Development of a modified process for the kilogram-scale synthesis of c-Met/ALK inhibitor HS-10168

Article abstract of DOI:10.1021/acs.oprd.6b00402

A modified synthetic route to c-Met/ALK inhibitor HS-10168 has been developed on a kilogram scale. The key steps of the new process include a Suzuki coupling reaction of nitro-containing bromopyridine 6 and para-phenol boronate 9 to give intermediate 10, which was then converted to its triflate 11. The phosphorus group was introduced by coupling of 11 and dimethylphoshine oxide 8 to give compound 12, which was reduced to produce HS-10168.

Full text of DOI:10.1021/acs.oprd.6b00402

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Communication
Development of a Modified Process for the Kilogram-
Scale Synthesis of c-Met/ALK inhibitor HS-10168
Jun Yu, and Jinjia Wang
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00402 • Publication Date (Web): 06 Jan 2017
Downloaded from http://pubs.acs.org on January 9, 2017
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Development of a Modified Process for the
KilogramꢀScale Synthesis of cꢀMet/ALK inhibitor
HSꢀ10168
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Jun Yu,* JinJia Wang
The Research Academy of Jiangsu Hansoh Pharmaceutical Co., LTD, Dongjin Road,
Huaguoshan Avenue, Lianyungang, Jiangsu, 222069, P. R. China.
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Abstract: A modified synthetic route to cꢀMet/ALK inhibitor HSꢀ10168 has been developed on a
kilogram scale. The key steps of the new process include a Suzuki coupling reaction of nitro
containing bromopyridine 6 and paraꢀphenol boronate 9 to give the intermediate 10 which was
then converted into its triflate 11. The phosphorus group was introduced by coupling of 11 and
dimethylphoshine oxide 8 to give compound 12, which was reduced to produce HSꢀ10168.
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Key words: cꢀMet/ALK inhibitor, HSꢀ10168, catalyst, Suzuki reaction
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INTRODUCTION
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HSꢀ10168 is a potent and selective Mesenchymal epithelial transition factor/Anaplastic
lymphoma kinase(cꢀMet/ALK) inhibitor which has advanced into Phase I clinical trials.1,2 The
original gramꢀscale synthetic route to HSꢀ10168 developed by the medicinal chemistry group
was used for preparation of the compound for early biological screening. As a result of the robust
antitumor activity of HSꢀ10168 observed in tumor xenograft mouse models, the preclinical
development was rapidly accelerated which resulted in a great increase in drug substance
demand. This paper describes the development of a scalable synthetic process that enabled
kilogramꢀscale production of HSꢀ10168.
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RESULTS AND DISSCUSSION
The original medicinal chemistry route towards HSꢀ10168 is shown in scheme 12 and involved a
Suzuki coupling of two key structural elements, bromopyridine 1 and the phosphorus containing
phenylboronic acid 2 under N2 atmosphere. The bromopyridine 1 was synthesized in a 3 step
sequence, starting with nitration of 5ꢀbromoꢀ3ꢀhydroxylpyridine 3 to give compound 4. The
Mitsunobu reaction of 4 and the chiral alcohol (S)ꢀ5 provided the compound 6. Chemoselective
reduction of the nitro group of 6 with iron and acetic acid afforded the desired intermediate 1.
The phosphorus containing phenylboronic acid 2 was obtained by the palladium catalyzed
coupling reaction of the 2ꢀfluoroꢀ4ꢀbromoꢀphenylboronic 7 and dimethylphoshine oxide 8.
Scheme 1. Original medicinal chemistry route to HSꢀ10168.
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Although this route was successfully used to prepare gramꢀscale of HSꢀ10168 for use in early
preclinical studies, the scaleꢀup of this route still suffered from some challenges. Firstly, the
Suzuki coupling between 1 and 2 failed to go to completion and gave a complex mixture of
products. The yield of the final product obtained by semiꢀpreparative HPLC was very low (28%).
