Ammonium fluoride → 2-tert-butoxycarbonylamino-3-methyl-butyric acid 5-(4-amino-2-oxo-2H-pyrimidin-1-yl)-4-hydroxy-2-hydroxymethyl-4-methyl-tetrahydro-furan-3-yl ester

HRID 1818442Notes

Reaction equation

HRID 1818442 reaction equation
C([SiH2][O:6][C:7](C1C=CC=CC=1)(C1C=CC=CC=1)[CH:8]1[CH:12]([O:13][C:14](=[O:27])[CH:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:16]([CH3:18])[CH3:17])[C:11]([OH:29])([CH3:28])[CH:10]([N:30]2[CH:35]=[CH:34][C:33]([N:36]=CN(C)C)=[N:32][C:31]2=[O:41])[O:9]1)(C)(C)C.[NH4+].[F-]>CO>[NH2:36][C:33]1[CH:34]=[CH:35][N:30]([CH:10]2[O:9][CH:8]([CH2:7][OH:6])[CH:12]([O:13][C:14](=[O:27])[CH:15]([NH:19][C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH:16]([CH3:18])[CH3:17])[C:11]2([OH:29])[CH3:28])[C:31](=[O:41])[N:32]=1

Participants

4

Reactant 2

HCID 25516Ammonium fluorideHCID 1317271912-tert-butoxycarbonylamino-3-methyl-butyric acid 2-(tert-butyl-diphenyl-silanyloxy-methyl)-5-[4-(dimethylamino-methyleneamino)-2-oxo-2H-pyrimidin-1-yl]-4-hydroxy-4-methyl-tetrahydro-furan-3-yl ester

Product 1

HCID 98468572-tert-butoxycarbonylamino-3-methyl-butyric acid 5-(4-amino-2-oxo-2H-pyrimidin-1-yl)-4-hydroxy-2-hydroxymethyl-4-methyl-tetrahydro-furan-3-yl ester

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

The prior art process shown in FIG. 5 comprised reacting benzoylcytosine, BSA and SnCl4/acetonitrile with 1,2,3,5-tetra-O-benzoyl-2-C-methyl-β-D-ribofuranose (4) to form 4-benzoylamino-1-(3,4-dibenzoyloxy-5-benzoyloxymethyl-3-methyl-tetrahydrofuran-2-yl)-1H-pyrimidin-2-one (5a); reacting (5a) with NH3 in methanol and chromatographically separating the product, 4-amino-1-(3,4-dihydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan-2-yl)-1H-pyrimidin-2-one (6), also known as β-D-2′-C-methyl-cytidine; reacting (6) with Me2NCH(OMe)2 in DMF at room temperature for 1.5 hours to form N-[1-(3,4-dihydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan-2-yl)-2-oxo-1,2-dihydro-pyrimidin-4-yl]-N,N-dimethyl-formamidine (7); reacting (7) with TBDPSCl and pyridine at room temperature for 6 hours to provide N′-{1-[5-(tert-butyl-diphenyl-silanyloxymethyl)-3,4-dihydroxy-3-methyl-tetrahydro-furan-2-yl]-2-oxo-1,2-dihydro-pyrimidin-4-yl}-N,N-dimethyl-formamidine (8); reacting (8) with N-Boc-L-valine, DEC and DMAP in THF/DMF at room temperature for 2 days and subjecting the product formed from this reaction to HPLC in order to provide 2-tert-butoxycarbonylamino-3-methyl-butyric acid 2-(tert-butyl-diphenyl-silanyloxy-methyl)-5-[4-(dimethylaminomethyleneamino)-2-oxo-2H-pyrimidin-1-yl]-4-hydroxy-4-methyl-tetrahydro-furan-3-yl ester (9a); refluxing (9a) with NH4F in MeOH for about 3 hours to remove the silyl and amino-protecting groups, and subjecting the product to chromatographic purification to provide 2-tert-butoxycarbonylamino-3-methyl-butyric acid-5-(4-amino-2-oxo-2H-pyrimidin-1-yl)-4-hydroxy-2-hydroxymethyl-4-methyl-tetrahydro-furan-3-yl ester (10); and finally reacting (10) with HCl in EtOAc at room temperature to provide 2-amino-3-methyl-butyric acid 5-(4-amino-2-oxo-2H-pyrimidin-1-yl)-4-hydroxy-2-hydroxymethyl-4-methyl-tetrahydro-furan-3-yl ester, dihydrochloride salt (11) as a final product.

Workup

  1. customto remove the silyl and amino-
  2. customto chromatographic purification

Sources & evidence

ORD record
ord-44eb773d928a45cab6c0e73232e81022
Source dataset
uspto-grants-2009_10
Patent number
US07598373B2

Reaction notes

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