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

Reaction equation

HRID 14994 reaction equation
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

Participants

9

Reactant 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

Product 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

Reagents, catalysts & solvents 4

HCID 679Dimethyl SulfoxideSolventHCID 702EthanolSolventHCID 8471TriethylamineSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
70 °C

Procedure

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.

Workup

  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

Sources & evidence

ORD record
ord-827583916b25464a889047e96fac70ef
Source dataset
uspto-grants-2010_06
Patent number
US07732440B2

Linked notes

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