Total syntheses of AF-2785 and gamendazole-experimental male oral contraceptives

Article abstract of DOI:10.1080/00397911.2012.696306

Both AF-2785 and gamendazole are experimental male oral contraceptives. The total syntheses of these two compounds are achieved in good yields. Copyright

Full text of DOI:10.1080/00397911.2012.696306

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Total Syntheses of AF-2785 and
Gamendazole—Experimental Male Oral
Contraceptives
Arava Veerareddy a , Gogireddy Surendrareddy a & P. K. Dubey b
a Research and Development Centre, Suven Life Sciences Ltd. ,
Hyderabad , India
b Department of Chemistry , J.N.T. University , Hyderabad , India
Published online: 03 Jun 2013.
To cite this article: Arava Veerareddy , Gogireddy Surendrareddy & P. K. Dubey (2013): Total
Syntheses of AF-2785 and Gamendazole—Experimental Male Oral Contraceptives, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
43:16, 2236-2241
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Synthetic Communications1, 43: 2236–2241, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2012.696306
TOTAL SYNTHESES OF AF-2785 AND
GAMENDAZOLE—EXPERIMENTAL MALE ORAL
CONTRACEPTIVES
Arava Veerareddy,1 Gogireddy Surendrareddy,1 and
P. K. Dubey2
1Research and Development Centre, Suven Life Sciences Ltd.,
Hyderabad, India
2Department of Chemistry, J.N.T. University, Hyderabad, India
GRAPHICAL ABSTRACT
Abstract Both AF-2785 and gamendazole are experimental male oral contraceptives. The
total syntheses of these two compounds are achieved in good yields.
Supplemental materials are available for this article. Go to the publisher’s online edition
of Synthetic Communications1 to view the free supplemental file.
Keywords Buchwald–Hartwig coupling; indazole-3-carboxylic acid; Knoevenagel
condensation; male oral contracaptives
INTRODUCTION
Female oral contraceptive drugs are widely available in the market by several trade
names, including Altravera, Brevicon, Levora, and i-pill, whereas potentially safer, more
convenient, and more effective oral male contraceptives are not yet commercially avail-
able. However, there are some experimental drugs.[1–11] AF-2785 1, gamendazole 2, loni-
damine 3, and adjudin 4 are most promising among the experimental Fig. 1, drugs.
AF-2785 and gamendazole fall into the indazole-3-acrylic acid class, and
lonidamine and adjudin fall into indazole-3-carboxylic acid class.
George et al.[12] reported the synthesis of gamendazole 2 from 2-chloro-5-tri-
fluoromethyl-1-nitrobenzene in overall yield of 31.5%, whereas Silvestrini and
Cheng[13] reported AF-2785 1 in an overall yield of <20%.
Received April 4, 2012.
Address correspondence to Arava Veerareddy, Research and Development Centre, Suven Life
Sciences Ltd., Plot No. 18, Phase III, Jeedimetla, Hyderabad 500055, India. E-mail: reddyvenis@
rediffmail.com
2236

TOTAL SYNTHESES OF AF-2785 AND GAMENDAZOLE
2237
Figure 1. Experimental drugs.
We recently developed[14] a methodology for the synthesis of indazole-3-
carboxylic acids from 2-halo benzoic acids via 2-halo-a -ketoacids. As both
AF-2785 and gamendazole show very promising results as male antifertility agents,
we developed high-yielding syntheses for both of them.
RESULTS AND DISCUSSION
2-Halo benzoic acid is converted into aroyl chloride and then to aroyl cyanide
in an overall yield of 82%. Aroyl cyanides 5 are converted to 2-halophenyl glyoxylate
ester 7 via ketoamide 6 in 85% yields as shown in Scheme 1. Direct conversion of
aroyl cyanide 5 to ester 7 is also reported[15] but with lesser yields.
The 2-halophenylglyoxylate 7 esters are reacted with monosubstituted hydra-
zines 8 to give hydrazones 9. The monosubstituted hydrazones 9 are cyclized to give
indazole esters 10. This cyclization is best conducted (see Table 1) in the presence of
DPPF ꢀ PdCl2 in 94.54% yield as shown in Scheme 2.
Scheme 1. Synthesis of 2-halophenylglyoxalate.
Table 1. Conversion of 9 to 10
No.
Catalyst=base=solvent
Temp. (ꢁC)
10 (%) yield
1
2
3
4
CuI=L-Proline=Cs2CO3=DMSO
CuI=L-Proline=K2CO3=DMSO
dppf.Pdcl2=Cs2CO3=DMSO
dppf.Pdcl2=Cs2CO3=DMSO
60–65
60–65
25–28
25–28
—
—
83.3 (R ¼ H)
94.5 0 (R ¼ CF3)

