New and Practical Synthesis of Gedatolisib

Article abstract of DOI:10.1021/acs.oprd.7b00298

A new, practical, and convergent synthetic route of gedatolisib, an antitumor agent, is developed on a hectogram scale which avoids the Pd coupling method. The key step is adopting 6-(4-nitrophenyl)-1,3,5-triazine-2,4-diamine and 2,2′-dichlorodiethyl ether to prepare the key 4,4′-(6-(4-nitrophenyl)-1,3,5-triazine-2,4-diyl)dimorpholine in 77% yield and 98.8% purity. Gedatolisib is obtained in 48.6% yield over five simple steps and 99.3% purity (HPLC). Purification methods of the intermediates and the final product involved in the route are given.

Full text of DOI:10.1021/acs.oprd.7b00298

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Full Paper
New and Practical Synthesis of Gedatolisib
Xiangyu Liu, Guoqing Zhu, Lingai Li, Yaowei Liu, Feng Wang, Xiaoping Song, and Yongjun Mao
Org. Process Res. Dev., Just Accepted Manuscript • Publication Date (Web): 30 Nov 2017
Downloaded from http://pubs.acs.org on November 30, 2017
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New and Practical Synthesis of Gedatolisib
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Xiangyu Liu,† Guoqing Zhu,† Lingai Li,† Yaowei Liu,† Feng Wang, † Xiaoping Song,‡ Yongjun
Mao*, †
† College of Chemistry and Chemical Engineering, Shanghai University of Engineering Science,
333 Longteng Rd., Shanghai 201620, China.
‡ Key Laboratory of Tropical Medicinal Plant Chemistry of Ministry of Education, Hainan
Normal University, 99 South Longkun Rd., Haina 571158, China.
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SYNOPSIS TOC
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New and Practical Synthesis of Gedatolisib
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ABSTRACT
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A new, practical and convergent synthetic route of gedatolisib, an antitumor agent, is developed
on a hectogram scale which avoids the Pd coupling method. The key step is adopting 6-(4-
nitrophenyl)-1,3,5-triazine-2,4-diamine and 2,2'-dichlorodiethyl ether to prepare the key 4,4'-(6-
(4-nitrophenyl)-1,3,5-triazine-2,4-diyl)dimorpholine in 77% yield and 98.8% purity. Gedatolisib
is obtained in 48.6% yield over five simple steps and 99.3% purity (HPLC). Purification methods
of the intermediates and the final product involved in the route are given.
Key Words Gedatolisib, Antitumor agent, New route, Organic process, Hectogram scale.
INTRODUCTION
Gedatolisib (1, Scheme 1), also known as PKI-587 and PF-05212384, is an agent targeting the
phosphatidylinositol 3 kinase (PI3K) and mammalian target of rapamycin (mTOR) in the
PI3K/mTOR signaling pathway, that inhibits PI3K-α, β, γ, δ isoforms and mTOR with IC50 of
0.4, 6.0, 5.4, 6.0 and 1.6 nM respectively, with potential antitumor activity.1, 2 It was developed
by Pfizer for the treatment of acute myeloid leukemia which is now in phase III clinical study.3
4−6
The synthetic routes of gedatolisib were developed and reported so far,
which adopted
almost the same method, as shown in Scheme 1. Cyanuric chloride and morpholine were reacted
at basic condition to give 4,4'-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholine (4) in 64% yield,
which was coupled with 4-aminophenylboronic acid pinacol ester (5), catalyzed by 5 mol%
Pd(PPh3)4, to give 4-(4,6-dimorpholino-1,3,5-triazin-2-yl)aniline (6) in 88% yield on a 30 g scale.
The subsequent steps included addition with 4-isocyanatobenzoate (7), esterolysis and amidation,
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the title compound 1 was obtained in 37% yield over five steps (from compound 2) on a 45 g
scale. The intermediates in this route, such as compound 5 and 7, were also needed to prepare.
This procedure gave a Pd residue > 20 ppm, which is not conform to API preparation.6
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Scheme 1. Reported synthetic route of 1a
aReagents and conditions: (a) TEA, acetone, –10oC to 0oC, 64%; (b) 5 mol% Pd(PPh3)4, Na2CO3,
DME, reflux, 5 h, 88%; (c) CH2Cl2, rt, 5 h, 90%; (d) LiOH, H2O, THF, MeOH, reflux, 2 h, 92%;
(e) CDI, DMAP, THF, 50oC, 18 h, then DMAC, 17 h, 80%.
