Reacción #164435

Ecuación de reacción

N-Acetyl-β-neuraminic Acid Benzyl ester

Carbobenzyloxy-L-Valine

1-Chloro-N,N,-2-trimethyl-1-propenylamine

→

( 1-5 )

Rendimiento 32.0%

5-Acetylamino-6-[3-(2-benzyloxycarbonylamino-3-methyl-butyryloxy)-1,2-dihydroxy-propyl]-2,4-dihydroxy-tetrahydro-pyran-2-carboxylic acid benzyl ester

Rendimiento 32.0%

Disolventes

pyridine

dichloromethane

Condiciones de reacción

Tratamiento posterior

1. 1
   workup.ADDITIONby dropwise addition via a syringe
2. 2
   Otroresulting in a clear colorless solution
3. 3
   workup.WAITThe solution immediately turns yellow and is kept at 0° C. and under an argon atmosphere for 3 hours
4. 4
   OtroThe cooling bath is then removed
5. 5
   workup.WAITthe solution kept at rt for overnight
6. 6
   Otroresulting in a cloudy suspension
7. 7
   OtroThe solvents are removed under high vacuum
8. 8
   Otrodoes not exceed 50° C.
9. 9
   Otroto give a light yellow oil
10. 10
    OtroIn order to remove traces of pyridine
11. 11
    Otrothe oil is triturated with toluene
12. 12
    Otroagain evaporated under high vacuum
13. 13
    workup.DISSOLUTIONThe remaining oil is dissolved in minimum amount of dichloromethane (DCM)
14. 14
    Otropurified by flash chromatography (Mobile Phase: DCM/Methanol=96/4 to 88/12 over 24 minutes)

Procedimiento

To a solution of Carbobenzyloxy-L-Valine (1.35 g, 5.37 mmol) in anhydrous dichloromethane (12 mL) at 0° C. under argon is added 1-Chloro-N,N,-2-trimethyl-1-propenylamine (848 μL, 6.34 mmol) by dropwise addition via a syringe. The resulting solution is then stirred at 0° C. for 10 minutes resulting in a clear colorless solution. To this solution is then added the N-Acetyl-β-neuraminic Acid Benzyl ester (1-2), previously dissolved in anhydrous pyridine (8.0 mL) via dropwise addition. The solution immediately turns yellow and is kept at 0° C. and under an argon atmosphere for 3 hours. The cooling bath is then removed and the solution kept at rt for overnight resulting in a cloudy suspension. The solvents are removed under high vacuum being careful that the temperature bath does not exceed 50° C. to give a light yellow oil. In order to remove traces of pyridine, the oil is triturated with toluene and again evaporated under high vacuum. The remaining oil is dissolved in minimum amount of dichloromethane (DCM) and loaded directly unto a silica gel column (Silicycle-FLH-R10030B-ISO80, 80 g Cartridge) and purified by flash chromatography (Mobile Phase: DCM/Methanol=96/4 to 88/12 over 24 minutes). Combination of the purest fractions yields 996 mg (32% yield) of pure (1-5) as a white solid. LC/MS: (+) ESI: m/z=633.2 [M+1]; 655.2 [M+Na, major signal); retention time=3.69 min. 1H NMR (400 MHz, d4-MeOD) δ 7.12-7.37 (m, 11H), 5.08-5.17 (m, 2H), 4.95-5.03 (m, 2H), 4.28 (dd, J=11.6, 2.0 Hz, 1H, C-9), 4.18 (dd, J=11.6, 6.0 Hz, 1H, C-9′), 4.05-4.06 (m, 1H), 3.91-3.98 (m, 1H), 3.89 (dd, J=10.5, 1.2 Hz, 1H), 3.80-3.86 (m, 11H), 3.70 (t, 1H), 3.41-3.43 (m, 1H), 2.14 (dd, J=12.8, 4.8 Hz, 1H), 1.98-2.08 (m, 1H), 1.91 (s, 3H), 1.79-1.89 (m, 1H), 0.80-0.84 (m, 6H); 13C NMR (400 mHz, d4-MeOD) δ 173.7, 170.9, 158.9, 136.2, 137.1, 129.6, 129.5, 129.4, 129.1, 129.0, 128.8, 96.7, 72.0, 70.3, 69.3, 68.3, 68.0, 67.8, 61.1, 54.4, 40.7, 32.1, 22.7, 19.6, 18.4.

Fuente