Synthesis and SAR of 1,4,5,6-tetrahydropyridazines as potent cannabinoid CB1 receptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2009.08.007

The synthesis and structure-activity relationship studies of 1,4,5,6-tetrahydropyridazines are described. The target compounds 3-5 represent a novel class of potent and selective CB₁ receptor antagonists.

Full text of DOI:10.1016/j.bmcl.2009.08.007

Bioorganic & Medicinal Chemistry Letters 19 (2009) 5675–5678
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and SAR of 1,4,5,6-tetrahydropyridazines as potent cannabinoid
CB1 receptor antagonists
*
Jos H. M. Lange , Arnold P. den Hartog, Martina A. W. van der Neut, Bernard J. van Vliet, Chris G. Kruse
Solvay Pharmaceuticals, Chemical Design and Synthesis Unit, Research Laboratories, C. J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis and structure–activity relationship studies of 1,4,5,6-tetrahydropyridazines are described.
The target compounds 3–5 represent a novel class of potent and selective CB1 receptor antagonists.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 17 July 2009
Revised 3 August 2009
Accepted 4 August 2009
Available online 7 August 2009
Keywords:
Cannabinoid CB1
Antagonist
Inverse agonist
Scaffold hopping
Tetrahydropyridazine
Significant progress has been made in the molecular character-
ization of endogenous cannabinoids1 and their receptors2–4 during
thelast20 years. CannabinoidCB1 receptorantagonists showed clin-
ical efficacy in the treatment of obesity and improved cardiovascular
and metabolicrisk factors such as triglyceridelevels and HDL choles-
terol.5,6 However, the risk of psychiatric disorders has terminated7
many development programs for CB1 receptor blockers for obesity
and has suspended market access of rimonabant 1. It is interesting
to note that CB1 receptor antagonists have also been related8,9 to
the potential treatment of several CNS diseases, including smoking
and alcohol addiction and cognitive disorders as well as in the poten-
tial treatment of peripherally-mediated disorders such as liver
fibrosis, cancer, arthritis and chronic bronchitis.
isosteric replacements of the non-aromatic dihydropyrazole moi-
ety16 based on 2 by several other five-membered heterocycles
such as the 4,5-dihydroimidazole, imidazole or oxazole scaffold,
were recently published.17 Surprisingly, the resulting compounds
were devoid of CB1 antagonistic activity in vitro as well as
in vivo in a rodent feeding model. On the contrary, replacement
of the central aromatic pyrazole ring in 1 by imidazoles13,18,19 or
oxazole20 led to retained CB1 antagonistic activities.
Cl
Scaffold hopping and bioisosteric approaches—in combination
with results from pharmacological screening programs—have led
to the discovery of selective CB1 receptor antagonists from differ-
ent chemical structure classes. However, the majority of the re-
ported CB1 receptor antagonists and inverse agonists can be
described in terms of a general pharmacophore model.10–12
Based on this CB1 pharmocophore knowledge, scaffold hopping
approaches seem rather straightforward and have been success-
fully applied in many cases.13–15 However, it should be borne in
mind that such chemical structure modifications will often lead
to fully inactive compounds. This is due to the typical complexity
of structure–activity relationships. For example, a number of bio-
Cl
N
N
O
H
N
N
O
S O
N
N N
H
N
Cl
Cl
Cl
Rimonabant (1)
Ibipinabant (2)
These remarkable results prompted us to design an alternative
scaffold hopping modification based on 2 to produce analogues
which do have retained CB1 antagonistic properties. We envisioned
that enlargement of the 4,5-dihydropyrazole ring in 2 to a non-aro-
* Corresponding author. Tel.: +31 (0) 294 479731; fax: +31 (0) 294 477138.
E-mail address: jos.lange@solvay.com (J.H.M. Lange).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.08.007

5676
J. H. M. Lange et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5675–5678
matic six-membered heterocyclic scaffold would lead to pharma-
cologically active 1,4,5,6-tetrahydropyridazine analogues based
on results from in silico CB1 receptor docking studies. The chiral
center in the resulting 1,4,5,6-tetrahydropyridazines is expected
to be important—as it is for ibipinabant16—but this chirality aspect
was not included in this preliminary study. It is interesting to note
The pharmacological results of the target compounds 3–5 and
the corresponding dihydropyrazole analogues 18–20 are given in
Table 1. They were evaluated in vitro at the human CB1 and CB2
receptor, stably expressed into Chinese Hamster Ovary (CHO)
cells,16 utilizing radioligand binding studies (displacement of the
specific binding of [3H]-CP-55,940). CB1 receptor antagonism16
was measured using a CP-55,940 induced arachidonic acid release
functional assay, using the same recombinant cell line.
