Synthesis of a Precursor of the Antiviral Agent A-315675

Article abstract of DOI:10.1134/S1070428019020167

Ethyl 2-(acetylamino)-3-methoxy-3-methylhexanoate, a key precursor of the known pyrrolidine antiviral agent A-315675, was synthesized starting with the readily available acetoacetic ester.

Full text of DOI:10.1134/S1070428019020167

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2019, Vol. 55, No. 2, pp. 241–244. © Pleiades Publishing, Ltd., 2019.
Russian Text © V.A. Egorov, F.A. Gimalova, 2019, published in Zhurnal Organicheskoi Khimii, 2019, Vol. 55, No. 2, pp. 294–298.
Synthesis of a Precursor of the Antiviral Agent A-315675
a
a,
V. A. Egorov and F. A. Gimalova *
a
Ufa Institute of Сhemistry, Ufa Federal Research Center, Russian Academy of Sciences,
pr. Oktyabrya 71, Ufa, Bashkortostan, 450054 Russia
*
e-mail: fangim@anrb.ru
Received August 1, 2018; revised August 24, 2018; accepted September 27, 2018
Abstract—Ethyl 2-(acetylamino)-3-methoxy-3-methylhexanoate, a key precursor of the known pyrrolidine
antiviral agent A-315675, was synthesized starting with the readily available acetoacetic ester.
Keywords: neuraminidase inhibitors, A-315675, antiviral activity, acetoacetic ester, allyl bromide, precursors,
synthesis
DOI: 10.1134/S1070428019020167
Antiviral drugs are used for prevention and
treatment of seasonal influenza epidemics, and are
considered as an economically effective way to reduce
the risk of rapid spread of pandemic disease [1, 2]. The
main antiviral drugs include M2 ion channel protein inhi-
bitors (adamantane derivatives [3, 4]) and more active neu-
raminidase inhibitors [5, 6], such as Relenza (Zanamivir)
subsequent reduction of oxime 4 in acetic acid and one
-pot acylation in the presence of acetic anhydride gave
amide 5 [13] (Scheme 2).
Further on we suggested to prepare hydroxy ester 6
by the Reformatsky reaction of compound 5 with
propyl bromide and Zn in DMF. However, the reaction
took an unusual pathway to form azirine 7 in a low
yield, rather than the expected tertiary alcohol 6
[7], Tamiflu (Oseltamivir) [8], and Peramivir [9].
(
Scheme 2). The structure of compound 7 was
Fairly recently, researchers from the Abbott have
confirmed by NMR spectroscopy and mass
spectrometry. We also failed to prepare compound 6 by
the reaction of keto ester 5 with propylmagnesium
bromide in THF.
discovered new pyrrolidine neuraminidase inhibitors 1
A-192558) and 2 (A-315675) [10, 11], which proved
quite potent antiviral agents (Scheme 1).
(
In the present work, searching for synthetic
approaches to precursors of compound 2, we prepared
compound 3 starting with acetoacetic acid. Compound
In view of the failure to synthesize compound 3 by
the reaction with n-PrBr, we chose an alternative
version of the Reformatsky reaction (Scheme 3). The
reaction of compound 5 with allyl bromide and Zn in
DMF formed adduct 8 as a mixture of diastereomers in
a good total yield. Compound 8 was then hydrogenated
with hydrogen in МеОН in the presence of 10% Pd/C
3
was intended to be further used in the synthesis of А-
3
15675 by the [C+NC+CC] coupling scheme [12].
The first step involved the synthesis of oxime 4
from acetoacetic ester by a known procedure. The
Scheme 1.
H N
CO H
2
2
CO H
2
O
MeO
H
H
NH
F3C
N
N
AcHN
OEt
OMe
O
NHAc
O
N
1
(A -192558)
2 (A-315675)
3
2
41

2
42
EGOROV, GIMALOVA
Scheme 2.
