Diisopropylethylamine → 7-Fluoro-3-methyl-1-[2-(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}piperidin-1-yl)ethyl]quinazoline-2,4(1H,3H)-dione

HRID 255297Notes

Reaction equation

HRID 255297 reaction equation
FC(F)(F)C(O)=O.[NH2:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([F:27])[CH:25]=3)[C:20](=[O:28])[N:19]([CH3:29])[C:18]2=[O:30])[CH2:11][CH2:10]1.C(N(CC)C(C)C)(C)C.[O:40]=[C:41]1[CH2:46][O:45][C:44]2[CH:47]=[CH:48][C:49]([CH:51]=O)=[N:50][C:43]=2[NH:42]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O>[F:27][C:24]1[CH:25]=[C:26]2[C:21]([C:20](=[O:28])[N:19]([CH3:29])[C:18](=[O:30])[N:17]2[CH2:16][CH2:15][N:12]2[CH2:11][CH2:10][CH:9]([NH:8][CH2:51][C:49]3[CH:48]=[CH:47][C:44]4[O:45][CH2:46][C:41](=[O:40])[NH:42][C:43]=4[N:50]=3)[CH2:14][CH2:13]2)=[CH:22][CH:23]=1

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 5049666Sodium triacetoxyborohydrideHCID 218737373-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehydeHCID 667742531-[2-(4-Aminopiperidin-1-yl)ethyl]-7-fluoro-3-methylquinazoline-2,4(1H,3H)-dione trifluoroacetate salt2×

Product 1

HCID 159824057-Fluoro-3-methyl-1-[2-(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}piperidin-1-yl)ethyl]quinazoline-2,4(1H,3H)-dioneYield 21%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent2×

Procedure

1-[2-(4-Aminopiperidin-1-yl)ethyl]-7-fluoro-3-methylquinazoline-2,4(1H,3H)-dione trifluoroacetate salt (Intermediate 134) (0.476 mmol, 380 mg crude) was converted to the free base with N,N-diisopropylethylamine (0.5 mL, 3.0 mmol) and reacted with 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (102 mg, 0.571 mmol) and sodium triacetoxy borohydride (222 mg, 1.05 mmol) as described for Example 55. The reaction was diluted with dichloromethane and water. The layers were separated. The aqueous layer was extracted with dichloromethane twice. The combined organic layers were dried over magnesium sulfate and evaporated at reduced pressure. Chromatography on silica gel using methanol in dichloromethane (0-9%) with 1% concentrated ammonium hydroxide (aqueous) gave the product as a waxy material. This material was taken up in dichloromethane and washed well with water. The organic phase was dried over magnesium sulfate and evaporated to obtain the title compound as a colorless solid (48 mg, 21%).

Workup

  1. customThe layers were separated
  2. extractionThe aqueous layer was extracted with dichloromethane twice
  3. dry with materialThe combined organic layers were dried over magnesium sulfate
  4. customevaporated at reduced pressure
  5. customgave the product as a waxy material
  6. washwashed well with water
  7. dry with materialThe organic phase was dried over magnesium sulfate
  8. customevaporated

Sources & evidence

ORD record
ord-6f1589b029764d08a265a92b10b7299e
Source dataset
uspto-grants-2011_01
Patent number
US07875715B2

Reaction notes

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