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 1818450Notes

Reaction equation

HRID 1818450 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]>CCO>[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 702EthanolSolvent

Procedure

In another preferred embodiment of the present invention, compound (6) is reacted with Me2NCH(OMe)2 in DMF to form (7), N-[1-(3,4-dihydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan-2-yl)-2-oxo-1,2-dihydro-pyrimidin-4-yl]-N,N-dimethylformamidine, which is the amino-protected form of (i); reacting (2) with TBDPSCl and imidazole in DCM to provide the 5′-silyl-protected form of (6) as 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), where the use of DCM provides the advantage of having greater control over disilyl by-product formation; reacting (8) with N—Boc-L-valine, EDC and DMAP in DCM at room temperature to form 2-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 (2); removing the silyl and amino-protecting groups by reacting (9) with NH4F in MeOH in the presence of approximately 10 mole equivalents of ethyl acetate to prevent cleavage of the 3′-O-valinyl ester by liberated ammonia, and refluxing the mixture 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 EtOH 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. customremoving the silyl and amino-
  2. temperaturerefluxing the mixture
  3. customto 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)

Sources & evidence

ORD record
ord-fb1bebb8d82e48dea0e6068a8645c2ba
Source dataset
uspto-grants-2009_10
Patent number
US07598373B2

Reaction notes

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