1,1,1-Trifluoropropan-2-yl carbonochloridate → 1,1,1-Trifluoropropan-2-yl 4-(4-(4-(methylsulfonyl)phenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

HRID 1877909Notes

Reaction equation

HRID 1877909 reaction equation
Cl.F[C:3]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:6]=[CH:5][C:4]=1[NH:13][C:14]1[C:19]2[O:20][CH2:21][CH2:22][N:23]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[C:18]=2[N:17]=[CH:16][N:15]=1.Cl[C:31]([O:33][CH:34]([CH3:39])[C:35]([F:38])([F:37])[F:36])=[O:32]>C(Cl)Cl>[CH3:12][S:9]([C:7]1[CH:8]=[CH:3][C:4]([NH:13][C:14]2[C:19]3[O:20][CH2:21][CH2:22][N:23]([CH:24]4[CH2:25][CH2:26][N:27]([C:31]([O:33][CH:34]([CH3:39])[C:35]([F:38])([F:37])[F:36])=[O:32])[CH2:28][CH2:29]4)[C:18]=3[N:17]=[CH:16][N:15]=2)=[CH:5][CH:6]=1)(=[O:11])=[O:10]

Participants

4

Reactant 2

HCID 582703481,1,1-Trifluoropropan-2-yl carbonochloridateHCID 67038626N-(2-fluoro-4-(methylsulfonyl)phenyl)-8-(piperidin-4-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine hydrochloric acid salt

Product 1

HCID 670386641,1,1-Trifluoropropan-2-yl 4-(4-(4-(methylsulfonyl)phenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylateYield 51%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

To a suspension of N-(2-fluoro-4-(methylsulfonyl)phenyl)-8-(piperidin-4-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine hydrochloric acid salt from Example 8A (35.5 mg, 0.08 mmol) in CH2Cl2 (1.5 mL) was added DIEP (70 μL, 0.40 mmol, Aldrich) followed by addition of 1,1,1-trifluoropropan-2-yl chloroformate (⅓ of the material from Step A, 0.33 mmol) in CH2Cl2 (0.5 mL). The reaction mixture was stirred for 30 min and then evaporated under the reduced pressure to yield the crude product which was purified by preparative HPLC(C18 column; 10-100% acetonitrile in water containing 0.05% trifluoroacetic acid) to give the desired product (33.9 mg, off-white solid, 51%) upon lyophilization. 1H NMR (500 MHz, CDCl3, 50° C.). δ 8.42 (t, J=8.25 Hz, 1H), 8.31 (brs, 1H), 8.14 (s, 1H), 7.59-7.78 (m, 2H), 5.18-5.34 (m, 1H), 4.78-4.93 (m, 1H), 4.22-4.41 (m, 4H), 3.47-3.55 (m, 2H), 3.04 (s, 3H), 2.88-3.07 (m, 2H), 1.79 (m, 2H), 1.60-1.75 (m, 2H), 1.42 (d, J=6.60 Hz, 3H).). LRMS (ESI) 548 (M+H)+.

Workup

  1. additionwas added DIEP (70 μL, 0.40 mmol, Aldrich)
  2. customevaporated under the reduced pressure
  3. customto yield the crude product which
  4. customwas purified by preparative HPLC(C18 column

Sources & evidence

ORD record
ord-e4b3a2e918d34a85b007821d881b1aaa
Source dataset
uspto-grants-2012_11
Patent number
US08314095B2

Reaction notes

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