1,2-Dichloroethane → 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

HRID 1818440Notes

Reaction equation

HRID 1818440 reaction equation
[C:1]([SiH2:5][O:6][C:7]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH:8]1[O:12][CH:11]([N:13]2[CH:18]=[CH:17][C:16]([N:19]=[CH:20][N:21]([CH3:23])[CH3:22])=[N:15][C:14]2=[O:24])[C:10]([OH:26])([CH3:25])[CH:9]1[OH:27])([CH3:4])([CH3:3])[CH3:2].[C:40]([NH:47][C@H:48]([C:52](O)=[O:53])[CH:49]([CH3:51])[CH3:50])([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([SiH2:5][O:6][C:7]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH:8]1[CH:9]([O:27][C:52](=[O:53])[CH:48]([NH:47][C:40]([O:42][C:43]([CH3:44])([CH3:46])[CH3:45])=[O:41])[CH:49]([CH3:51])[CH3:50])[C:10]([OH:26])([CH3:25])[CH:11]([N:13]2[CH:18]=[CH:17][C:16]([N:19]=[CH:20][N:21]([CH3:22])[CH3:23])=[N:15][C:14]2=[O:24])[O:12]1)([CH3:2])([CH3:3])[CH3:4]

Participants

6

Reactant 3

HCID 111,2-DichloroethaneHCID 83693Boc-L-ValineHCID 131727192N'-{1-[5-(tert-butyl-diphenyl-silanyloxy-methyl)-3,4-dihydroxy-3-methyl-tetrahydro-furan-2-yl]-2-oxo-1,2-dihydro-pyrimidin-4-yl}-N,N-dimethyl-formamidine2×

Product 1

HCID 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

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6344DichloromethaneSolvent

Procedure

As one nonlimiting example of the invention, if the 3′-valinyl ester is preferred, the esterification process may include the steps depicted in FIG. 4, namely: reacting β-D-2′-C-methyl-cytidine 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-dimethyl-formamidine, which is the amino-protected form of (VI); reacting (7) with TBDPSCl and imidazole in DCM to provide the 5′-silyl-protected form of (7) 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); reacting (8) with N—Boc-L-valine, EDC, and DMAP in DCM to form 2-tert-butoxycarbonylamino-3-methyl-butyric acid 2-(tert-butyl-diphenyl-silanyloxymethyl)-5-[4-(dimethylamino-methyleneamino)-2-oxo-2H-pyrimidin-1-yl]-4-hydroxy-4-methyl-tetrahydro-furan-3-yl ester (9); removing the silyl and amino-protecting groups by reacting (9) with NH4F in MeOH with the addition 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), which is purified by simple crystallization; 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-tetrahydrofuran-3-yl ester, dihydrochloride salt (11) as a final product.

Sources & evidence

ORD record
ord-6c100f0835e0476cb8361c49acdebd43
Source dataset
uspto-grants-2009_10
Patent number
US07598373B2

Reaction notes

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