Discovery of novel phenethylpyridone derivatives as potent melanin-concentrating hormone 1 receptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2009.07.023

Novel phenethylpyridone derivatives were identified as potent human melanin-concentrating hormone 1 receptor (MCH-1R) antagonists. A search for surrogates for the 4-(2-aminoethoxy)phenyl moiety of 1 resulted in discovery of 2-[4-(aminomethyl)phenyl]ethyl substructure as in 6a. Successive optimization of the right-hand moiety led to the identification of a number of potent derivatives.

Full text of DOI:10.1016/j.bmcl.2009.07.023

Bioorganic & Medicinal Chemistry Letters 19 (2009) 5186–5190
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of novel phenethylpyridone derivatives as potent
melanin-concentrating hormone 1 receptor antagonists
*
Makoto Ando , Etsuko Sekino, Yuji Haga, Minoru Moriya, Masahiko Ito, Junko Ito, Hisashi Iwaasa,
Akane Ishihara, Akio Kanatani, Norikazu Ohtake
Department of Medicinal Chemistry, Tsukuba Research Institute, Merck Research Laboratories, Banyu Pharmaceutical Co., Ltd, Okubo-3, Tsukuba, Ibaraki 300-2611, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel phenethylpyridone derivatives were identified as potent human melanin-concentrating hormone 1
receptor (MCH-1R) antagonists. A search for surrogates for the 4-(2-aminoethoxy)phenyl moiety of 1
resulted in discovery of 2-[4-(aminomethyl)phenyl]ethyl substructure as in 6a. Successive optimization
of the right-hand moiety led to the identification of a number of potent derivatives.
Ó 2009 Published by Elsevier Ltd.
Received 1 May 2009
Revised 2 July 2009
Accepted 3 July 2009
Available online 9 July 2009
Keywords:
Melanin-concentrating hormone 1 receptor
antagonist
Phenethylpyridone
Anti-obesity
Melanin-concentrating hormone (MCH) is a cyclic 19-amino
acid polypeptide that is expressed predominantly in the lateral
hypothalamus (LH). The LH is a region of the brain involved in the
regulation of feeding, the neuroendocrine axis, and thermogenesis.
Biology and pharmacology results suggest that MCH is an impor-
tant mediator of energy homeostasis. Mice lacking prepro-MCH
are lean, hypophagic, and have an elevated metabolic rate.1
Conversely, prepro-MCH overexpression in mice results in a greater
susceptibility to obesity.2 Furthermore, overexpression of MCH
mRNA has been found in obese rodents, such as ob/ob, db/db, and
Ay/a mice.3–5 Exogenous administration of MCH stimulates food
intake,3,6 and chronic ICV infusion of the MCH7,8 or a related
MCH-1R agonist9 produces obesity with hyperphagia. Even when
pair-feeding is employed to prevent hyperphagia, ICV infusion of
MCH still produces anabolic changes.10 The effects of MCH are med-
iated through G protein-coupled receptors located in the CNS, and
thus far two receptor subtypes, MCH-1R and MCH-2R, have been
identified.11–14 Since rodents possess only MCH-1R, all pharmaco-
logical effects of MCH in rodents are likely mediated via
MCH-1R.15 Recently, peptide and non-peptidic MCH-1R antagonists
have been developed, and both antagonists produced anti-obese
effects in diet-induced obese rats.9,16,17 Collectively, these data
indicate that MCH-1R plays an important role in the development
of obesity, suggesting that MCH antagonists could be effective
therapeutic agents for the treatment of obesity in humans.
Our group has previously reported on a novel series of phenylpyri-
dones exemplified by 1 (Fig. 1), which exhibit potent binding activity
(IC50 = 5.6 nM).18 We subsequently searched for surrogates for the
4-(2-aminoethoxy)phenyl moiety on the right-hand part of 1 to iden-
tify structurally distinct substructures tolerated for MCH-1R binding
activity. As a consequence, 2-[4-(aminomethyl)phenyl]ethyl analogs,
such as 6a, were found to have MCH-1R activity equal to the related
phenylpyridone compound 1. This letter will describe the synthesis
and structure–activity relationships (SAR) of the novel phenethyl-
pyridone class of MCH-1R antagonists.
