Synthesis and Evaluation of Novel Trehalase Inhibitors
J. Agric. Food Chem., Vol. 49, No. 11, 2001 5281
Sch em e 2. Gen er a l Syn th etic Rou te for F lu or in e-Con ta in in g 4,4-Dih yd r oxylm eth yl-2-a n ilin ooxa zolin es a n d
Th ia zolin es (1-10)
Data for C4. 61.50 g, yield 82%; obtained as colorless liquid;
bp 110-112 °C /8 Torr. Rf ) 0.80 (petroleum ether). IR (KBr,
cm-1) υmax 2000, 1580, 1480. m/z 187 (M+), 189 (M+2+).
Data for C5. 65.02 g, yield 86%; obtained as colorless liquid;
bp 80-82 °C /8 Torr. Rf ) 0.85 (petroleum ether). IR (KBr,
cm-1) υmax 2018, 1500, 1490. m/z 189 (M+).
Gen er a l Syn th etic P r oced u r e for F lu or in e-Su bsti-
tu ted N-P h en yl-N′-tr i(h yd r oxylm eth yl) m eth ylth iou r ea s
(D1-D5). A mixture of the corresponding arylisothiocyanate
(C1-C5) (0.02 mol), tri (hydroxylmethyl)methylamine (2.662
g, 0.022 mol), and ethyl acetate (30 mL) was refluxed for 12
h. After the mixture cooled, it was concentrated under reduced
pressure to give the crude products, which were dissolved in
water (20 mL), stirred for 30 min, extracted with ethyl acetate
(3 × 20 mL), and dried over anhydrous magnesium sulfate.
The resulting colorless liquid was concentrated under reduced
pressure to give the desired intermediates (D1-D5) for the
following reaction.
cm-1) υmax 3280, 3100, 2880, 1640, 1500, 1240, 1050, 850, 820,
1
720. H NMR (CD3COCD3) δ 7.36 (m, 1H, ArH), 6.99 (t, J )
9.7 Hz, 1H, ArH), 6.88 (t, J ) 8.5 Hz, 1H, ArH), 3.73 and 3.67
(ABq, J ) 11.0 Hz, 4H, CH2OH), 3.28 (s, 2H, SCH2). Anal.
Calcd. (%) for C11H12F2N2O2S: C, 48.18; H, 4.38; N, 10.22.
Found: C, 48.35; H, 4.33; N, 10.07.
Compound 8. 1.28 g, yield 46%; obtained as white powdery
crystals; mp 195-196 °C. Rf ) 0.35 (ethyl acetate). IR (KBr,
cm-1) υmax 3280, 3100, 2880, 1640, 1495, 1195, 1050, 870, 820,
1
770. H NMR (CD3COCD3) δ 7.26-7.40 (m, 2H, ArH), 7.17 (t,
J ) 9.0 Hz, 1H, ArH), 3.71 and 3.67 (ABq, J ) 10.9 Hz, 4H,
CH2OH), 3.32 (s, 2H, SCH2). Anal. Calcd. (%) for C11H12
-
ClFN2O2S: C, 45.44; H, 4.13; N, 9.64. Found: C, 45.21; H, 4.28;
N, 9.49.
Compound 10. 1.17 g, yield 42%; obtained as white powdery
crystals; mp 202-204 °C. Rf ) 0.35 (ethyl acetate). IR (KBr,
cm-1) υmax 3280, 3100, 2950, 2880, 1630, 1505, 1220, 1045, 815.
1H NMR (D2O) δ 7.36 (m, 1H, ArH), 7.05 (m, 1H, ArH), 3.75
and 3.67 (ABq, J ) 10.9 Hz, 4H, CH2OH), 3.30 (s, 2H, SCH2).
Anal. Calcd. (%) for C11H11F3N2O2S: C, 45.21; H, 3.77; N, 9.59.
Found: C, 45.19; H, 3.66; N, 9.67.
Gen er a l Syn th etic P r oced u r e for F lu or in e-Con ta in in g
4,4-Dih yd r oxylm eth yl-2-a n ilin o oxa zolin es (1, 3, 5, 7, 9).
The fluorine-substituted N-phenyl-N-tri(hydroxylmethyl)-
methylthiourea (D1-D5) (0.01 mol) was dissolved in CH3-
COCH3/Et2O (1:6, v/v) (30 mL). To the reaction mixture was
added in batch yellow HgO (15 g, 0.07 mol). After 24 h, the
resulting mixture was filtered through silicon gel, and the
filtrate was concentrated under reduced pressure to give the
crude products, which were purified on TLC plates to give the
desired products (1, 3, 5, 7, and 9).
Data for D1. 3.67 g, yield 67%; obtained as light yellow oily
product. Rf ) 0.40 (ethyl acetate).
Data for D2. 3.12 g, yield 57%; obtained as yellow sticky
solid. Rf ) 0.45 (ethyl acetate).
Data for D3. 3.39 g, yield 58%; obtained as light yellow oily
product. Rf ) 0.40 (ethyl acetate).
Data for D4. 2.21 g, yield 59%; obtained as yellow sticky
solid. Rf ) 0.40 (ethyl acetate). IR (KBr, cm-1) υmax 3250, 3050,
2880, 1600, 1530, 1500, 1450, 1050, 870, 820, 770. 1H NMR
(CD3COCD3) δ 7.93 (m, 1H, ArH), 7.46 (m, 1H, ArH), 7.27 (t,
J ) 9.0 Hz, 1H, ArH), 3.85 (s, 6H, CH2OH).