The coupling of 2ꢀfluoroꢀ4ꢀbromoꢀphenylboronic 7 and dimethylphoshine oxide 8 also gave a
complex mixture of products because of the selfꢀcoupling reaction of 7 under the palladium
catalyzed reaction conditions. This led to the formation of 2 in a low yield of 38%.
Central to the development work was to drive the Suzuki coupling to completion in order to give
a clean reaction profile and eliminate the semiꢀpreparative HPLC preparation of the final product.
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The coupling partners of Suzuki coupling reaction are a halide and an organoboron compound.3
In the original medicinal chemistry route, the bromopyridine 1 with an electronꢀdonating amine
group was used as the halide. It is noted that the presence of an electronꢀwithdrawing group such
as nitro group in the arylhalide benefits the progression of the coupling reaction due to the
accelerating effect in the oxidative addition step.3 Thus, the nitro containing bromopyridine 6
would be a better choice for the halide substrate. On the other hand, the scaleꢀup preparation of
the phosphorus containing phenylboronic acid 2 was challenging because of the easy selfꢀ
coupling of the starting material 7 under the palladium catalyzed conditions. Our strategy was to
use paraꢀphenol boronate 9 instead of 2 to couple with 6 to give compound 10, and avoided the
formation of the homoꢀcoupling side product. Compound 10 could be easily converted into its
triflate 11. The phosphorus group could be introduced by coupling of 11 and 8 to give compound
12, which was reduced to produce the final product (Scheme 2).
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Scheme 2. The synthetic strategy to HSꢀ10168.
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On the basis of the above considerations, the modified synthetic route to HSꢀ10168 was designed
as shown in Scheme 3. The boronation of 4ꢀbromoꢀ3ꢀfluorophenol 13 with
bis(pinacolato)diboron 14 was smoothly realized by using Pd(PPh3)4(5 mol%) as the catalyst and
potassium acetate as the base in 1,4ꢀdioxane at reflux.4 The desired intermediate 9 was obtained
in 86% yield within 3 h. The Suzuki coupling of nitro containing bromopyridine 6 and paraꢀ
phenol boronate 9 was conducted also using Pd(PPh3)4 (4 mol%) as the catalyst and sodium
carbonate (Na2CO3) as the base in the solvent mixture of dimethoxyethane (DME) and water at
80 ℃. Unfortunately, the reaction failed to reach completion and gave a complex mixture of
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products after 19 h. It is noted that Pd(PPh3)4 often is a capricious catalyst5 because of its airꢀ
sensitivity, which might led to the failure of Suzuki coupling. In order to improve the efficiency
of
the
reaction,
a
more
robust
and
active
catalyst
[1,1’ꢀ
bis(diphenylphosphino)ferrocene]dichloropalladium(II)
dichloromethane
complex
(PdCl2(dppf)2·CH2Cl2) (5 mol%), was tried instead of Pd(PPh3)4 using Na2CO3 as the base in the
solvent mixture of methanol, DME and water at reflux. It was found that this catalytic system not
only successfully gave complete reaction but also provided a more clean reaction profile within 1
h. Further investigation indicated that 1 mol% of PdCl2(dppf)2·CH2Cl2 was enough for the
completion of the reaction although a longer reaction time 5 h was required. Upon reaction
completion, EtOAc and water were added. The separated aqueous phase was reꢀextracted with
EtOAc. The combined organic phase was washed with aqueous HCL and brine. After
concentration of organic solvent, the residue was dissolved in EtOAc, followed by the slow
addition of hexane to guarantee the deposition of black viscous byproduct. The upper clear
solution was decanted, the black viscous residue was reꢀdissolved in EtOAc and hexane was
added slowly. After deposition of black viscous byproduct again, the upper clear solution was
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decanted. The combined organic phase was then concentrated and the resulting product was
dried under vacuum to afford 10 in 89% yield.The intermediate 10 was easily converted into its
triflate using Tf2O in dichloromethane at room temperature, and the intermediate 11 was
obtained in 71% isolated yield.6 The coupling reaction of 11 and dimethylphoshine oxide 87 was
carried out still using PdCl2(dppf)2·CH2Cl2 (5 mol %) as the catalyst and triethylamine as the
base in acetonitrile at reflux temperature.8,9 The reaction successfully provided the desired
intermediate 12 but with low conversion of 11 being about 60% even after 24 h. Increasing the
loading of catalyst to 10 mol% led to a complete reaction within 1.5 h. Other palladium catalyst
including Pd(PPh3)4, Pd(PPh3)2Cl2, Pd(OAc)2 and Pd(dba)2 were also tested, but none of them
showed superior results over PdCl2(dppf)2·CH2Cl2. Reduction of intermediate 12 with ironꢀ
HCl/ethanol system produced the HSꢀ10168 within 59% yield for two steps.