In order to develop a practical and commercial process of preparing gedatolisib, a new
synthetic route was designed and studied, in order to avoid the Pd coupling method. The key step
is adopting 6-(4-nitrophenyl)-1,3,5-triazine-2,4-diamine (12) and 2,2'-dichlorodiethyl ether (13)
to prepare the key intermediate 4,4'-(6-(4-nitrophenyl)-1,3,5-triazine-2,4-diyl)dimorpholine (14),
which is depicted in Scheme 2.
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Scheme 2. Improved synthetic route of 1a
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aReagents and conditions: (a) KOH, EtOH, reflux, 3 h, 83%; (b) NaH, DMF, 65oC, 2 h, 77%; (c)
H2, Ni, THF, rt, 12 h, 95%; (d) pyridine, CH2Cl2, 0oC, 3 h, 91%; (e) DMSO, 65oC, 3 h, 88%.
RESULTS AND DISCUSSION
Starting from dicyandiamide and 4-nitrobenzonitrile, 6-(4-nitrophenyl)-1,3,5-triazine-2,4-
diamine (12) was prepared by adopting the method described by Simons,7 with 83% isolated
yield and > 97% purity (HPLC) without extra purification operation. The reaction optimization
conditions are depicted in Table 1, including solvents, reaction temperature, and the molar ratio
of base (KOH). The experiment results indicated that KOH was more like a catalyst since 0.4 eq
of KOH given the best yield. Enhancing the molar ratio of KOH will consume more
dicyandiamide to complete the reaction, while the isolated yield was reduced since side product
was given. The reaction temperature was another determination factor since the reaction was not
complete at 60oC, and the yield was more than 80% at 78oC. While side products were given
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when the reaction was carried out at 120oC. In consideration of the solvents, DME (1,2-
dimethoxyethane) and EtOH were selected and the latter gave better results. The best reaction
condition was established as the item 8 in Table 1.
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Table 1 Modification of the preparing 12a, b
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Item
Solvent
DME
DME
DME
DME
DME
EtOH
EtOH
10 : 11 : KOH (mol)
1.1 : 1
T (oC)
60
time (h)
Yield %
/
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4
1.1 : 1 : 0.1
1.1 : 1 : 0.5
1.1 : 1 : 0.5
1.1 : 1 : 1
90
<10% (TLC)
48.8%
90
120
90
49.6%
Side product
<40% (TLC)
81%
1.1 : 1 : 0.5
1.1 : 1 : 0.5
60
78
8
9
EtOH
EtOH
1.1 : 1 : 0.4
1.5 : 1 : 1
78
78
3
3
83%
Low isolated yield
aReactions were performed with 10 (22–30 mmol) and 11 (20 mmol) in solvents (20 vol of 10). bAll reactions
were run in one-pot.
Under NaH (60% mineral oil dispersion)/DMF (N, N-dimethylformamide) condition,8
compound 12 reacted with 2,2'-dichlorodiethyl ether to give the key dimorpholine intermediate
14 in 77% yield after modification, as shown in Table 2. During the conditions optimization, we
selected TEA (triethylamine), K2CO3 and NaH as the base and adopted DMF, DMAC
(dimethylacetamide), o-dichlorobenzene, diglyme, n-butanol as the solvents, respectively. This
reactions were carried in different conditions. The experimental results shown that TEA or
K2CO3 were too weak to give product, while NaH/DMF would give better yield. In order to
reduce the mole ratio of 2,2'-dichlorodiethyl ether and NaH to substrate 12, and more crucially to
reduce the risk of operating NaH, the modification was carried out by adding the solution of 12
and 13 in DMF to NaH/DMF suspension at 65oC via peristaltic pump, 14 was obtained in 77%
isolated yield with 98.8% purity (HPLC). During the optimization, we found that mixing the
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materials together (one-pot operation), the mole ratio of compound 12 : 13 : NaH was 1 : 4 : 9 at
least to convert the materials while the isolated yield was only around 40%. What’s more, foam
generated obviously when the reaction temperature reached to 50oC.
