1
General Microwave-assisted Procedures for the Expedient
Synthesis of Substituted Heterocycles
M. Brad Nolt
Technology Enabled Synthesis Group, Department of Medicinal Chemistry, Merck Research Laboratories
(West Point), Merck & Co., Inc.
October 19, 2006
2
•Merck’s Technology Enabled Synthesis (TES) Group and Microwave Reactors in Organic Synthesis
•Triazines
•Canthines
•Imidazoles
•Quinoxalines and Fused Heterocyclic Pyrazines
•Quinoxalones
•5-Aminooxazoles
Contents
3
•The TES group specializes in rapid lead discovery
•Focus is on analog library synthesis
•Rapidly developing programs and external competition are challenges that drive our efforts to maximize efficiency
•Assisted by four single-mode microwave reactors and automated mass-guided purification
Technology Enabled Synthesis Group
4
•Approximately 96% of all reactions requiring heating are conducted in the microwave reactor
•Advantages of microwave heating are shorter reaction times, diminution of side products, and increased yields
•Organic synthesis procedures using microwave heating are often scaleable
TES and Microwave Reactors
5
Heterocycle Formation
HN
N
O
R1
R2
R1
O
O
R2
N
NNR1
R2 R3
N
HNR1
R2
R3
N
N
N
N
R1
R2
R1
R2
Het
R3
O
OR1
EtO
triazines
imidazoles
quinoxalines
pyrazines
quinoxalinones
N
O OR1
OOH
R2
N
O NR3R4
O
OR1
R2
aminooxazoles
(1)
(2)
(3)HN
RO2C CO2R
O
R
6
Triazines
N
NN
N
NNR1
R2 Het (R3)
1
26
5 3
4
•The triazine ring system is a key component in commercial dyes, herbicides, insecticides and pharmaceutical compositions
•The 1,2,4-triazine core structure is valuable for accessing a variety of ring systems via an intramolecular Diels-Alder reaction
Generic and target 3-heterocyclic-1,2,4-triazines
Shipe, W. D.; Yang, F.; Zhao, Z.; Wolkenberg, S. E.; Nolt, M. B.; Lindsley, C. W. Heterocycles, in press.
7
Triazine Synthesis
O
NH
+ N
NNPh
Ph
HN
N
NH4OAc(10 equiv.)
AcOH
180°C, MWI5 min
N
HN
1
2
385% yield
H2N
Ph
O
O
Ph
R3O
NH
+ N
NNR1
R2 R3
NH4OAc(excess)
AcOHreflux, 6-24 hH2N
R1
O
O
R2
(1)
(2)
• Conventional heating with heterocyclic diketones or heterocyclic acylhydrazides produced the target material in <30% yield with multiple side products
• Optimization of microwave heating conditions led to the synthesis of previously unknown 3
Zhao, Z.; Leister, W. H.; Strauss, K. A.; Wisnoski, D. D.; Lindsley, C. W. Tetrahedron Lett. 2003, 44, 1123-1127.
8
Triazine Synthesis – Scope of acyl hydrazides
aYields for analytically pure compounds fully characterized by LCMS, NMR, and HRMS.
PhPh
O
OR N
HNH2
O
+
NH4OAc (10 equiv.)AcOH
180°C, MWI5 min
N
NNPh
Ph R
entry RCONHNH2 product yield (%)a
1
2
3
4
5
84
80
92
90
81
NH
NH2
O
O
NN
NNPh
PhN
O
NH
NH2
O
NN N
NNPh
Ph NN
NH
NH2
O
S
NN
NNPh
Ph
N
S
NH
NH2
O
N
NNPh
Ph
NH
NH2
O
N
NNPh
Ph
NN
N N
O O
1
9
Triazines – Scope of diketones
R1R2
O
ONH
NH2
O
+
NH4OAc (10 equiv.)AcOH
180°C, 5 min N
NNR1
R2
entry R1COCOR2 product yield (%)a
1
2
3
4
92
N
NN
N
O
O
NN
O
N
NN
N
O
N
NNPh
N
O
N
NNPh
N
O
NN
O
O
O
O
O
O
O
OPh
O
OPh
NN
O
O
64 (75)b,c
69 (80)b,c
90
MWI
aYields for analytically pure compounds fully characterized by LCMS, NMR, and HRMS. bYields when reaction times extended to 10 min. c1:1 mixture of regioisomers
10
Canthines
NN
12
A B C
D46
8
11
Canthine Tetracyclic Skeleton
• First isolated from Pentaceras australis in 1952
• Canthines are a tetracyclic subclass of β-carboline alkaloids that possess an additional D-ring
• Members of this family have exhibited a wide range of pharmacological activities including antifungal, antiviral, and antitumor properties
Ohmoto, T.; Koike, K. The Alkaloids; Brossi, A. Ed; Academic Press: New York, NY, 1989, Vol. 63, pp 135-170.