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Scheme 3. Modified synthetic route to HSꢀ10168
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OH
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F
Br
O
O
O
O
9
KOAc/Pd(PPh3)4
1,4ꢀdioxane
86%
B B
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F
O
B
O
9
Cl
OH
Cl
F
OH
Tf2O
Pyridine/DCM
71%
O
Br
O
F
F
Cl
Pd(dppf)2Cl2 CH2Cl2,
Na2CO3,
Cl
O2N
N
O2N
N
10
6
MeOH/DME/H2O
89%
H
P
Cl
F
OTf
Cl
F
P
O
O
8
O
Fe/HCl
EtOH
O
F
F
Pd(dppf)2Cl2 CH2Cl2,
TEA/AcCN
Cl
Cl
O2N
N
O2N
N
59% for two steps
12
11
Cl
O
F
P
O
F
Cl
H2N
N
HS-10168
CONCLUSION
We have developed a modified synthetic process that enabled a kilogramꢀscale production of
HSꢀ10168. The process features a robust Suzuki coupling reaction of nitro containing
bromopyridine 6 with paraꢀphenol boronate 9, followed by a phosphorus group introduction by
coupling of the triflate 11 with dimethylphoshine oxide 8. The process was repeated in several
campaigns on 1kg scale to support the preclinical and early clinical trials.
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EXPERIMENTAL SECTION
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General information. All reagents were purchased from the suppliers without further
purification. Proton NMR data were collected on a Bruker AVANCE 400 at 400 MHz for proton
or on a Bruker AVANCE 500 at 500 MHz for proton and 125 MHz for carbon. IR spectra were
recorded on a Nicolet FTꢀIR spectrometer in KBr pellets. Mass spectral analyses were performed
on Agilent 6224 QꢀTOF mass spectrometer equipped with an electronꢀspray ionization source.
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5-bromo-2-nitropyridin-3-ol (4)
5ꢀbromopyridinꢀ3ꢀol (1690g，8.67 mol) was added to concentrated sulfuric acid (95ꢀ98%，4.23
L，77.67 mol) in portions within 45 min at 0~10 ℃. Then HNO3 (65%，845 mL，12.21 mol)
was added dropwise over 1 h while maintaining temperature at 0~10 ℃. The resulting mixture
was warmed to room temperature and stirred for 20 h. The reaction mixture was slowly poured
into (within 10 min) ice water (13 L) and stirred for 45 min. The precipitated solid was filtered
and washed with ice water (2.5 L × 3). The filter cake was dried at ordinary pressure (50 ℃, 18 h)
1
to give compound 4 (1.35 kg, 63% yield) as a yellow solid. H NMR（400 MHz, DMSOꢀd6）δ
(ppm) 7.85 (d, J = 2.0 Hz, 1H), 8.16 (d, J = 1.6 Hz, 1H), 12.07 (brs, 1H).
