-one (20) into
intermediate 10. In the key synthetic reaction, the intermediate
8 was formed by two-step heck reaction-ring close sequence
employing crotonic acid followed by acetic anhydride. After
oxidizing the 2-position methylthio group while introduc-
ing bromine, intermediate 8 aforded intermediate 10. This
strategy could also assist in developing a facile route for pre-
paring 6-bromo-8-cyclopentyl-5-methyl-2-(methylsulfnyl)
pyrido[2,3-d] pyrimidin-7(8H) (10). The next steps could
share intermediate but involve diferent reagents with previ-
ous route. After cross-coupling reaction, Heck reaction, aque-
ous workup, intermediate 11 gave Palbociclib. Overall, this
method ofered a route based on good yields, with low cost,
readily controllable reaction conditions and reduced environ-
mental hazards.
Palbociclib was first synthesized by Pfizer in 2005,
involved substitution reaction, a series of redox reactions,
Wittig-Horner reaction, bromination reaction, cross-cou-
pling reaction, Stille reaction, Boc deprotection procedure,
and hydrolysis reaction. The starting material 4-chloro-
2-methylthio-pyrimidine-5-carboxylic acid ethyl ester (2)
was expensive and the synthesis process required eleven-
step sequence (Scheme 1) (Toogood et al. 2005; Vander-
Wel et al. 2005). According to this procedure to prepare
Palbociclib would encountered problems that required
optimization of the original synthetic procedures. In a two-
step reduction–oxidation sequence employing lithium alu-
minum hydride followed by manganese (IV) to convert ester
3 to aldehyde 5, this step required an ultra-low temperature
(− 78 °C) and isolation of air and water to add reducing
agent (LiAlH4). It also required strict conditions to use
Grignard reagents to convert aldehyde 5 to alcohols 6 and
to use NaH in Wittig-Horner reaction to synthesize methyl
sulfdes 8. These represented difculties if carried out on a
large scale. In summary, this synthetic route was fairly labor
intensive, not only required harsh conditions but also used
expensive and unstable reagents. In addition, the method
had a long route and a low yield (3–4%), not suitable for
industrialization.
An alternative way for the preparation of Palbo-
ciclib has been reported in relatively high yield from
Fig. 1 Palbociclib
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Scheme 1 The frst synthetic strategy for the preparation of Palbociclib
Scheme 2 The second synthetic strategy for the preparation of Palbociclib
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Scheme 3 The third synthetic strategy for the preparation of Palbociclib
Scheme 4 The new synthetic strategy for the preparation of the Palbociclib
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Chemical Papers
concentrated in vacuo. The residue was purifed by passing
the organic extract through a silica gel column using PE/EA
(25:1) to give the product 22 (Elliott 1981). White solid;
yield 73%; m.p. 48.5–50.1 °C; 1H NMR (300 MHz, CDCl3)
δ 8.54 (s, 1H), 2.55 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
172.1, 159.5, 114.1, 14.7; HRMS ([M+H]+): m/z calcd for
[(C5H4BrClN2S)+H]+: 240.90254, found: 240.90203.
Experimental
Materials and instruments
The solvents, reagents and materials were commercially
available and were used without further purifcation unless
otherwise noted. All reactions were monitored by thin-layer
chromatography (TLC) on silica gel plates (GF-254, Qing-
dao Ocean Chemical Company, China). Silica gel column
chromatography (CC) (200–300 mesh, Qingdao Marine
chemical industry corporation, China). Melting points
were determined on a YRT-3 drug melting point meter and
were uncorrected. NMR spectra were recorded on a Bruker
Avance DPX-300 MHz/500 MHz instrument in CDCl3 with
tetramethylsilane (TMS) as an internal reference and the
chemical shifts (δ) were reported in parts per million (ppm).
High resolution mass spectra (HRMS) were obtained from
Agilent 1100 LC/MS Spectrometry Services.