that the 1,4,5,6-tetrahydropyridazine constitutes
a privileged
structure21 since this heterocyclic moiety occurs in many pharma-
cologically active compounds acting at different molecular targets,
such as ACAT inhibitors,22 progesterone receptor ligands,23 alloste-
ric GABAA receptor modulators24 and neuraminidase inhibitors.25
These considerations guided us to the design of three dedicated
target compounds 3–5. The 1,4,5,6-tetrahydropyridazines 3–5
have been synthesized as depicted in Scheme 1. Commercially
available benzyl 4-chlorophenyl ketone 6 was reacted22 with
methyl bromoacetate 7 to yield ester adduct 8 in an excellent
95% yield. Hydrolysis of 8 led to the corresponding carboxylic acid
9 in 88% yield. Treatment of 9 with hydrazine hydrate gave the 4,5-
dihydropyridazin-3-one22 10 in a yield of 81% The key 1,4,5,6-tetr-
ahydropyridazine intermediate 11 was quantitatively obtained
from 10 by reduction with LiAlH4 in THF. Subsequent coupling of
11 with the building blocks 12–14 afforded 15–17, respectively,
in yields ranging from 73% to 75%. The intermediates 15–17 were
chlorinated with phosphorus oxychloride in the presence of DMAP
and reacted with methylamine to furnish the target compounds 3–
5 in yields ranging from 81% to 82%.
Cl
Cl
Cl
N
N
N
N
N
N
H
H
H
N
N
N
O
S O
O
S O
N
O
S O
N
N
N
N
F
F
Cl
18
19
20
The CB1 receptor binding data of the target compounds 3–5 re-
vealed that their somewhat larger 1,4,5,6-tetrahydropyridazine
scaffold as compared to the dihydropyrazole moiety in 18–20 has
only a small influence on the observed CB1 receptor affinities (Ta-
ble 1). Moreover, the functional CB1 receptor antagonistic proper-
ties of 3–5 are in line with the observed values of 18–20. The
1,4,5,6-tetrahydropyridazines 3–5 showed approximately five to
eight fold CB1/2 receptor subtype selectivities. It is interesting to
note that in particular compound 18 from the original dihydropy-
razole series elicited a much higher (ꢀ40-fold) CB1/2 receptor sub-
type selectivity value, whereas compounds 19 and 20 elicit more
comparable values as compared to 4 and 5, respectively. It can
therefore be concluded that the 1,4,5,6-tetrahydropyridazine scaf-
fold is a valid bioisosteric replacement of the 4,5-dihydropyrazole
moiety in this series of CB1 receptor antagonists.
In order to verify the success of our design efforts, the CB1
antagonistic activities of 3–5 were compared with the correspond-
ing dihydropyrazole analogs 18,16 1926 and its 4,4-difluoropiperine
analogue 20. The synthesis of the novel compound 20 is depicted in
Scheme 2.
4,4-Difluoropiperidine.HCl 21 was reacted with sulfamide in
butylacetate in the presence of Hünig’s base to produce the sulfam-
ide derivative 22 in 84% yield. Subsequent treatment of 22 with di-
tert-butyl dicarbonate in the presence of DMAP gave the carbamate
ester 14 in 91% yield. Coupling of the dihydropyrazole building
block27 23 with 14 afforded 24 in 76% yield,28 which was succes-
sively chlorinated with POCl3 in the presence of DMAP and reacted
with methylamine to give the difluorinated target compound 20 in
a yield of 91%.
O
OH
Cl
Cl
Cl
Cl
O
O
a)
b)
c)
O
O
N
O
N
H
O
6
8
9
10
O
S
R
H
N
R
Cl
Cl
O
O
Cl
3
4
5
O
Cl
d)
f) ,g)
12-14
N
N
10
N
N
N
O
N
O
e)
N
HN
S
O
N
S
R
N
H
N
H
F
F
O
O
R
11
15-17
Scheme 1. Reagents and conditions: (a) methyl bromoacetate (7), NaH, DMSO, rt, 1 h; (b) aqueous 25% NaOH, EtOH/H2O = 1/1 (v/v), rt, 16 h; (c) H2NNH2ꢁH2O, EtOH, reflux,
16 h; (d) LiAlH4, THF, reflux, 30 min; (e) toluene, reflux, 2 h; (f) POCl3, DMAP, CH2Cl2, reflux, 3 h; (g) CH3NH2.HCl, DIPEA, CH2Cl2, 6 °C ? rt, 16 h.

