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

HRID 77253

Reaction equation

HRID 77253 reaction equation
[C:1]([NH:11][C@H:12]([C:16]([OH:18])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].ClC(N(C)C)=C(C)C.[CH2:27]([O:34][C:35]([C@:37]1([O:48][C@@H:47]([C@@H:49]([C@@H:51]([CH2:53]O)[OH:52])[OH:50])[C@H:42]([NH:43][C:44](=[O:46])[CH3:45])[C@@H:40]([OH:41])[CH2:39]1)[OH:38])=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl.N1C=CC=CC=1>[CH2:27]([O:34][C:35]([C:37]1([OH:38])[CH2:39][CH:40]([OH:41])[CH:42]([NH:43][C:44](=[O:46])[CH3:45])[CH:47]([CH:49]([OH:50])[CH:51]([OH:52])[CH2:53][O:17][C:16](=[O:18])[CH:12]([NH:11][C:1]([O:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:2])[CH:13]([CH3:14])[CH3:15])[O:48]1)=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1

Participants

6

Reactant 3

HCID 6407921-Chloro-N,N-2-trimethylpropenylamineHCID 726987N-Carbobenzoxy-L-valineHCID 10894618N-Acetyl-beta-neuraminic Acid Benzyl ester

Product 1

HCID 895320285-Acetylamino-6-[3-(2-benzyloxycarbonylamino-3-methyl-butyryloxy)-1,2-dihydroxy-propyl]-2,4-dihydroxy-tetrahydro-pyran-2-carboxylic acid benzyl esterYield 32%

Reagents, catalysts & solvents 2

HCID 1049PyridineSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

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.

Workup

  1. additionby dropwise addition via a syringe
  2. customresulting in a clear colorless solution
  3. waitThe solution immediately turns yellow and is kept at 0° C. and under an argon atmosphere for 3 hours
  4. customThe cooling bath is then removed
  5. waitthe solution kept at rt for overnight
  6. customresulting in a cloudy suspension
  7. customThe solvents are removed under high vacuum
  8. customdoes not exceed 50° C.
  9. customto give a light yellow oil
  10. customIn order to remove traces of pyridine
  11. customthe oil is triturated with toluene
  12. customagain evaporated under high vacuum
  13. dissolutionThe remaining oil is dissolved in minimum amount of dichloromethane (DCM)
  14. custompurified by flash chromatography (Mobile Phase: DCM/Methanol=96/4 to 88/12 over 24 minutes)

Sources & evidence

ORD record
ord-228b1a52fc4e4e9a8708fdc0785eecd7
Source dataset
uspto-grants-2014_09
Patent number
US08840926B2

Linked notes

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