Diisopropylethylamine → tert-butyl 4-(4-chloro-3-fluorophenyl)-4-(1-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-4-carbonyl)piperidine-1-carboxylate

HRID 2200290Notes

Reaction equation

HRID 2200290 reaction equation
Cl.Cl.[CH3:3][C@H:4]1[C:12]2[C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][CH:9]=[N:8][C:7]=2[C@H:6]([OH:19])[CH2:5]1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][C:30]([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([F:43])[CH:37]=2)([C:33](O)=[O:34])[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].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>C(Cl)Cl>[Cl:42][C:39]1[CH:40]=[CH:41][C:36]([C:30]2([C:33]([N:16]3[CH2:15][CH2:14][N:13]([C:11]4[C:12]5[C@H:4]([CH3:3])[CH2:5][C@@H:6]([OH:19])[C:7]=5[N:8]=[CH:9][N:10]=4)[CH2:18][CH2:17]3)=[O:34])[CH2:29][CH2:28][N:27]([C:25]([O:24][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:26])[CH2:32][CH2:31]2)=[CH:37][C:38]=1[F:43]

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 66618034(5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochlorideHCID 666180441-(Tert-butoxycarbonyl)-4-(4-chloro-3-fluorophenyl)piperidine-4-carboxylic acid

Product 1

HCID 66618478tert-butyl 4-(4-chloro-3-fluorophenyl)-4-(1-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-4-carbonyl)piperidine-1-carboxylateYield 22.9%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

(5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (35.0 mg, 0.114 mmol) and 1-(tert-butoxycarbonyl)-4-(4-chloro-3-fluorophenyl)piperidine-4-carboxylic acid (40.8 mg, 0.114 mmol) were dissolved in DCM (1.1 mL) and treated with DIEA (0.0595 ml, 0.342 mmol) at ambient temperature. The mixture was allowed to homogenize before the HBTU (47.5 mg, 0.125 mmol) was added in one lot. The reaction was allowed to stir for four hours to completion by LCMS analysis of the crude. The reaction was diluted with DCM, washed with diluted NaHCO3 solution, washed with water, washed with brine, and separated. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by chromatography (silica gel eluted with 5% methanol in ethyl acetate) to afford the pure tert-butyl 4-(4-chloro-3-fluorophenyl)-4-(1-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-4-carbonyl)piperidine-1-carboxylate (15.0 mg, 22.9% yield) as a pale yellow oil. MS (APCI+) [M+H] +574; Rf: 2.92.

Workup

  1. additionwas added in one lot
  2. washwashed with diluted NaHCO3 solution
  3. washwashed with water
  4. washwashed with brine
  5. customseparated
  6. dry with materialThe organic layer was dried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customThe residue was purified by chromatography (silica gel eluted with 5% methanol in ethyl acetate)

Sources & evidence

ORD record
ord-34c1d482d488407eb6092b09307344c0
Source dataset
uspto-grants-2016_06
Patent number
US09359340B2

Reaction notes

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