Hydrochloric Acid → Des-6-[4-(2-hydroxyethyl)-1-piperazinyl]-6-chloro-O-pivalate Dasatinib

HRID 1437120Notes

Reaction equation

HRID 1437120 reaction equation
[C:1]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=1[NH:16][C:17]([C:19]1[S:23][C:22]([NH2:24])=[N:21][CH:20]=1)=[O:18])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Cl:25][C:26]1[CH:31]=[C:30](Cl)[N:29]=[C:28]([CH3:33])[N:27]=1.Cl>C1COCC1>[C:1]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=1[NH:16][C:17]([C:19]1[S:23][C:22]([NH:24][C:30]2[CH:31]=[C:26]([Cl:25])[N:27]=[C:28]([CH3:33])[N:29]=2)=[N:21][CH:20]=1)=[O:18])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]

Participants

5

Reactant 3

HCID 313Hydrochloric AcidHCID 2349974,6-Dichloro-2-methylpyrimidineHCID 25022847HCID 25022847, compound

Product 1

HCID 25022848Des-6-[4-(2-hydroxyethyl)-1-piperazinyl]-6-chloro-O-pivalate DasatinibYield 66%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
18 °C

Procedure

To a solution of compound 10a (2.21 g, 6 mmol) and 4,6-dichloro-2-methylpyrimidine (11a, 1.18 g, 7.2 mmol) in THF (30 mL) was added a solution of NaOBu-t in THF (30% w/w, 7.4 mL) at temperature between 10° C. to 18° C. The reaction mixture was stirred at 18° C. for 1.5 h. It was then cooled to 0° C. A solution of 1N HCl (14.0 mL) was added. The mixture then was partitioned between EtOAc and H2O (1:1, 200 mL). The organic phase was separated, and the aqueous layer was extracted with EtOAc (100 mL). The combined extracts were concentrated in vacuo. The residue was subjected to a flash column using 50% EtOAc in hexane to give crude compound 12a which was triturated with 10% EtOAc in hexane to give compound 12a (1.95 g, 66% yield). 1H NMR (500 MHz, CDCl3) δ 1.19 (s, 9H), 2.73 (s, 3H), 5.12 (s, 2H), 6.93 (s, 1H), 7.21-7.49 (m, 3H), 8.21 (s, 1H), 8.98 (s, 1H).

Workup

  1. temperatureIt was then cooled to 0° C
  2. customThe mixture then was partitioned between EtOAc and H2O (1:1, 200 mL)
  3. customThe organic phase was separated
  4. extractionthe aqueous layer was extracted with EtOAc (100 mL)
  5. concentrationThe combined extracts were concentrated in vacuo
  6. customto give crude compound 12a which
  7. customwas triturated with 10% EtOAc in hexane

Sources & evidence

ORD record
ord-29395563eb2f426287544ad8f0391756
Source dataset
uspto-grants-2009_11
Patent number
US07622473B2

Reaction notes

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