Synthesis of 5‑bromo‑N‑cyclopentyl‑2‑(methylthio)
pyrimidin‑4‑amine (23)
To a solution of 4-chloro-5-bromo-2-(methylthio) pyrimi-
dine (22, 10.70 g, 44.8 mmol) in dioxane (40 mL), DIPEA
(14.77 mL, 89.4 mmol) and cyclopentylamine (5.56 mL,
67.0 mmol) were added into the solution. After comple-
tion of the addition, the reaction mixture was stirred at
100 °C for 4 h. After quenching with water, the solution
was extracted with ethyl acetate and saturated NaHCO3
solution three times. The combined organic phases were
dried over MgSO4, filtered, and concentrated in vacuo.
The residue was purifed by passing the organic extract
through a silica gel column using PE/EA (15:1) to give
the product 23 (patent WO2004065378). Yellow oil; yield
90%; 1H NMR (300 MHz, CDCl3) δ 8.03 (s, 1H), 5.24 (s,
1H), 4.42-4.33 (m, 1H), 2.48 (s, 3H), 2.12–2.06 (m, 2H),
1.77–1.62 (m, 4H), 1.51–1.45 (m, 2H); 13C NMR (75 MHz,
CDCl3) δ 170.3, 157.1, 154.8, 99.8, 52.9, 33.2, 23.8, 14.4;
HRMS ([M+Na]+): m/z calcd for [(C10H14BrN3S)+Na]+:
311.99690, found 311.99651.
Synthesis of 4‑chloro‑2‑(methylthio) pyrimidine (21)
To a solution of 2-methylthio-4-ketopyrimidine (20, 10 g,
70.3 mmol) in DCM (20 mL) and DMF (10 mL) mixed solu-
tion, thionyl chloride (3.07 mL, 42.2 mmol) solution was
slowly added dropwise while heating. After addition, the
reaction mixture was stirred at 40 °C for 3 h. After quench-
ing with saturated NaHCO3 the solution was adjusted to a
neutral pH and the solution was extracted three times with
DCM. The organic phases were washed with saturated
NaHCO3 solution and saturated NaCl solution and dried
over anhydrous Na2SO4. After fltering to remove the anhy-
drous Na2SO4, the solution was distilled at 40 °C to remove
solvents under atmospheric pressure to give the product 21
(Katritzky et al. 1989; Davey et al. 2007). Yellow oil; yield
Synthesis of 8‑cyclopentyl‑5‑methyl‑2‑(methylthio)
pyrido[2,3‑d] pyrimidin‑7(8H)‑one (8)
To a solution of 5-bromo-N-cyclopentyl-2-(methylthio)
pyrimidin-4-amine (23, 11.64 g, 40.4 mmol) and cro-
tonic acid (5.22 g, 60.6 mmol) in DMF (100 mL), DIPEA
(28.14 mL, 166.4 mmol) were added. Then palladium
dibenzylcarbonitrile (465 mg, 1.2 mmol) and tri-o-tol-
ylphosphorus (860 mg, 3.0 mmol) were added under a
nitrogen atmosphere. After completion of the addition,
the reaction mixture was stirred at 130 °C for 24 h under
nitrogen protection. After 24 h, acetic anhydride (25 mL)
was added and the solution was stirred at 70 °C for 4 h.
Then the mixture was cooled, diluted with MTBE (100 mL)
and then extracted with NH4Cl, NaHCO3 and water. The
organic phases were combined, dried MgSO4, fltered, and
concentrated in vacuo. The residue was purifed by pass-
ing the organic extract through a silica gel column using
PE/EA (15:1) to give the product 8 (Toogood et al. 2005;
VanderWel et al. 2005). Gray white solid; yield 76%; m.p.
201.2–202.4 °C; 1H NMR (300 MHz, CDCl3) δ 8.68 (s, 1H),
6.41 (s, 1H), 5.97–5.82 (m, 1H), 2.61 (s, 3H), 2.36 (m, 5H),
2.06 (s, 2H), 1.87 (s, 2H), 1.69 (d, J= 10.3 Hz, 3H); 13C
1
88%; H NMR (300 MHz, CDCl3) δ 8.38 (d, J = 5.2 Hz,
1H), 6.99 (d, J = 5.2 Hz, 1H), 2.53 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 174.0, 161.0, 158.0, 116.4, 14.3; HRMS
([M+H]+): m/z calcd for [(C5H5ClN2S)+H]+: 160.99404;
found 160.99335.