2238
A. VEERAREDDY, G. SURENDRAREDDY, AND P. K. DUBEY
Scheme 2. Synthesis of 1-substituted indazole-3-carboxylate.
The indazole-3-carboxylic esters 10 were reduced with sodium borohydride to
alcohol 11 and were oxidized to aldehyde 12 with MnO2. The aldehyde is converted
to acrylic acids with malonic acid (Knoevenagel condensation) to give 88–95.6%
yield of the final compounds, as shown in Scheme 3.
In conclusion we have reported a high-yielding syntheses of AF-2785 1 and
gamendazole 2. The final products 1 and 2 are completely in agreement with the
reported[12,13] ones by all spectral means.
Scheme 3. Synthesis of AF-2785 and gamendazole.

TOTAL SYNTHESES OF AF-2785 AND GAMENDAZOLE
2239
EXPERIMENTAL
All reagents were obtained commercially, were of the highest commercial qual-
ity, and were used without further purification. Solvents were freshly distilled and
used. Melting points were determined in open capillaries and are uncorrected.
Thin-layer chromatography (TLC) or high-performance liquid chromatography
(HPLC) routinely checked the purity of all compounds. Infrared (IR) spectra were
recorded on a Perkin-Elmer model 2000 instrument in KBr phase. 1H NMR
(400 MHz) and 13C NMR (100 MHz) spectra were recorded in CDCl3 or dimethyl
sulfoxide (DMSO) using a Brucker instrument, and mass spectra were recorded
on a Perkin-Elmer mass spectrometer operating at 70 eV.
Preparation of (E)-3-(1-(2,4-Dichlorobenzyl)-1H-indazol-3-yl)acrylic
Acid (AF-2785) (1)
1-(2,4-Dichlorobenzyl)-1H-indazole-3-carbaldehyde
12
(R ¼ H)
(2.0 g,
0.0065 mol), malonic acid (1.35 g, 0.013 mol), and piperdine (20.0 mg) were added
to a solution of pyridine (10.0 ml) at room temperature. The reaction mass was
heated to 65 ꢁC and stirred for 2 h. After completion of the reaction, the mass was
cooled to rt, and water (50.0 ml) was added and stirred for 30 min at rt. Reaction
mass pH was adjusted to 2.0–2.5 with concentrated HCl at 20–25 ꢁC, and ethyl acet-
ate (20.0 ml) was added and stirred for 30 min at rt. Organic layer was separated and
washed with brine solution (5.0 ml) at rt. The organic layer was dried over anhydrous
Na2SO4 and distilled off under vacuum to get the crude compound. To this crude,
hexane (5.0 ml) was added, heated to 50 ꢁC, stirred for 30 min, cooled to rt, stirred
for 30 min, and filtered to give the solid, which was washed with hexane to get the
desired product 1 as a colorless solid (wt 2.0 g, yield 88.0%, HPLC purity 99.56%,
1
DSC: 200.09–201.7 ꢁC). IR (KBr) (cmꢂ1): 3429, 1689, 1629, 1308, 746; H NMR
(400 MHz, CDCl3): d 5.78 (2H, s), 6.67 (1H, d, J ¼ 16.24 Hz), 6.93 (1H, d,
J ¼ 8.36 Hz), 7.30 (1H, t), 7.35–7.38 (1H, dd, J1 ¼ 8.34 Hz, J2 ¼ 2.05 Hz), 7.47 (1H,
t), 7.68 (1H, d, J ¼ 2.01), 7.75–7.79 (2H, m), 8.10 (1H, d, J ¼ 8.19 Hz), 12.52, (1H,
s); 13C NMR (100 MHz, CDCl3): d 49.73, 110.82, 120.51, 121.10, 122.23, 122.88,
127.54, 128.08, 129.37, 131.18, 133.53, 133.67, 133.73, 135.07, 140.22, 141.43,
167.79. MW for C17H12Cl2N2O2: calcd.: 347.1, observed: 347.1 and 349.1 [M þ 2].
Anal. calcd. for C17H12Cl2N2O2: C, 58.81; H, 3.48; N, 8.07. Found: C, 58.82; H,
3.50; N, 8.10.
Preparation of (E) 3-(1-(2,4-Dichlorobenzyl)-6-(trifluoromethyl)-1H-
indazol-3-yl)acrylic Acid (R ¼ CF3) (Gamendazole) (2)
1-(2,4-Dichlorobenzyl)-6-(trifluoromethyl)-1H-indazole-3-carbaldehyde
12
(R ¼ CF3) (5.0 g, 0.013 mol), malonic acid (2.78 g, 0.0268 mol), and piperdine
(50.0 mg) were added to a solution of pyridine (25.0 ml) at room temperature. The
reaction mass was heated to 65 ꢁC and stirred for 2 hrs. After completion of the reac-
tion, the mass was cooled to rt, water (50.0 ml) was added, and it was stirred for
30 min. Reaction mass pH was adjusted to 2.0–2.5 with concentrated HCl at
20–25 ꢁC and extracted with ethyl acetate (100.0 ml). The organic layer was