The synthesis of compounds described herein is outlined in
Schemes 1–3. Synthesis of phenethylpyridone derivatives 6a, 6b,
6h, 6i, and 6l–n are illustrated in Scheme 1. Pyridone 8 was cou-
pled with 10, 11, or 12 in the presence of potassium carbonate or
cesium carbonate to give intermediates 14a–c. Deprotection of
compounds 14a–c by treatment with 1 N hydrochloric acid or
tetrabutylammonium fluoride, followed by chlorination with SOCl2
and subsequent coupling with corresponding amines, furnished
F
O
N
O
N
O
1
hMCH-1R IC50: 5.6 nM
* Corresponding author. Tel.: +81 29 877 2218; fax: +81 29 877 2029.
E-mail address: andoumkt@gmail.com (M. Ando).
Figure 1. Structure and hMCH-1R binding activity of compound 1.
0960-894X/$ - see front matter Ó 2009 Published by Elsevier Ltd.
doi:10.1016/j.bmcl.2009.07.023

M. Ando et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5186–5190
5187
F
F
O
O
a
RX
N
Y
N
R1
Z
X
O
OPro
O
8: R1 = H
14a: X = Y = CH, Z = CH2, Pro = TBS
9: R1 = OH
14b: X = N, Y = CH, Z = CH2, Pro = MOM
14c: X = CH, Y = N, Z = CH2, Pro = TBS
14d: X = Y = CH, Z = O, Pro = TBS
b or c
d
6a, 6b, 6h, 6i, 6l−n
TsO
TsO
TsO
N
RX =
OTBS
OMOM
OTBS
10
11
MsO
OTBS
N
12
13
Scheme 1. Preparation of phenethylpyridone derivatives 6a, 6b, 6h, 6i, and 6l–n. Reagents and conditions: (a) RX, Cs2CO3 or K2CO3, DMF, 80 °C, 2–17 h, 37–64%; (b) 1 N HCl,
THF or MeOH, rt or reflux, 2–18 h, 27–100%; (c) TBAF, THF, rt, 1 h, 89%; (d) (i) SOCl2, CHCl3, 0 °C to rt, 1 h, (ii) amine, K2CO3, NMP, 80 °C, ON, 37–63% over two steps.
outlined in Scheme 2. Reductive alkylation of 6i with the corre-
sponding carbonyl compound gave phenethylpyridones 6c–f.
Alkylation of 6i with corresponding alkyl halides afforded desired
compounds 6g, 6j, and 6k. Preparation of 2–4 and 7 are described
in Scheme 3. Pyridone 8 was coupled with bromobenzene 14 in the
presence of copper iodide, followed by removal of the THP group
and a subsequent coupling reaction with 2-(pyrrolidin-1-yl)etha-
nol to give compound 2. Treatment of 8 with compound 1519
followed by deprotection of the methoxymethyl (MOM) group
afforded 16, which was converted to compound 3 by coupling with
1,2-bromoethane and successive amination with pyrrolidine. The
intermediate 16 was also converted to 4 by alkylation with (3-bro-
mopropyl)pyrrolidine hydrobromide. Pyridone 8 and phenetylal-
cohol 17 were coupled under Mitsunobu conditions20 followed
a
6c−f
F
O
N
H
O
N
6g, 6j, 6k
6i
b
Scheme 2. Synthesis of phenethyl pyridone derivatives 6c–g, 6j, and 6k. Reagents
and conditions: (a) aldehyde or ketone, ZnCl2, NaBH3CN, rt, ON, 23–53%; (b) RX,
K2CO3, CH3CN, 80 °C, ON, 38–51%.
desired phenethylpyridones 6a, 6b, 6h, 6i, 6l, and 6m. Compound
6n was prepared from N-hydroxypyridone 919 and 1319 in the
same manner. Compounds 6c–g, 6j, and 6k were synthesized as
Br
OTHP
14
F
O
e
a
2
NH
8
7
OMOM
O
MsO
b
HO
15
Br
F
17
O
c or d
3, 4
N
OH
O
16
Scheme 3. Preparation of derivatives 2–4 and 7. Reagents and conditions: (a) (i) 14, CuI, K2CO3, pyridine, DMF, reflux, 18 h, 73%, (ii) cat. PPTS, EtOH, reflux, 2 h, (iii) 2-
(pyrrolidin-1-yl)ethanol, ADDP, t-Bu3P, THF, 0 °C to rt, 19 h, 31% over two steps; (b) (i) 15, Cs2CO3, DMF, 80 °C, 4 h, 13%, (ii) 1 N HCl, MeOH, rt, 0 °C to rt, 17 h, 94%; (c) (i) 1,2-
dibromoethane, Cs2CO3, CH3CN, 80 °C, 48 h, 55%, (ii) pyrrolidine, NMP, 150 °C, MW, 5 min, 57%; (d) 1-(3-bromopropyl)pyrrolidine hydrobromide, K2CO3, DMF, 80 °C, 11 h,
43%; (e) (i) 17, ADDP, t-Bu3P, CH2Cl2, rt, 17 h, 29%, (ii) pyrrolidine, cat. Pd2(dba)3, cat. BINAP, NaOt-Bu, toluene, 80 °C, 20 h, 70%.