O
O
NaNO , AcOH
2
CO Et
_
CO
NOH
Et
2
2
0°C r.t., 2 h
4
CH3
PrBr, Zn
O
N
o
COCH3
DMF, 100 C
PrO C
2
Zn, Ac O-AcOH
CO
NHAc
Et
2
2
7
1
8-20 h
PrMgBr, THF
OH
CO Et
2
5
NHAc
6
to obtain hydroxy ester 6 in a quantitative yield. The
methylation of the tertiary OH group in the latter under
the action of MeI in DMF in the presence of NaH and
and 125.77 MHz, respectively, internal reference TMS.
The mass spectra were run on a Shimadzu LCMS-
2010EV and a Thermo Finnigan MAT 95XP
instruments (ionizing voltage 70 eV). Elemental
analysis was performed on a EuroVector EURO EA-
+
–
catalytic quantities of Bu N I gave the target ester 3 in
4
a moderate yield.
3
000 CHNS analyzer. Reaction progress was
Thus, starting with the readily available acetoacetic
ester, we synthesized a key precursor of the known
pyrrolidine antiviral agent А-315675, which has all
necessary functional groups for further assembly of the
target structure.
monitored by TLC on Sorbfil plates (Russia),
development by heating or treatment with alkaline
potassium permanganate. The synthesized compounds
were isolated by column chromatography on silica gel
(Macherey−Nagel, Germany; 30−60 g/g compound).
EXPERIMENTAL
Ethyl 2-(acetylamino)-3-methoxy-3-methylhexa-
noate (3). To a cold (0°С) solution of 0.1 g (0.43 mmol)
compound 6 in 1.0 mL of DMF, we added 31 mg
(0.65 mmol) of 50% NaH and then 0.05 mL (0.86 mmol)
of CH I and 19.4 mg (0.086 mmol) of Bu NI. The
The IR spectra were obtained on a Shimadzu IR-
1
13
Prestige-21 spectrometer in thin films. The Н and С
NMR spectra were recorded on a Bruker AM-300
spectrometer at 300.13 and 75.47 MHz, respectively,
and a Bruker AVANCE-500 spectrometer at 500.13
3
4
mixture was stirred for 48 h and decomposed with
NH Cl. The aqueous layer was extracted with CH Cl
4
2
2
Scheme 3.
O
O
CH =CHCH Br
HO
2
2
CO Et
2
Zn, DMFA
OEt
NHAc
NHAc
5
8, 65%
MeO
O
O
NaH,
DMFA
HO
H , Pd/C
2
OEt
MeOH
MeI, Bu NI
OEt
4
NHAc
, 98%
NHAc
6
3, 40%
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 2 2019

SYNTHESIS OF A PRECURSOR OF THE ANTIVIRAL AGENT A-315675
243
1
3
(
3 × 15 mL). The combined organic extracts were
(1H, NCH). С NMR spectrum (CDCl , 125 MHz), δ,
3
dried over MgSO and evaporated to isolate 42 mg
ppm: 13.50 (CH ), 16.44 (CH ), 21.05 (CH ), 22.60
4
3
2
3
2
(
40%) of product 6 as oil. Found, %: C 58.43, H 9.67,
(CH ), 41.66 (CH ), 59.76 (C ), 60.79 (OCH ), 72.72
3 2 2
3
N 5.58. C H NO . Calculated, %: C 58.75, H 9.45, N
(C ), 170.65 (NHC=O), 171.97 (CO Et).
1
2
23
4
2
+
5
2
[
.71. Mass spectrum, m/z (I , %): 246 [M + H] (2),
28 [M + H – H O] (100), 214 [M – OCH ] (2), 187
M + H – OEt] (36).
