Sodium Chloride → 2,2-dimethylmalonic acid 5-{(R)-(4-{amino(2,2-dimethylpropoxycarbonylimino)methyl}phenylamino)-[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]methyl}-2-pyrimidin-2-yl-2H-[1,2,4]triazol-3-yloxymethyl ester t-butyl ester

HRID 2089628Notes

Reaction equation

HRID 2089628 reaction equation
[CH3:1][C:2]([CH3:46])([CH3:45])[CH2:3][O:4][C:5](=[O:44])[N:6]=[C:7]([NH2:43])[C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH:15]([C:29]2[N:33]=[C:32]([O:34][CH2:35]Cl)[N:31]([C:37]3[N:42]=[CH:41][CH:40]=[CH:39][N:38]=3)[N:30]=2)[C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH2:25][CH2:26][OH:27])[C:17]=2[F:28])=[CH:10][CH:9]=1.[C:47]([O:51][C:52](=[O:59])[C:53]([CH3:58])([CH3:57])[C:54]([OH:56])=[O:55])([CH3:50])([CH3:49])[CH3:48].[I-].[Na+].C(=O)([O-])O.[K+].[Cl-].[Na+]>C(OCC)(=O)C.O.CC(N(C)C)=O>[C:47]([O:51][C:52](=[O:59])[C:53]([CH3:58])([CH3:57])[C:54]([O:56][CH2:35][O:34][C:32]1[N:31]([C:37]2[N:42]=[CH:41][CH:40]=[CH:39][N:38]=2)[N:30]=[C:29]([C@H:15]([NH:14][C:11]2[CH:12]=[CH:13][C:8]([C:7]([NH2:43])=[N:6][C:5]([O:4][CH2:3][C:2]([CH3:46])([CH3:45])[CH3:1])=[O:44])=[CH:9][CH:10]=2)[C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH2:25][CH2:26][OH:27])[C:17]=2[F:28])[N:33]=1)=[O:55])([CH3:50])([CH3:48])[CH3:49]

Participants

9

Reactant 5

HCID 5234Sodium ChlorideHCID 5238Sodium IodideHCID 2544153-(Tert-butoxy)-2,2-dimethyl-3-oxopropanoic acidHCID 516893Potassium BicarbonateHCID 67470504[1-amino-1-[4-({(5-chloromethoxy-1-pyrimidin-2-yl-1H-[1,2,4]triazol-3-yl)-[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]methyl}amino)phenyl]methylidene]carbamic acid 2,2-dimethylpropyl ester

Product 1

HCID 682128502,2-dimethylmalonic acid 5-{(R)-(4-{amino(2,2-dimethylpropoxycarbonylimino)methyl}phenylamino)-[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]methyl}-2-pyrimidin-2-yl-2H-[1,2,4]triazol-3-yloxymethyl ester t-butyl ester

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8857Ethyl AcetateSolventHCID 31374DimethylacetamideSolvent

Procedure

A mixture of [1-amino-1-[4-({(5-chloromethoxy-1-pyrimidin-2-yl-1H-[1,2,4]triazol-3-yl)-[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]methyl}amino)phenyl]methylidene]carbamic acid 2,2-dimethylpropyl ester (170 mg), 2,2-dimethylmalonic acid mono-t-butyl ester [CAS No. 143688-40-8] (490 mg), sodium iodide (390 mg), potassium hydrogen carbonate (182 mg), and DMA (25 mL) was stirred at 50° C. overnight. After cooling the mixture to room temperature, 1:1 mixture of water and saturated aqueous sodium chloride and ethyl acetate were added thereto, and the resulting mixture was extracted. The aqueous layer was reextracted with ethyl acetate twice. All the organic layers were combined, washed with water, 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) to obtain a racemate of the captioned compound.

Workup

  1. additionwere added
  2. extractionthe resulting mixture was extracted
  3. washwashed with water
  4. dry with materialdried over anhydrous magnesium sulfate
  5. filtrationThe desiccant was filtered off
  6. customthe filtrate obtained
  7. concentrationwas concentrated under reduced pressure
  8. customThe residue obtained
  9. customwas purified by silica gel column chromatography (mixed solvent of heptane-ethyl acetate)
  10. customto obtain a racemate of the captioned compound

Sources & evidence

ORD record
ord-33c42e358211445e8479160002c29b98
Source dataset
uspto-grants-2013_05
Patent number
US08436009B2

Reaction notes

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