Citric Acid → HCID 57504382, compound

HRID 1098015Notes

Reaction equation

HRID 1098015 reaction equation
C[Al](C)C.[CH3:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[Cl:13][C:14]1[C:15]([N:20]2[C:24]3=[N:25][CH:26]=[N:27][C:28]([O:29][C@@H:30]([CH2:35][O:36][C@H:37]([CH3:41])[CH2:38][O:39][CH3:40])[C:31](OC)=[O:32])=[C:23]3[CH:22]=[N:21]2)=[N:16][CH:17]=[CH:18][CH:19]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[Cl:13][C:14]1[C:15]([N:20]2[C:24]3=[N:25][CH:26]=[N:27][C:28]([O:29][C@@H:30]([CH2:35][O:36][C@H:37]([CH3:41])[CH2:38][O:39][CH3:40])[C:31]([NH:12][C:9]4[CH:8]=[CH:7][C:6]([CH3:5])=[CH:11][N:10]=4)=[O:32])=[C:23]3[CH:22]=[N:21]2)=[N:16][CH:17]=[CH:18][CH:19]=1

Participants

8

Reactant 4

HCID 311Citric AcidHCID 153482-Amino-5-methylpyridineHCID 16682925TrimethylaluminumHCID 59279549HCID 59279549, compound2×

Product 1

HCID 57504382HCID 57504382, compoundYield 47.4%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 1140TolueneSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

Trimethylaluminium (0.334 mL, 0.67 mmol) was added to 5-methylpyridin-2-amine (69.1 mg, 0.64 mmol) in toluene (8 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 20 minutes. (2S)-Methyl 2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-3-((R)-1-methoxypropan-2-yloxy)propanoate (Intermediate Y8) (245 mg, 0.58 mmol) in toluene (2 mL) was added and the reaction was allowed to warm to room temperature and then heated at reflux for 24 hours. The reaction mixture was allowed to cool and neutralised with citric acid (1M, aq) and then diluted with water (50 mL) and ethyl acetate (50 mL). The organic layer was separated and the aqueous layer re-extracted with ethyl acetate (50 mL). The combined organics were dried (MgSO4), filtered and evaporated. The crude product was purified by preparative HPLC (Phenomenex Gemini C 18 110A (axia) column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents to afford the product (137 mg, 47.4%). 1H NMR (400 MHz, DMSO) δ 1.10 (d, 3H), 2.26 (s, 3H), 3.23-3.42 (m, 5H), 3.76-3.85 (m, 1H), 4.10-4.16 (m, 2H), 5.95-6.00 (m, 1H), 7.55-7.60 (m, 1H), 7.68-7.73 (m, 1H), 7.86 (d, 1H), 8.14-8.18 (m, 1H), 8.24-8.29 (m, 1H), 8.54 (s, 2H), 8.62-8.67 (m, 1H), 10.21 (s, 1H) m/z (ESI+) (M+H)+=498.16; HPLC tR=1.84 min.

Workup

  1. temperatureto warm to room temperature
  2. temperatureheated
  3. temperatureat reflux for 24 hours
  4. temperatureto cool
  5. customThe organic layer was separated
  6. extractionthe aqueous layer re-extracted with ethyl acetate (50 mL)
  7. dry with materialThe combined organics were dried (MgSO4)
  8. filtrationfiltered
  9. customevaporated
  10. customThe crude product was purified by preparative HPLC (Phenomenex Gemini C 18 110A (axia) column, 5μ silica, 19 mm diameter, 100 mm length)

Sources & evidence

ORD record
ord-0d6fa924dfdd4c62a095b7851dac49b4
Source dataset
uspto-grants-2012_03
Patent number
US08143263B2

Reaction notes

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