Synthesis of 4‑chloro‑5‑bromo‑2‑(methylthio)
pyrimidine (22)
To a solution of 4-chloro-2-(methylthio)-pyrimidine (21,
9.90 g, 61.6 mmol) in MeOH (28 mL) and MeCN (20 mL)
mixed solution, NBS (13.16 g, 73.9 mmol) was added
(2×6.58 g). After the additions, the reaction mixture was
stirred at room temperature. After quenching with saturated
Na2SO3 solution, the solution was extracted with DCM
and saturated NaHCO3 solution three times. The com-
bined organic phases were dried over MgSO4, fltered, and
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NMR (75 MHz, CDCl3) δ 163.0, 154.1, 144.0, 122.0, 111.0,
53.8, 28.4, 25.8, 17.2, 14.5; HRMS ([M+Na]+): m/z calcd
for [(C14H17N3OS)+Na]+: 298.09903, found 298.09853.
1.95–1.84 (m, 2H), 1.74–1.64 (m, 2H), 1.49 (s, 9H); 13C
NMR (75 MHz, CDCl3) δ 159.05, 157.84, 156.40, 154.96,
154.77, 145.59, 143.64, 143.49, 136.80, 127.04, 117.62,
113.67, 108.20, 80.26, 77.16, 55.29, 49.90, 43.62, 28.58,
28.44, 26.16, 18.19; HRMS ([M + H]+): m/z calcd for
[(C27H34BrN7O3)+H]+: 586.19651, found 586.19626.
Synthesis of 6‑bromo‑8‑cyclopentyl‑5‑me‑
thyl‑2‑(methylsulfnyl) pyrido[2,3‑d] pyrimi‑
din‑7(8H)‑one (10)
Synthesis of tert‑butyl 4‑(6‑((6‑(1‑butoxyvinyl)‑8‑cy‑
clopentyl‑5‑methyl‑7‑oxo‑7,8‑dihydropyrido[2,
3‑d] pyrimidin‑2‑yl) amino) pyridin‑3‑yl) pipera‑
zine‑1‑carboxylate (17)
To a solution of 8-cyclopentyl-5-methyl-2-(methylthio)
pyrido[2,3-d] pyrimidin-7(8H)-one (8, 8.49 g, 14.7 mmol) in
MeCN (100 mL), acetic acid (177 µL, 3.1 mmol), H2O (580
µL, 32.1 mmol) and NBS (17.22 g, 96.8 mmol) were added.
After completion of the addition, the reaction mixture was
stirred at room temperature for 8 h. After quenching with
water (70 mL), the solution was stirred for 10 min, fltered.
The flter cake was washed with water to obtain a white
solid. After purifcation by recrystallization with ethanol
(50 mL), the product was dried in vacuo to give the product
10 (Toogood et al. 2005; VanderWel et al. 2005). White
solid; yield 86%; m.p. 158.3–160.4 °C; 1H NMR (300 MHz,
CDCl3) δ 9.09 (s, 1H), 6.12–5.96 (m, 1H), 2.97 (s, 3H),
2.69 (s, 3H), 2.24–2.06 (m, 4H), 1.92 (d, J =9.8 Hz, 2H),
1.72–1.62 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 175.41,
160.68, 157.91, 156.66, 145.22, 126.59, 116.88, 58.30,
42.89, 31.30, 31.20, 28.60, 21.04; HRMS ([M + Na]+):
m/z calcd for [(C14H16BrN3O2S)+Na]+: 394.00243, found
394.00248.
To a solution of tert-butyl 4-(6-((6-bromo-8-cyclopentyl-
5-methyl-7-oxo-7,8-dihydropyrido[2,3-d] pyrimidin-2-yl)
amino) pyridin-3-yl) piperazine-1-carboxylate (11, 6.71 g,
11.5 mmol) in n-butanol (67 mL), n-butyl vinyl ether
(4.86 mL, 34.4 mmol), and diisopropylethylamine (4.80 mL,
27.6 mmol) was added. Then palladium acetate (52.5 mg,
0.23 mmol) and bis(2-diphenylphosphinophenyl) ether
(154 mg, 0.28 mmol) were added under a nitrogen atmos-
phere. After completion of the addition, the reaction mixture
was stirred at 85 °C overnight under nitrogen protection.
