1,3-Bis(diphenylphosphino)propane → ethyl 10-methyl-8-[1-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-2-(3-oxocyclopentyl)ethyl]-5,5-dioxo-5,10-dihydrophenothiazine-3-carboxylate

HRID 14994

反応式

HRID 14994 の反応式
Br[C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[C:11]1[CH:10]=[C:9]([CH:17]([CH2:27][CH:28]3[CH2:36][CH2:35][C:30]4([O:34]CCO4)[CH2:29]3)[C:18]([NH:20][C:21]3[CH:25]=[CH:24][N:23]([CH3:26])[N:22]=3)=[O:19])[CH:8]=[CH:7][C:6]=1[S:5]2(=[O:38])=[O:37].CN1C2C=C(C[C:55]([O:57][CH2:58][CH3:59])=[O:56])C=CC=2S(=O)(=O)C2C1=CC=CC=2.CN1C=CC(N)=N1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(O)C.CS(C)=O.C(OCC)(=O)C.C(N(CC)CC)C>[CH3:16][N:12]1[C:13]2[CH:14]=[CH:15][C:2]([C:55]([O:57][CH2:58][CH3:59])=[O:56])=[CH:3][C:4]=2[S:5](=[O:37])(=[O:38])[C:6]2[C:11]1=[CH:10][C:9]([CH:17]([C:18](=[O:19])[NH:20][C:21]1[CH:25]=[CH:24][N:23]([CH3:26])[N:22]=1)[CH2:27][CH:28]1[CH2:36][CH2:35][C:30](=[O:34])[CH2:29]1)=[CH:8][CH:7]=2

参加物

9

反応物 4

HCID 812191,3-Bis(diphenylphosphino)propaneHCID 1372541-Methyl-3-aminopyrazoleHCID 580242102-(7-bromo-10-methyl-5,5-dioxo-5,10-dihydrophenothiazin-2-yl)-3-(1,4-dioxaspiro[4.4]non-7-yl)-N-(1-methyl-1H-pyrazol-3-yl)propionamideHCID 59340971Ethyl (10-methyl-5,5-dioxo-5,10-dihydrophenothiazin-2-yl)acetate

生成物 1

HCID 58024214ethyl 10-methyl-8-[1-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-2-(3-oxocyclopentyl)ethyl]-5,5-dioxo-5,10-dihydrophenothiazine-3-carboxylate

試薬・触媒・溶媒 4

HCID 679Dimethyl Sulfoxide溶媒HCID 702Ethanol溶媒HCID 8471Triethylamine溶媒HCID 8857Ethyl Acetate溶媒

反応条件

温度
70 °C

実験手順

A solution of 445 mg of 2-(7-bromo-10-methyl-5,5-dioxo-5,10-dihydrophenothiazin-2-yl)-3-(1,4-dioxaspiro[4.4]non-7-yl)-N-(1-methyl-1H-pyrazol-3-yl)propionamide (prepared analogously to Example 1 from ethyl (10-methyl-5,5-dioxo-5,10-dihydrophenothiazin-2-yl)acetate, T-iodomethyl-1,4-dioxa-spiro[4.4]nonane and commercially available 1-methyl-1H-pyrazole-3-amine) is dissolved in 8 ml of anhydrous ethanol and 8 ml of DMSO, and 0.74 ml of triethylamine and 76 mg of 1,3-bis(diphenylphosphino)propane are added under argon. The reaction solution is flushed with argon, and 35 mg of palladium acetate are then added. The reaction mixture is stirred at 70° C. and 1 bar of CO for three hours. The cooled reaction mixture is diluted by addition of 200 ml of ethyl acetate and washed with in each case 100 ml of water and saturated sodium chloride solution, dried over MgSO4 and then concentrated under reduced pressure. The residue is dissolved in 25 ml of acetone, and 3 ml of 10% strength hydrochloric acid are added. The reaction mixture is stirred at room temperature for three hours. The reaction mixture is then washed with saturated NaHCO3 solution, dried over MgSO4 and then concentrated under reduced pressure. The residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate=1:1=>ethyl acetate=>ethyl acetate:methanol=99:1. This gives 844 mg of ethyl 10-methyl-8-[1-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-2-(3-oxocyclopentyl)-ethyl]-5,5-dioxo-5,10-dihydrophenothiazine-3-carboxylate.

後処理

  1. customThe reaction solution is flushed with argon, and 35 mg of palladium acetate
  2. additionare then added
  3. customThe cooled reaction mixture
  4. washwashed with in each case 100 ml of water and saturated sodium chloride solution
  5. dry with materialdried over MgSO4
  6. concentrationconcentrated under reduced pressure
  7. dissolutionThe residue is dissolved in 25 ml of acetone
  8. addition3 ml of 10% strength hydrochloric acid are added
  9. stirringThe reaction mixture is stirred at room temperature for three hours
  10. washThe reaction mixture is then washed with saturated NaHCO3 solution
  11. dry with materialdried over MgSO4
  12. concentrationconcentrated under reduced pressure
  13. customThe residue is purified on silica gel using the mobile phase n-heptane

出典と根拠

ORDレコード
ord-827583916b25464a889047e96fac70ef
出典データセット
uspto-grants-2010_06
特許番号
US07732440B2

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