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Table 2 Modification of the reaction of 12 to 14a, b
Item
Solvent
12 : 13 : Base (mol)
1 : 4 : 9 (Et3N)
1 : 4 : 5 (K2CO3)
1 : 4 : 9 (NaH)
1 : 4 : 9 (NaH)
1 : 4 : 9 (NaH)
1 : 4 : 9 (NaH)
1 : 4 : 9 (NaH)
Catalyst
T (oC)
60–90
60–110
60
time (h)
Yield %
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1
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DMF
NaI
4
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4
/
DMF
NaI
/
DMF
NaI
41%
DMAC
/
/
/
/
60
35%
o-dichlorobenzene
diglyme
n-butanol
/
60–140
60–120
60–110
<20% (TLC)
<20% (TLC)
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DMF
DMF
1 : 2.2 : 4.2 (NaH)
1 : 2.2 : 4.2 (NaH)
/
/
65
65
3
2
~30% (TLC)
77%c
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aReactions were performed with 6-(4-nitrophenyl)-1,3,5-triazine-2,4-diamine 12 (25 mmol), 2,2'-
b
dichlorodiethyl ether and NaH (60%) under a argon atmosphere. Unless otherwise noted, all reactions were
c
run in one-pot. This item was carried out by adding 12 and 13 solution to NaH/DMF suspension at 65oC
through peristaltic pump.
Comparatively to the one-pot operation, the reaction materials 12 and 13 were dissolved in
DMF at 65oC and added via peristaltic pump to the NaH/DMF suspension over 2 h. The flow
speed is set up to 4 mL/min, a solution of 12 (80.0 g, 0.35 mol) and 13 (112.5 g, 0.79 mol) in
DMF (400 mL, flask B) was added to the suspension of 60% NaH over mineral oil (60 g, 1.5
mol) in 300 mL DMF (flask A) at 65oC. To investigate the safety of this step, the reaction
calorimetry, the gas evolution rate and the volumetric measurement data were detected. The
reaction calorimetry data was tested based on the experimental results from oxygen bomb
calorimeter (HR-15, Shanghai Testing Instrument Co.). The combustion heat of compound 12
and 14 were calculated respectively based on Eq. 1 (corrected by benzoic acid to get the
parameter K) and the Reynolds temperature correction curves were obtained and depicted in
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Figure 1 to 3. Since the molar combustion heat of 2,2'-dichlorodiethyl ether 13 (–2502.7 kJ/mol),
H2 (–285.8 kJ/mol) and NaH (–282.5 kJ/mol) are known (as shown in Table 3),9 so we can
calculate the reaction calorimetry of the reaction of 12 to 14 is –1753.1 kJ/mol, as shown in Eq.
2.
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Figure 1. The Reynolds temperature correction curve of benzoic acid.
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Figure 2. The Reynolds temperature correction curve of compound 12.
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Figure 3. The Reynolds temperature correction curve of compound 14.
Table 3 The molar combustion heat of the related compounds a, b
∆ꢀꢁꢂꢃ (kJ/mol)
Compounds
12
13
14
NaH
NaCl
H2
ꢄ4512.3 a
ꢄ2502.7 b
ꢄ7751.3 a
ꢄ282.5 b
0 b
ꢄ285.8 b
aThe molar combustion heat data was calculated based on the experimental results from oxygen bomb
calorimeter. bThe molar combustion heat data was reported.
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The above reaction was carried out in a flask with mark to measure the reactant volume, and
the gas evolution rate was detected by float flowmeter (DK800-4F, Changfa Instrument Co.,
China). The volumetric measurement data was depicted in Figure 4, which shown that there was
no volume violent change in the flask A so the reaction was controllable.
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Figure 4. Volumetric measurement for 12 to 14 in flask A.
The gas evolution rate was shown in Figure 5. From the diagram we can see that during the
material charging from Flask B to A (20–120 min), the gas evolution rate was between 2.7–4.0
L/20 min. While the evolution rate declined sharply after the charging, which indicated that the
reaction was complete.
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Figure 5. Gas evolution rate for 12 to 14.
Treated compound 14 at H2/Raney Ni condition at room temperature to give 4-(4,6-
dimorpholino-1,3,5-triazin-2-yl)aniline (6) in 96% yield, with 98.8% purity (HPLC). Many
methods are effectual for nitro-compounds reduction and catalytic hydrogenation is a clean and
convenient way. With regard to this step, no more conditions were optimized besides adoption
MeOH and EtOH as the solvents in view of cost. While material 14 and product 6 have poor
solubility in alcohol solvents so THF (tetrahydrofuran) was chosen as the solvent.
The aniline compound 6 was reacted with phenyl carbonochloridate to give the phenyl
carbamate intermediate 15 in 91% yield. In order to establish the urea part of the final product,
the phenylcarbamate group was introduced as the leaving group. Firstly, an one-pot method was
tried by treating compound 6, 16 and triphosgene in acetonitrile while the experiment failed.