(R)-5-bromo-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-2-nitropyridine (6)
Diisopropyl azodicarboxylate (1.27 kg ， 6.27 mol) was added dropwise to a solution of
compound 4 (1.11 kg，5.07 mol), compound 5 (1.01 kg，4.83 mol) and triphenylphosphine
(1.65 kg，6.27 mol) in THF (4 L) over 3 h while maintaining temperature at 0~15 ℃. Then the
mixture was warmed to room temperature and stirred for 20 h. Hexane (8 L) was added to the
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mixture and stirred for 1h. The resulting precipitate was filtered and washed with a mixture (1.5
L × 2) of ethyl acetate/hexane (v/v = 1:2.5). The combined filtrate was concentrated, and then iꢀ
propanol (4.5 L) was added. The resulting slurry was granulated for 15 h. The slurry was filtered,
the filter cake was washed with iꢀpropanol (650 mL × 2) and dried at ordinary pressure (50 ℃,
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18 h) to give the compound 6 (1.47 kg, 71% yield) as a yellow solid. The HPLC purity was
99.36% and the ee value was over 99.8%. 1H NMR（400 MHz, DMSOꢀd6）δ (ppm) 1.81(d, J =
6.4 Hz, 3H), 6.40(q, J = 6.4 Hz, 1H), 7.50ꢀ7.54(m, 1H), 7.60ꢀ7.64(m, 1H), 7.88 (d, J = 1.6 Hz,
1H), 8.30 (d, J = 1.6 Hz, 1H).
3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol ( 9)
A mixture of 4ꢀbromoꢀ3ꢀfluorophenol 13 (1.21 kg，6.31 mol), bis(pinacolato)diboron 14 (2.06
kg
，
8.12
mol),
potassium
acetate
(1.54
kg
，
15.71
mol),
and
Tetrakis(triphenylphosphine)palladium (0.36 kg，0.32 mol) in dioxane (14 L) was refluxed for 3
h. Then cooling to room temperature, the mixture was filtered through celite and washed with
ethyl acetate (1.5 L × 2). The filtrate was poured into water (25 L) and extracted with ethyl
acetate (10 L × 3). The combined organic phase was washed with brine (20 L × 2) and dried over
anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum to about 1ꢀ2 L at
40ꢀ45 ℃. The residue was suspended in petrol ether (8.0 L) and stirred for 20 h. The resulting
precipitated solid was filtered, and the filter cake was washed with petrol ether (1.5 L × 2) and
dried under vacuum (40 ℃, 5 h) to give compound 9 (1.29 kg, 86% yield) as a brown solid. The
HPLC purity was 93.9%. 1H NMR (400 MHz, DMSOꢀd6) δ (ppm) 1.18ꢀ1.27 (m, 12H), 6.49 (dd,
J = 11.2, 2.0 Hz, 1H), 6.63 (dd, J = 8.4, 2.0 Hz, 1H), 7.46ꢀ7.50 (m, 1H), 10.29 (s, 1H).