1
rel
Minor isomer. Н NMR spectrum (methanol-d ,
+
+
4
2
3
5
00 MHz), δ, ppm: 0.93 t (3H, CH , J 7.0 Hz), 1.20 s
+
3
(
3H, CH ), 1.30 t (3H, CH , J 7.1 Hz), 1.49 m (4H,
3 3
1
Major isomer. Н NMR spectrum (CDCl , 500 MHz),
CH ), 2.03 s (3H, CH ), 4.19 m (2H, OCH ), 4.48 s
3
2 3 2
1
3
δ, ppm: 0.87 t (3H, CH , J 7.3 Hz), 1.27 t (3H, CH , J
(1H, NCH). С NMR spectrum (CDCl , 125 MHz), δ,
3
3
3
7
.1 Hz), 1.44 s (3H, CH ), 1.67 m (4H, CH ), 2.12 s
ppm: 13.09 (CH ), 16.44 (CH ), 21.05 (CH ), 22.32
3
2
3
2
3
2
(
3H, CH ), 3.19 s (3H, OCH ), 4.18 q (2H, OCH , J
(CH ), 41.63 (CH ), 59.72 (C H), 60.79 (OCH ), 73.11
3
3
2
3 2 2
1
3
3
7
1
.1 Hz), 5.37 s (1H, CH). С NMR spectrum (CDCl ,
(C ), 170.65 (NHC=O), 171.91 (CO Et).
2
3
25 MHz), δ, ppm: 14.16 (CH ), 14.87 (CH ), 17.18
3
3
Propyl 1-acetyl-3-methyl-1H-azirene-2-carbo-
xylate (7). To a stirred solution of 0.2 g (1.07 mmol) of
keto ester 5 and 0.14 mL (1.55 mmol) of propyl
bromide in 5 mL of DMF, we added in portions over
the course of 15 min 0.105 g (1.61 mmol) of Zn dust.
The mixture was stirred for 2 h at 100°С. After cooling
to room temperature, 5 mL of saturated aqueous
(CH ), 21.01 (CH ), 21.80 (CH ), 39.09 (CH ), 60.99
2 3 3 2
2
3
(
C ), 60.74 (OCH ), 79.88 (C ), 172.28 (NHC=O),
2
1
70.40 (CO Et).
2
1
Minor isomer. Н NMR spectrum (CDCl , 500 MHz),
3
δ, ppm: 0.93 t (3H, CH , J 7.2 Hz), 1.13 s (3H, CH ),
1
3
3
.27 t (3H, CH , J 7.1 Hz), 1.67 m (4H, CH ), 2.12 s
3
2
(
7
3H, CH ), 3.24 s (3H, OCH ), 4.19 q (2H, OCH , J
.0 Hz), 5.54 s (1H, CHN). С NMR spectrum
NH
CH
were dried over MgSO
4
4
Cl was added, and the mixture was extracted with
Cl (3 × 20 mL). The combined organic extracts
, the solvent was evaporated,
3
3
2
1
3
2
2
(CDCl , 125 MHz), δ, ppm: 14.11 (CH ), 14.68 (CH ),
3
3
3
1
5
8.03 (CH ), 20.28 (CH ), 21.74 (CH ), 38.25 (CH ),
and the residue was subjected to column chroma-
tography (EtOAc–petroleum ether, 1 : 1) to isolate
50 mg (25%) of compound 7 as an oil. Н NMR
2
2
3
3
2
3
9.01 (C ), 60.65 (OCH ), 80.25 (C ), 170.40
2
1
(
NHC=O), 172.28 (CO Et).
2
spectrum (CDCl , 500 MHz), δ, ppm: 0.99 t (3H, CH ,
3
3
Ethyl 2-(acetylamino)-3-oxobutanoate (5) was
J 7.2 Hz), 1.78 sextet (2H, CH , J 7.2 Hz), 2.39 s (3H,
2
prepared as described in [13]. Yield 70% (after two
13
CH ), 2.57 s (3H, CH ), 4.26 t (2H, CH , J 7.0 Hz). С
1
3
3
2
stages). Н NMR spectrum (CDCl , 500 MHz), δ,
3
NMR spectrum (CDCl , 125 MHz), δ, ppm: 10.42 (CH ),
3
3
ppm: 1.22 t (3H, CH , J 7.1 Hz), 1.99 s (3H, CH ),
3
3
1
1
1.92 (CH ), 13.70 (CH ), 22.05 (CH ), 66.36 (OCH ),
3 3 2 2
2
.30 s (3H, CH ), 4.18 q (2H, OCH , J 7.2 Hz), 5.21
3
2
3
2
27.41 (C ), 155.92 (C ), 159.43 (CO Pr), 162.51
1
3
2
d.d (1Н, CH, J 3.8, 6.6 Hz), 6.97 m (1Н, NH).