Data for D5. 1.78 g, yield 47%; obtained as light yellow oily
product. Rf ) 0.40 (ethyl acetate).
Gen er a l Syn th etic P r oced u r e for F lu or in e-Con ta in in g
4,4-Dih yd r oxylm eth yl-2-a n ilin o th ia zolin es (2, 4, 6, 8, 10).
The fluorine-substituted N-phenyl-N-tri(hydroxylmethyl)-
methylthiourea (D1-D5) (0.01 mol) was dissolved in concen-
trated HCl (10 mL). The reaction mixture obtained was stirred
for 45 min at 90 °C. After cooling to room temperature, the
mixture was neutralized by using NaOH (10 N) in an ice bath.
The resulting precipitate was filtered and recrystallized from
absolute ethanol to give the desired products (2, 4, 6, 8, and
10).
Compound 1. 1.19 g, yield 49%; obtained as white powdery
solid; mp 156-157 °C. Rf ) 0.40 (ethyl acetate). IR (KBr, cm-1
)
1
υmax 3150, 2920, 2880, 1670, 1605, 1495, 1250, 1050, 745. H
NMR (CD3COCD3) δ 7.60 (m, 1H, ArH), 7.02-7.08 (m, 2H,
ArH), 6.93-6.97 (m, 1H, ArH), 4.29 (s, 2H, OCH2), 3.64 (s, 4H,
CH2OH). Anal. Calcd. (%) for C11H13FN2O3: C, 55.00; H, 5.42;
N, 11.67. Found: C, 55.06; H, 5.33; N, 11.63.
Compound 3. 1.31 g, yield 54%; obtained as white powdery
solid; mp 135-136 °C. Rf ) 0.40 (ethyl acetate). IR (KBr, cm-1
)
υ
max 3220, 3100, 2930, 2880, 1650, 1600, 1510, 1220, 1050, 840.
Compound 2. 1.39 g, yield 57%; obtained as white powdery
crystals; mp 171-172 °C. Rf ) 0.35 (ethyl acetate). IR (KBr,
cm-1) υmax 3150, 2920, 2880, 1630, 1605, 1495, 1230. 1H NMR
(CD3COCD3) δ 7.36 (m, 1H, ArH), 7.05-7.09 (m, 2H, ArH),
7.00 (m, 1H, ArH), 3.73 and 3.65 (ABq, J ) 10.9 Hz, 4H, CH2-
OH), 3.28 (s, 2H, SCH2). Anal. Calcd. (%) for C11H13FN2O2S:
C, 51.56; H, 5.08; N, 10.94. Found: C, 51.42; H, 4.95; N, 10.93.
Compound 4. 1.36 g, yield 56%; obtained as white powdery
crystals; mp 202-203 °C. Rf ) 0.40 (ethyl acetate). IR (KBr,
1H NMR (CD3COCD3) δ 7.57 (dd, J ) 8.3 and 4.7 Hz, 2H, ArH),
7.00 (m, 2H, ArH), 4.23 (s, 2H, OCH2), 3.64 and 3.62 (ABq, J
) 11.0 Hz, 4H, CH2OH). Anal. Calcd. (%) for C11H13FN2O3:
C, 55.00; H, 5.42; N, 11.67. Found: C, 55.16; H, 5.37; N, 11.58.
Compound 5. 1.36 g, yield 52%; obtained as white powdery
solid; mp 147-148 °C. Rf ) 0.35 (ethyl acetate). IR (KBr, cm-1
)
υ
max 3300, 3070, 2890, 1710, 1600, 1510, 1255, 1050, 840, 820,
1
800. H NMR (CD3COCD3) δ 7.44 (m, 1H, ArH), 6.92 (t, J )
9.9 Hz, 1H, ArH), 6.88 (t, J ) 8.6 Hz, 1H, ArH), 4.30 (s, 2H,
OCH2), 3.66 and 3.60 (ABq, J ) 11.1 Hz, 4H, CH2OH). Anal.
Calcd. (%) for C11H12F2N2O3: C, 51.16; H, 4.65; N, 10.85.
Found: C, 51.23; H, 4.44; N, 10.79.
1
cm-1) υmax 3300, 3100, 2880, 1620, 1500, 1200, 1050, 840. H
NMR (CDCl3) δ 7.36 (m, 2H, ArH), 7.00 (t, J ) 8.9 Hz, 2H,
ArH), 3.69 and 3.66 (ABq, J ) 11.0 Hz, 4H, CH2OH), 3.29 (s,
2H, SCH2). Anal. Calcd. (%) for C11H13FN2O2S: C, 51.56; H,
5.08; N, 10.94. Found: C, 51.34; H, 4.97; N, 11.09.
Compound 7. 1.08 g, yield 39%; obtained as white powdery
solid; mp 150-151 °C. Rf ) 0.35 (ethyl acetate). IR (KBr, cm-1
)
Compound 6. 1.12 g, yield 43%; obtained as white powdery
crystals; mp 207-208 °C. Rf ) 0.35 (ethyl acetate). IR (KBr,
υmax 3250, 3100, 2930, 2840, 1650, 1610, 1505, 1260, 1020, 860,
1
820, 790. H NMR (CD3COCD3) δ 7.80 (m, 1H, ArH), 7.37 (m,