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(R)-4-(5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-6-nitropyridin-3-yl)-3-fluorophenol (10)
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[1,1ꢀBis(diphenylphosphino)ferrocene]dichloropalladium(Ⅱ) dichloromethane complex (74.90 g,
9
97.54 mmol) and sodium carbonate (2.59 kg, 24.38 mol) was added to a solution of Compound 6
(4.00 kg, 9.75 mol), 9 (3.25 kg , 13.66 mol) in DME (17 L), MeOH (8.5 L) and purified water
(8.5 L) at room temperature. The reaction was refluxed for 5 h. After cooling to room
temperature, ethyl acetate (40 L) and water (40 L) were added to the mixture and then the phases
were separated. The lower aqueous phase was reꢀextracted with ethyl acetate (40 L). The
combined organic phase was washed with aqueous 2N HCl (30 L), brine (30 L x 2) and dried
over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum to a constant
weight at 40ꢀ45 ℃. The residue was dissolved in ethyl acetate (17 L) and hexane (35 L) was
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added slowly to the mixture. After stirring for 17 h, the upper clear solution was decanted. The
residue was reꢀdissolved in ethyl acetate (4 L). Hexane (4 L) was added slowly to the mixture
and the mixture was stirred for 2~3 h. The upper clear solution was decanted. After concentration
of the combined organic phase under vacuum at 40ꢀ45 ℃, the resulting product was dried under
vacuum (40 ℃, 16~18 h), affording 10 (3.81 kg, 89% yield) as a yellow solid. 1H NMR（400
MHz, DMSOꢀd6）δ (ppm) 1.81 (d, J = 6.4 Hz, 3H), 6.53 (q, J = 6.4 Hz, 1H), 6.71ꢀ6.75 (m, 1H),
6.78ꢀ6.81 (m, 1H), 7.40ꢀ7.52 (m, 2H), 7.58ꢀ7.61 (m, 2H), 8.23 (s, 1H), 10.45 (s, 1H).
(R)-4-(5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-6-nitropyridin-3-yl)-3-fluorophenyl
trifluoromethanesulfonate (11)
Trifluoromethanesulfonic anhydride (4.07 L, 24.20 mol) was added to a solution of 10 (3.81 kg,
8.64 mol) and pyridine (2.78 L, 34.55 mol) in dichloromethane over 5ꢀ6 h, while maintaining the
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internal temperature at 25~30 ℃. The reaction mixture was agitated for another 17ꢀ19 h until the
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8
9
reaction was deemed complete by TLC. Then the mixture was washed with water (35 L x 2). The
combined aqueous phase was reꢀextracted with dichloromethane (35 L). The combined organic
phase was washed by brine (40 L) and dried over anhydrous Na2SO4. After concentration of the
organic phase under vacuum to a constant weight, the residue was purified on silica gel column
to give the crude product. Then the product was suspended in hexane and stirred for 2ꢀ3 h. The
slurry was filtered, the filter cake was dried under vacuum (40 ℃, 16~18 h), affording 11 (3.52
10
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kg, 71% yield) as a light yellow solid. 1H NMR（400 MHz, DMSOꢀd6）δ (ppm) 1.81 (d, J = 6.8
Hz, 3H), 6.42 (q, J = 6.4 Hz, 1H), 7.48ꢀ7.53 (m, 1H), 7.57ꢀ7.63 (m, 2H), 7.81 (s, 1H), 7.84ꢀ7.89
(m, 2H), 8.36 (s, 1H).
(R)-(4-(5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-6-nitropyridin-3-yl)-3-
fluorophenyl)dimethylphosphine oxide (12)
[1,1`ꢀBis(diphenylphosphino)ferrocene]dichloropalladium(Ⅱ) dichloromethane complex (0.10
kg，0.12 mol) was added to a solution of compound 11 (3.52 kg, 6.13 mol), compound 8 (1.10
kg, 14.11 mol) and triethylamine (3.42 L, 24.54 mol) in acetonitrile (6 L) and the reaction was
refluxed for 1ꢀ1.5 h until the reaction was deemed complete by TLC. After cooling to room
temperature, water (20 L) was added with stirring followed by ethyl acetate (25 L), and then the
phases were separated. The water phase was reꢀextracted with ethyl acetate (10 L). The
combined organic phase was washed with brine (15 L) and dried over anhydrous Na2SO4. After
filtration, the filtrate was concentrated under vacuum to a constant weight at 40ꢀ45 ℃to give
compound 12 (3.71 kg) as a brown oil. The intermediate 12 was used for the next step without
further purification. 1H NMR（400 MHz, DMSOꢀd6）δ (ppm) 1.72 (s, 3H), 1.76 (s, 3H), 1.81 (d,
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J = 6.8 Hz, 3H), 6.42 (q, J = 6.4 Hz, 1H), 7.49ꢀ7.53 (m, 1H), 7.58ꢀ7.62 (m, 1H), 7.74ꢀ7.82 (m,
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2H), 8.36 (s, 1H).