С
+
(NC=O). Mass spectrum, m/z (I , %): 184 [M + H]
rel
NMR spectrum (CDCl , 125 MHz), δ, ppm: 13.86
+
3
(
100), 225 [M + H + CH CN] (83%), 142 [M + H –
3
(
(
(
CH ), 22.41 (CH ) 28.01 (CH ), 62.52 (OCH ), 63.05
+
3
3
3
2
C H ] (11%).
3
7
CHN), 166.12 (NHCO), 170.25 (CO Et), 198.83
2
C=O).
Ethyl N-acetyl-3-allyl-3-methylserinate (8). To a
vigorously stirred solution of 1.0 g (5.34 mmol) of
keto ester 5 and 0.686 (8.02 mmol) of allyl bromide in
Ethyl 2-(acetylamino)-3-hydroxy-3-methylhexa-
noate (6). To a solution of 0.61 g (2.66 mmol) of
compound 8 in 20 mL of MeOH, we added 0.3 g of
0% Pd/C, and the mixture was stirred under hydrogen
for 48 h. The catalyst was filtered off, and the filtrate
5
1
mL of DMF, we added in portions over the course of
5 min 1.10 g (17.0 mmol) of Zn dust. Active reaction
1
accompanied by heat release was observed. After 2 h,
the reaction mixture was acidified with saturated
aqueous NH Cl and extracted with CH Cl (3 × 20 mL).
was evaporated to isolate 0.61 g (98%) of product 6 as
+
4
2
2
an oil. Mass spectrum, m/z (I , %): 232 [M + H]
rel
The organic layer was dried over MgSO , the solvent
+
+
4
(
(
100), 214 [M + H – H O] (39), 187 [M + H – OEt]
2
was evaporated, and the residue was subjected to
column chromatography (EtOAc–petroleum ether, 1 : 1)
to isolate 0.77 g (65%) of product 8 as an oil. IR
36).
1
Major isomer. Н NMR spectrum (methanol-d ,
4
–
1
5
(
00 MHz), δ, ppm: 0.92 t (3H, CH , J 7.2 Hz), 1.23 s
spectrum, ν, cm : 3342, 3338, 3078, 2982, 2939,
1731, 1648, 1603, 1534, 1518, 1446, 1375, 1341,
1296, 1259, 1206, 1157, 1132, 1026, 924. Mass
3
3H, CH ), 1.28 t (3H, CH , J 7.2 Hz), 1.49 m (4H,
3 3
CH ), 2.03 s (3H, CH ), 4.19 m (2H, OCH ), 4.43 s
2
3
2
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 2 2019

2
44
EGOROV, GIMALOVA
+
spectrum, m/z (I , %): 230 [M + H] (70), 212 [M –
2. Moscona, A., N. Engl. J. Med., 2005, vol. 353, p. 2633.
rel
+
+
doi 10.1056/NEJMp058291
OH] (100%), 187 [M + H – CH CO] (24).
3
3
. Davies, W.L., Grunert, R.R., Haff, R.F., McGahen, J.W.,
Neumayer, E.M., Paulshock, M., Watts, J.C., Wood, T.R.,
Hermann, E.C., and Hoffmann, C.E., Science, 1964,
vol. 144, p. 862. doi 10.1126/science.144.3620.862
1
Major isomer. Н NMR spectrum (CDCl , 500 MHz),
δ, ppm: 1.20 s (3H, CH ), 1.28 t (3H, CH , J 7.0 Hz),
.19 s (3H, CH ), 2.26 m (2H, CH ), 3.04 d (1H, OH, J
9.7 Hz), 4.22 m (2H, OCH ), 4.53 d (1H, CH, J 8.7 Hz),
.13 m (2H, =CH ), 5.83 m (1H, =CH), 7.11 d (1H,
NH, J 8.9 Hz). С NMR spectrum (CDCl , 125 MHz),
3
3
3
2
1
5
3 2
2
4. Zlydnikov, D.M., Kubar, O.I., Kovaleva, T.P., and
Kamforin, L.E., Rev. Infect. Dis., 1981, vol. 3, p. 408.