5188
M. Ando et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5186–5190
c
TsO
a or b
MeOOC
OH
OTBS
X
X
10: X = CH
12: X = N
18: X = CH
19: X = N
Scheme 4. Preparation of intermediates 10 and 12. Reagents and conditions: (a) 18, TBSCl, imidazole, THF, 0 °C to rt, 17 h, 65%; (b) 19, TBSCl, Et3N, DMF, rt, 13 h, 90%; (c) (i)
LAH, THF, À78 °C to rt, 1–17 h, 54–100%, (ii) TsCl, Et3N, cat. DMAP, CHCl3, 0 °C to rt, ON, 76–89%.
N
N
TsO
N
a
b
OH
OMOM
OMOM
20
21
11
Scheme 5. Preparation of intermediate 11. Reagents and conditions: (a) MOMCl, NaH, DMF, À20 °C, 30 min, 30%; (b) (i) 37% aq formaldehyde, 150 °C, 17 h, 28%, (ii) TsCl, Et3N,
cat. DMAP, 0 °C to rt, 14 h, 87%.
by reaction with pyrrolidine in the presence of a palladium catalyst
to furnish compound 7.
MOM-protected 2-picoline, which was then thermally treated with
formaldehyde followed by treatment with tosyl chloride to afford
tosylate 11.21
Key intermediates 10 and 12 were prepared according to
Scheme 4. The hydroxyl group of phenylacetates 1819 and 19 was
protected using tert-butyldimethylsilyl chloride followed by
reduction of the ester and subsequent tosylation of the resulting
hydroxyl group to give intermediates 10 and 12. Synthesis of tos-
ylate 11 is outlined in Scheme 5. Compound 20 was converted to
A series of phenethylpyridone derivatives were tested in a
[
125I]MCH binding assay using Chinese hamster ovary (CHO-K1)
cell membranes expressing human recombinant MCH-1R recep-
tors.22 Selected compounds were evaluated for metabolic stability
using human and mouse hepatic microsomes.23 Modification of
the linkage and substituent position of the aminoalkyl group in
the right part of 1 was initiated to identify structurally diverse
substructures (Table 1). 3-Aminoethoxy substitution as in 2 was
detrimental to potency. Introduction of a methylene linkage
between a pyridone and a phenyl ring as in 3 dramatically im-
proved hMCH-1R activity compared to 2. Aminopropoxy analogue
4 was equipotent to the aminoethoxy compound 3. Removal of
the methylene oxy linker between the phenyl group and the
pyrrolidine as in 519 provided significant reduction in hMCH-1R
potency. Importantly, installation of an ethylene chain into 5
resulted in derivative 6a with a comparable potency to 1. When
a methylene linkage of 6a was removed as in 7, a complete loss
of potency was observed. On the basis of these preliminary
results, the phenethyl derivative 6a was selected as a template
for further SAR studies.
Variation of substituents of the amine moiety of 6a was exam-
ined (Table 2). The binding and metabolic stability profiles of
diethylamine 6b were similar to those of the parent 6a. Di(n-pro-
pyl)amine 6c displayed a slightly improved hMCH-1R potency,
although the metabolic turnover was much higher than 6a in both
humans and mice. Next, one of the n-propyl groups of 6c was
replaced by a variety of functional groups. Replacement with steri-
cally more demanding substituents such as isopropyl, 2-methyl-
propyl, and cyclopentyl as in 6d–f resulted in a comparable
activity to 6a, but these derivatives showed low metabolic stability
in hepatic microsomes. Shortening the n-propyl group of 6c as in
6g–i conferred significant improvement in microsomal stability,
and the n-propylamine 6i was found to be the most potent ana-
logue, displaying a twofold increase of potency relative to 6a.