Methyl chloroformate was also used to instead of phenyl carbonochloridate, while the
subsequent reaction with compound 16 given bad results.
The title gedatolisib (1) was obtained by treating compound 15 with (4-aminophenyl)(4-
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(dimethylamino)piperidin-1-yl)methanone (16) in DMSO with 88% yield and 99.3% purity
(HPLC). Compound 16 can be prepared based on Gopalsamy’s method in good yield.10 So the
urea formation of gedatolisib using amide 16 and 15 is a more convergent approach than the
reported synthesis. There were no more conditions optimization about last step since the related
published methods was simple and practical.11 Most of the work was focus on the purification
method. Finally the crude product of 1 was stirred and heated in EtOAc-EtOH (1:1 vol) and the
product can be purified up to standard.
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CONCLUSION
A new and practical synthetic route of gedatolisib (1) is designed and developed on a
hectogram scale which avoid the Pd coupling method. The key step is adopting 1,3,5-triazine-
2,4-diamine compound 12 and dichlorodiethyl ether 13 to prepare the key intermediate 4,4'-(6-
(4-nitrophenyl)-1,3,5-triazine-2,4-diyl)dimorpholine (14) in ~80% yield and > 98% purity.
Several modifications are carried out in this step and the optimal condition is established. The
title compound 1 is obtained in 48.6% yield over five simple steps (calculated from 4-
nitrobenzonitrile) and 99.3% purity (HPLC). Purification methods of the intermediates and the
final product involved in the route are also given, which make this process environmentally
friendly, cost-effective, and feasible for scale-up operation.
EXPERIMENTAL SECTION
General. All commercially available chemicals and solvents were used as received without
1
any further purification. H NMR spectra were recorded on a Bruker UltraShield 400 Plus
spectrometer using TMS as an internal standard. Mass spectra were obtained from a Finnigan
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MAT-95/711 spectrometer. The HPLC data were acquired using a Waters 2487 UV/Visible
Detector and Waters 515 Binary HPLC Pump. The purity of the compounds were based on the
areas of HPLC UV.
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6-(4-Nitrophenyl)-1,3,5-triazine-2,4-diamine (12). KOH (17.0 g, 0.30 mmol) was added
and stirred in ethanol (1 L) to give a solution. Then dicyanodiamide (71.0 g, 0.84 mol) and 4-
nitrobenzonitrile (112.5 g, 0.76 mol) were added into the solution and heated to reflux for 3 h.
The resulting solution was cooled to room temperature and filtrated, washed with ethanol (150
mL × 2), and dried at atmospheric pressure (50°C, 4 h) to give product 12 (146.4 g, 83%) as a
white solid. 1H NMR(400 MHz, DMSO-d6): δ 6.92 (brs, 4H), 8.34 (d, J = 8.8 Hz, 2H), 8.45 (d, J
= 8.8 Hz, 2H). HPLC conditions: Column: Agilent Eclipse XDB-C18 (250 mm × 4.6 mm × 5
µm); Detection: 220 nm; Flow rate: 1.0 mL/min; Temperature: 30 °C; Injection load: 1 µL;
Solvent: MeOH; Concentration: 0.5 mg/mL; Run time: 20 min; Mobile phase A: water; Mobile
phase B: MeOH/TEA = 100:0.1; Gradient program: time (min): 20; % of mobile phase A: 20; %
of mobile phase B: 80; tR = 4.299 min, purity: 97.10%.
4,4'-(6-(4-Nnitrophenyl)-1,3,5-triazine-2,4-diyl)dimorpholine (14). Flask A:
A
suspension of NaH (60% mineral oil dispersion, 60.0 g, 1.5 mol) and DMF (300 mL) was stirred
and heated to 65oC under argon.
Flask B: A mixture of 1,3,5-triazine-2,4-diamine 12 (80.0 g, 0.35 mol) and dichlorodiethyl
ether 13 (112.5 g, 0.79 mol) in DMF (400 mL) was stirred and heated to 65oC under argon to
give a solution.
