A HIGH-YIELD AND COST-EFFECTIVE SYNTHESIS OF SPIROTETRAMAT
1777
cis-8-Methoxy-1,3-diazaspiro[4.5]decane-2,4-di-
one (5). Ammonium carbonate, 95 g (1 mol), and
sodium cyanide, 60 g (1.2 mol), were added to
1500 mL of water under stirring. Compound 4,
(128 g, 1 mol), was then added, and the mixture
was stirred for 15 h at 50°C. After completion of the
reaction (TLC), the mixture was cooled down to 25°C
and stirred for 2 h. The mixture was filtered, and the
filter cake was washed with cold methanol and dried to
get compound 5 (53 g, 44.6%) as white powder,
Methyl cis-1-[2-(2,5-dimethylphenyl)acetamido]-
4-methoxycyclohexane-1-carboxylate (8). A Satu-
rated aqueous solution of potassium carbonate (200 g,
1.5 mol) was added slowly to a solution of compound
7 (190 g, 1 mol) in ethyl acetate. (2,5-Dimethylphenyl)-
acetyl chloride (2) [19] (200 g, 1.1 mol) was added
slowly to the mixture at 0–5°C, and the mixture was
stirred for 2 h at 25°C. The reaction was assumed to
be complete when less than 2% of 7 remained in the
reaction mixture (HPLC). The mixture was added to
650 g of water and stirred for 1 h at 30°C, and the
organic phase was separated and concentrated under
reduced pressure. Petroleum ether (820 g) was
added to the residue, the mixture was refluxed for
0.5 h, and the precipitate was filtered off and dried to
obtain compound 8 (90%) as white powder, mp 235–
237°C [13]. 1H NMR spectrum (CDCl3), δ, ppm: 1.11–
1.19 m (2H, CH2), 1.71 s (1H, CH), 1.77–1.90 m (4H,
CH2), 2.03 d (2H, CH2, J = 16.0 Hz), 2.27 s (3H, CH3),
2.32 s (3H, CH3), 3.11–3.18 m (1H, CH), 3.31 s (3H,
OCH3), 3.53 s (2H, CH2), 3.70 s (3H, OCH3), 5.44 s
(1H, CH), 7.03 d (2H, Harom, J = 8.0 Hz), 7.11 d
(1H, NH, J = 8.0 Hz). 13C NMR spectrum (CDCl3),
δC, ppm: 18.93, 20.92, 26.68, 30.03, 41.88, 52.41,
55.80, 57.86, 128.66, 130.75, 131.10, 132.96, 133.99,
170.60, 173.98.
1
mp 180–182°C [12]. H NMR spectrum (CDCl3), δ,
ppm: 1.37–1.47 m (2H, CH2), 1.57-1.67 m (4H, CH2),
1.91–1.95 m (2H, CH2), 3.13–3.19 m (1H, CH), 3.23 s
(3H, OCH3), 8.44 s (1H, NH), 10.61 s (1H, NH).
13C NMR spectrum (DMSO-d6), δC, ppm: 26.35,
31.34, 54.86, 61.32, 76.52, 156.27, 178.36.
cis-1-Amino-4-methoxycyclohexane-1-carboxylic
acid (6). Calcium hydroxide (220 g, 3.0 mol) was
added to 800 mL of water under stirring at 40°C.
Compound 5 (100 g, 0.5 mol) was then added, and the
mixture was stirred for 45 h at 95°C. The reaction was
assumed to be complete when the concentration of 5
was less than 3% (HPLC). The mixture was cooled
to 60°C, and the pH value was adjusted to pH 3 with
50% sulfuric acid. After adding 150 g of water and
25 g of active carbon, the mixture was stirred for 1 h at
80°C and filtered while hot. The filtrate was con-
centrated, and water was removed by refluxing with
toluene (400 g). The residue was cooled to 30°C and
filtered to obtain insoluble compound 6 (92%) as gray
cis-3-(2,5-Dimethylphenyl)-4-hydroxy-8-me-
thoxy-1-azaspiro[4.5]dec-3-en-2-one (9). A solution
of compound 8 (250 g, 0.75 mol) in DMF (450 mL)
was added dropwise to a solution of sodium methoxide
(60 g, 1.1 mol) in DMF (150 mL) under nitrogen atmo-
sphere at 20–30°C, and the mixture was stirred for 2 h.
The reaction was assumed to be complete when less
than 2% of 8 remained in the mixture (HPLC). The
mixture was concentrated to a viscous liquid under
reduced pressure and cooled to 40°C. Water (100 mL)
was added slowly in portions, and the mixture was
stirred for 15 min. A 6% aqueous solution of sodium
hydroxide (500 mL) was added slowly, the mixture
was stirred for 20 min, the aqueous phase was acidified
to pH 3 with hydrochloric acid, the mixture was stirred
for 30 min, and the precipitate was filtered off. Yield
273 g (91.1%), white powder, mp 251–255°C [14].
1H NMR spectrum (DMSO-d6), δ, ppm: 1.17 s (1H,
CH), 1.39–1.55 m (4H, CH2), 1.87–1.98 m (4H, CH2),
2.08 s (3H, CH3), 2.25 s (3H, CH3), 3.08–3.15 m (1H,
CH), 3.36 s (1H, CH), 6.88 s (1H, CH), 6.98 d (1H,
CH, J = 8.0 Hz), 7.07 d (1H, CH, J = 8.0 Hz), 8.15 s
(1H, NH), 10.66 s (1H, OH). 13C NMR spectrum
(DMSO-d6), δC, ppm: 19.15, 20.49, 27.51, 32.11,
54.89, 59.08, 77.58, 104.61, 127.53, 129.32, 130.68,
131.52, 133.60, 134.21, 171.64, 172.62.
1
powder, mp 166–170°C [12]. H NMR spectrum
(DMSO-d6), δ, ppm: 1.12 t (1H, CH, J = 8.0 Hz), 1.34–
1.43 m (2H, CH2), 1.60–1.65 m (2H, CH2), 1.80–
1.90 m (4H, CH2), 3.15 s (1H, CH), 3.21 s (3H, OCH3),
7.49 s (2H, NH2).
Methyl cis-1-amino-4-methoxycyclohexane-1-
carboxylate (7). Compound 6 (86 g, 0.5 mol) was
dissolved in 320 mL of methanol under stirring, the
solution was heated to 60°C, and thionyl chloride
(70 g, 0.6 mol) was slowly added over a period of 2–
3 h. The mixture was refluxed for 10 h until it con-
tained less than 1% of 6 (HPLC), methanol was
removed under reduced pressure, and cyclohexane
(400 mL) was added to the residue. Methanol was
taken away by a water divider, the mixture was cooled
down to 30°C, and compound 7 (92%) was filtered off.
1
Gray powder, mp 171–173°C [12]. H NMR spectrum
(CDCl3), δ, ppm: 1.90–1.95 m (4H, CH2), 2.02–2.09 m
(2H, CH2), 2.26–2.32 m (2H, CH2), 3.31 m (4H, CH2),
3.81 s (3H, OCH3), 8.92 s (2H, NH2). 13C NMR spec-
trum (CDCl3), δC, ppm: 29.23, 29.59, 53.33, 55.61,
59.62, 75.63, 171.00.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 10 2020