Introduction of a fluorine or methoxy group on the ethyl group
of 6g did not provide a benefit of intrinsic potency and metabolic
stability as in 6j and 6k. In this SAR study, various amine functions
were tolerated in terms of hMCH-1R activity, and the n-propyl
derivative 6i was identified as the most potent compound.
Table 1
Human MCH-1R binding activity of compounds 1–7a
F
O
N
R1
O
Compound
R1
hMCH-1R IC50 (nM)
5.6
1
N
N
O
O
2
>1000
29
3
N
O
O
4
30
N
5
>1000
5.0
N
6a
N
Having established the optimum substituents on the amine
part, insertion of a hetero atom into a phenyl ring and ethylene
linkage of 6i was finally investigated as shown in Table 3. The
3-aminopyridine analog 6l showed improved microsomal stability
in mice and a slight decrease of potency. The 2-aminopyridine
7
>1000
N
The values represent the means for n = 2. Inhibition of [125I]MCH binding to
a
hMCH-1R in CHO cells.

M. Ando et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5186–5190
5189
Table 2
Table 3
SAR of derivatives 6a–ka
SAR of derivatives 6i and 6l–na
F
F
O
O
N
N
R1
O
R2
O
R2
hMCH-1Rb (IC50, nM)
Metabolic stabilityc
(% remaining)
Compound
R1
hMCH-1Rb
(IC50, nM)
Metabolic stabilityc
(% remaining)
Compound
Human
Mouse
Human
Mouse
6i
2.6
7.0
11
85
62
H
N
6a
6b
6c
5.0
5.9
3.3
60
39
N
N
N
54
1
26
1
6l
91
87
72
93
76
74
H
N
N
6m
N
N
H
N
6d
6e
5.2
4.9
4
0
1
0
O
6n
34
H
N
a
The values represent the means for n = 2.
Inhibition of [125I]MCH binding to hMCH-1R in CHO cells.
% Remaining after 30 min incubation in hepatic microsomes.
b
c
N
6f
6g
6h
6i
3.5
4.4
3.5
2.6
5.4
1
26
58
85
0
1
6
In summary, we have modified the right part of our previously
N
N
identified series of phenylpyridones to provide a new series of
MCH-1R antagonists. Representative compounds 6i and 6l have
been shown to be potent with good hepatic microsomal stability.
In addition, both compounds displayed excellent selectivity over
10 diverse and unrelated binding sites (IC50 > 5
lM for adrenergic
a
1, opiate ( , d), histamine H1-4, adenosine A2a, and muscarinic
l, j
22
62
0
M1). Further evaluation of this series is ongoing, including pharma-
cokinetics and in vivo efficacy in rodents.
N
H
N
Acknowledgments
We thankKazuhideImagakiandShoheiHondaforthemicrosomal
stability assay, and Mioko Hirayama for the counter-screen assay.
OMe
F
6j
N
References and notes
1. Shimada, M.; Tritos, N. A.; Lowell, B. B.; Flier, L. S.; Maratos-Flier, E. Nature
1998, 396, 670.
6k
11
0
0
2. Ludwig, D. S.; Tritos, N. A.; Mastaitis, J. W.; Kulkarni, R.; Kokkotou, E.; Elmquist,
J.; Lowell, B.; Flier, J. S.; Maratos-Flier, E. J. Clin. Invest. 2001, 107, 379.
3. Qu, D. Q.; Ludwig, D. S.; Gammeltoft, S.; Piper, M.; Pelleymounter, M. A.; Cullen, M.
J.; Mathes, W. F.; Przypek, J.; Kanarek, R.; MaratosFlier, E. Nature 1996, 380, 243.
4. Mizuno, T. M.; Kleopoulos, S. P.; Bergen, H. T.; Roberts, J. L.; Priest, C. A.; Mobbs,
C. V. Diabetes 1998, 47, 294.
N
a
The values represent the means for n = 2.
b
c
Inhibition of [125I]MCH binding to hMCH-1R in CHO cells.
% Remaining after 30 min incubation in hepatic microsomes.
