Synthesis of dimebon and of its tetrathiomolybdate

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Synthesis of Dimebon and of its
Tetrathiomolybdate
Om P. Goela & Roman Dembinskib
a SSV Therapeutics Inc., 3995 Holden Drive, Ann Arbor, MI, 48103,
U.S.A.
b Department of Chemistry and Center for Biomedical Research,
Oakland University, 2200 N. Squirrel Rd., Rochester, MI, 48309,
U.S.A.
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Published online: 13 May 2015.
To cite this article: Om P. Goel & Roman Dembinski (2015) Synthesis of Dimebon and of its
Tetrathiomolybdate, Organic Preparations and Procedures International: The New Journal for Organic
Synthesis, 47:3, 220-226, DOI: 10.1080/00304948.2015.1025017
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Organic Preparations and Procedures International, 47:220–226, 2015
Copyright Ó Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2015.1025017
Synthesis of Dimebon and of its Tetrathiomolybdate
Om P. Goel1 and Roman Dembinski2
1SSV Therapeutics Inc., 3995 Holden Drive, Ann Arbor, MI 48103, U.S.A.
2Department of Chemistry and Center for Biomedical Research, Oakland
University, 2200 N. Squirrel Rd., Rochester, MI 48309, U.S.A.
Latrepirdine, also known as dimebolin and commercialized in the form of a dihydrochlo-
ride salt as dimebon (10), is an antihistamine drug used clinically in Russia since 1983.
Dimebon is a non-selective antihistamine that displays cognitive enhancing abilities and
does not inhibit acetylcholinesterase activity. It exhibits neuroprotective activity in cellu-
lar models of Alzheimer’s and Huntington’s disease1 and preserves cognitive function
following administration to AF64A lesioned rats. It protects neurons against the neuro-
toxic action of the b-amyloid fragments of amyloid precursor protein (APP).2 In 2000,
the potential use of dimebon in slowing down the progression of mild to mid-stages of
Alzheimer’s disease (AD) was suggested by Russian scientists.3,4 Numerous clinical
studies were initiated in the United States and in 2009, Pfizer and Medivation initiated a
phase III trial aiming for FDA approval. However, these clinical trials failed to show
benefit from dimebon in the treatment of AD patients.5
Concurrently, AD research had begun to examine the role of copper in Ab amyloid
peptides’ aggregation and toxicity in the brain. Studies have shown that CuC2 and Ab
peptides form complexes that induce Ab aggregation and cause cognitive deficits.6,7 Fur-
thermore, higher serum copper levels in AD patients compared to cognitively normal
individuals support a role for CuC2 in AD pathophysiology.8–11 Thus, various drugs
including clioquinol12,13 and ammonium tetrathiomolybdate (TM) – a potent CuC2 com-
plexing agent used to bind circulating excess CuC2 in patients with Wilson’s disease14,15
– have been tested to modulate the amount of CuC2 in AD models. Ammonium tetrathio-
molybdate was shown to lower insoluble b-amyloid levels in transgenic mice (Tg2576)
over expressing APP.16 Memantine, antagonist of N-methyl-D-aspartate (NMDA), is
widely prescribed to treat AD patients. Goel has described the preparation of memantine
tetrathiomolybdate,17 which is dual-acting by virtue of combining in one molecular entity
the neuroprotective NMDA antagonist activity of memantine with the strong copper-com-
plexing properties of thiomolybdate ion. Thus, it was natural to synthesize latrepirdine
tetrathiomolybdate for testing in AD models and this required the preparation of dimebon
since at the time this research was initiated,17 it was not commercially available even in
small quantities.18
Received September 17, 2014; in final form December 15, 2014.
Address correspondence to Roman Dembinski, Department of Chemistry, Oakland University,
2200 N. Squirrel Rd., Rochester, MI 48309, U.S.A. E-mail: dembinsk@oakland.edu
Om P. Goel, SSV Therapeutics Inc., 3995 Holden Drive, Ann Arbor, MI 48103, U.S.A. E-mail:
omp.goel@jivapharma.com
220

Synthesis of Dimebon and of its Tetrathiomolybdate
221
The original synthesis of title compound 10 involves the hydroamination of 2-
methyl-5-vinylpyridine,19–25 a compound prone to polymerization, to give N-(pyridiny-
lethyl)toluidine (7). Although if needed, a sample of 2-methyl-5-vinylpyridine may be
generated by vacuum pyrolysis of the polymerized material, it must be stored in the
freezer at –20ꢀC.26 Thus, we decided to modify an approach to dimebon and now describe
a readily reproducible process to prepare compound 10 and its tetrathiomolybdate (11),
starting from methyl 6-methylnicotinate (1) as illustrated in Scheme 1.