11
Conventional Canthine Preparation
Benson, S. C.; Li, J.-H.; Snyder, J. K. J. Org. Chem. 1992, 57, 5285-5287.
• Despite the development of this straightforward protocol, limited diversity has existed at the C1 and C2 positions of synthethetic canthines
N
R1R2
O
O
NH4OAc (excess)AcOH, reflux
6-24 h
CONHNH2
N
(55-62%)4 6
5
triisopropylbenzene
reflux, 1.5 to 20 hN
N
R1
R2
7(72-93%)
R1, R2 = H, CH3, CO2Et
R1 = Ph, R2 = H
NN
N
R1
R2
12
Microwave-assisted Canthine Synthesis
Lindsley, C. W.; Wisnoski, D. D.; Wang, Y.; Leister, W. H.; Zhao, Z. Tetrahedron Lett. 2003, 44, 4495-4498.
Lindsley, C. W.; Bogusky, M. J.; Leister, W. H.; McClain, R. T.; Robinson, R. G.; Barnett, S. F.; Defeo-Jones, D.; Ross, C. W.; Hartman, G. D. Tetrahedron Lett. 2005, 46, 2779-2782.
entry time (min) temp (°C) 6 : 7a
1
2
3
4
5
6
7
5
10
20
40
60
40
40
180
180
180
180
180
200
220
9 : 1
7 : 3
2 : 1
1 : 1
1 : 2
1 : 5
1 : 19
PhPh
O
O
NH4OAc (excess)AcOH
temp, time
NN
PhPhN
NN
N
PhPh
:N CONHNH2
Optimization of Microwave Procedure
Ratios determined by analytical LCMS.
• 10 to 700-fold reduction in reaction times
• This procedure lead to the synthesis of unnatural canthines that inhibit Akt
13
Canthines
NN
NN N
N
N
N
CO2Et
CO2Et
F
F
NN
NN
NN
O
O
Me
Me
NN
Ph
NN
PhMe
Me
8 (81%) 9 (83%) 10 (59%) 11 (62%)
12 (34%) 13 (26%) 14a 14b
(1:1)
(62%)
Lindsley, C. W.; Wisnoski, D. D.; Wang, Y.; Leister, W. H.; Zhao, Z. Tetrahedron Lett. 2003, 44, 4495-4498.
14
Imidazoles
N
HN1
2
3
4
5
N
HN
R1
R3
R2
Generic and target imidazoles
• Imidazoles are components of many natural products, dyes, herbicides, fungicides, catalysts, and pharmaceutical compounds
• Synthetic route via the formamidesynthesis uses glyoxal, formaldehyde and ammonia, and heating for four to six hours
(a) Grimmett, M. R. Comprehensive Heterocyclic Chemistry; Katrizky, A. R.; Rees, C. W., Eds.; Pergamon: Oxford, 1984; Vol. 5, pp 457-498. (b) Grimmett, M. R. Comprehensive Heterocyclic Chemistry II; Katrizky, A. R.; Rees, C. W.; Scriven , W. F. V., Eds.; Pergamon: New York, 1996; Vol. 3, p 77.
15
Imidazoles
O
O
Ph
Ph
O
H Ph N
HNPh
Ph
Phconditions
entry temp (°C) conversion (%)a
1 242 513 6145 87
98
time (min)6080
100120140160
555555
68
67 718 829 95
160160160
0.513
1 17 18
Wolkenberg, S. E.; Wisnoski, D. D.; Leister, W. W.; Wang, Y.; Zhao, Z.; Lindsley, C. W. Org. Lett. 2004, 6, 1453-1456.
