Sodium Carbonate → methyl 4-(3-(4-((1,3-dimethyl-1H-pyrazol-4-yl)methyl)piperazin-1-yl)pyrazin-2-yl)benzoate

HRID 220592Notes

Reaction equation

Cl[C:2]1[C:3]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=3)[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[CH3:22][O:23][C:24]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)=[O:25].C(=O)([O-])[O-].[Na+].[Na+].Cl.CN1C(C)=C(CN2CCN(C3C(C4C=CC(C(OC)C)=CC=4)=NC=CN=3)CC2)C=N1>[Pd](Cl)Cl.C1(P(CNCP(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO.C(O)C>[CH3:20][N:18]1[CH:19]=[C:15]([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:3]3[C:2]([C:29]4[CH:30]=[CH:31][C:26]([C:24]([O:23][CH3:22])=[O:25])=[CH:27][CH:28]=4)=[N:7][CH:6]=[CH:5][N:4]=3)[CH2:9][CH2:10]2)[C:16]([CH3:21])=[N:17]1

Participants

Conditions

Temperature: 140 °C

Procedure

Charge a microwave tube with 3′-chloro-4-(1,3-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (0.150 g, 0.490 mmoles), bis[(diphenylphosphanyl)methyl]-amine palladium (II) dichloride polymer bound (0.061 g, 0.049 mmoles, 0.1 eq), 4-(methoxycarbonyl)phenylboronic acid (0.176 g, 0.98 mmoles, 2 eq), sodium carbonate (0.192 g, 1.8 mmoles, 3.7 eq) and 3 ml of ethanol. Seal the reaction and heat under microwave conditions at 140° C. for 30 min. Cool down reaction and apply crude material to an SCX column prewashed with 10 ml methanol. Wash material with 10 ml of methanol, and release the product with 20 ml of a 2 N-ammonia/methanol solution. Purify the crude brown oil by reverse phase chromatography (28% isocratic acetonitrile/0.01 M ammonium bicarbonate in water, 80 ml/min., for 8 min., on a 30×75 mm, C18 Xterra column) to provide methyl 4-(3-(4-((1,3-dimethyl-1H-pyrazol-4-yl)methyl)piperazin-1-yl)pyrazin-2-yl)benzoate as a white solid (0.051 g, 26% yield, ES+(m/z) 407 [M+H]). Convert the purified material to the hydrochloride salt by stirring a solution of the free base (0.045 g, 0.294 mmoles) in acetonitrile (5 ml) at room temperature and add 1 N HCl in water (0.294 ml, 0.294 mmoles) to give a yellow solution. After 5 min., freeze the solution and lyophilize to give the title compound as a white solid (0.056 g, 100% yield, ES+(m/z) 407 [M+H]).

Workup

customSeal
customthe reaction
temperatureCool down reaction and apply crude material to an SCX column
customPurify the crude brown oil by reverse phase chromatography (28% isocratic acetonitrile/0.01 M ammonium bicarbonate in water, 80 ml/min.

Sources & evidence

ORD record: ord-c9595486ffde4647bd7a32b6b61e8aac
Source dataset: uspto-grants-2012_06
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08202873B2

Reaction notes

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