The synthesis of 10 was carried out via an efficient route. Reduction of methyl 6-
methylnicotinate (1) gave hydroxymethyl derivative 2,27 which was converted to the
chloromethylpyridine 3.27,28 Reaction of chloride 3 with potassium cyanide afforded the
pyridinylacetonitrile 4,29 which was hydrolyzed to carboxylic acid 5. Condensation of 5
with p-toluidine yielded amide 6, which was then reduced to the N-(pyridinylethyl)tolui-
dine 7. Nitrosation of 7 using sodium nitrite led to corresponding N-nitroso compound
8,19 which was then reduced to hydrazine 919 using zinc/acetic acid. The Fischer Indole
Synthesis30 was accomplished by treatment of compound 9 with N-methylpiperidone in
presence of an acid catalyst, leading to dimebon 10.24 Although several of the intermedi-
ates, e. g. 2–4, 7–10, are known, we report details of their preparation since the proce-
dures for their preparation have been simplified and/or improved.
Two methods were investigated for the preparation of dimebon tetrathiomolybdate
(11). The first involved the reaction of dihydrochloride 10 with ammonium tetrathiomo-
lybdate in water to give the product 11 in 82% yield (Scheme 1). In the second procedure
(not illustrated), dimebon free base was generated by addition of sodium hydroxide to
Scheme 1. Synthesis of Dimebon 10 and of its Tetramolybdate 11

222
Goel and Dembinski
dihydrochloride 10 in water and isolated in 96% yield. Following reaction with ammo-
nium tetrathiomolybdate in ethanol/water gave the same material, albeit in only 37%
yield.
In conclusion, a synthetic scheme has been devised for the preparation of multigram
quantities of dimebon. Dimebon was converted into its tetrathiomolybdate salt. Elabora-
tion of these procedures offers ready access to these compounds of medicinal interest.
Experimental Section
Commercial materials were used as received. Column chromatography was carried out on
silica gel (Dynamic Adsorbents, 32–63 m). NMR spectra were obtained with a Bruker
Avance III spectrometer (1H of 400 MHz and 13C of 100 MHz). The chemical shifts are
reported in d (ppm) values relative to CDCl3 or DMSO-d6 (7.26/2.50 ppm, 77.16/
39.52 ppm respectively). Mass spectra were recorded on Agilent 6520 Q-TOF LC/MS
and Hewlett Packard 5973 GC/MS instruments. IR and UV-visible spectra were acquired
on a Bruker Alpha-P ATR and Cary 50 spectrometers, respectively.
(6-Methylpyridin-3-yl)methanol (2)27
To a solution of LiAlH4 (80.0 g, 2.11 mol) in anhydrous THF (1 L) at 0ꢀC, a solution of
methyl 6-methylnicotinate (1, 200 g, 1.32 mol) in THF (1 L) was added dropwise. After
stirring at 0ꢀC for 3 h, the reaction mixture was quenched with saturated aqueous Na2SO4
(ca. 150 mL, 0.43 mol) at 0ꢀC. The mixture was filtered, and the solid washed with ethyl
acetate. The organic layer of filtrate was separated and dried over anhydous MgSO4. Sol-
vent was removed to give 2 as a yellow oil (160 g, 98%). Its 1H NMR data data matched
those previously reported.27,28 HPLC > 99%.
5-(Chloromethyl)-2-methylpyridine (3)28,29
A solution of 2 (50.0 g, 0.406 mol) in THF (450 mL) was cooled down to 0ꢀC, and thio-
nyl chloride (31 mL, 0.43 mol) was added dropwise. After the addition, the mixture was
refluxed for 30 min. The solid was collected, washed with ether and suspended in ether
(ca. 0.5 L). Aqueous sodium hydroxide (10%) was added with stirring to the pH of 8. The
ether solution was dried over anhydrous MgSO4, filtered, and evaporated to give 3 as a
1
yellow oil (42.0 g, 73%), which was then used in the following reaction. Its H NMR
data matched those previously reported.28 HPLC 99%.