Optimization of Microwave Procedure
• Ultimately, heating at 180°C for five minutes provided nearly complete conversion to 18
Reactions run in acetic acid with 0.2 mmol each of 1, 17 and 10 equiv. of NH4OAc.aRatios determined by analytical LCMS, isolated yield for entry 6, 88%
16Wolkenberg, S. E.; Wisnoski, D. D.; Leister, W. W.; Wang, Y.; Zhao, Z.; Lindsley, C. W. Org. Lett. 2004, 6, 1453-1456.
Imidazoles – aldehyde variations
O
O
Ph
Ph
O
H R N
HNPh
Ph
R
NH4OAc (10 equiv.)AcOH
180 °C, 5 min
entry product yield (%)a
N
HNPh
Ph
F1 97
N
HNPh
Ph
CN2 88
N
HNPh
Ph
OMe3 87
4N
HNPh
Ph
93O
MWI1
• The procedure is successful with electron withdrawing and donating substitution on the aldehyde
aIsolated yields for analytically pure compounds after neutralization andfiltration
17Wolkenberg, S. E.; Wisnoski, D. D.; Leister, W. W.; Wang, Y.; Zhao, Z.; Lindsley, C. W. Org. Lett. 2004, 6, 1453-1456.
Imidazoles – diketone variations
O
O
R1
R2
O
H Ph N
HNR1
R2
Ph
NH4OAc (10 equiv.)AcOH
180 °C, 5 minMWI17
entry product yield (%)a
N
HN
1 89
O
O
N
HN
2 95
MeO2C
MeO2C
N
HN
3 99
MeO
MeO
N
HN
4 94
Me
Me
N
HN
5 94
Me
Me
N
HN
Me6 93
Me
entry product yield (%)a
aIsolated yields for analytically pure compounds obtained after neutralization of the reaction mixture then filtration
18
O
O
Me
Me
O
H Me N
HNMe
Me
MeAcOH
180 °C, 5 min
NH4OAc
76%
N
NMe
Me
Me
Ph
Ph
Cl-
BnCl,CH3CN
5 minMWI
lepidiline B
MWI
+
N
HNPh
Ph
AcOH
180 °C, 5 min
NH4OAc
99%O NMe2
OHC
O NMe2
Ph
Ph
O
O
trifenagrel
MWI
+
Wolkenberg, S. E.; Wisnoski, D. D.; Leister, W. W.; Wang, Y.; Zhao, Z.; Lindsley, C. W. Org. Lett. 2004, 6, 1453-1456.
Cui, B.; Zheng, B. L.; He, K.; Zheng, Q. Y. J. Nat. Prod. 2003, 66, 1101.
Abrahams, S. L.; Hazen, R. J.; Batson, A. G.; Phillips, A. P. J. Pharmacol. Exp. Ther. 1989, 249, 359.
Imidazoles
•Natural product isolated from the roots of L. meyenii
•Micromolar cyctotoxicity against several human cancer cell lines
•Potent 2,4,5-triaryl imidazolearachidonate cyclooxygenaseinhibitor
•Existing procedure requires two hours of reflux
19
Quinoxaline and Fused HeterocyclicPyrazines
N
N
N
NR1
R2
R3
1
3
7
6
2N
NR1
R2
Het
Generic and target quinoxaline and fused heterocyclic pyrazines
•Quinoxalines have demonstrated pharmaceutical value as antiviral agents, antibiotics, and kinase inhibitors
•The most common synthetic route requires the condensation of an aryl 1,2-diamine with a 1,2-dicarbonyl compound by refluxing in ethanol or acetic acid for two to 12 hours
20
Quinoxaline
Ph
Ph O
O
H2N
H2N+
N
NPh
Ph
1 19 20
entry conditions yield
1
2
EtOH/AcOH, reflux, 2-12 hr
9:1 MeOH/AcOH, 160 °C (MWI), 5 min
34-85
99
conditions
•Optimal conditions give nearly complete conversion to product 20
•This general procedure gives quinoxalines in high yields with tolerance for variations of the 1,2-diketone and 1,2-diamine
Zhao, Z.; Wisnoski, D. D.; Wolkenberg, S. E.; Leister, W. H.; Wang, Y.; Lindsley, C. W. Tetrahedron Lett.2004, 45, 4873-4876.
