Citric Acid → HCID 66869146, compound

HRID 42977Notes

Reaction equation

HRID 42977 reaction equation
[CH2:1]([O:3][C:4]([N:6]1[CH:14]2[CH:9]([C:10](O)([C:15]#[C:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][CH2:12][CH2:13]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>>[CH2:1]([O:3][C:4]([N:6]1[CH:14]2[C:9](=[C:10]([C:15]#[C:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][CH2:12][CH2:13]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]

Participants

6

Reactant 5

HCID 311Citric AcidHCID 8471TriethylamineHCID 14798Sodium HydroxideHCID 24813Phosphorus oxychlorideHCID 57459671HCID 57459671, compound

Product 1

HCID 66869146HCID 66869146, compoundYield 1.1%

Conditions

Temperature
0 °C

Procedure

A solution of 4-hydroxy-4-phenylethynyl-octahydro-indole-1-carboxylic acid ethyl ester (1.0 g, 3.19 mmol), triethylamine (2.2 ml, 16 mmol) and phosphorous oxychloride 0.877 ml, 10 mmol) is heated to 40° C. for 4 hours. The dark mixture is cooled to 0° C. and treated with 1M sodium hydroxide (5 ml) and then acidified with a 10% aqueous citric acid solution. The mixture is extracted with dichloromethane, the organic extracts are washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue is chromatographed on silica with hexane and diethyl ether (4:1 v/v). The first product containing fractions afforded (±)-(RS)-4-phenylethynyl-2,3,5,6,7,7a-hexahydro-indole-1-carboxylic acid ethyl ester (10 mg, 1%) as a yellowish oil. 1H-NMR (400 MHz; CDCl3): 7.44 (m, 2H), 7.32 (m, 3H), 4.24-3.97 (m, 3H), 3.8 (m, 1H), 3.25 (m, 1H), 2.93 (m, 1H), 2.56 (m, 1H), 2.28 (m, 2H), 1.90 (m, 1H), 1.60 (m, 2H), 1.28 (t, J=7 Hz, 3H), 1.14 (m, 1H). ES-MS (+): 296.1. After collecting a mixture of the two products (475 mg, 50%), the third product containing fractions yielded (±)-(3RS,7aRS)-4-phenylethynyl-2,3,3a,6,7,7a-hexahydro-indole-1-carboxylic acid ethyl ester (64 mg, 7%) as a yellowish oil. 1H-NMR (400 MHz; CDCl3): 7.43 (m, 2H), 7.31 (m, 3H), 6.27 (m, 1H), 4.15 (m, 2H), 4.01-3.83 (m, 1H), 3.46 (m, 2H), 2.82 (m, 1H), 2.37-1.82 (m, 5H), 1.57 (m, 1H), 1.27 (t, J=7 Hz, 3H). ES-MS (+): 296.2.

Workup

  1. extractionThe mixture is extracted with dichloromethane
  2. washthe organic extracts are washed with brine
  3. dry with materialdried over anhydrous magnesium sulfate
  4. customevaporated in vacuo
  5. customThe residue is chromatographed on silica with hexane and diethyl ether (4:1 v/v)
  6. additionThe first product containing fractions

Sources & evidence

ORD record
ord-1884829e4da945468858b9f4c07b777e
Source dataset
uspto-grants-2013_09
Patent number
US08536229B2

Reaction notes

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