(R)-diethyl 1-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)azetidine-3,3-dicarboxylate → (R)-1-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid

HRID 1809540Notes

Reaction equation

HRID 1809540 reaction equation
[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][C@H:22]4[N:27]3[CH2:30][C:29](C(OCC)=O)([C:31]([O:33]CC)=[O:32])[CH2:28]3)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2]>CO.[OH-].[Na+]>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][C@H:22]4[N:27]3[CH2:30][CH:29]([C:31]([OH:33])=[O:32])[CH2:28]3)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2]

Participants

4

Reactant 1

HCID 67313928(R)-diethyl 1-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)azetidine-3,3-dicarboxylate

Product 1

HCID 58344872(R)-1-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acidYield 33.1%

Reagents, catalysts & solvents 2

HCID 14798Sodium HydroxideCatalystHCID 887MethanolSolvent

Conditions

Temperature
50 °C

Procedure

To a stirred solution of crude (R)-diethyl 1-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)azetidine-3,3-dicarboxylate (93 mg, 0.17 mmol) in MeOH (2 mL) was added 6 N NaOH (5 drops). The resulting solution was heated to 50° C. in a closed vial. After 24 h the solution was concentrated, dissolved in water, neutralized with 1N HCl, and heated at 100° C. After 15 h, additional 1N HCl was added, and the mixture was stirred at 105° C. for 24 h. The mixture was diluted with water and extracted with DCM and EA. The organic layers were combined, dried over Na2SO4, and purified by preparative HPLC to provide 25 mg (33%) of (R)-1-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylic acid 202. LCMS-ESI (m/z) calculated for C25H24N4O4: 444.5; found 445.2 [M+H]+, tR=2.55 min. Compound 203 was made in an analogous fashion.

Workup

  1. concentrationAfter 24 h the solution was concentrated
  2. dissolutiondissolved in water
  3. temperatureheated at 100° C
  4. additionadditional 1N HCl was added
  5. additionThe mixture was diluted with water
  6. extractionextracted with DCM and EA
  7. dry with materialdried over Na2SO4
  8. custompurified by preparative HPLC

Sources & evidence

ORD record
ord-337487925b9547cfa130973631bbae4e
Source dataset
uspto-grants-2013_01
Patent number
US08362048B2

Reaction notes

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