Then the mixture was cooled to 80 °C, and water (10.5 mL)
and n-butanol (20 mL) were added. Then the mixture was
stirred for 0.5 h and then quickly fltered. Water (24.5 mL,
3.5 vol) and 1,2-diaminopropane (2.96 mL, 34.4 mmol) were
added and stirred at 70 °C for 0.5 h. The aqueous phase was
removed, the organic phase was programmed to cool to room
temperature and a large amount of yellow solid precipitated.
The solids were fltered and washed twice with n-butanol
(7 mL) and three times with methyl t-butyl ether (7 mL). The
product was dried in vacuo to give the product 17 (Maloney
et al. 2016). Yellow solid; yield 80%; 1H NMR (500 MHz,
DMSO-d6) δ 9.89 (s, 1H), 8.86 (s, 1H), 8.06 (s, 1H), 7.90 (d,
J=9.0 Hz, 1H), 7.48 (d, J=11.4 Hz, 1H), 5.82 (t, J=8.7 Hz,
1H), 4.47 (s, 1H), 4.05 (s, 1H), 3.77 (t, J = 6.2 Hz, 2H),
3.48 (s, 4H), 3.11 (s, 4H), 2.37 (s, 3H), 2.23 (s, 2H), 1.90
(s, 2H), 1.74 (s, 2H), 1.64–1.60 (m, 3H), 1.43 (s, 9H), 1.39-
1.35 (m, 1H), 0.91 (t, J=7.3 Hz, 2H); 13C NMR (126 MHz,
DMSO-d6) δ 160.96, 158.22, 157.33, 155.26, 154.68,
153.76, 145.03, 143.06, 142.58, 136.03, 125.81, 125.45,
114.69, 106.66, 87.83, 78.95, 66.85, 52.91, 48.55, 39.52,
30.35, 28.00, 27.48, 25.04, 18.81, 14.42, 13.56; HRMS
([M+H]+): m/z calcd for [(C33H45N7O4)+H]+:604.36091,
found 604.36086.
Synthesis of tert‑butyl 4‑(6‑((6‑bromo‑8‑cyclopen‑
tyl‑5‑methyl‑7‑oxo‑7,8‑dihydropyrido[2,3‑d] pyrimi‑
din‑2‑yl) amino) pyridin‑3‑yl) piperazine‑1‑carboxy‑
late (11)
To a solution of 6-bromo-8-cyclopentyl-5-methyl-
2-(methylsulfnyl) pyrido[2,3-d] pyrimidin-7(8H)-one (10,
9.80 g, 26.4 mmol) in dimethyl carbonate (100 mL), tert-
butyl 4-(6-aminopyridin-3-yl) piperazine-1-carboxylate
(11.02 g, 39.6 mmol) was added under a nitrogen atmos-
phere. After completion of the addition, the reaction mixture
was stirred at 110 °C for 25 h under nitrogen protection.
