Guanidine Hydrochloride → Benzyl 4-[3-(2-aminopyrimidin-4-yl)-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-7-yl]piperidine-1-carboxylate

HRID 1785399Notes

Reaction equation

HRID 1785399 reaction equation
[C:1]([C:4]1[N:8]2[CH:9]=[CH:10][C:11]([CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:20])[CH2:15][CH2:14]3)=[CH:12][C:7]2=[N:6][C:5]=1[C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)(=O)[CH3:2].[CH3:36]N(C(OC)OC)C.Cl.[NH2:45][C:46]([NH2:48])=[NH:47].C[O-].[Na+]>CO.C1(C)C=CC=CC=1>[NH2:47][C:46]1[N:48]=[C:1]([C:4]2[N:8]3[CH:9]=[CH:10][C:11]([CH:13]4[CH2:14][CH2:15][N:16]([C:19]([O:21][CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)=[O:20])[CH2:17][CH2:18]4)=[CH:12][C:7]3=[N:6][C:5]=2[C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH:2]=[CH:36][N:45]=1

Participants

7

Reactant 4

HCID 5742Guanidine HydrochlorideHCID 78373Dimethylformamide dimethyl acetal2×HCID 10942334Sodium MethoxideHCID 58774431Benzyl 4-[3-acetyl-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-7-yl]piperidine-1-carboxylate

Product 1

HCID 69055315Benzyl 4-[3-(2-aminopyrimidin-4-yl)-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-7-yl]piperidine-1-carboxylate

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 1140TolueneSolvent

Conditions

Temperature
100 °C

Procedure

A 28 mL Pyrex Plus tube was charged with ketone 35 (420 mg, 0.89 mmol), DMFDMA (530 mg, 4.45 mmol) and toluene (10 mL). The reaction was heated to 100° C. for 7 hours, after which more DMFDMA (530 mg, 4.45 mmol) was added, and the reaction was allowed to heat at 100° C. for 12 more hours. The reaction was then concentrated under reduced pressure, and then dissolved in 1-propanol (20 mL). The reaction was then charged with guanidine-HCl (128 mg, 1.34 mmol) and sodium methoxide (305 □L of a 25% (w/w) solution in methanol, 1.34 mmol), and the reaction was heated to 80° C. for 18 hours. The reaction was then concentrated under reduced pressure, then dissolved in 10 mL CH2Cl2, then loaded onto a 40 g Isco RediSep normal phase silica cartridge, and purified on an Isco OptiX10 CombiFlash instrument using a gradient that started at 100% heptane and ended at 100% ethyl acetate. Fractions containing desired product were pooled and concentrated under reduced pressure. Yield of 37: 190 mg (41% over both steps). 1H NMR (400 MHz, CDCl3) δ 1.62 (m, 2H), 1.88 (m, 2H), 2.74 (m, 1H), 2.91 (m, 2H), 4.34 (bs, 2H), 5.14 (s, 2H), 5.21 (s, 2H), 6.48 (d, J=5.2 Hz, 1H), 6.74 (d, J=7.2 Hz, 1H), 7.09 (t, J=8.8 Hz, 2H), 7.34 (m, 5H), 7.44 (bs, 1H), 7.60 (m, 2H), 8.08 (d, J=5.2 Hz, 1H), 9.40 (d, J=7.2 Hz, 1H). MS (ESI+) 523.7.

Workup

  1. temperatureto heat at 100° C. for 12 more hours
  2. concentrationThe reaction was then concentrated under reduced pressure
  3. dissolutiondissolved in 1-propanol (20 mL)
  4. temperature1.34 mmol), and the reaction was heated to 80° C. for 18 hours
  5. concentrationThe reaction was then concentrated under reduced pressure
  6. dissolutiondissolved in 10 mL CH2Cl2
  7. custompurified on an Isco OptiX10 CombiFlash instrument
  8. additionFractions containing desired product
  9. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-8d9e4fd23fab4936add64df3c80e7f2e
Source dataset
uspto-grants-2009_03
Patent number
US07504501B2

Reaction notes

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