(6-Methylpyridin-3-yl)acetonitrile (4)29
A mixture of 3 (15.0 g, 0.106 mol), potassium cyanide (10.4 g, 0.160 mol), methanol
(200 mL), and water (100 mL) was refluxed for 18 h. Water (100 mL) was added, and
the mixture was extracted with ether (3 £ 100 mL). The ether solution was washed with
brine and dried over anhydrous MgSO4. Silica gel column chromatography (hexanes/
1
ethyl acetate) gave 4 as a colorless oil (7.0 g, 50%). H NMR (CDCl3): d 8.45 (d, J D
2.0 Hz, 1H), 7.61 (dd, J D 8.0, 2.4 Hz, 1H), 7.16 (d, J D 8.8 Hz, 1H), 3.73 (s, 2H), 2.57
(s, 3H).

Synthesis of Dimebon and of its Tetrathiomolybdate
(6-Methylpyridin-3-yl)acetic Acid Hydrochloride (5)
223
A mixture of 4 (35.0 g, 0.265 mol) in conc. hydrochloric acid (750 mL) was refluxed for
3 h. The solvent was removed to yield crude 5 as a white solid (45.0 g, 91%). HPLC
1
100%. MS 152 (MC, 100%). H NMR (CDCl3): d 8.32 (br s, 1H), 7.60 (dd, J D 8.0,
2.0 Hz, 1H), 7.12 (d, J D 8.0 Hz, 1H), 4.64 (s, 2H, CH2), 4.10 (br s, 1H), 2.49 (s, 3H).
N-(4-Methylphenyl)-2-(6-methylpyridin-3-yl)acetamide (6)
To a solution of 5 (66.0 g, 0.352 mol) in dichloromethane (800 mL), p-toluidine (45.0 g,
0.420 mol), 1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide (101 g, 1.53 mol), 1-
hydroxybenzotriazole hydrate (9.5 g, 0.062 mol), and triethylamine (50 mL, 0.36 mol)
were added. The mixture was stirred (mechanical stirrer) for 5 h at 5ꢀC (ice/water bath).
The mixture was washed with water and dried over anhydrous MgSO4. The filtered solu-
tion was concentrated to dryness. Silica gel chromatography gave 6 as a white solid
(48 g, 57%), which was then subsequently used without characterization.
4-Methyl-N-[2-(6-methylpyridin-3-yl)ethyl]aniline (7)
A solution of 6 (48.0 g, 0.200 mol) in anhydrous THF (400 mL) was cooled to 0ꢀC, and a
solution of NaBH4 (37.8 g, 1.00 mol) in THF added while the temperature was main-
tained at 0ꢀC, followed by dropwise addition of BF3ꢁEt2O (272 g, 243 mL, 1.91 mol).
After stirring for 18 h, 2N HCl was added with stirring to the pH of 2. The mixture was
refluxed for 2 h, cooled to room temperature, and pH was adjusted to 8 with 2% NaOH.
The mixture was extracted with ether (3 £ 150 mL); combined extracts were dried over
anhydrous MgSO4 and concentrated to dryness to give 7 a white solid (45.0 g, 95%). Its
1H spectral data matched those reported.24
4-Methyl-N-[2-(6-methylpyridin-3-yl)ethyl]-N-nitrosoaniline (8)19,24
To a mixture of ethanol (30 mL) and 1N HCl (33 mL), amine 7 (7.3 g, 0.032 mol) was
added portionwise. The mixture was stirred (stir bar) and cooled to 0–5ꢀC, and a solution
of NaNO2 (2.4 g, 0.035 mol) in water (150 mL) was added dropwise. The mixture was
allowed to warm to room temperature and then cooled to 0–5ꢀC. The solid was collected,
1
washed with water, ether, and dried to give 8 as a yellow solid (7.0 g, 89%). Its H
spectral data matched those reported.24 HPLC > 93%. MS 256 ((MC1)C, 100%), (M–
NOC1)C, 80%).
