Diisopropylethylamine → (R)-tert-butyl 3-((S)-1-(4-chlorophenyl)-2-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-oxoethyl)morpholine-4-carboxylate

HRID 1916417Notes

Reaction equation

HRID 1916417 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][C@H:9]1[C@H:14]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:27][C@H:28]1[C:36]2[C:35]([N:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)=[N:34][CH:33]=[N:32][C:31]=2[C@@H:30]([OH:43])[CH2:29]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C@@H:14]([C@@H:9]2[CH2:10][O:11][CH2:12][CH2:13][N:8]2[C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[C:15]([N:40]2[CH2:41][CH2:42][N:37]([C:35]3[C:36]4[C@H:28]([CH3:27])[CH2:29][C@H:30]([OH:43])[C:31]=4[N:32]=[CH:33][N:34]=3)[CH2:38][CH2:39]2)=[O:17])=[CH:23][CH:22]=1

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 66618065HCID 66618065, compoundHCID 66845288(S)-2-((R)-4-(tert-Butoxycarbonyl)morpholin-3-yl)-2-(4-chlorophenyl)acetic acid

Product 1

HCID 66845593(R)-tert-butyl 3-((S)-1-(4-chlorophenyl)-2-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-oxoethyl)morpholine-4-carboxylate

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

(S)-2-((R)-4-(tert-Butoxycarbonyl)morpholin-3-yl)-2-(4-chlorophenyl)acetic acid (0.051 g, 0.143 mmol) was combined with (5R,7S)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (0.0440 g, 0.143 mmol), and then slurried in methylene chloride (1.4 mL). The suspension was treated with diisopropylethylamine (0.0749 mL, 0.430 mmol) and then with HBTU (0.0544 g, 0.143 mmol). The mixture was then stirred at ambient temperature for 60 hours. The reaction was quenched with 10% Na2CO3 and separated. The reaction mixture was washed with methylene chloride (3×), and the combined organics were then dried with Na2SO4 and concentrated in vacuo. The resulting residue was subjected to chromatography on SiO2 (Biotage 12M) eluting with methylene chloride (96 mL) then 0% to 5% MeOH/methylene chloride (500 mL) and 5% MeOH/methylene chloride (96 mL). The desired material eluted cleanly in approximately 1% MeOH/methylene chloride to yield (R)-tert-butyl 3-((S)-1-(4-chlorophenyl)-2-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-oxoethyl)morpholine-4-carboxylate as an oil. (81.2 mg, 99%).

Workup

  1. customThe reaction was quenched with 10% Na2CO3
  2. customseparated
  3. washThe reaction mixture was washed with methylene chloride (3×)
  4. dry with materialthe combined organics were then dried with Na2SO4
  5. concentrationconcentrated in vacuo
  6. washeluting with methylene chloride (96 mL)
  7. washThe desired material eluted cleanly in approximately 1% MeOH/methylene chloride

Sources & evidence

ORD record
ord-83700d5c89b340f58e3ca287d9583b46
Source dataset
uspto-grants-2013_12
Patent number
US08618097B2

Reaction notes

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