2-Hydroxy-1,2,3-propanetricarboxylic acid hydrate (1:1) → 10-(3-Hydroxymethyl-azetidin-1-yl)-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester

HRID 528750Notes

Reaction equation

HRID 528750 reaction equation
C(O[C:6]([N:8]1[CH2:11][CH:10]([CH2:12][OH:13])[CH2:9]1)=O)(C)(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CCN(C(C)C)C(C)C.[C:35]([O:39][C:40]([N:42]1[CH2:56][CH2:55][C:46]2=C(Cl)[N:48]3[C:52]([N:53]=[C:45]2[CH2:44][CH2:43]1)=[CH:51][CH:50]=[N:49]3)=[O:41])([CH3:38])([CH3:37])[CH3:36].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl.O.[Cl-].[Na+].O>[C:35]([O:39][C:40]([N:42]1[CH2:56][CH2:55][C:46]2=[C:6]([N:8]3[CH2:9][CH:10]([CH2:12][OH:13])[CH2:11]3)[N:48]3[C:52]([N:53]=[C:45]2[CH2:44][CH2:43]1)=[CH:51][CH:50]=[N:49]3)=[O:41])([CH3:38])([CH3:36])[CH3:37]

Participants

9

Reactant 5

HCID 222302-Hydroxy-1,2,3-propanetricarboxylic acid hydrate (1:1)HCID 81531DiisopropylethylamineHCID 521998p-Toluenesulfonic acid monohydrateHCID 10583745tert-Butyl 3-(hydroxymethyl)azetidine-1-carboxylateHCID 4692812210-Chloro-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester

Product 1

HCID 4692812310-(3-Hydroxymethyl-azetidin-1-yl)-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 57417360Sodium chloride; waterSolvent

Procedure

A mixture of 2.57 g (13.75 mmol) 3-hydroxymethyl-azetidine-1-carboxylic acid tert-butyl ester and 2.62 g (13.75 mmol) para-toluenesulfonic acid monohydrate in 14 mL DCM was stirred at room temperature for 16 hours. After evaporation of the solvent, the residue was dissolved in 28 mL EtOH, then 4.8 mL (27.5 mmol) DIPEA followed by 4.03 g (12.5 mmol) 10-chloro-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester were added and the reaction mixture was heated under reflux for 24 hours. The mixture was allowed to cool to room temperature and the solvent was evaporated. 300 mL DCM was added to the mixture, the organic layer was washed sequentially with 100 mL saturated solution of NaHCO3, a mixture of 1.94 g (9.23 mmol) citric acid monohydrate in 100 mL H2O and 100 mL saturated brine, then was dried over MgSO4. After filtration and evaporation of the solvent the product was purified by column chromatography (Biotage silica 40+M, heptane/EtOAc 1:1 to EtOAc).

Workup

  1. customAfter evaporation of the solvent
  2. dissolutionthe residue was dissolved in 28 mL EtOH
  3. additionwere added
  4. temperaturethe reaction mixture was heated
  5. temperatureunder reflux for 24 hours
  6. temperatureto cool to room temperature
  7. customthe solvent was evaporated
  8. addition300 mL DCM was added to the mixture
  9. washthe organic layer was washed sequentially with 100 mL saturated solution of NaHCO3
  10. dry with materialwas dried over MgSO4
  11. filtrationAfter filtration and evaporation of the solvent the product
  12. customwas purified by column chromatography (Biotage silica 40+M, heptane/EtOAc 1:1 to EtOAc)

Sources & evidence

ORD record
ord-c614be4ba23a42a9b41f4b7dc3acf343
Source dataset
uspto-grants-2016_05
Patent number
US09346816B2

Reaction notes

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