2-Methyl-5-{2-[1-(4-methylphenyl)hydrazinyl]ethyl}pyridine (9)19
To a solution of 8 (44.0 g, 0.172 mol) in methanol (500 mL), zinc dust (85.0 g, 1.30 mol)
was slowly added over 10 min. The mixture was cooled to 0ꢀC, and a solution of acetic
acid (100 mL) in water (50 mL) was added over 2 h. TLC indicated absence of starting
material. The pH was adjusted to 13 with aqueous NaOH, and the product was extracted
with ether (3 £ 150 mL). The ether solution was dried over anhydrous MgSO4 and con-
centrated to dryness. Silica gel chromatography gave 9 as a white solid (20.0 g, 49%). Its
1H spectral data matched those reported.24

224
Goel and Dembinski
2,3,4,5-Tetrahydro-2,8-dimethyl-5-[2-(6-methyl-3-pyridyl)ethyl]-1H-pyrido[4,3-b]
indole Dihydrochloride (Latrepirdine Dihydrochloride, Dimebon, 10)
To a solution of hydrazine 9 (1.8 g, 0.074 mol) and N-methyl-4-piperidone (0.93 g,
0.082 mol) in benzene (30 mL), was added p-toulenesulfonic acid monohydrate (20 mg,
1.1 mmol). The mixture was refluxed for 17 h, the water generated being removed using
a Dean-Stark apparatus. Removal of the solvent gave a residue that was dissolved in
hydrogen chloride saturated ethanol solution (ca. 50 mL), and the solution was saturated
with HCl gas. The mixture was refluxed for 2 h, cooled to room temperature and added to
ice-water. The pH was adjusted to 13 with 30% aqueous NaOH, and the mixture was
extracted into ether (3 £ 100 mL), dried over anhydrous MgSO4 and concentrated to dry-
ness. Silica gel chromatography of the solid residue gave latrepirdine free base (2.0 g,
85%), which was converted to its hydrochloride salt by addition to a hydrogen chloride
saturated methanol solution (ca. 30 mL). The solid was collected, washed with ether, and
dried to give 10 as a white solid (1.9 g, 65%), mp. 264–266ꢀC. MS 319 (MC, 86%). UV-
1
Vis (e, M¡1 cm¡1; H2O; 3.1 £ 10¡5 M) 225 (60,000), 270 (21,000). H NMR (DMSO-
d6): d 11.49 (br s, 1H), 8.54 (s, 1H), 8.20 (d, J D 8.0 Hz, 1H), 7.70 (d, J D 8.2 Hz, 1H),
7.35 (d, J D 8.4 Hz, 1H), 7.19 (s, 1H), 6.93 (d, J D 8.3 Hz, 1H), 4.48 (d, J D 13.8 Hz,
1H), 4.38 (t, J D 6.8 Hz, 2H), 4.26–4.14 (m, 1H), 3.73–3.62 (m, 2H), 3.20–2.95 (m, 4H),
2.91 (s, 3H), 2.67 (s, 3H), 2.36 (s, 3H); 13C{1H} 151.6, 145.8, 140.7, 135.0, 134.5, 130.9,
127.9, 127.0, 124.5, 122.9, 117.3, 109.7, 101.5, 50.1, 49.5, 43.0, 41.5, 31.7, 21.0, 19.2,
18.8.
2,3,4,5-Tetrahydro-2,8-dimethyl-5-[2-(6-methyl-3-pyridyl)ethyl]-1H-pyrido[4,3-b]
indole Tetrathiomolybdate (Latrepirdine Tetrathiomolybdate, 11)
Latrepirdine dihydrochloride (10, dimebon, 0.391 g, 0.997 mmol) was dissolved in dis-
tilled water (4 mL) and the solution was filtered to remove insoluble material, which was
rinsed with water (4 mL). To the combined filtrate and wash, a clear (filtered) solution of
ammonium tetrathiomolybdate (0.262 g, 1.01 mmol) in water (7 mL) was added drop-
wise. The mixture was stirred (stir bar) and then heated on a steam bath (ca. 50ꢀC) for
5 min. The mixture was cooled to room temperature and then placed in an ice bath. The
solid that precipitated was collected, washed with cold distilled water (3 mL) and ether
(3 mL), dried in air and under vacuum to give 11 as a dark orange solid (0.447 g, 82%),
mp. 142–145ꢀC (dec.).