5. Hanada, R.; Nakazato, M.; Matsukura, S.; Murakami, N.; Yoshimatsu, H.; Sakata,
T. Biochem. Biophys. Res. Commun. 2000, 268, 88.
6. Rossi, M.; Choi, S. J.; Oshea, D.; Miyoshi, T.; Ghatei, M. A.; Bloom, S. R.
Endocrinology 1997, 138, 351.
analog 6m was fourfold less potent than 6i. Introduction of an oxy-
gen atom into the ethylene linker as in 6n resulted in significant
loss of potency. Among the derivatives possessing potent MCH-
1R potency and good microsomal stability, compounds 6i and 6l
were evaluated for their in vitro functional activity.22 Both deriva-
tives exhibited potent antagonistic activity (6i: IC50 = 20 nM, 6l:
IC50 = 27 nM). It should be noted that compounds 6i and 6l had
low human ether-a-go-go related gene (hERG) binding activity
(6i: hERG IC50 = 4200 nM, 6l: hERG IC50 = 5100 nM).24
7. Marsh, D. J.; Weingarth, D. T.; Novi, D. E.; Chen, H. Y.; Trumbauer, M. E.; Chen,
A. S.; Guan, X. M.; Jiang, M. M.; Feng, Y.; Camacho, R. E.; Shen, Z.; Frazier, E. G.;
Yu, H.; Metzger, J. M.; Kuca, S. J.; Shearman, L. P.; Gopal-Truter, S.; MacNeil, D.
J.; Strack, A. M.; MacIntyre, D. E.; Van der Ploeg, L. H. T.; Qian, S. Proc. Natl. Acad.
Sci. U.S.A. 2002, 99, 3240.
8. Gomori, A.; Ishihara, A.; Ito, M.; Mashiko, S.; Matsushita, H.; Yumoto, M.; Ito,
M.; Tanaka, T.; Tokita, S.; Moriya, M.; Iwaasa, H.; Kanatani, A. Am. J. Physiol.
Endocrinol. Metab. 2003, 284, E583.
9. Shearman, L. P.; Camacho, R. E.; Stribling, D. S.; Zhou, D.; Bednarek, M. A.;
Hreniuk, D. L.; Feighner, S. D.; Tan, C. P.; Howard, A. D.; Van der Ploeg, L. H. T.;
MacIntyre, D. E.; Hickey, G. J.; Strack, A. M. Eur. J. Pharmacol. 2003, 475, 37.

5190
M. Ando et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5186–5190
10. Ito, M.; Gomori, A.; Ishihara, A.; Oda, Z.; Mashiko, S.; Matsushita, H.; Yumoto,
M.; Ito, M.; Sano, H.; Tokita, S.; Moriya, M.; Iwaasa, H.; Kanatani, A. Am. J.
Physiol. Endocrinol. Metab. 2003, 284, E940.
20. Coupling of 8 with 17 was conducted according to a literature procedure. See
the following reference: Comins, D. L.; Jianhua, G. Tetrahedron Lett. 1994, 35,
2819.
11. Saito, Y.; Nothacker, H. P.; Wang, Z. W.; Lin, S. H. S.; Leslie, F.; Civelli, O. Nature
1999, 400, 265.
21. Tullock, C. W.; McElvain, S. M. J. Am. Chem. Soc. 1939, 61, 961.
22. For [125I]MCH binding and FLIPR assay protocols, see Moriya, M.; Kishino, H.;
Sakuraba, S.; Sakamoto, T.; Suga, T.; Takahashi, H.; Suzuki, T.; Ito, M.; Ito, J.;
Moriya, R.; Takenaga, N.; Iwaasa, H.; Ishihara, A.; Kanatani, A.; Fukami, T.
Bioorg. Med. Chem. Lett. 2009, 19, 3568.
23. For microsomal stability assay protocol, see: Mitsuya, M.; Ogino, Y.; Kawakami,
K.; Uchiyama, M.; Kimura, T.; Numazawa, T.; Hasegawa, T.; Ohtake, N.;
Noguchi, K.; Mase, T. Bioorg. Med. Chem. Lett. 2000, 8, 825. Human and mouse
hepatic microsomes were purchased from Xenotech and BD Gentest,
respectively.
12. Chambers, J.; Ames, R. S.; Bergsma, D.; Muir, A.; Fitzgerald, L. R.; Hervieu, G.;
Dytko, G. M.; Foley, J. J.; Martin, J.; Liu, W. S.; Park, J.; Ellis, C.; Ganguly, S.; Konchar,
S.; Cluderay, J.; Leslie, R.; Wilson, S.; Sarau, H. M. Nature 1999, 400, 261.
13. Hill, J.; Duckworth, M.; Murdock, P.; Rennie, G.; Sabido-David, C.; Ames, R. S.;
Szekeres, P.; Wilson, S.; Bergsma, D. J.; Gloger, I. S.; Levy, D. S.; Chambers, J. K.;
Muir, A. I. J. Biol. Chem. 2001, 276, 20125.