21
Quinoxaline – 1,2-diamine variations
Ph
Ph O
O
H2N
H2NR+
9:1 MeOH/AcOHR
N
NPh
Ph
entry product yield (%)a
1
2
3
4
N
NPh
Ph
N
NPh
Ph
N
NPh
Ph
N
NPh
Ph
NH2
OMe
Cl
CO2CH3
99
97
96
98
160 °C, 5 minMWI
1
N
NPh
Ph
N
NPh
Ph
N
NPh
Ph
N
NPh
Ph
N
NH
F
NH
N
CN
5
6
7
8
entry product yield (%)a
99
99
95
95
aYields for analytically pure compounds fully characterized by LCMS, NMR, and HRMS.
Zhao, Z.; Wisnoski, D. D.; Wolkenberg, S. E.; Leister, W. H.; Wang, Y.; Lindsley, C. W. Tetrahedron Lett.2004, 45, 4873-4876.
22
Quinoxaline – 1,2-diketone variations
aYields for analytically pure compounds fully characterized by LCMS, NMR, and HRMS.
9:1 MeOH/AcOH
160 °C, 5 minMWIR2
R1 O
O
H2N
H2NR3+ R3
N
NR1
R2
entry product yield (%)a
1
2
3
N
N
N
N
N
N
Ph
N
N
NH2
Cl
N
NH
NNH
NN
O
O
NN
N
N CO2CH3O
O
98
95
99
N
NPhN
NH
N
N
96
95
83
4
5
6
entry product yield (%)a
Zhao, Z.; Wisnoski, D. D.; Wolkenberg, S. E.; Leister, W. H.; Wang, Y.; Lindsley, C. W. Tetrahedron Lett.2004, 45, 4873-4876.
23
R2
R1 O
O
H2N
H2N+
N
NR1
R2
entry product yield (%)a
1
2
3
97
94
92
NN
N
NN
NNN
NN
NO
O
N N
9:1 MeOH/AcOH
160 °C, 5 minMWI21
Pyrido[2,3-b]pyrazines
aYields for analytically pure compounds fully characterized by LCMS, NMR, and HRMS.
Zhao, Z.; Wisnoski, D. D.; Wolkenberg, S. E.; Leister, W. H.; Wang, Y.; Lindsley, C. W. Tetrahedron Lett.2004, 45, 4873-4876.
24
R2
R1 O
O
H2N
H2N
+N
NR1
R2
entry product yield (%)a
1
2
3
74
77
69
N
N
N
NNN
N
NO
O
S S
S
S
S
F
F
9:1 MeOH/AcOH
60 °C, 5 minMWI
22
Thieno[3,4-b]pyrazines
aYields for analytically pure compounds fully characterized by LCMS, NMR, and HRMS.
Zhao, Z.; Wisnoski, D. D.; Wolkenberg, S. E.; Leister, W. H.; Wang, Y.; Lindsley, C. W. Tetrahedron Lett.2004, 45, 4873-4876.
25
Quinoxalinones
HN
N
O
R1
R2
HN
N
O
3 6
71
Generic and target quinoxalinones
•Although infrequently found in nature, the core structure of quinoxalinones is contained in biologically active structures with antifungal, antimicrobial, and analgesic activities
•Fernández et al. have carried out aqueous cyclocondensations of ethyl pyruvate and 1,2-diaminobenzene catalyzed by strong acids, classically called the Hinsberg reaction
Carta, A.; Sanna, P.; Loriga, M.; Setzu, M. G.; La Colla, P.; Savelli, F. Farmaco 2002, 57, 19-25.
Abasolo, M. I.; Gaozza, C. H.; Fernández, B. M. J. Heterocyclic Chem. 1987, 29, 129-133.
