Hydrochloric Acid → 4-(aminomethyl)-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide

HRID 422990Notes

Reaction equation

HRID 422990 reaction equation
F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(OC([NH:32][CH2:33][C:34]1([C:49]([OH:51])=O)[CH2:39][CH2:38][N:37]([C:40]2[C:41]3[CH:48]=[CH:47][NH:46][C:42]=3[N:43]=[CH:44][N:45]=2)[CH2:36][CH2:35]1)=O)(C)(C)C.C(N(CC)C(C)C)(C)C.[NH2:61][CH:62]([C:66]1[CH:71]=[CH:70][C:69]([Cl:72])=[CH:68][CH:67]=1)[CH2:63][CH2:64][OH:65].Cl>CN1C(=O)CCC1.O1CCOCC1>[NH2:32][CH2:33][C:34]1([C:49]([NH:61][CH:62]([C:66]2[CH:67]=[CH:68][C:69]([Cl:72])=[CH:70][CH:71]=2)[CH2:63][CH2:64][OH:65])=[O:51])[CH2:39][CH2:38][N:37]([C:40]2[C:41]3[CH:48]=[CH:47][NH:46][C:42]=3[N:43]=[CH:44][N:45]=2)[CH2:36][CH2:35]1

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 170394353-Amino-3-(4-chlorophenyl)propan-1-ol2×HCID 446042214-((tert-butoxycarbonylamino)methyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid2×

Product 1

HCID 426022594-(aminomethyl)-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamideYield 81%

Reagents, catalysts & solvents 2

HCID 13387N-methyl-2-pyrrolidoneSolvent2×HCID 312751,4-DioxaneSolvent

Conditions

Temperature
50 °C

Procedure

O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (106 mg, 0.28 mmol) was added to 4-((tert-butoxycarbonylamino)methyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 12) (100 mg, 0.27 mmol) and N,N-diisopropylethylamine (0.055 mL, 0.32 mmol) in NMP (5 mL) at 22° C. The resulting solution was stirred at 50° C. for 10 minutes then cooled to ambient temperature. 3-Amino-3-(4-chlorophenyl)propan-1-ol (Intermediate 29) (49.5 mg, 0.27 mmol) was added as a solution in NMP (2 mL) and the mixture was stirred at 22° C. for 16 hours. 4M HCl in dioxane (1 mL) was added and the mixture was stirred at 22° C. for a further 24 hours. The mixture was concentrated and the residue was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 30% (2M NH3 in MeOH) in DCM and pure fractions were evaporated to dryness to afford crude product. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 4-(aminomethyl)-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (0.095 g, 81%) as a white solid.

Workup

  1. temperaturethen cooled to ambient temperature
  2. stirringthe mixture was stirred at 22° C. for 16 hours
  3. stirringthe mixture was stirred at 22° C. for a further 24 hours
  4. concentrationThe mixture was concentrated
  5. customthe residue was purified by ion exchange chromatography
  6. washThe desired product was eluted from the column
  7. custompure fractions were evaporated to dryness
  8. customto afford crude product
  9. customThe crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length)
  10. additionFractions containing the desired compound
  11. customwere evaporated to dryness

Sources & evidence

ORD record
ord-357ea5d8976a4f9989ada5d7deb3ce3a
Source dataset
uspto-grants-2012_01
Patent number
US08101623B2

Reaction notes

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