Diisopropylethylamine → (3S)-tert-butyl 3-methyl-4-(5-methyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

HRID 625039Notes

Reaction equation

HRID 625039 reaction equation
Cl[C:2]1[C:3]2[CH:10]([CH3:11])[S:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:12][C@H:13]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16][CH2:15][NH:14]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.C(OCC)(=O)C>[CH3:12][C@@H:13]1[N:14]([C:2]2[C:3]3[CH:10]([CH3:11])[S:9][CH2:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:15][CH2:16][N:17]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:18]1

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 7023035(S)-1-Boc-3-methylpiperazineHCID 717438984-Chloro-5-methyl-5,7-dihydrothieno[3,4-d]pyrimidine

Product 1

HCID 67459796(3S)-tert-butyl 3-methyl-4-(5-methyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylateYield 64%

Reagents, catalysts & solvents 2

HCID 8857Ethyl AcetateSolventHCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
120 °C

Procedure

To a solution of 4-chloro-5-methyl-5,7-dihydrothieno[3,4-d]pyrimidine (5 g, 27 mmol) and 2-(S)-methyl-4-Boc-piperazine (5.4 g, 27 mmol) in NMP (20 mL) was added DIEA (5 mL, 29 mmol). The mixture was heated to 120° C. for 24 hours. After cooling, the mixture was diluted with ethyl acetate (500 mL) and washed with water (6×200 mL). The organic phase was dried and concentrated to afford (3S)-tert-butyl 3-methyl-4-(5-methyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (6 g, 64%). 1H NMR (CDCl3, 400 MHz) δ 8.55 (s, 1H), 4.81 (m, 1H), 4.45 (m, 1H). 4.18 (m, 3H), 3.90 (m, 1H), 3.75 (m, 1H), 3.44-3.29 (m, 2H), 2.96 (m, 1H), 1.52 (m, 12H), 1.14 (d, J=6.4 Hz, 3H). MS (APCI+) [M+H]+ 351. The residue was purified by chiral HPLC separation (OD 250×20 mm; acetonitrile, 2 mL/min). The first peak (RT=3.93 min) was (S)-tert-butyl 3-methyl-4-((R)-5-methyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate and the secondary (RT=4.26 min) was (S)-tert-butyl 3-methyl-4-((S)-5-methyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate.

Workup

  1. temperatureAfter cooling
  2. washwashed with water (6×200 mL)
  3. customThe organic phase was dried
  4. concentrationconcentrated

Sources & evidence

ORD record
ord-b85d8eb55af04c45bed2fb985738fac4
Source dataset
uspto-grants-2016_04
Patent number
US09303040B2

Reaction notes

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