After 25 h, the reaction solution was cooled to room tem-
perature, diluted with water and then extracted with dichlo-
romethane and saturated NaHCO3 solution. The combined
organic phases were dried over MgSO4, fltered, and con-
centrated in vacuo. The residue was purifed by passing the
organic extract through a silica gel column using DCM/
MeOH (40:1) to give the product 11 (Toogood et al. 2005;
VanderWel et al. 2005; Duan et al. 2016). Yellow solid;
yield 47%; m.p. >250 °C; 1H NMR (300 MHz, CDCl3) δ
8.82 (s, 1H), 8.43 (s, 1H), 8.21 (d, J = 9.0 Hz, 1H), 8.04
(d, J=2.5 Hz, 1H), 7.35 (dd, J=9.1, 2.8 Hz, 1H), 5.99 (p,
J = 8.7 Hz, 1H), 3.68–3.55 (m, 4H), 3.20–3.04 (m, 4H),
2.61 (s, 3H), 2.40–2.22 (m, 2H), 2.13 (t, J = 9.6 Hz, 2H),
Synthesis of 6‑acetyl‑8‑cyclopentyl‑5‑me‑
thyl‑2‑((5‑(piperazin‑1‑yl) pyridin‑2‑yl) amino)
pyrido[2,3‑d] pyrimidin‑7(8H)‑one (Palbociclib, 1)
To a solution of tert-butyl 4-(6-((6-(1-butoxyvinyl)-8-cy-
clopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d] pyrimi-
din-2-yl) amino) pyridin-3-yl) piperazine-1-carboxylate
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(17, 5.57 g, 9.22 mmol) in water (50.5 mL) and n-butanol
(60.0 mL), hydrochloric acid solution (36 wt%, 0.93 g,
9.22 mmol) was added when the mixture was heated to
70 °C. The mixture was stirred for 6 h. Upon reaction com-
pletion, anisole (45.5 mL, 45.27 g, 41.8 mmol) was added
followed by sodium hydroxide solution (50 wt%, 0.15 g,
1.87 mmol), and the mixture was stirred for 2 h. The aque-
ous phase was removed, and the organic phase was washed
twice with water (250 mL) before being distilled atmos-
pherically to an end temperature of 120 °C. After cooling,
the solution was placed in refrigerator overnight. A large
amount of yellow solid was precipitated, suction fltered.
And the solid was washed with n-butanol and dried in
vacuo to give product 1 (Toogood et al. 2005; VanderWel
et al. 2005; Duan et al. 2016; Chekal et al. 2016). Yellow
solid; yield 76%; m.p. 199.3-201.5 °C; 1H NMR (300 MHz,
DMSO) δ 10.00 (s, 1H), 8.94 (s, 1H), 8.03 (d, J =2.6 Hz,
1H), 7.83 (d, J = 9.0 Hz, 1H), 7.43 (dd, J = 9.0, 2.8 Hz,
1H), 5.88–5.74 (m, 1H), 3.10–3.02 (m, 4H), 2.89–2.81 (m,
4H), 2.42 (s, 3H), 2.31 (s, 3H), 2.27–2.17 (m, 2H), 1.88
(s, 2H), 1.77 (d, J=9.9 Hz, 2H), 1.63–1.53 (m, 2H), 1.24
(s, 1H); 13C NMR (75 MHz, DMSO) δ 202.32, 160.71,
158.54, 158.17, 154.72, 144.08, 144.04, 142.00, 135.28,
129.00, 124.51, 115.16, 106.49, 52.86, 49.38, 45.35, 39.52,
31.22, 27.48, 25.00, 13.53; HRMS ([M+H]+): m/z calcd for
[(C24H29N7O2)+H]+: 448.24553, found 448.24585.
and monodentate phospine agents as ligand (Mizoroki et al.
1971; Heck and Nolley 1972). However, initial attempts to
obtain compound 8 from 23 through reactions with crotonic
acid were not successful with Pd(OAc)2 as catalyst, PPh3 as
ligand and TEA as base. Then, screening the combination of
ligand and base of this reaction system, including TEA and
(o-CH3Ph)3P, DIPEA and PPh3, DIPEA and (o-CH3Ph)3P,
K2CO3 and PPh3, K2CO3 and (o-CH3Ph)3P, gave an unsat-
isfactory result (no reaction) with Pd(OAc)2 as catalyst. In
further attempts to synthesize intermediate 8, we changed
the palladium catalyst and also screened the combination
of ligand and base. When using Pd(PhCN)2Cl2 as catalyst,
(o-CH3Ph)3P as ligand and DIPEA as base successfully gave
rise to product. This one pot-two step method (Heck reac-
tion, ring close sequence) achieved 76% yield.
In the present procedure, the 2-position oxidation of
methylthio and the introduction of bromine could be com-
pleted in one step. The literature confrmed that aromatic
sulfdes are oxidized cleanly to sulfoxides in aqueous media
when treated with N-bromosuccinimide (Harville and Reed
1968; Carpino and Williams 1974; Surendra et al. 2005).