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fluorophenyl)dimethylphosphine oxide (HS-10168)
Concentrated hydrochloric acid (1.71 L，17.07 mol) was added to a solution of compound 12
(3.71 kg，7.76 mol) in ethanol (32.5 L) followed by iron powder (2.61 kg，46.55 mol) and the
mixture was refluxed for 2ꢀ2.5 h until the reaction was deemed complete by TLC. The mixture
was then cooled to 50oC and the solvent was removed under vacuum. The residue was diluted
with ethyl acetate (50 L) and aqueous 2.5 N NaOH (50 L). After standing, the mixture was
filtered through celite and the filter cake was washed with ethyl acetate/methanol (4:1, 5 L × 4).
Then the phases were separated and the water phase was reꢀextracted with ethyl acetate (22.0 L).
The combined organic phase was diluted with purified water (75 L), and concentrated
hydrochloric acid (6 L) was added with agitation. Then the organic phase was separated and
washed with aqueous 2 N hydrochloric acid (14 L). The combined aqueous washes were
extracted with ethyl acetate, followed by neutralization with aqueous 7.5 N sodium hydroxide
(14 L) and then extracted with ethyl acetate (22 L × 3). The combined organic phase was washed
with aqueous 2 N sodium hydroxide (50 L), purified water (50 L × 2), brine (50 L × 2) separately
and dried over anhydrous Na2SO4. After filtration and concentration organic phase under
vacuum to a constant weight at 40ꢀ45oC, the residue was purified on silica gel column to give the
crude product. The product was suspended in acetone (1.7 L) and stirred for 17ꢀ18 h. The
resulting slurry was filtered and washed with acetone (0.5 L). The filter cake was dried at
atmospheric pressure (45 ℃, 17ꢀ18 h) to afford the crude product of HS-10168 (1.70 kg, 59%
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yield for two steps) as a yellow solid. The HPLC purity was 99.44% and the ee value was over
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99.8%. The palladium level is 3.2 ppm. H NMR（500 MHz, CDCl3）δ (ppm) 1.75 (s, 3H),
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1.77 (s, 3H), 1.86 (d, J = 6.7 Hz, 3H), 5.12 (brs, 2H), 6.08 (q, J = 6.6 Hz, 1H), 6.99 (s, 1H), 7.04ꢀ
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7.07 (m, 1H), 7.28ꢀ7.31 (m, 1H), 7.40ꢀ7.43 (m, 1H), 7.44ꢀ7.53 (m, 2H), 7.85 (s, 1H). C NMR
(125 MHz): δ(ppm) 17.7, 18.2, 18.8, 72.5, 116.4ꢀ116.6, 117.3, 117.4ꢀ117.7, 120.3, 121.9ꢀ122.0,
125.5ꢀ125.6, 128.9, 129.5ꢀ129.6, 129.9, 130.0ꢀ130.1, 134.9ꢀ136.7, 135.6ꢀ135.7, 136.7, 139.1,
150.4, 156.4ꢀ158.4, 158.3ꢀ160.5; IR (KBr): 3478, 3268, 3081, 2982, 1627, 1514, 1483, 1551,
1455, 1427, 1397, 1189, 1274, 1096, 860, 819, 775 cmꢀ1; MS(m/z):471.06 [M + H]+.
ASSOCIATED CONTENT
Supporting Information.
NMR, IR and mass spectra are provided in the Supporting Information. This material is available
free of charge via Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Email:sttyj@sina.com
ACKNOWLEDGMENT
We thank Xiaowei Zhang and Long Xiong for helpful discussions. We thank Yan Wang for
analytic support. Jiangsu Hansoh Pharmaceutical Co., LTD is highly appreciated.
REFERENCES
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