Cesium carbonate → ethyl 5-((tert-butoxycarbonyl(2-methyl-6-(((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methoxy)pyrimidin-4-yl)amino)methyl)-1,3,4-thiadiazole-2-carboxylate

HRID 2175414Notes

Reaction equation

HRID 2175414 reaction equation
[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[S:14][C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:12][N:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:21]1[CH:26]=[C:25]([O:27][CH2:28][C@H:29]2[CH2:31][C@@H:30]2[C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][N:33]=2)[N:24]=[C:23]([CH3:39])[N:22]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:1]([O:5][C:6]([N:8]([CH2:9][C:10]1[S:14][C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:12][N:11]=1)[C:21]1[CH:26]=[C:25]([O:27][CH2:28][C@H:29]2[CH2:31][C@@H:30]2[C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][N:33]=2)[N:24]=[C:23]([CH3:39])[N:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 867295664-chloro-2-methyl-6-(((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methoxy)pyrimidineHCID 867295725-(Tert-butoxycarbonylamino-methyl)-[1,3,4]thiadiazole-2-carboxylic acid ethyl ester

Product 1

HCID 86729573ethyl 5-((tert-butoxycarbonyl(2-methyl-6-(((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methoxy)pyrimidin-4-yl)amino)methyl)-1,3,4-thiadiazole-2-carboxylateYield 63%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 1140TolueneSolvent

Conditions

Temperature
85 °C

Procedure

The mixture of ethyl 5-((tert-butoxycarbonylamino) methyl)-1,3,4-thiadiazole-2-carboxylate (9-5) (1.0 g, 3.48 mmol), 4-chloro-2-methyl-6-(((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methoxy)pyrimidine (9-6), Pd(OAc)2 (66 mg, 0.29 mmol), BINAP (199 mg, 0.319 mmol) and Cesium carbonate (1.133 g, 3.48 mmol) in toluene (10 mL) was heated to 85° C. under nitrogen for overnight. The solvent was removed under reduced pressure and the residue was purified by chromatography with gradient eluant (PE/EA=10/1; 5/1). The product was obtained as an orange syrup (1.0 g, 63%). 1H NMR (500 MHz, CDCl3) δ 8.26 (s, 1H), 7.35 (dd, J=7.9, 1.8 Hz, 1H), 7.19 (s, 1H), 7.05 (d, J=7.9 Hz, 1H), 5.59 (s, 2H), 4.50 (q, J=7.1 Hz, 2H), 4.35 (m, 2H), 2.53 (s, 3H), 2.27 (s, 3H), 2.13-2.03 (m, 1H), 1.89-1.87 (m, 1H), 1.48-1.43 (m, 12H), 1.32-1.24 (m, 1H), 1.05-1.02 (m, 1H); LRMS (ESI) calculated M+H for C26H32N6O5S: 541.6. Found: 541.2.

Workup

  1. customThe solvent was removed under reduced pressure
  2. customthe residue was purified by chromatography with gradient eluant (PE/EA=10/1; 5/1)

Sources & evidence

ORD record
ord-8892b0b9706c4a1ba382ba69478ac738
Source dataset
uspto-grants-2015_06
Patent number
US09062059B2

Reaction notes

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