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 1818449Notes

Reaction equation

HRID 1818449 reaction equation
NC1C=CN(C2C(O)(C)C(O)C(CO)O2)C(=O)N=1.[C:19]([SiH2:23][O:24][C:25]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[CH:26]1[O:30][CH:29]([N:31]2[CH:36]=[CH:35][C:34]([N:37]=[CH:38][N:39]([CH3:41])[CH3:40])=[N:33][C:32]2=[O:42])[C:28]([OH:44])([CH3:43])[CH:27]1[OH:45])([CH3:22])([CH3:21])[CH3:20].[C:58]([NH:65][C@H:66]([C:70](O)=[O:71])[CH:67]([CH3:69])[CH3:68])([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:19]([SiH2:23][O:24][C:25]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)([C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)[CH:26]1[CH:27]([O:45][C:70](=[O:71])[CH:66]([NH:65][C:58]([O:60][C:61]([CH3:62])([CH3:64])[CH3:63])=[O:59])[CH:67]([CH3:69])[CH3:68])[C:28]([OH:44])([CH3:43])[CH:29]([N:31]2[CH:36]=[CH:35][C:34]([N:37]=[CH:38][N:39]([CH3:40])[CH3:41])=[N:33][C:32]2=[O:42])[O:30]1)([CH3:20])([CH3:21])[CH3:22]

Participants

7

Reactant 4

HCID 111,2-DichloroethaneHCID 83693Boc-L-ValineHCID 138710334-amino-1-(3,4-dihydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)pyrimidin-2(1H)-oneHCID 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 6344DichloromethaneSolvent2×

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. customprovides the advantage
  2. customat room temperature

Sources & evidence

ORD record
ord-aa164de2cc174256a060c89580872851
Source dataset
uspto-grants-2009_10
Patent number
US07598373B2

Reaction notes

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