doi 10.1093/cnids/3.3.408
2
1
3
3
δ, ppm: 14.06 (CH ), 23.20 (CH ), 23.94 (CH ), 43.55
5. Colman, P.M., Varghese, J.N., Laver, W.G., Nature,
3
3
3
3
(
CH ), 58.83 (CHN), 61.88 (OCH ), 73.44 (C ),
1983, vol. 303, p. 41. doi 10.1038/30304a0
2
2
1
20.04 (=CH ), 132.10 (=CH), 170.95 (CO Et), 173.01
6. Cooper, N.J., Sutton, A.J., Abrams, K.R., Wailoo, A.,
Turner, D., and Nicholson, K.G., BMJ, 2003, vol. 326,
p. 1235. doi 10.1136/bmj.326.7401.1235
2
2
(NHC=O).
1
Minor isomer. Н NMR spectrum (CDCl , 500 MHz),
3
7
. Von Itzstein, M., Wu, W.Y., Kok, G.B., Pegg, M.S.,
Dyason, J.C., Jin, B., Van Phan, T., Smythe, M.L.,
White, H.F., Oliver, S.W., Colman, P.M., Varghese, J.H.,
Ryan, D.M., Woods, J.M., Bethell, R.C., Hotham, V.J.,
Cameron, J.M., and Penn, C.R., Nature, 1993, vol. 363,
p. 418. doi 10.1038/363418a0
δ, ppm: 1.20 s (3H, CH ), 1.29 t (3H, CH , J 7.0 Hz),
3
3
2
1
5
8
1
5
1
.19 s (3H, CH ), 2.26 m (2H, CH ), 3.08 d (1H, OH, J
3 2
8.3 Hz), 4.22 m (2H, OCH ), 4.56 d (1H, CH, J 8.9 Hz),
2
.13 m (2H, =CH ), 5.83 m (1H, =CH), 7.07 (1H, NH, J
2
13
.2 Hz). С NMR spectrum (CDCl , 125 MHz), δ, ppm:
3
4.03 (CH ), 23.20 (CH ), 23.71 (CH ), 43.85 (CH ),
8. Hayden, F.G., Belshe, R., Villanueva, C., Lanno, R.,
Hughes, C., Small, I., Dutkowski, R., Ward, P., Carr, J.,
J. Infect. Dis., 2004, vol. 189, p. 440. doi 10.186/381125
3
3
3
2
3
9.27 (CHN), 61.93 (OCH ), 73.81 (C ), 119.64 (=CH ),
2
2
32.29 (=CH), 170.90 (CO Et), 173.01 (NHC=O).
2
9
. Bantia, S., Arnold, C.S., Parker, C.D., Upshaw, R., and
ACKNOWLEDGMENTS
Chand, P., Antiviral Res., 2006, vol. 69, p. 39. doi
1
0.1016/j.antiviral.2005.10.002
Analyses were performed using the equipment of
1
0. Wang, G.T., Chen, Y., Wang, S., Gentles, R., Sowin, T.,
Kati, W., Muchmore, S., Giranda, V., Stewart, K.,
Sham, H., Kempf, D.I., and Laver, W.G., J.
Med. Chem., 2001, vol. 44, p. 1192. doi 10.1021/
jm000468c
the Khimiya Center for Collective Use, Ufa Institute of
Сhemistry, Ufa Federal Research Center, Russian
Academy of Sciences.
FUNDING
11. Zhao, C., Maring, C., Sun, M., Stewart, K., Stoll, V.,
Xu, Y., Gu, Y., Krueger, A., Herrin, T., Herrin, T.,
Sham, H., Laver, W.G., Madigan, D., Kennedy, A., Kati, W.,
Montgomery, D., Saldivar, A., Kempf, D., and
Kohlbrenner, W., 13 International Conference on
Antiviral Research, Baltimore, MD, April; Antiviral
Research., 2000, 46, A53, Abstract 58. doi 10.1016/
S0166-3542(00)90389-9
The work was funded through the State Contract
no. АААА-А17-117011910032-4.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
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