J. H. M. Lange et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5675–5678
5677
Cl
Cl
SO2NH2
N
SO2NHCO2-t-Bu
N
H
N
N
N
N
O
c)
N
O
d), e)
a)
b)
O
NH
S
N
Cl
F
F
F
F
N
S
N
N
H
F
F
O
O
.HCl
21
22
14
N
F
F
N
F
F
H
23
24
20
Scheme 2. Reagents and conditions: (a) sulfamide, DIPEA, butylacetate, reflux, 16 h; (b) di-tert-butyl dicarbonate, Et3N, DMAP, toluene, 50 °C, 2 h; (c) toluene, reflux, 3 h; (d)
POCl3, DMAP, CH2Cl2, reflux, 3 h; (e) CH3NH2ꢁHCl, DIPEA, 6 °C ? rt, 16 h.
17. Srivastava, B. K.; Soni, R.; Joharapurkar, A.; Sairam, K. V. V. M.; Patel, J. Z.;
Goswami, A.; Shedage, S. A.; Kar, S. S.; Salunke, R. P.; Gugale, S. B.; Dhawas, A.;
Kadam, P.; Mishra, B.; Sadhwani, N.; Unadkat, V. B.; Mitra, P.; Jain, M. R.; Patel,
P. R. Bioorg. Med. Chem. Lett. 2008, 18, 963.
Table 1
Pharmacological results of compounds 3–5 and 18–20
Compound
Ki(CB1)a, nM
pA2(CB1)b
Ki(CB2)c, nM
18. Dyck, B.; Goodfellow, V. S.; Phillips, T.; Grey, J.; Haddach, M.; Rowbottom, M.;
Naeve, G. S.; Brown, B.; Saunders, J. Bioorg. Med. Chem. Lett. 2004, 14, 1151.
19. Smith, R. A.; Fathi, Z.; Achebe, F.; Akuche, C.; Brown, S. E.; Choi, S.; Fan, J.;
Jenkins, S.; Kluender, H. C. E.; Konkar, A.; Lavoie, R.; Mays, R.; Natoli, J.;
O’Connor, S. J.; Ortiz, A. A.; Su, N.; Taing, C.; Tomlinson, S.; Tritto, T.; Wang, G.;
Wirtz, S. N.; Wong, W.; Yang, X. F.; Ying, S.; Zhang, Z. Bioorg. Med. Chem. Lett.
2007, 17, 2706.
3
4
5
18
19
20
43 12
9.0 0.2
8.7 0.3
9.0 0.1
8.7 0.3
8.7 0.3
9.2 0.3
318 80
571 216
247 135
>1000
1321 264
219 91
74
47
25
5
3
7
152 68
12.2 4.6
20. Plummer, C. W.; Finke, P. E.; Mills, S. G.; Wang, J.; Tong, X.; Doss, G. A.; Fong, T.
M.; Lao, J. Z.; Schaeffer, M. T.; Chen, J.; Shen, C. P.; Stribling, D. S.; Shearman, L.
P.; Strack, A. M.; Van der Ploeg, L. H. T. Bioorg. Med. Chem. Lett. 2005, 15, 1441.
21. Bondensgaard, K.; Ankersen, M.; Thøgersen, H.; Hansen, B. S.; Wulff, B. S.;
Bywater, R. P. J. Med. Chem. 2004, 47, 888.
a
Displacement of specific CP-55,940 binding in CHO cells stably transfected with
human CB1 receptor, expressed as Ki SEM (nM).
b
[3H]-Arachidonic acid release in CHO cells expressed as pA2 SEM values.
Displacement of specific CP-55,940 binding in CHO cells stably transfected with
c
human CB2 receptor, expressed as Ki SEM (nM). The values represent the mean
result based on at least three independent experiments.
22. Toma, L.; Giovannoni, M. P.; Dal Piaz, V.; Kwon, B.-M.; Kim, Y.-K.; Gelain, A.;
Barlocco, D. Heterocycles 2002, 57, 39.
23. Combs, D. W.; Reese, K.; Phillips, A. J. Med. Chem. 1995, 38, 4878.
24. Rybczynski, P. J.; Combs, D. W.; Jacobs, K.; Shank, R. P.; Dubinsky, B. J. Med.
Chem. 1999, 42, 2403.
