Diisopropylethylamine → (R,E)-6-amino-9-(1-(4-(cyclopropyl(methyl)amino)but-2-enoyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one

HRID 1887062Notes

Reaction equation

HRID 1887062 reaction equation
[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]([C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:19][CH:18]=1)[C:5](=[O:16])[N:6]2[C@@H:11]1[CH2:15][CH2:14][NH:13][CH2:12]1.Cl.[CH:31]1([N:34]([CH3:41])[CH2:35][CH:36]=[CH:37][C:38](O)=[O:39])[CH2:33][CH2:32]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]([C:17]1[CH:18]=[CH:19][C:20]([O:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:21][CH:22]=1)[C:5](=[O:16])[N:6]2[C@@H:11]1[CH2:15][CH2:14][N:13]([C:38](=[O:39])/[CH:37]=[CH:36]/[CH2:35][N:34]([CH:31]2[CH2:33][CH2:32]2)[CH3:41])[CH2:12]1

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 86691225(R)-6-amino-7-(4-phenoxyphenyl)-9-(pyrrolidin-3-yl)-7H-purin-8(9H)-oneHCID 866912264-(Cyclopropyl(methyl)amino)but-2-enoic acid hydrochloride

Product 1

HCID 86691224(R,E)-6-amino-9-(1-(4-(cyclopropyl(methyl)amino)but-2-enoyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-oneYield 24.6%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

A solution of (R)-6-amino-7-(4-phenoxyphenyl)-9-(pyrrolidin-3-yl)-7H-purin-8(9H)-one (62) (95 mg, 0.24 mmol), 4-(cyclopropyl(methyl)amino)but-2-enoic acid hydrochloride (69 mg, 0.36 mmol) and DIPEA (213 μL, 1.2 mmol) in 5 mL dry DMF was cooled to 0° C. HBTU (190 mg, 0.49 mmol) was added in one portion. The reaction mixture was allowed to warm to rt, and stirred for 2 hrs under N2, then purified directly by Gilson using 10 to 95% acetonitrile in water (0.2% NH3.H2O) to give (R,E)-6-amino-9-(1-(4-(cyclopropyl(methyl)amino)but-2-enoyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one (63) (31 mg, 17.7%) as a light yellow solid. LC-MS (ESI): m/z (M+1) 526. 1H NMR (400 MHz, DMSO) δ 8.14 (d, J=6.0 Hz, 1H), 7.55-7.34 (m, 4H), 7.30-7.08 (m, 5H), 6.76-6.59 (m, 1H), 6.36 (dd, J=37.4, 15.1 Hz, 1H), 5.82 (d, J=9.1 Hz, 2H), 5.20-4.99 (m, 1H), 4.11-3.40 (m, 4H), 3.26 (dd, J=17.7, 6.4 Hz, 2H), 2.78-2.59 (m, 1H), 2.24 (d, J=12.4 Hz, 3H), 1.80-1.63 (m, 1H), 0.51-0.37 (m, 2H), 0.37-0.24 (m, 2H).

Workup

  1. custompurified directly by Gilson

Sources & evidence

ORD record
ord-14ad64572acf4c2f861d69b46ed6cfa2
Source dataset
uspto-grants-2013_08
Patent number
US08501724B1

Reaction notes

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