Dichloromethane → Ethyl 1-[5-[2-(ethylcarbamoylamino)-6-methoxy-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-methyl-piperidine-4-carboxylate

HRID 712332Notes

Reaction equation

HRID 712332 reaction equation
Br[C:2]1[C:3]([O:17][CH3:18])=[CH:4][C:5]2[S:9][C:8]([NH:10][C:11]([NH:13][CH2:14][CH3:15])=[O:12])=[N:7][C:6]=2[CH:16]=1.[CH3:19][C:20]1([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:25][CH2:24][N:23]([C:26]2[N:31]=[CH:30][C:29](B3OC(C)(C)C(C)(C)O3)=[CH:28][N:27]=2)[CH2:22][CH2:21]1.C(Cl)Cl.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:14]([NH:13][C:11]([NH:10][C:8]1[S:9][C:5]2[CH:4]=[C:3]([O:17][CH3:18])[C:2]([C:29]3[CH:28]=[N:27][C:26]([N:23]4[CH2:24][CH2:25][C:20]([CH3:19])([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:21][CH2:22]4)=[N:31][CH:30]=3)=[CH:16][C:6]=2[N:7]=1)=[O:12])[CH3:15]

Participants

8

Reactant 4

HCID 6344DichloromethaneHCID 10796Cesium carbonateHCID 596030851-(5-Bromo-6-methoxy-1,3-benzothiazol-2-yl)-3-ethyl-urea2×HCID 66976878Ethyl 4-methyl-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)piperidine-4-carboxylate

Product 1

HCID 86664042Ethyl 1-[5-[2-(ethylcarbamoylamino)-6-methoxy-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-methyl-piperidine-4-carboxylate

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
110 °C

Procedure

1-(5-Bromo-6-methoxy-1,3-benzothiazol-2-yl)-3-ethyl-urea (Intermediate 11) (200 mg, 66 mass %, 0.40 mmol), ethyl 4-methyl-1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]piperidine-4-carboxylate (crude, 638 mg, 47 mass %, 0.80 mmol) and Pd(dppf)Cl2.DCM (16 mg, 0.02 mmol) were dissolved in dioxane (7.5 mL) in a microwave vial and a solution of cesium carbonate (391 mg, 1.20 mmol) in water (2.5 mL) was added. The vial was capped, the mixture degassed and heated in the microwave at 110° C. for 30 minutes. The mixture was poured into water, extracted into EtOAc (4×20 mL) and the organic layers washed with brine, dried over Na2SO4 and concentrated to dryness in vacuo. A yellow solid was obtained and the mixture purified by chromatography, Biotage SP4, 12 g Si cartridge, 0-5% MeOH in DCM. The relevant fractions were combined to give a brown solid which was further purified by chromatography, Biotage SP4, 12 g Si cartridge, 50% EtOAc in hexane (isocratic) then the column flushed with EtOAc. The relevant fractions were combined to give Compound 191 as a white solid, 110 mg (55%). 1H NMR (MeCN-d3): δ 1.19 (3H, t, J=7.2 Hz), 1.26 (3H, s), 1.29 (3H, t, J=7.1 Hz), 1.49 (2H, ddd, J=14.0, 10.5 and 4.1 Hz), 2.14 (2H, m), 3.32 (4H, m), 3.87 (3H, s), 4.20 (2H, q, J=7.1 Hz), 4.37 (2H, dt, J=14.0 and 4.1 Hz), 6.16 (1H, br s), 7.51 (1H, s), 7.61 (1H, s), 8.55 (2H, s), 8.77 (1H, br s). MS: 499.12 [M+H]+.

Workup

  1. customThe vial was capped
  2. customthe mixture degassed
  3. additionThe mixture was poured into water
  4. extractionextracted into EtOAc (4×20 mL)
  5. washthe organic layers washed with brine
  6. dry with materialdried over Na2SO4
  7. concentrationconcentrated to dryness in vacuo
  8. customA yellow solid was obtained
  9. customthe mixture purified by chromatography, Biotage SP4, 12 g Si cartridge, 0-5% MeOH in DCM
  10. customto give a brown solid which
  11. customwas further purified by chromatography, Biotage SP4, 12 g Si cartridge, 50% EtOAc in hexane (isocratic)
  12. customthe column flushed with EtOAc

Sources & evidence

ORD record
ord-b89c4e9fdee54aa2b09e365a69de12de
Source dataset
uspto-grants-2015_11
Patent number
US09181234B2

Reaction notes

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