Acetic Acid → HCID 86708575, compound

HRID 921699Notes

Reaction equation

HRID 921699 reaction equation
[Cl:1][C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:6][C:5]([C:14]#[N:15])=[CH:4][C:3]=1[NH:16][C:17]1[N:22]=[C:21]([NH:23][CH:24]2[CH2:26][CH2:25]2)[C:20]2=[N:27][CH:28]=[C:29]([C:30]#[N:31])[N:19]2[N:18]=1.C(OC)(OC)OC.O=[C:40]1[CH2:43][N:42](C(OC(C)(C)C)=O)[CH2:41]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[NH:42]1[CH2:43][CH:40]([N:11]2[CH2:10][CH2:9][CH:8]([C:7]3[C:2]([Cl:1])=[C:3]([NH:16][C:17]4[N:22]=[C:21]([NH:23][CH:24]5[CH2:25][CH2:26]5)[C:20]5=[N:27][CH:28]=[C:29]([C:30]#[N:31])[N:19]5[N:18]=4)[CH:4]=[C:5]([C:14]#[N:15])[CH:6]=3)[CH2:13][CH2:12]2)[CH2:41]1

Participants

7

Reactant 5

HCID 176Acetic AcidHCID 9005Trimethyl orthoformateHCID 15194043-Oxo-azetidine-1-carboxylic acid tert-butyl esterHCID 5003444Sodium cyanoborohydrideHCID 867085272-((2-Chloro-5-cyano-3-(piperidin-4-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile

Product 1

HCID 86708575HCID 86708575, compound

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

To a suspension of 2-((2-chloro-5-cyano-3-(piperidin-4-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 208)(60 mg, 0.138 mmol) in a mixture solvent of methanol (0.7 ml)/CH2CL2 (0.7 ml) was added trimethyl orthoformate (0.7 mL, 6.33 mmol), (The suspension converted to a clear solution within 1 min.), tert-butyl 3-oxoazetidine-1-carboxylate (237 mg, 1.383 mmol), and acetic acid (0.032 mL, 0.553 mmol). The mixture was stirred at Rt for 40 min and then sodium cyanoborohydride (87 mg, 1.383 mmol) was added and stirred at room temperature for overnight. The reaction mixture was partitioned between EtOAc and diluted aq. NaHCO3, The aqueous layer was extracted with EtOAc; the combined organic layer was washed with brine and concentrated. The crude intermediate was purified by prep HPLC (100×30 mm Luna C18 column, Solvent A=10% Methanol, 90% H2O, 0.1% TFA; solvent B=90% Methanol, 10% H2O, 0.1% TFA, Flow rate 42 ml per min, 20-100% B, over 20 min). The HPLC fractions containing the intermediate were applied onto a cartridges of Phenomenex Strata-X-C 33 um cation mixed-mode polymer. This was washed with methanol and product was eluted with 2 N solution of ammonia in methanol/DCM (1:1). Removal of the solvents left 46 mg intermediate as a white solid which was dissolved in DCM (2 ml) and TFA (1 ml) was added. The resulting mixture was stirred at room temperature for 0.5 hour. Removal of the solvent and the residue was taken in MeOH/DCM and applied onto a cartridges of Phenomenex Strata-X-C 33 um cation mixed-mode polymer. This was washed with methanol and product was eluted with 2 N solution of ammonia in methanol/DCM (1:1). Removal of the solvents left the product (39 mg) as a white solid

Workup

  1. stirringstirred at room temperature for overnight
  2. customThe reaction mixture was partitioned between EtOAc and diluted aq. NaHCO3
  3. extractionThe aqueous layer was extracted with EtOAc
  4. washthe combined organic layer was washed with brine
  5. concentrationconcentrated
  6. customThe crude intermediate was purified by prep HPLC (100×30 mm Luna C18 column, Solvent A=10% Methanol, 90% H2O, 0.1% TFA; solvent B=90% Methanol, 10% H2O, 0.1% TFA, Flow rate 42 ml per min, 20-100% B, over 20 min)
  7. additionThe HPLC fractions containing the intermediate
  8. additionmixed-mode polymer
  9. washThis was washed with methanol and product
  10. washwas eluted with 2 N solution of ammonia in methanol/DCM (1:1)
  11. customRemoval of the solvents
  12. waitleft 46 mg intermediate as a white solid which
  13. dissolutionwas dissolved in DCM (2 ml)
  14. additionTFA (1 ml) was added
  15. stirringThe resulting mixture was stirred at room temperature for 0.5 hour
  16. customRemoval of the solvent
  17. additionmixed-mode polymer
  18. washThis was washed with methanol and product
  19. washwas eluted with 2 N solution of ammonia in methanol/DCM (1:1)
  20. customRemoval of the solvents
  21. waitleft the product (39 mg) as a white solid

Sources & evidence

ORD record
ord-2dbd700ab4e74d3c9f7f7b699c400db9
Source dataset
uspto-grants-2016_03
Patent number
US09273057B2

Reaction notes

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