14. Sailer, A. W.; Sano, H.; Zeng, Z. Z.; McDonald, T. P.; Pan, J.; Pong, S. S.; Feighner,
S. D.; Tan, C. P.; Fukami, T.; Iwaasa, H.; Hreniuk, D. L.; Morin, N. R.; Sadowski, S.
J.; Ito, M.; Ito, M.; Bansal, A.; Ky, B.; Figueroa, D. J.; Jiang, Q. P.; Austin, C. P.;
MacNeil, D. J.; Ishihara, A.; Ihara, M.; Kanatani, A.; Van der Ploeg, L. H. T.;
Howard, A. D.; Liu, Q. Y. Proc. Natl. Acad. Sci. U.S.A. 2001, 98, 7564.
15. Tan, C. P.; Sano, H.; Iwaasa, H.; Pan, J.; Sailer, A. W.; Hreniuk, D. L.; Feighner, S.
D.; Palyha, O. C.; Pong, S. S.; Figueroa, D. J.; Austin, C. P.; Jiang, M. M.; Yu, H.; Ito,
J.; Ito, M.; Ito, M.; Guan, X. M.; MacNeil, D. J.; Kanatani, A.; Van der Ploeg, L. H.
T.; Howard, A. D. Genomics 2002, 79, 785.
24. Butcher, J. W.; Claremon, D. A.; Connolly, T. M.; Dean, D. C.; Karczewski, J.;
Koblan, K. S.; Kostura, M. J.; Liverton, N. J.; Melillo, D. G. Radioligand and
Binding Assay. World Patent Application WO 02/05860, 2002.
16. Borowsky, B.; Durkin, M. M.; Ogozalek, K.; Marzabadi, M. R.; DeLeon, J.; Lagu,
B.; Heurich, R.; Lichtblau, H.; Shaposhnik, Z.; Daniewska, I.; Blackburn, T. P.;
Branchek, T. A.; Gerald, C.; Vaysse, P. J.; Forray, C. Nat. Med. 2002, 8, 825.
17. Borowsky, B.; Durkin, M. M.; Ogozalek, K.; Marzabadi, M. R.; DeLeon, J.;
Heurich, R.; Lichtblau, H.; Shaposhnik, Z.; Daniewska, I.; Blackburn, T. P.;
Branchek, T. A.; Gerald, C.; Vaysse, P. J.; Forray, C. Nat. Med. 2002, 8, 1039.
18. (a) Ito, M.; Ishihara, A.; Gomori, A.; Egashira, S.; Matsushita, H.; Mashiko, S.; Ito,
J.; Ito, M.; Nakase, K.; Haga, Y.; Iwaasa, H.; Suzuki, T.; Ohtake, N.; Moriya, M.;
Sato, N.; MacNeil, D. J.; Takenaga, N.; Tokita, S.; Kanatani, A. Eur. J. Pharmacol.,
submitted for publication.; (b) Otake, N.; Haga, Y.; Naya, A.; Mizutani, S;
Kanatani, A. PCT Int. Appl. WO2005085200.
19. The preparation of compounds 5, 9, 13, 15, and 19 is as follows.
1) Cu(OAc)2, MS 4 Å pyridine,
CH2Cl2, rt, ON
2) LAH, THF, CHCl3, 0 °C, 1 h
3) MsCl, Et3N, CHCl3, rt, 1h
4) pyrrolidine, K2CO3, DMF,
50 °C, 5 h
F
F
(HO)2B
O
O
5
NH
CO2Me
11% over 4 steps
O
O
1) POCl3, reflux, 2 h
2) mCPBA, CHCl3, rt
18 h
F
O
NH
N
37% over 2 steps
O
Cl
TFAA, CH3CN
rt, 24 h
9
90%
1) TBSCl, NaH, THF,
0 °C−rt, 4.5 h
2) MsCl, Et3N, THF,
rt, 2.5 h
HO
13
OH
51% over 2 steps
1) NaH, MOMCl, DMF
0 °C−rt, ON
2) MsCl, Et3N, EtOAc
0 °C−rt, 1 h
15
HO
NC
OH
76% over 2 steps
1) conc H2SO4, MeOH, reflux,
16 h
2) mCPBA, CHCl3, rt, 19 h
MeOOC
N
O
N
54% over 2 steps
TFAA, CH2Cl2, reflux
2.5 h
19
72%