Reacción #1591124

Ecuación de reacción

hydrochloride

2-[[(3S)-12-[[4-(methylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]methoxy]acetamide hydrochloride

HCHO

NaBH3CN

→

2-[[(3S)-12-[[4-(dimethylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]methoxy]acetamide

Rendimiento 36.9%

Disolventes

methanol

water

Condiciones de reacción

Tratamiento posterior

1. 1
   workup.STIRRINGthe resulting solution was stirred for 2 h at room temperature
2. 2
   Extracciónextracted with 3×20 mL of chloroform/i-PrOH
3. 3
   ConcentraciónThe combined organic layers were concentrated under vacuum
4. 4
   OtroThe crude product (80 mg) was purified by preparative HPLC under the following conditions (SHIMADZU)
5. 5
   workup.WAITmobile phase: water with 0.05% NH4HCO3 and CH3CN (6.0% CH3CN up to 53.0% in 13 min)
6. 6
   OtroThe product-containing fractions were collected
7. 7
   Otropartially evaporated
8. 8
   Otroto remove water and CH3CN under reduced pressure
9. 9
   workup.WAITThe residue was lyophilized overnight

Procedimiento

A solution of tert-butyl N-(4-[[(3S)-3-[(carbamoylmethoxy)methyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (115 mg, 0.23 mmol, 1.00 equiv) in dichloromethane (4 mL) cooled down to 0° C. was added hydrochloric acid (12 M, 0.5 mL). The resulting solution was stirred for 1 h at 0° C. and concentrated in vacuo to give 2-[[(3S)-12-[[4-(methylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]methoxy]acetamide hydrochloride (100 mg, crude) as a light yellow solid. The crude hydrochloride (100 mg) dissolved in methanol (3 mL) was added HCHO (37%, 0.5 mL) and stirred for 1 h at 0° C. Then NaBH3CN (44.35 mg, 0.71 mmol) was added and the resulting solution was stirred for 2 h at room temperature. The reaction mixture was diluted with water, extracted with 3×20 mL of chloroform/i-PrOH. The combined organic layers were concentrated under vacuum. The crude product (80 mg) was purified by preparative HPLC under the following conditions (SHIMADZU): column: SunFire Prep C18, 19*150 mm 5 um; mobile phase: water with 0.05% NH4HCO3 and CH3CN (6.0% CH3CN up to 53.0% in 13 min); flow rate: 20 mL/min; UV detection at 254/220 nm. The product-containing fractions were collected and partially evaporated to remove water and CH3CN under reduced pressure. The residue was lyophilized overnight to give the desired 2-[[(3S)-12-[[4-(dimethylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]methoxy]acetamide (35 mg) as a white solid. MS (ES): m/z 405 [M+H]+. 1H NMR (300 MHz, CD3OD): δ 8.44 (1H, s), 5.28-5.21 (1H, m), 3.94-3.88 (3H, m), 3.61-3.56 (2H, m), 3.14-2.97 (2H, m), 2.67-2.54 (2H, m), 2.42-2.31 (10H, m), 2.02 (2H, d), 1.62-1.43 (4H, m).

Fuente