25. Zhang, L.; Williams, M. A.; Mendel, D. B.; Escarpe, P. A.; Chen, X.; Wang, K.-Y.;
Graves, B. J.; Lawton, G.; Kim, C. U. Bioorg. Med. Chem. Lett. 1999, 9, 1751.
26. Lange, J. H. M.; van Stuivenberg, H. H.; Veerman, W.; Wals, H. C.; Stork, B.;
Coolen, H. K. A. C.; McCreary, A. C.; Adolfs, T. J. P.; Kruse, C. G. Bioorg. Med.
Chem.Lett. 2005, 15, 4794.
Novel 1,4,5,6-tetrahydropyridazines 3–5 were designed as po-
tential CB1 receptor antagonists. Whereas former bioisosteric
replacement efforts of the dihydropyrazole ring in 2 with other
five-membered heterocyclic moieties failed, it is demonstrated
herein that scaffold hopping to a six-membered 1,4,5,6-tetrahydro-
pyridazine ring constitutes a successful strategy to obtain potent
CB1 receptor antagonists.
27. Grosscurt, A. C.; Van Hes, R.; Wellinga, K. J. Agric. Food Chem. 1979, 27, 406.
28. The purity of the compounds used in the pharmacological assays was P95%,
based on 1H NMR (400 MHz) peak integration measurements. Selected data for
compounds 3–5, 11, 14, 15–17, 20 and 24. Compound 3: mp 198–199 °C; 1H
NMR (400 MHz, CDCl3) d 1.98–2.18 (m, 2H), 3.12 (dt, J = 13 Hz and 4 Hz, 1H),
3.38 (d, J ꢀ 5 Hz, 3H), 4.10–4.20 (m, 2H), 7.07 (br d, J = 7 Hz, 2H), 7.22–7.41 (m,
8H), 7.53 (br d, J = 8 Hz, 2H), 7.88 (br d, J = 9 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d 26.4, 32.2, 38.0, 38.2, 127.2, 127.4, 127.5, 127.9, 128.7, 128.8, 129.2, 134.5,
135.6, 137.2, 140.4, 144.0, 148.0, 154.1 (broad); ESI+-MS exact mass calcd for
C24H22Cl2N4O2SNa m/z, 523.0738 ([MNa+]), found: 523.0788. Compound 4: mp
204–205 °C; 1H NMR (400 MHz, CDCl3) d 1.42–1.50 (m, 2H), 1.62–1.71 (m, 4H),
2.06–2.25 (m, 2H), 3.10 (br t, J = 5 Hz, 4H), 3.18 (dt, J = 13 Hz and 4 Hz, 1H), 3.37
(d, J = 5 Hz, 3H), 4.19 (br d, J = 5 Hz, 1H), 4.41 (br d, J = 13 Hz, 1H), 7.11 (br d,
J = 7 Hz, 2H), 7.16–7.36 (m, 6H), 7.52 (br d, J = 9 Hz, 2H); 13C NMR (100 MHz,
CDCl3) d 23.9, 25.1, 26.5, 32.0, 37.6, 38.1, 47.9, 127.2, 127.4, 128.0, 128.8, 129.2,
134.8, 135.2, 140.9, 146.0, 154.2 (broad); ESI+-MS exact mass calcd for
C23H29ClN5O2S m/z, 474.1731 ([MH+]), found: 474.1770. Synthesis of
compound 5: To a magnetically stirred solution of 17 (1.27 g, 2.56 mmol)
dissolved in CH2Cl2 (30 ml) was added DMAP (1.37 g; 11.24 mmol), followed by
slow addition of POCl3 (0.30 ml; 3.32 mmol; solution in CH2Cl2 (3 ml)). The
reaction mixture was heated at reflux temperature for 3 h. After cooling to 6 °C,
CH3NH2ꢁHCl (0.78 g; 11.50 mmol) was added, followed by dropwise addition of
DIPEA (3.06 ml; 17.9 mmol). The reaction mixture was stirred overnight at
room temperature. HCl (1 N) was added to acidify the mixture. The layers were
separated. The organic layer was dried over Na2SO4, filtered and concentrated in
vacuo. Flash chromatographic purification (silica gel, gradient: CH2Cl2?