26
Quinoxalinones
O OEt
O+
H2N
H2N
10% aq. HClHN
N
O
5 min, MWI
23 19 24
entry temperature conversion (%)a
1
2
3
84
90
97
60
100
125
Optimization of Microwave Procedure
aConversion determined by LCMS
•With prototypical substrate 23, conversion to product was nearly quantitative with heating at 125°C for five minutes
Yang, F.; Shipe, W. D.; Lindsley, C. W. previously unpublished work
27
Quinoxalinones
aDetermined by LCMS. bIsolated as a 3:1 mixture of regioisomers (major isomer shown)
O OEt
O+
H2N
H2N
10% aq. HClHN
N
O
5 min, 125 °CMWI
23
entry product conversion (%)a
1
2
3
4
87
96
100
90
R R
HN
N
O
HN
N
O
HN
N
O
Cl
HN
N
O OMe
HN
N
O F
HN
N
O NO2
b
HN
N
O COOMe
5
6
7
91
51
26
entry product conversion (%)a
b
Yang, F.; Shipe, W. D.; Lindsley, C. W. previously unpublished work
28
entry time temperature conversion (%)a
DMF, cat. AcOH
MWI
O OEt
O+
H2N
H2N
HN
N
O
23 19 24
1
2
3
4
5
6
7
5
10
20
5
5
15
5
160
160
160
170
180
180
190
1
2
2
100
100
100
100
Quinoxalinones
Re-optimization of Microwave Procedure
•The re-optimized procedure improved the conversion to target material and also proved to be general with electron-deficient aryl 1,2-diamines
aConversion determined by LCMS
Yang, F.; Shipe, W. D.; Lindsley, C. W. previously unpublished work
29
Quinoxalinones – scope of 1,2-diamine
entry product conversion (%)a
1
2
3
4
82
80
100
89
O OEt
O
+H2N
H2N
DMF, cat. AcOH
5 min, 180 °CMWI
R
HN
NR
O
25
HN
N
O
HN
N
O
HN
N
O Cl
Cl
HN
N
O
Cl
HN
N
O
COOMe
HN
N
O
NO2
entry product conversion (%)a
91
89
5
6
aConversion determined by LCMS
Yang, F.; Shipe, W. D.; Lindsley, C. W. previously unpublished work
30
Quinoxalinones – scope of α-ketoester
aDetermined by LCMS.
Yang, F.; Shipe, W. D.; Lindsley, C. W. previously unpublished work
entry product conversion (%)a
1
2
3
82
100
95
O OEt
OR
+H2N
H2N
DMF, cat. AcOH
5 min, 180 °CMWI
HN
N
O
R19
HN
N
O
HN
N
O
F3C
HN
N
O
HN
N
O
HN
N
O
4
5
100
93
entry product conversion (%)a
31
entry product isolated yield (%)a
1
2
3
4
69
74
60
59
O OEt
OR
+H2N
H2N
DMF, cat. AcOH
5 min, 180 °CMWI
HN
N
O
R19
HN
N
O
F3C
HN
N
O
HN
N
O
HN
N
O
Quinoxalinones
• Products are insoluble in solvents suitable for chromatographic separation
• Precipitation in methanol gives analytically pure quinoxzalinones
aYields for analytically pure compounds fully characterized by LCMS, NMR, and HRMS.
Yang, F.; Shipe, W. D.; Lindsley, C. W. previously unpublished work
32
O OEt
O +H2N
H2N
HN
N
O
10% aq. HCl
5 min, 125 °CMWI N
NH
27 (97%)
28 (2%)
1926
Quinoxalinones
Unexpected side product
•While the appearance of side products was rare, 28 is presumable formed from the reaction with the carbonyl group of 26, followed by oxidative decarboxylation
Yang, F.; Shipe, W. D.; Lindsley, C. W. previously unpublished work
33
5-Aminooxazoles
O
OHHO
OHO
N
ON
29
N
NHN
O
O
NH2
30
N
O
OMe
CbzHN
Ph
31
N O
HN
O
HN
MeOO
32
OOMe
O
HN
MeO2C
N
O OR1
N
O NR3R4R2 R2
NR2
R1O
R4R3N
O
O
3433 35
O
NR3R4 OR1
O
• The 5-aminooxazole moiety exists in antibiotics, inhibitors of ricin and shiga toxins, peptidomimetics, and a Rafkinase inhibitor
Biologically active 5-aminooxazoles
Cornforth rearrangement
• We have accessed these structures via a microwave Cornforth rearrangement, to give the thermodynamically stable product 35
34
5-Aminooxazoles
NH2
OEtO
OEt
O Cl
O
NH
EtO
O
OEt
OO
Ph
N
OPh OEt
OEt
O
TFAA aq. KOH N
OPh OEt
OH
O
R1R2NH,PS-DCC,HOBt
N
OPh OEt
NR1R2
O
N
OPh NR1R2
OEt
O
100°C
180°C
DIEA
MWI
MWI MWI
+
36 37
• Using a procedure borrowed from Dewar, we have incorporated microwave heating into a dramatically faster reaction sequence
• The result is a 200-fold reduction in reaction time while generating 5-aminooxazoles in good yield
Nolt, M. B.; Smiley, M. A.; Varga, S. L.; McClain, R. T.; Wolkenberg, S. E.; Lindsley, C. W. Tetrahedron 2006, 62, 4698-4704.
