Benzylamine → Tirbanibulin

HRID 545159Notes

Reaction equation

HRID 545159 reaction equation
[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][C:23](OC)=[O:24])=[N:20][CH:21]=3)=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1(OC)C=CC=CC=1>C1(C)C=CC=CC=1>[O:1]1[CH2:2][CH2:3][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][C:23]([NH:34][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:24])=[N:20][CH:21]=3)=[CH:14][CH:15]=2)[CH2:5][CH2:6]1

Participants

5

Reactant 3

HCID 7504BenzylamineHCID 7519AnisoleHCID 44185422Methyl 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetate

Product 1

HCID 23635314TirbanibulinYield 81.1%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Procedure

A 1 L single-necked round-bottomed flask was charged with 7 (61.4 g, 0.172 mol), benzyl amine (55.6 g, 0.519 mol, 3 eq), and anhydrous anisole (300 g) and then stirred at reflux until reaction was essentially complete (23 h, 165° C. oil bath temperature; internal temperature was 147° C.) and then allowed to cool to near room temperature. A portion (1 mL) of the reaction mixture was diluted with toluene (1 mL) resulting in the complete crystallization of that portion. This seed was then added to the reaction mixture and allowed to stand until the whole reaction mixture had crystallized to a single block. Toluene (150 mL) was added and the mixture swirled to break up the solid. Heptane/toluene (1:1, 100 mL) was added and the solid mixture broken up further. Finally, heptane (50 mL, then 25 mL) was added and the mixture broken up even further, allowing to stand an additional 30 min before filtering the solid. Filtration of the solid, washing with 2:1 toluene/heptane (300 mL), 1:2 toluene/heptane (300 mL), and then heptane (2×300 mL), and then drying (air, then high vac) gave 60.16 g (yield of 81%) of title product as a white solid (>98.9% AUC). Another 2.5 g of less pure (97.4%) material was obtained from the mother liquors.

Workup

  1. temperatureat reflux until reaction
  2. custom(23 h, 165° C. oil bath temperature; internal temperature was 147° C.)
  3. customresulting in the complete crystallization of that portion
  4. additionThis seed was then added to the reaction mixture
  5. customto stand until the whole reaction mixture
  6. customhad crystallized to a single block
  7. additionToluene (150 mL) was added
  8. additionHeptane/toluene (1:1, 100 mL) was added
  9. additionFinally, heptane (50 mL, then 25 mL) was added
  10. filtrationbefore filtering the solid
  11. filtrationFiltration of the solid
  12. washwashing with 2:1 toluene/heptane (300 mL), 1:2 toluene/heptane (300 mL)
  13. dry with materialheptane (2×300 mL), and then drying (air

Sources & evidence

ORD record
ord-53811775ec494ccbbd62ee88e8938626
Source dataset
uspto-grants-2011_05
Patent number
US07935697B2

Reaction notes

Loading…