Carbonic acid, rubidium salt (1:2) → Acetic acid 2-{3-[(R)-(4-{amino[2-methylallyloxycarbonylimino]methyl}phenylamino)-(5-isopropoxycarbonyloxymethoxy-1-pyrimidin-2-yl-1H-[1,2,4]triazol-3-yl)methyl]-2-fluoro-5-methoxyphenoxy}ethyl ester

HRID 2089707

Reaction equation

HRID 2089707 reaction equation
[NH2:1][C:2](=[N:39][C:40]([O:42][CH2:43][C:44]([CH3:46])=[CH2:45])=[O:41])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@@H:10]([C:27]2[NH:31][C:30](=[O:32])[N:29]([C:33]3[N:38]=[CH:37][CH:36]=[CH:35][N:34]=3)[N:28]=2)[C:11]2[C:12]([F:26])=[C:13]([CH:21]=[C:22]([O:24][CH3:25])[CH:23]=2)[O:14][CH2:15][CH2:16][O:17][C:18](=[O:20])[CH3:19])=[CH:5][CH:4]=1.[CH:47]([O:50][C:51](=[O:55])[O:52][CH2:53]Cl)([CH3:49])[CH3:48].C(=O)([O-])[O-].[Rb+].[Rb+].CC(N(C)C)=O>O.C(OCC)(=O)C>[NH2:1][C:2](=[N:39][C:40]([O:42][CH2:43][C:44]([CH3:46])=[CH2:45])=[O:41])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C@@H:10]([C:27]2[N:31]=[C:30]([O:32][CH2:53][O:52][C:51]([O:50][CH:47]([CH3:49])[CH3:48])=[O:55])[N:29]([C:33]3[N:38]=[CH:37][CH:36]=[CH:35][N:34]=3)[N:28]=2)[C:11]2[C:12]([F:26])=[C:13]([CH:21]=[C:22]([O:24][CH3:25])[CH:23]=2)[O:14][CH2:15][CH2:16][O:17][C:18](=[O:20])[CH3:19])=[CH:7][CH:8]=1

Participants

7

Reactant 4

HCID 11431Carbonic acid, rubidium salt (1:2)HCID 31374DimethylacetamideHCID 14787051Chloromethyl isopropyl carbonateHCID 136334037Acetic acid 2-{3-[(R)-{4-[amino(2-methylallyloxycarbonylimino)methyl]phenylamino}-(5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]-triazol-3-yl)methyl]-2-fluoro-5-methoxyphenoxy}ethyl ester

Product 1

HCID 86677417Acetic acid 2-{3-[(R)-(4-{amino[2-methylallyloxycarbonylimino]methyl}phenylamino)-(5-isopropoxycarbonyloxymethoxy-1-pyrimidin-2-yl-1H-[1,2,4]triazol-3-yl)methyl]-2-fluoro-5-methoxyphenoxy}ethyl ester

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Procedure

Under nitrogen atmosphere, a mixture of acetic acid 2-{3-[(R)-{4-[amino(2-methylallyloxycarbonylimino)methyl]phenylamino}-(5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]-triazol-3-yl)methyl]-2-fluoro-5-methoxyphenoxy}ethyl ester (Example 45, 250 mg), carbonic acid chloromethyl ester isopropyl ester [CAS No. 35180-01-9] (121 mg), rubidium carbonate (73.2 mg) and DMA (10 mL) was stirred at 85° C. for 90 minutes. After cooling the mixture to room temperature, ethyl acetate and water were added thereto. The organic layer was collected, the aqueous layer was reextracted with ethyl acetate, and all the organic layers were combined. The organic layer was sequentially washed with water and with saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate obtained was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (mixed solvent of heptane-ethyl acetate-methanol) to obtain the acetic acid 2-{3-[(R)-(4-{amino[2-methylallyloxycarbonylimino]methyl}phenylamino)-(5-isopropoxycarbonyloxymethoxy-1-pyrimidin-2-yl-1H-[1,2,4]triazol-3-yl)methyl]-2-fluoro-5-methoxyphenoxyl}ethyl ester as a solid.

Workup

  1. customThe organic layer was collected
  2. washThe organic layer was sequentially washed with water and with saturated aqueous sodium chloride solution
  3. dry with materialdried over anhydrous magnesium sulfate
  4. filtrationThe desiccant was filtered off
  5. customthe filtrate obtained
  6. concentrationwas concentrated under reduced pressure
  7. customThe residue obtained
  8. customwas purified by silica gel column chromatography (mixed solvent of heptane-ethyl acetate-methanol)

Sources & evidence

ORD record
ord-402b054046ea41debbe9094ef3313fea
Source dataset
uspto-grants-2013_05
Patent number
US08436009B2

Linked notes

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