35
5-Aminooxazoles
Optimization of Microwave-assisted Cornforth rearrangement
• We determined that microwave heating at 180°C for five minutes gave the most favorable results
• Trifluorotoluene is a high boiling solvent with sufficient dipole for rapid microwave heating
aDetermined by LCMS. R1R2= piperidine
entry solvent temperature time product:starting materiala
1
2
3
4
5 PhCF3
CH3CN 150 °C
160 °C
170 °C
180 °C
180 °C
10 min
10 min
10 min
10 min
5 min
1:99
31:69
42:58
99:1
99:1
CH3CN
CH3CN
CH3CN
N
OPh OEt
NR1R2
O
N
OPh NR1R2
OEt
Oconditions
MWI
36 37
Nolt, M. B.; Smiley, M. A.; Varga, S. L.; McClain, R. T.; Wolkenberg, S. E.; Lindsley, C. W. Tetrahedron 2006, 62, 4698-4704.
36
5-Aminooxazoles
HN
HN
F
NH2
H2NS
H2NO
O5
HN
H2N NHBoc5
H2N
N
1
2
3
4
5
6
7
8
100 °C, 5 min
100 °C, 5 minPS-DIEA (1 eq.)
100 °C, 5 min
100 °C, 5 minPS-DIEA (1 eq.)
100 °C, 5 minPS-DIEA (1 eq.)
100 °C, 5 min
100 °C, 5 min
100 °C, 5 min
180 °C, 5 min
180 °C, 5 min
180 °C, 5 min
180 °C, 5 min
180 °C, 5 min
180 °C, 5 min
180 °C, 5 min
180 °C, 5 min
98
47
99
51
76
85
99
82
N
OPh OEt
OH
O
N
OPh OEt
NR1R2
O
N
OPh NR1R2
OEt
37
O
MWI MWI
36
entry amine coupling cond rearrang cond yield (%) entry amine coupling cond rearrang cond yield (%)
Nolt, M. B.; Smiley, M. A.; Varga, S. L.; McClain, R. T.; Wolkenberg, S. E.; Lindsley, C. W. Tetrahedron 2006, 62, 4698-4704.
37
5-Aminooxazoles
NH2
OMeO
OMe
OCl
O
NH
MeO
O
OMe
OO
N
O OMe
OMe
O
aq. KOH N
O OMe
OH
O
N
O OMe
N
O
N
O N
OMe
38
OBn OBn
OBn OBn
O
OBn
80 °C
180 °C
CCl3COCl
OBn
piperidine,PS-DCC,HOBt
MWI MWI
MWI
+
O
OHHO
OHO
N
ON
29 OOMe
• We have demonstrated the utility of this procedure in the formal synthesis of 4-(methoxycarbonyl)-2-(1-normon-2-yl)-5-piperidin-1-yloxazole (29)
• Intermediate 38 was obtained in 29% overall yield
• Deprotection followed by halogenation and olefinationwould provide 29
Nolt, M. B.; Smiley, M. A.; Varga, S. L.; McClain, R. T.; Wolkenberg, S. E.; Lindsley, C. W. Tetrahedron 2006, 62, 4698-4704.
38
Conclusion
• Microwave heating can significantly shorten reaction times and increase efficiency
• We have demonstrated the effectiveness of microwave-assisted heating in the formation of heterocyclic targets
• Microwave reactors have become an integral part ofmethod development in TES
Products Reaction Development
Microwave as enabling technology
Microwave as driving force
39
Acknowledgements
Technology Enabled Synthesis Group Former Members
James BarrowJaime BundaApril CoxChristopher DenicolaRay McClainJames MulhearnSteven SharikWilliam ShipeCorey ThebergeScott WolkenbergF. Vivien YangZhijian Zhao
Todd AndersonWilliam LeisterCraig LindsleyDavid D. Wisnoski
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