Acetone → N-((1'-benzyl-1-(5-ethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4'-piperidine]-4-yl)methyl)propan-2-amine

HRID 529146Notes

Reaction equation

HRID 529146 reaction equation
F[C:2](F)(F)[C:3](O)=O.FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[CH2:22]([N:29]1[CH2:34][CH2:33][C:32]2([C:42]3[C:37](=[CH:38][CH:39]=[CH:40][C:41]=3[CH2:43][NH2:44])[N:36]([C:45]3[C:46]4[CH:53](CC)[CH2:52][CH2:51][C:47]=4[N:48]=[CH:49][N:50]=3)[CH2:35]2)[CH2:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[CH3:56][C:57]([CH3:59])=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(N)(C)C>ClCCCl>[CH2:22]([N:29]1[CH2:34][CH2:33][C:32]2([C:42]3[C:37](=[CH:38][CH:39]=[CH:40][C:41]=3[CH2:43][NH:44][CH:57]([CH3:59])[CH3:56])[N:36]([C:45]3[C:46]4[CH:53]([CH2:2][CH3:3])[CH2:52][CH2:51][C:47]=4[N:48]=[CH:49][N:50]=3)[CH2:35]2)[CH2:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1

Participants

6

Reactant 4

HCID 180AcetoneHCID 6363IsopropylamineHCID 5049666Sodium triacetoxyborohydrideHCID 86651813(1'-benzyl-1-(5-ethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4'-piperidine]-4-yl)methanamine tris(2,2,2-trifluoroacetate)

Product 1

HCID 69811460N-((1'-benzyl-1-(5-ethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4'-piperidine]-4-yl)methyl)propan-2-amineYield 18%

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent

Procedure

(1′-Benzyl-1-(5-ethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)methanamine tris(2,2,2-trifluoroacetate) (606 mg, 0.762 mmol) was stirred in a solution of acetone (0.280 mL, 3.81 mmol) and DCE (5 mL) for 15 minutes. NaBH(OAc)3 (323 mg, 1.52 mmol) was added in one portion and resulted in vigorous evolution of gas. After 1 hour at room temperature, LCMS suggested complete conversion to the desired isopropylamine. The reaction was concentrated and partitioned between EtOAc and 10% aqueous K2CO3. The organic was washed with brine, dried over Na2SO4 and concentrated to a crude residue. The racemic crude was purified by silica gel chromatography (gradient: 5-100% (80 DCM: 19 MeOH: 1 NH4OH)/DCM). Purification provided N-((1′-benzyl-1-(5-ethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)methyl)propan-2-amine (68 mg, 0.137 mmol, 18.0% yield) as an oil. 1H NMR (CDCl3, 400 MHz) δ 8.62 (s, 1H), 7.27-7.33 (m, 5H), 7.24 (m, 1H), 7.18 (t, 1H), 6.96 (d, 1H), 3.95 (m, 4H), 3.54 (s, 2H), 3.27 (m, 1H), 2.84-2.99 (m, 5H), 2.63 (dt, 1H), 2.03-2.31 (m, 4H), 1.86 (m, 1H), 1.70 (dd, 2H), 1.42 (m, 2H), 1.15-1.119 (m, 7H), 0.78 (t, 3H). MS (APCI+) [M+H]: 496.3. Separation of isomers was conducted by preparative HPLC using a Chiralpak AD-H column (4.6×100 mm). The compound was eluted with 25% methanol/water (0.1% TEA additive) at 3 mL/min and 120 bars.

Workup

  1. customresulted in vigorous evolution of gas
  2. concentrationThe reaction was concentrated
  3. custompartitioned between EtOAc and 10% aqueous K2CO3
  4. washThe organic was washed with brine
  5. dry with materialdried over Na2SO4
  6. concentrationconcentrated to a crude residue
  7. customThe racemic crude was purified by silica gel chromatography (gradient: 5-100% (80 DCM: 19 MeOH: 1 NH4OH)/DCM)
  8. customPurification

Sources & evidence

ORD record
ord-ed62a519a65e485f80d3798e0c9fdd89
Source dataset
uspto-grants-2016_05
Patent number
US09346805B2

Reaction notes

Loading…