Anal. Calcd for C21H25N3MoS4ꢁH2O: C, 44.91; H, 4.85; N, 7.48; S, 22.84. Found: C,
45.12; H, 4.97; N, 7.43; S, 22.56.
UV-Vis (e, M¡1 cm¡1; DMSO; 1.7 £ 10¡5 M): 320 (15,000), 475 (9,800). 1H NMR
(DMSO-d6): d 8.17 (s, 1H), 7.49 (d, J D 8.1 Hz, 1H), 7.39 (d, J D 8.1 Hz, 1H), 7.22 (s,
1H), 7.16 (d, J D 8.1 Hz, 1H), 6.98 (d, J D 8.1 Hz, 1H), 4.45–4.18 (m, 4H), 3.60–3.12
(m, 2H), 3.03–2.85 (m, 7H), 2.41 (s, 3H), 2.38 (s, 3H).
References
1. I. Okun, S. E. Tkachenko, A. Khvat, O. Mitkin, V. Kazey, and A.V. Ivachtchenko, Curr. Alz-
heimer Res., 7, 97 (2010).
2. M. Giorgetti, J. A. Gibbons, S. Bernales, I. E. Alfaro, C. D. La Rochelle, T. Cremers, C. A.
Altar, R. Wronski, B. Hutter-Paier, and A. A. Protter, J. Pharm. Exp. Ther. 333, 748 (2010).

Synthesis of Dimebon and of its Tetrathiomolybdate
225
3. N. N. Lermontova, N. V. Lukoyanov, T. P. Serkova, E. A. Lukoyanova, and S. O. Bachurin,
Bull. Exp. Biol. Med., 129, 544 (2000).
4. N. S. Zefirov, A. Z. Afanasiev, S. V. Afanasieva, S. O. Bachurin, S. E. Tkachenko, V. V. Gri-
goriev, M. A. Jurovskaya, V. P. Chetverikov, E. E. Bukatina, and I. V. Grigorieva, US Patent
7,071,206 (2006); Chem. Abstr., 126, 338861 (1997).
5. M. Sweetlove, Pharm. Med., 26, 113 (2012).
6. C. S. Atwood, R. D. Moir, X. Huang, R. C. Scarpa, N. M. E. Bacarra, D. M. Romano, M. A.
Hartshorn, R. E. Tanzi, and A. I. Bush, J. Biol. Chem., 273, 12817 (1998).
7. C. S. Atwood, R. C. Scarpa, X. Huang, R. D. Moir, W. D. Jones, D. P. Fairlie, R. E. Tanzi, and
A. I. Bush, J. Neurochem., 75, 1219 (2000).
8. R. Squitti, D. Lupoi, P. Pasqualetti, G. Dal Forno, F. Vernieri, P. Chiovenda, L. Rossi, M. Cor-
tesi, E. Cassetta, and P. M. Rossini, Neurology, 59, 1153 (2002).
9. Squitti, P. Pasqualetti, G. Dal Forno, F. Moffa, E. Cassetta, D. Lupoi, F. Vernieri, L. Rossi, M.
Baldassini, and P. M. Rossini, Neurology, 64, 1040 (2005).
10. R. Squitti, G. Barbati, L. Rossi, M. Ventriglia, G. Dal Forno, S. Cesaretti, F. Moffa, I. Caridi, E.
Cassetta, P. Pasqualetti, L. Calabrese, D. Lupoi, and P. M. Rossini, Neurology, 67, 76 (2006).
11. L. Rossi, R. Squitti, L. Calabrese. G. Rotilio, and P. M. Rossini, J. Nutr. Health Aging, 11, 408
(2007).
12. C. W. Ritchie, A. I. Bush, A. Mackinnon, S. Macfarlane, M. Mastwyk, L. MacGregor, L. Kiers,
R. Cherny, Q. X. Li, A. Tammer, D. Carrington, C. Mavros, I. Volitakis, M. Xilinas, D. Ames,
S. Davis, K. Beyreuther, R. E. Tanzi, and C. L. Masters, Arch. Neurol., 60, 1685 (2003). Erra-
tum: Arch. Neurol., 61, 776 (2004).
