Hydrochloric Acid → [4-(7-Amino-6-pyridin-4-yl-3-quinolin-3-yl-pyrazolo[1,5-a]pyrimidin-5-yl)-cyclohexyl]-acetic acid

HRID 2047067Notes

Reaction equation

HRID 2047067 reaction equation
[N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].C([O:18][C:19](=[O:64])[CH2:20][CH:21]1[CH2:26][CH2:25][CH:24]([C:27]2[C:32](Br)=[C:31]([N:34](COCC[Si](C)(C)C)COCC[Si](C)(C)C)[N:30]3[N:51]=[CH:52][C:53]([C:54]4[CH:55]=[N:56][C:57]5[C:62]([CH:63]=4)=[CH:61][CH:60]=[CH:59][CH:58]=5)=[C:29]3[N:28]=2)[CH2:23][CH2:22]1)C.Cl>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:34][C:31]1[N:30]2[N:51]=[CH:52][C:53]([C:54]3[CH:55]=[N:56][C:57]4[C:62]([CH:63]=3)=[CH:61][CH:60]=[CH:59][CH:58]=4)=[C:29]2[N:28]=[C:27]([CH:24]2[CH2:23][CH2:22][CH:21]([CH2:20][C:19]([OH:18])=[O:64])[CH2:26][CH2:25]2)[C:32]=1[C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 11430Potassium CarbonateHCID 2734379(Pyridin-4-yl)boronic acidHCID 66733730(4-{7-[Bis-(2-trimethylsilanyl-ethoxymethyl)-amino]-6-bromo-3-quinolin-3-yl-pyrazolo[1,5-a]pyrimidin-5-yl}-cyclohexyl)-acetic acid ethyl ester

Product 1

HCID 70216820[4-(7-Amino-6-pyridin-4-yl-3-quinolin-3-yl-pyrazolo[1,5-a]pyrimidin-5-yl)-cyclohexyl]-acetic acidYield 9.6%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

4-Pyridine boronic acid (0.156 mmol, 20 mg), K2CO3 (0.234 mmol, 33 mg), and Pd(PPh3)4 (0.008 mmol, 10 mg) was added to a solution of (4-{7-[bis-(2-trimethylsilanyl-ethoxymethyl)-amino]-6-bromo-3-quinolin-3-yl-pyrazolo[1,5-a]pyrimidin-5-yl}-cyclohexyl)-acetic acid ethyl ester (0.078 mmol, 60 mg) in dioxane (1 mL). To this suspension was added distilled H2O (0.2 mL). The resulting reaction mixture was stirred at 100° C. under argon for 18 hours. The reaction mixture was concentrated in vacuo. The crude mixture was dissolved in 2:1 MeOH:H2O (1.5 mL) and was treated with 2N NaOH(aq) (0.5 mL). The resulting reaction mixture was stirred at room temperature for 18 hours. Aqueous hydrochloride solution (1.0 N, 2 ml) was added to the reaction mixture and the resulting solution was stirred at 65° C. for 2 h. The solution was concentrated in vacuo and purified by prep-LC to afford the title compound (3.6 mg) as a mixture of cis and trans isomers: LC/MS RT=2.84 min. Mass calculated for, M+H 479.21, observed 479.21.

Workup

  1. additionTo this suspension was added
  2. distillationdistilled H2O (0.2 mL)
  3. customThe resulting reaction mixture
  4. concentrationThe reaction mixture was concentrated in vacuo
  5. dissolutionThe crude mixture was dissolved in 2:1 MeOH
  6. additionH2O (1.5 mL) and was treated with 2N NaOH(aq) (0.5 mL)
  7. customThe resulting reaction mixture
  8. stirringwas stirred at room temperature for 18 hours
  9. stirringthe resulting solution was stirred at 65° C. for 2 h
  10. concentrationThe solution was concentrated in vacuo
  11. custompurified by prep-LC

Sources & evidence

ORD record
ord-86d0e2a26e2b445b9ec6219efb404a4b
Source dataset
uspto-grants-2013_11
Patent number
US08591943B2

Reaction notes

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