Hydrochloric Acid → 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

HRID 272276Notes

Reaction equation

HRID 272276 reaction equation
[NH2:1][C:2]1[CH:7]=[CH:6][N:5]([CH:8]2[O:12][CH:11]([CH2:13][OH:14])[CH:10]([O:15][C:16](=[O:29])[CH:17]([NH:21]C(OC(C)(C)C)=O)[CH:18]([CH3:20])[CH3:19])[C:9]2([OH:31])[CH3:30])[C:4](=[O:32])[N:3]=1.[ClH:33]>CCOC(C)=O>[ClH:33].[ClH:33].[NH2:1][C:2]1[CH:7]=[CH:6][N:5]([CH:8]2[O:12][CH:11]([CH2:13][OH:14])[CH:10]([O:15][C:16](=[O:29])[CH:17]([NH2:21])[CH:18]([CH3:20])[CH3:19])[C:9]2([OH:31])[CH3:30])[C:4](=[O:32])[N:3]=1

Participants

4

Reactant 2

HCID 313Hydrochloric AcidHCID 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

Product 1

HCID 727580282-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

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Procedure

In another method to synthesize the compounds of the invention, shown in FIG. 1b, benzoylcytosine, BSA and SnCl4/acetonitrile are reacted with 1,2,3,5-tetra-O-benzoyl-2-C-methyl-β-D-ribofuranose (1) to form 4-benzoylamino-1-(3,4-dibenzoyloxy-5-benzoyloxymethyl-3-methyl-tetrahydro-furan-2-yl)-1H-pyrimidin-2-one (2a); reacting (2a) 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 (3), also known as β-D-2′-C-methyl-cytidine; reacting (3) 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 (4); reacting (4) 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-2yl]-2-oxo-1,2-dihydro-pyrimidin-4-yl}-N,N-dimethyl-formamidine (5); reacting (5) 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 (6); refluxing (6) 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 (7); and finally reacting (7) 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 (8) as a final product.

Workup

  1. customat room temperature

Sources & evidence

ORD record
ord-b187b8a2ceaa4ab98f010ae515d87490
Source dataset
uspto-grants-2008_11
Patent number
US07456155B2

Reaction notes

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