Hence, intermediate 8 converted to intermediate 10 with the
transformation of two functional groups. This method not
only avoided long reaction times and hazardous reagents,
but also shortened the reaction steps and increased the yield
of the intermediate 10.
Attempts to the cross-coupling reaction between inter-
mediate 10 and tert-butyl 4-(6-aminopyridin-3-yl) pipera-
zine-1-carboxylate encountered a certain resistance. Initial
attempt to the cross-coupling reaction was carried out in
toluene at 110 °C. This method only achieved a yield of
26%. Considering the production of sulfnic acid at the end
of the reaction, the base including Et3N, K2CO3, K3PO4 was
added to the reaction system. However, this operation did
not improve the yield. And obtained intermediate 11 from
intermediate 10 through reactions with tert-butyl 4-(6-ami-
nopyridin-3-yl) piperazine-1-carboxylate was not success-
ful, when K2CO3, K3PO4 as base. The further attempts to
synthesize intermediate 11 used diferent polarity solvents
including toluene, dimethyl carbonate, THF, dioxane and
acetonitrile. We found that got a slightly better yield with
dimethyl carbonate as solvents.
Results and discussion
Our novel eight-step synthesis of Palbociclib was shown
in Scheme 4. Starting material 20 was commercially avail-
able, inexpensive and readily prepared from thiouracil by
methylation reaction. The reaction between the reactants was
readily controllable, generated by conventional heating and
stirring operations in common solvent. The determining step
in the route was the procedure for synthesizing intermediate
8 and intermediate 11.
In a previous report, intermediate 8 was obtained by
the Wittig-Horner reaction with (EtO)2P(O)CHXCO2Et
(Scheme 1). This process involved a complex operating
procedure and relatively long reaction route. Hence, we
inspired by Scheme 2 to adopt the strategy of Heck reac-
tion and amidation ring closure reaction. After nucleophilic
substitution by thionyl chloride, bromination, nucleophilic
substitution by cyclopentylamine, starting material 20 gave
intermediate 23. Then intermediate 23 was reacted sequen-
tially, in one pot, with crotonic acid and acetic anhydride
to convert to intermediate 8. Heck reaction is a coupling
reaction of an unsaturated halogenated hydrocarbon with an
olefn to form a substituted olefn using a strong base with
palladium catalysis and nitrogen protection. Heck reaction
commonly used divalent palladium compounds as catalyst
Conclusions
In summary, we demonstrated a facile route to synthe-
size Palbociclib starting from commercial 2-methylthio-
4-ketopyrimidine (20). A practical chromatography-free
method of post-processing to purify 4-chloro-2-(methylthio)
pyrimidine (21), 6-bromo-8-cyclopentyl-5-methyl-
2-(methylsulfinyl) pyrido[2,3-d] pyrimidin-7(8H) (10),
tert-butyl 4-(6-((6-(1-butoxyvinyl)-8-cyclopentyl-5-methyl-
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Chemical Papers
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7-oxo-7,8-dihydropyrido[2,3-d] pyrimidin-2-yl) amino)
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8-cyclopentyl-5-methyl-2-((5-(piperazin-1-yl) pyridin-2-yl)
amino) pyrido[2,3-d] pyrimidin-7(8H)-one (Palbociclib, 1)
was ofered, which was suitable for large-scale manufac-
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yield, inexpensive starting materials, readily controllable
and cleaner reaction conditions. This procedure has potential
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Chemical Papers
Afliations
Shu‑ting Li1 · Jun‑qing Chen1 · Cheng‑liang Feng2 · Wan‑feng Yang1 · Min Ji3
1
3
School of Chemistry and Chemical Engineering,
Southeast University, Nanjing 211189, Jiangsu,
People’s Republic of China
School of Biological Science and Medical
Engineering, Southeast University, Nanjing 210096,
People’s Republic of China
2
School of Pharmaceutical Engineering, Jiangsu College
of Engineering and Technology, Nantong 226000, Jiangsu,
People’s Republic of China
1 3