CH2Cl2/2% MeOH (v/v)) followed by crystallization gave 3-(4-chlorophenyl)-4-
phenyl-N-methyl-N-0[(4,4-difluoropiperidinyl)sulfonyl]-1,4,5,6-tetrahydropyridazi-
ne-1-carboxamidine (5) (1.12 g; 82% yield). mp 225–226 °C; 1H NMR (400 MHz,
CDCl3) d 2.03–2.25 (m, 6H), 3.17 (dt, J = 13 Hz and 4 Hz, 1H), 3.31 (br t, J = 5 Hz, 4H),
3.38 (d, J = 5 Hz, 3H), 4.20 (br d, J = 4 Hz, 1H), 4.36 (br d, J = 13 Hz, 1H), 7.09 (br d,
J = 7 Hz, 2H), 7.19–7.36 (m, 6H), 7.52 (br d, J = 9 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d 26.4, 31.8, 33.4 (t, JCF = 24 Hz), 37.7, 38.1, 44.4 (t, JCF = 6 Hz), 121.4 (t, JCF = 242 Hz),
127.3, 127.5, 127.9, 128.8, 129.2, 134.7, 135.4, 140.6, 146.8, 154.1 (broad); ESI+-MS
exact mass calcd for C23H26ClF2N5O2SNa m/z, 532.1362 ([MNa+]), found: 532.1385.
Synthesis of compound 11: To LiAlH4 (4.76 g, 125 mmol) was added THF (200 ml) at
0 °C. Compound22 10 (11.91 g, 41.8 mmol) was also dissolved in THF (200 ml) and
added dropwise to the magnetically stirred LiAlH4/THF solution at 0 °C. Hereafter,
Acknowledgment
Jan Jeronimus, Claudia Sewing and Hugo Morren are gratefully
acknowledged for supply and interpretation of the analytical data.
References and notes
1. Lambert, D. M.; Fowler, C. J. J. Med. Chem. 2005, 48, 5059.
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1990, 346, 561.
3. Munro, S.; Thomas, K. L.; Abu-Shaar, M. Nature 1993, 365, 61.
4. Brown, A. J. Br. J. Pharmacol. 2007, 152, 567.
5. van Gaal, L. F.; Rissanen, A. M.; Scheen, A. J.; Ziegler, O.; Roessner, S. Lancet
2005, 365, 1389.
6. Antel, J.; Gregory, P. C.; Nordheim, U. J. Med. Chem. 2006, 49, 4008.
7. Jones, D. Nat. Rev. Drug Disc. 2008, 7, 961.
8. Lange, J. H. M.; Kruse, C. G. Chem. Rec. 2008, 8, 156.
9. Di Marzo, V. Nat. Rev. Drug Disc. 2008, 7, 438.
10. Reggio, P. H. Curr. Pharm. Des. 2003, 9, 1607.
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12. Lange, J. H. M.; Kruse, C. G. Drug Discovery Today 2005, 10, 693.
13. Lange, J. H. M.; van Stuivenberg, H. H.; Coolen, H. K. A. C.; Adolfs, T. J. P.;
McCreary, A. C.; Keizer, H. G.; Wals, H. C.; Veerman, W.; Borst, A. J. M.; De Looff,
W.; Verveer, P. C.; Kruse, C. G. J. Med. Chem. 2005, 48, 1823.
14. Högenauer, E. K. Exp. Opin. Ther. Patents 2007, 17, 1457.
15. Muccioli, G. G.; Lambert, D. M. Exp. Opin. Ther. Patents 2006, 16, 1405.
16. Lange, J. H. M.; Coolen, H. K. A. C.; van Stuivenberg, H. H.; Dijksman, J. A. R.;
Herremans, A. H. J.; Ronken, E.; Keizer, H. G.; Tipker, K.; McCreary, A. C.;
Veerman, W.; Wals, H. C.; Stork, B.; Verveer, P. C.; den Hartog, A. P.; de Jong, N.
