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Formaldehyde → HCID 73054608, compound

HRID 1779026
Notes
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Reaction equation

HRID 1779026 reaction equation
C(O)(C(F)(F)F)=O.[NH2:8][C:9](=[O:53])[CH2:10][C:11]1[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:45][C:12]=1[CH2:13][CH2:14][C:15]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][N:18]=[C:17]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]3[CH2:37][CH2:36][N:35]([C:38](OC(C)(C)C)=O)[CH2:34][CH2:33]3)=[CH:28][CH:27]=2)[N:16]=1.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:38][N:35]1[CH2:36][CH2:37][CH:32]([C:29]2[CH:30]=[CH:31][C:26]([NH:25][C:17]3[N:16]=[C:15]([CH2:14][CH2:13][C:12]4[CH:45]=[C:46]([C:49]([F:52])([F:50])[F:51])[CH:47]=[CH:48][C:11]=4[CH2:10][C:9]([NH2:8])=[O:53])[C:20]([C:21]([F:22])([F:24])[F:23])=[CH:19][N:18]=3)=[CH:27][CH:28]=2)[CH2:33][CH2:34]1
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

6

Reactant 4

HCID 712FormaldehydeHCID 6422Trifluoroacetic acidHCID 5049666Sodium triacetoxyborohydrideHCID 86712676HCID 86712676, compound

Product 1

HCID 73054608HCID 73054608, compoundYield 26%

Reagents, catalysts & solvents 1

HCID 6344
Dichloromethane
Solvent

Procedure

TFA (0.1 mL) was added to a solution of tert-butyl 4-(4-((4-(2-(2-amino-2-oxoethyl)-5-(trifluoromethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (A62) (0.170 g, 0.261 mmol) in DCM (4 mL) and the resulting mixture stirred for 24 hours at room temperature. The volatiles were evaporated under reduced pressure then the residue adsorbed onto silica gel and purified by column chromatography (SiO2, 1-50% MeOH in DCM). The volatiles were removed in vacuo and the residue dissolved in dry MeOH (5 mL). Formaldehyde (37 wt. % in H2O; 0.030 mL, 0.36 mmol) was added and the resulting mixture was stirred for 30 minutes at room temperature. Sodium triacetoxyborohydride (0.077 g, 0.362 mmol) was added under nitrogen and the resulting mixture stirred at room temperature for 2 hours. The volatiles were evaporated under reduced pressure then the residue dissolved in EtOAc and washed with 10% NaHCO3 (20 mL). The organics were dried (MgSO4) and the volatiles removed under reduced pressure. The residue was adsorbed onto silica gel, then purified by silica gel column chromatography (Biotage Isolera, SiO2 cartridge, 50-100% MeOH in EtOAc then 10% NH3 in EtOH). Further purification by semi preparative HPLC was required to give the title compound 17 as a pale cream solid (0.011 g, 26%); 1H NMR (400 MHz, d4-MeOH) δ 8.55 (s, 1H), 7.67-7.60 (m, 2H), 7.50-7.40 (m, 3H), 7.28-7.19 (m, 2H), 3.74 (s, 2H), 3.54-3.40 (m, 2H), 3.31-3.25 (m, 2H), 3.14-3.12 (m, 2H), 2.95 (t, J=11.5 Hz, 2H), 2.80 (m, 4H), 2.08 (d, J=13.8 Hz, 2H), 1.97-1.92 (m, 2H). LCMS-B: rt 4.52 min; m/z 566 [M+H]+.

Workup

  1. customThe volatiles were evaporated under reduced pressure
  2. custompurified by column chromatography (SiO2, 1-50% MeOH in DCM)
  3. customThe volatiles were removed in vacuo
  4. dissolutionthe residue dissolved in dry MeOH (5 mL)
  5. stirringthe resulting mixture was stirred for 30 minutes at room temperature
  6. stirringthe resulting mixture stirred at room temperature for 2 hours
  7. customThe volatiles were evaporated under reduced pressure
  8. dissolutionthe residue dissolved in EtOAc
  9. washwashed with 10% NaHCO3 (20 mL)
  10. dry with materialThe organics were dried (MgSO4)
  11. customthe volatiles removed under reduced pressure
  12. custompurified by silica gel column chromatography (Biotage Isolera, SiO2 cartridge, 50-100% MeOH in EtOAc
  13. customFurther purification by semi preparative HPLC

Sources & evidence

ORD record
ord-2a4c4c9d67dd4bee9a661010a682e3c9
Source dataset
uspto-grants-2016_02
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09266864B2

Reaction notes

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