The solution in Flask B was added to Flask A through a peristaltic pump, setting the flow
speed at 4 mL/min until complete (~2 h). The reaction mixture was stirred at 65oC for another 1
h. Around 400 mL DMF was recovered under vacuum and the residue was poured into ice water
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(1.5 L) and stirred for 1 h. The resulting solid was filtered, washed with ethanol (200 mL × 2),
and dried at ordinary pressure (50°C, 4 h) to give a brown solid crude 14 (130 g), which was
stirred and heated in EtOH (400 mL) to reflux for 1 h, cooled to room temperature. The resulting
solid was filtered, washed with ethanol (200 mL × 2), and dried at atmospheric pressure (50°C, 4
h) to give 14 (100.2 g, 77%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3): δ 3.78 (m, 8H),
3.95 (m, 8H), 8.27 (d, J = 8.0 Hz, 2H), 8.53 (d, J = 8.0 Hz, 2H). ESI-MS (m/z) 372.3 (M + H).
HPLC conditions: Column: Agilent Eclipse XDB-C18 (250 mm × 4.6 mm × 5 µm); Detection:
254 nm; Flow rate: 0.8 mL/min; Temperature: 30 °C; Injection load: 1 µL; Solvent: MeOH;
Concentration: 0.5 mg/mL; Run time: 20 min; Mobile phase A: water; Mobile phase B:
MeOH/TEA = 100:0.1; Gradient program: time (min): 20; % of mobile phase A: 10; % of
mobile phase B: 90; tR = 5.131 min, purity: 98.85%.
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4-(4,6-Dimorpholino-1,3,5-triazin-2-yl)aniline (6). A suspension of dimorpholine 14
(93.0 g, 0.25 mol), Raney Ni (wet, 30 g) and THF (1 L) was stirred under H2 bag at room
temperature for 12 h. The resulting mixture was filtered through a Celite pad and the filter cake
was washed by THF (100 mL × 2). The combined filtrate was concentrated under vacuum to
give a light brown solid, which was stirred and heated in 50% THF-H2O (200 mL) to 50°C for 1
h, cooled to room temperature. The resulting solid was filtered, washed with 50% THF-H2O (70
mL × 2), and dried at atmospheric pressure (45°C, 4 h) to give 6 (81.2 g, 95%) as an off-white
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solid. H NMR (400 MHz, DMSO-d6): δ 3.64 (m, 8H), 3.78 (m, 8H), 5.70 (s, 2H), 6.57 (d, J =
8.4 Hz, 2H), 8.05 (d, J = 8.4 Hz, 2H). ESI-MS (m/z) 343.0 (M + H). HPLC conditions: Column:
Agilent Eclipse XDB-C18 (250 mm × 4.6 mm × 5 µm); Detection: 254 nm; Flow rate: 0.8
mL/min; Temperature: 30 °C; Injection load: 1 µL; Solvent: MeOH; Concentration: 0.5 mg/mL;
Run time: 20 min; Mobile phase A: water; Mobile phase B: MeOH/TEA = 100:0.1; Gradient
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program: time (min): 20; % of mobile phase A: 10; % of mobile phase B: 90; tR = 5.595 min,
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purity: 98.82%.
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Phenyl (4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)carbamate (15). A solution of
compound 6 (82.1 g, 0.24 mol), pyridine (28.4 g, 0.36 mol) in CH2Cl2 (600 mL) was stirred and
cooled at an ice-water bath to ~5oC. A solution of phenyl carbonochloridate (41.3 g, 0.26 mol) in
CH2Cl2 (120 mL) was added dropwise into the mixture over 1 h and stirred at 5oC for another 2
h. The reaction solution was washed with water (400 mL × 3), dried over anhydrous Na2SO4.
The organic solution was filtered and concentrated under vacuum to give the crude carbamate
product 15 (109 g) as a light yellow solid, which was stirred and heated in EtOAc-Hexane (1:1
vol) (240 mL) to 60°C for 1 h, cooled to room temperature. The resulting solid was filtered,
washed with EtOAc-Hexane (1:1 vol) (80 mL × 2), and dried at atmospheric pressure (45°C, 4 h)
to give 15 (100.9 g, 91%) as an off-white solid. 1H NMR (400MHz, CDCl3): δ 3.75–3.83 (m,
8H), 3.94 (brs, 8H), 7.16 (s, 1H), 7.23 (d, J = 8.4 Hz, 2H), 7.28 (m, 1H), 7.43 (t, J = 7.6 Hz, 2H),
7.55 (d, J = 9.6 Hz, 2H), 8.40 (d, J = 8.4 Hz, 2H). ESI-MS (m/z) 463.1 (M + H).
