4-Methylmorpholine → 3-(4-{[2-(4-Chloro-phenyl)-4-methoxycarbonylmethyl-thiazole-5-carbonyl]-amino}-2-methoxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester

HRID 554854Notes

Reaction equation

HRID 554854 reaction equation
CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[S:27][C:28]([C:36]([OH:38])=O)=[C:29]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[N:30]=2)=[CH:22][CH:21]=1.[C:39]([O:43][C:44]([N:46]1[CH2:49][CH:48]([O:50][C:51]2[CH:56]=[CH:55][C:54]([NH2:57])=[CH:53][C:52]=2[O:58][CH3:59])[CH2:47]1)=[O:45])([CH3:42])([CH3:41])[CH3:40].CN1CCOCC1>C1COCC1>[C:39]([O:43][C:44]([N:46]1[CH2:47][CH:48]([O:50][C:51]2[CH:56]=[CH:55][C:54]([NH:57][C:36]([C:28]3[S:27][C:26]([C:23]4[CH:22]=[CH:21][C:20]([Cl:19])=[CH:25][CH:24]=4)=[N:30][C:29]=3[CH2:31][C:32]([O:34][CH3:35])=[O:33])=[O:38])=[CH:53][C:52]=2[O:58][CH3:59])[CH2:49]1)=[O:45])([CH3:42])([CH3:41])[CH3:40]

Participants

6

Reactant 4

HCID 79724-MethylmorpholineHCID 111923Propylphosphonic anhydrideHCID 46835556Tert-butyl 3-(4-amino-2-methoxyphenoxy)azetidine-1-carboxylateHCID 674601572-(4-Chloro-phenyl)-4-methoxycarbonylmethyl-thiazole-5-carboxylic acid

Product 1

HCID 674633163-(4-{[2-(4-Chloro-phenyl)-4-methoxycarbonylmethyl-thiazole-5-carbonyl]-amino}-2-methoxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl esterYield 90%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
5 °C

Procedure

Mix 1-propanephosphonic acid cyclic anhydride (50% in EtOAc) (528.7 g, 831.3 mmol) and THF (1110 mL) and chill to 5° C. Add 2-(4-chloro-phenyl)-4-methoxycarbonylmethyl-thiazole-5-carboxylic acid (185.0 g, 593.43 mmol) followed by 3-(4-amino-2-methoxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (192.2 g, 914.4 mmol). Charge N-methylmorpholine (99 mL, 1247 mmol) dropwise over 15 min and remove the ice bath immediately after the addition. Heat the reaction to 65° C. for 16 h and quench with water (555 mL). Dilute with EtOAc (1110 mL) and partition the layers. Wash with saturated sodium bicarbonate (555 mL) and with brine (555 mL). Distill the organic solvent until <5% THF remains and then back-add with ethyl acetate as needed to a total of 740 mL solvent at the end of the distillation. Add heptane (230 mL) at 75° C. and seed with authentic product at 55° C. Allow to cool to room temperature, filter, and rinse twice with heptane-EtOAc (2×100 mL, 1:1). Dry in a vacuum oven at 40° C. to obtain 313.5 g (90%) of the title compound as an orange-brown solid. ES/MS m/z (35Cl) 586 [M−1]−.

Workup

  1. customremove the ice bath
  2. additionimmediately after the addition
  3. temperatureHeat
  4. customthe reaction to 65° C. for 16 h
  5. customquench with water (555 mL)
  6. additionDilute with EtOAc (1110 mL)
  7. custompartition the layers
  8. washWash with saturated sodium bicarbonate (555 mL) and with brine (555 mL)
  9. distillationDistill the organic solvent until <5% THF
  10. additionback-add with ethyl acetate
  11. distillationas needed to a total of 740 mL solvent at the end of the distillation
  12. customat 75° C.
  13. customat 55° C
  14. temperatureto cool to room temperature
  15. filtrationfilter
  16. washrinse twice with heptane-EtOAc (2×100 mL, 1:1)
  17. customDry in a vacuum oven at 40° C.

Sources & evidence

ORD record
ord-4cd4df9c072e401788255c31164f0b73
Source dataset
uspto-grants-2011_11
Patent number
US08049013B2

Reaction notes

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