Diethyl Ether → Ethyl 1-[5-[7-cyclohexyl-2-(ethylcarbamoylamino)-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-methyl-piperidine-4-carboxylate

HRID 712262Notes

Reaction equation

HRID 712262 reaction equation
[CH:1]1([Mg]Cl)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCOCC.[Li+].[Cl-].[CH2:16]([O:18][C:19]([C:21]1([CH3:49])[CH2:26][CH2:25][N:24]([C:27]2[N:32]=[CH:31][C:30]([C:33]3[CH:34]=[C:35](Br)[C:36]4[S:40][C:39]([NH:41][C:42]([NH:44][CH2:45][CH3:46])=[O:43])=[N:38][C:37]=4[CH:47]=3)=[CH:29][N:28]=2)[CH2:23][CH2:22]1)=[O:20])[CH3:17]>[Cl-].[Zn+2].[Cl-].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].C(Cl)Cl.C1COCC1>[CH:1]1([C:35]2[C:36]3[S:40][C:39]([NH:41][C:42](=[O:43])[NH:44][CH2:45][CH3:46])=[N:38][C:37]=3[CH:47]=[C:33]([C:30]3[CH:29]=[N:28][C:27]([N:24]4[CH2:25][CH2:26][C:21]([CH3:49])([C:19]([O:18][CH2:16][CH3:17])=[O:20])[CH2:22][CH2:23]4)=[N:32][CH:31]=3)[CH:34]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1

Participants

9

Reactant 4

HCID 3283Diethyl Ether2×HCID 433294Lithium ChlorideHCID 86663956Ethyl 1-(5-(7-bromo-2-(3-ethylureido)benzo[d]thiazol-5-yl)pyrimidin-2-yl)-4-methylpiperidine-4-carboxylateHCID 178478990HCID 178478990, compound

Product 1

HCID 86663975Ethyl 1-[5-[7-cyclohexyl-2-(ethylcarbamoylamino)-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-methyl-piperidine-4-carboxylate

Reagents, catalysts & solvents 4

HCID 3007855ZincchlorideCatalystHCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

Cyclohexylmagnesium chloride in Et2O (2.03 mL, 3.65 mmol) was added to a THF (2.5 mL) solution of LiCl (53 mg, 1.25 mmol) and 1M zinc chloride in Et2O (4.38 mL, 4.38 mmol) at rt, after which a grey precipitate immediately formed. After stirring at rt for 15 mins, a THF solution (3 mL) of 1-{5-[7-Bromo-2-(3-ethyl-ureido)-benzothiazol-5-yl]-pyrimidin-2-yl}-4-methyl-piperidine-4-carboxylic acid ethyl ester (100 mg, 182.66 mmol) and Pd(dppf)Cl2.DCM (10 mol %) and was allowed to stir at rt for 30 mins. Subsequent heating at reflux gave minimal formation of the desired product and an equimolar amount of the hydrodebrominated starting material. The reaction mixture was transferred to a microwave vessel and heated at 110° C. for 30 mins. The reaction mixture was quenched with 1M HCl (1×5 mL), extracted with EtOAc (10 mL), dried (MgSO4), concentrated in vacuo and subjected to reverse phase HPLC (60-80% water (0.1% FA):MeOH) to afford 2.7 mg (3% isolated yield) of a white solid.

Workup

  1. customafter which a grey precipitate immediately formed
  2. stirringto stir at rt for 30 mins
  3. temperatureSubsequent heating
  4. temperatureat reflux

Sources & evidence

ORD record
ord-3f4b23ccc3cf4763a6a13edc4e5c7dc5
Source dataset
uspto-grants-2015_11
Patent number
US09181234B2

Reaction notes

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