2240
A. VEERAREDDY, G. SURENDRAREDDY, AND P. K. DUBEY
separated, washed with brine solution (15.0 ml), and dried over anhydrous Na2SO4.
The organic layer was distilled off under vacuum to get the crude compound. To this
crude solid hexane (25.0 ml) was added, heated to 50 ꢁC, and stirred for 30 min at
50–55 ꢁC. It was cooled to rt and stirred for 30 min. The solids were filtered and
washed with hexane to get the desired product 2 as a colorless solid (wt 5.32 g, yield
95.6%, HPLC purity 99.30% DSC: 203.4 ꢁC). IR (KBr) (cmꢂ1): 3447, 1697, 1641,
1311, 1122, 872; 1H NMR (400 MHz, DMSO): d 5.90 (2H, s), 6.72 (1H, d,
J ¼ 16.22 Hz), 6.94 (1H, d, J ¼ 8.34 Hz), 7.36–7.39 (1H, dd, J1 ¼ 8.24 Hz,
J2 ¼ 1.42 Hz), 7.55 (1H, d, J ¼ 8.56 Hz), 7.69 (1H, d, J ¼ 1.46 Hz), 7.78 (1H, d,
J ¼ 16.22 Hz), 8.37 (1H, d, J ¼ 8.63 Hz), 8.40 (1H, s), 12.61 (1H, s); 19F NMR
(400 MHz, CDCl3): d ꢂ 59.97(CF3); 13C NMR (100 MHz, DMSO): d 50.05,
109.16, 118.73, 121.61, 122.76, 123.39, 123.98, 127.76, 128.11, 129.42, 131.26,
133.56, 133.65, 133.76, 134.10, 140.64, 140.70, 167.57. MW for C18H11Cl2F3N2O2
calcd. 415.19; observed: 415.3 and 417.2. HRMS: calcd.: 415.0228, observed:
415.0225.
ACKNOWLEDGMENT
The authors are grateful to Suven Life Sciences management for allowing them
to publish these results.
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