Gedatolisib (1). A solution of compound 15 (94.4 g, 0.204 mol) and (4-aminophenyl)(4-
(dimethylamino)piperidin-1-yl)methanone 16 (55.5 g, 0.224 mol) in DMSO (550 mL) was
stirred and heated to 65oC for 3 h. The reaction mixture was cooled to room temperature and
poured into ice water (1.4 L) and stirred for 1 h. The resulting solid was filtrated and dried at
45oC for 4 h to give the crude 1 (125 g) as a light yellow solid, which was stirred and heated in
EtOAc-EtOH (1:1 vol) (350 mL) to 70°C for 2 h, cooled to room temperature. The resulting
solid was filtered, washed with EtOAc-EtOH (1:1 vol) (80 mL × 2), and dried at atmospheric
pressure (45°C, 4 h) to give 1 (110.5 g, 88%) as an off-white solid. 1H NMR (400 MHz, DMSO-
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d6): δ 1.46 (brs, 2H), 1.89 (brs, 2H), 2.29 (s, 6H), 2.94 (brs, 2H), 3.76 (m, 8H), 3.89 (m, 8H),
7.09 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H), 8.28 (s, 1H), 8.31 (d,
J = 8.6 Hz, 2H), 8.48 (s, 1H). ESI-MS (m/z) 615.9 (M+H). HPLC conditions: Column: Agilent
Eclipse XDB-C18 (250 mm × 4.6 mm × 5 µm); Detection: 254 nm; Flow rate: 0.8 mL/min;
Temperature: 30 °C; Injection load: 1 µL; Solvent: MeOH; Concentration: 0.5 mg/mL; Run time:
20 min; Mobile phase A: water; Mobile phase B: MeOH/TEA = 100:0.1; Gradient program: time
(min): 20; % of mobile phase A: 10; % of mobile phase B: 90; tR = 2.598 min, purity: 99.34%.
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Corresponding Author
* College of Chemistry and Chemical Engineering, Shanghai University of Engineering Science,
333 Longteng Rd., Shanghai 201620, China. Fax: +86 21 67791214. E-mail:
yongjun.mao@hotmail.com.
ACKNOWLEDGMENT
This work was supported by the Key Laboratory of Tropical Medicinal Plant Chemistry of
Ministry of Education, Hainan Normal University (201604).
REFERENCES
(1) Gedaly, R.; Galuppo, R.; Musgrave, Y.; Angulo, P.; Hundley, J.; Shah, M.; Daily, M. F.;
Chen, C.; Cohen, D. A.; Spear, B. T.; Evers, B. M. J. Surg. Res. 2013, 185, 225–230.
(2) Venkatesan, A. M.; Dehnhardt, C. M.; Santos, E. D.; Chen, Z.; Santos, O. D.; Ayral-
Kaloustian, S.; Khafizova, G.; Brooijmans, N.; Mallon, R.; Hollander, I.; Feldberg L.;
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Lucas, J.; Yu, K.; Gibbons, J.; Abraham, R. T.; Chaudhary, I.; Mansour, T. S. J. Med. Chem.
2010, 53, 2636–2645.
7
8
(3) http://adisinsight.springer.com/drugs/800030590.
9
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52
53
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55
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60
(4) Zhao, X.; Tan, Q.; Zhang, Z.; Zhao, Y. Med. Chem. Res. 2014, 23, 5188–5196.
(5) Khafizova, G.; Potoski, J. R. PCT Int. Appl. WO 2010096619, 2010.
(6) Venkatesan, A. M.; Chen, Z.; Dehnhardt, C. M.; Dos Santos, O.; Delos Santos, E. G.; Zask,
A.; Verheijen, J. C.; Kaplan, J. A.; Richard, D. J.; Ayral-Kaloustian, S.; Mansour, T. S.;
Gopalsamy, A.; Curran, K. J.; Shi, M. PCT Int. Appl. WO 2009143317, 2009.
(7) Simons, J. K.; Saxton, M. R. Org. Synth. 1953, 33, 13–15.
(8) Boloor, A.; Kanouni, T.; Stafford, J. A.; Veal, J. M.; Wallace, M. B. U.S. Pat. Appl. Publ.
US 20160194323, 2016.
(9) https://m.cameochemicals.noaa.gov/search/simple.
(10) Gopalsamy, A.; Shi, M.; Zask, A.; Venkatesan, A. M.; Curran, K. J. PCT Int. Appl. WO
2010120996, 2010.
(11) Shieh, W. C.; McKenna, J.; Sclafani, J. A.; Xue, S.; Girgis, M.; Vivelo, J.; Radetich, B.;
Prasad, K. Org. Process Res. Dev. 2008, 12, 1146–1155.
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