M. J.; Adolfs, T. J. P.; Hoogendoorn, J.; Kruse, C. G. J. Med. Chem. 2004, 47, 627.

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J. H. M. Lange et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5675–5678
the mixture was successively stirred for 30 min at reflux temperature and cooled in
(m, 5H), 7.52 (br d, J = 9 Hz, 2H), 8.98 (br s, 1H). Compound 17: To a magnetically
stirred solution of 14 (1.04 g; 3.47 mmol) in toluene (20 ml) was added 11 (1.00 g;
3.47 mmol) and the resulting solution was heated at reflux temperature for 2 h. The
mixture was allowed to attain room temperature and the volatiles were removed in
vacuo. Diisopropyl ether (75 ml) was added to the residue and, after stirring for 15
minutes, compound 17 was filtered off (1.29 g; 75% yield). 1H NMR (400 MHz,
CDCl3) d 2.08–2.24 (m, 6H), 3.11 (dt, J = 13 and 4 Hz, 1H), 3.67 (br t, J = 6 Hz, 4H),
4.20–4.30 (m, 2H), 7.10 (br d, J = 7 Hz, 2H), 7.24–7.37 (m, 5H), 7.52 (br d, J = 9 Hz,
2H), 9.01 (br s, 1H). Selected analytical data for compound 20: mp 158.5–159.5 °C; 1H
NMR (600 MHz, CDCl3) d 2.05–2.14 (m, 4H), 3.24 (d, J = 7 Hz, 3 H), 3.26–3.34 (m, 4H),
4.10–4.18 (m, 1H), 4.57 (t, J = 12 Hz, 1H), 4.67 (dd, J = 12 and ꢀ5.5 Hz, 1H), 6.80 (br s,
1H), 7.15 (d, J = 8 Hz, 2H), 7.25–7.29 (m, 3H), 7.30–7.35 (m, 2H), 7.53 (d, J = 8 Hz,
2H); 13C NMR (100 MHz, CDCl3) d 31.5 (broad), 33.3 (t, JCF = 24 Hz), 44.3 (t,
JCF = 6 Hz), 50.9 (broad), 57.3, 121.4 (t, JCF = 242 Hz), 127.3, 128.1, 128.5, 128.6, 129.0,
129.5, 136.3, 139.2, 152.8 (broad), 156.4; ESI+-MS exact mass calcd for
C22H25ClF2N5O2S m/z, 496.1386 ([MH+]), found: 496.1429. Selected analytical data
for compound 24: mp 215–216 °C. 1H NMR (400 MHz, CDCl3) d 2.06–2.19 (m, 4H),
3.62–3.67 (m, 4H), 3.97 (dd, J = 11 and 5.5 Hz, 1H), 4.39 (t, J = 11 Hz, 1H), 4.76 (dd,
J = 11 and 5.5 Hz, 1H), 7.15 (br d, J = 8 Hz, 2H), 7.25–7.36 (m, 5H), 7.53 (br d, J = 8 Hz,
2H), 8.51 (br s, 1H).
an ice bath. 2 N NaOH was added carefully and the formed mixture was extracted
with EtOAc. The organic layer was successively dried over Na2SO4, filtered and
concentrated in vacuo to furnish 11 (12.04 g; 99.9%). 1H NMR (400 MHz CDCl3) d
1.95–2.04 (m, 1H), 2.28–2.39 (m,1H), 3.16–3.22 (m, 2H), 4.06 (dd, J = 6 and 3 Hz, 1H),
5.96 (br s, 1H), 7.14 (br d, J = 9 Hz, 2H), 7.17–7.32 (m, 5H), 7.45 (br d, J = 9 Hz, 2H).
Synthesis of compound 14: To a magnetically stirred solution of 22 (6.0 g, 30 mmol)
was successively added Et3N (4.4 ml, 31.5 mmol) and DMAP (0.37 g, 3 mmol) and
the resulting mixture was heated at 50 °C. Di-tert-butyl dicarbonate (7.9 g,
36 mmol) was dropwise added and the resulting mixture was heated at 50 °C for
2 h. The mixture was allowed to attain room temperature and toluene (100 ml) and
HCl (50 ml, 1 N) were successively added. The organic layer was successively
washed with water (twice), dried over Na2SO4, filtered and concentrated in vacuo to
afford 14 (8.21 g, 91%). mp 82–83 °C. 1H NMR (400 MHz, CDCl3) d 1.49 (s, 9H), 2.03–
2.15 (m, 4H), 3.53–3.58 (m, 4H), 6.98 (br s, 1H). Selected data for compounds 15–17:
Compound 15: 1H NMR (400 MHz, CDCl3) d 2.03–2.18 (m, 2H), 3.04 (dt, J = 14 and
5 Hz, 1H), 4.15–4.23 (m, 2H), 7.06 (br d, J = 7 Hz, 2H), 7.22–7.36 (m, 5H), 7.50–7.57
(m, 4H), 8.13 (br d, J = 9 Hz, 2H), 9.25 (br s, 1H). Compound 16: 1H NMR (400 MHz,
CDCl3) d 1.54–1.62 (m, 2H), 1.67–1.74 (m, 4H), 2.07–2.23 (m, 2H), 3.10 (dt, J = 14 and
5 Hz, 1H), 3.48 (br t, J = 5 Hz, 4H), 4.18–4.31 (m, 2H), 7.10 (d, J = 6 Hz, 2H), 7.24–7.36