13. A. R. White, T. Du, K. M. Laughton, I. Volitakis, R. A. Sharples, M. E. Xilinas, D. E. Hoke, R.
M. D. Holsinger, G. Evin, R. A. Cherny, A. F. Hill, K. J. Barnham, Q.-X. Li, A. I. Bush, and C.
L. Masters, J. Biol. Chem., 281, 17670 (2006).
14. G. J. Brewer, US Patents 6,855,340 (2005) and 7,758,898 (2010); Chem. Abstr., 147, 462270
(2007).
15. G. J. Brewer, F. Askari, M. T. Lorincz, M. Carlson, M. Schilsky, K. J. Kluin, P. Hedera, P. Mor-
etti, J,K. Fink, R. Tankanow, R. B. Dick, and J. Sitterly, Arch. Neurol., 63, 521 (2006).
16. J. F. Quinn, J. Bishop, and T. Wadsworth, Program No. 157.9/U20. 2007 Neuroscience Meeting
Planner. San Diego, CA: Society for Neuroscience, 2007, online.
17. O. P. Goel, US Patent 7,893,289 (2011); Chem. Abstr., 149, 322436 (2008).
18. Even now, it is currently available only in small quantities from Selleckchem ($370/50 mg,
http://www.selleckchem.com/products/Dimebon.html, accessed September 17, 2014; or out of
stock; accessed December 13, 2014), or more expensively from other vendors.
19. A. N. Kost, A. P. Terent’ev, E. V. Vinogradova, P. B. Terent’ev, and V. V. Ershov, J. Gen.
Chem. USSR, 30, 2538 (1960); Zh. Obsh. Khim., 30, 2556 (1960).
20. E. V. Vinogradova, K. Daut, A. N. Kost, and A. P. Terent’ev, J. Gen. Chem. USSR, 32, 1536
(1962); Zh. Obsh. Khim., 32, 1550 (1962).
21. A. N. Kost, M. A. Yurovskaya, T. V. Mel’nikova, and O. I. Potanina, Chem. Heterocycl. Comp.,
191 (1973); Khim. Geterotsikl. Soedin., 207 (1973).

226
Goel and Dembinski
22. S. Shadurski, I. K. Danusevich, A. N. Kost, and E. V. Vinogradova, USSR Patent. 1138164
(1985); Chem. Abstr., 102, 190810 (1985).
23. The amination reaction of vinylpyridine (vinylation of p-toluidine) reaction has been claimed in
the patent literature, but no synthetic details were available at the time this work was carried out.
24. M. Gao, M. Wang, G. D. Hutchins, and Q-H. Zheng, Bioorg. Med. Chem. Lett., 20, 2529
(2010).
25. For a recent alternative synthesis of dimebon see H. Dong, R. T. Latka, and T. G. Driver, Org.
Lett., 13, 2726 (2011).
26. We prepared 2-methyl-5-vinylpyridine by the reaction of 5-bromo-2-methylpyridine with
potassium vinyltrifluoroborate/palladium(II) chloride/PPh3/Ce2CO3/THF-H2O: G. A. Molander
and A. R. Brown, J. Org. Chem., 71, 9681 (2006).
27. E. van der Eycken, Z. Jidong, A. Kilonda, F. Compernolle, S. Toppet, G. Hoornaert, M. Van der
Auweraer, C. Jackers, W. Verbouwe, and F. C. de Schryver, J. Chem. Soc., Perkin Trans. 2, 928
(2002).
28. I. M. Bell, J. M. Erb, R. M. Freidinger, S. N. Gallicchio, J. P. Guare, M. T. Guidotti, R. A. Hal-
pin, D. W. Hobbs, C. F. Homnick, M. S. Kuo, E. V. Lis, D. J. Mathre, S. R. Michelson, J. M.
Pawluczy, D. J. Pettibone, D. R. Reiss, S. Vickers, P. D. Williams, and C. J. Woyden, J. Med.
Chem., 41, 2146 (1998).
29. C. Chen, K. M. Wilcoxen, C. Q. Huang, Y.-F. Xie, J. R. McCarthy, T. R. Webb, Y.-F. Zhu, J.
Saunders, X.-J. Liu, T.-K. Chen, H. Bozigian, and D. E. Grigoriadis, J. Med. Chem., 47, 4787
(2004).
30. D.L. Hughes, Org. Prep. Proced. Int., 25, 607 (1993).