Hydrochloric Acid → 3-Methoxymethyl-1-{2-[4-(4-pyrimidin-2-yl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-acetyl}-pyrrolidine-3-carboxylic acid [3-(2-cyclopropyl-pyridin-4-yl)-1-trityl-1H-indazol-5-yl]-amide

HRID 1038056Notes

Reaction equation

HRID 1038056 reaction equation
[CH3:1][O:2][C:3]([C:5]1([CH2:31][O:32]C)[CH2:9][CH2:8][N:7]([C:10](=[O:30])[CH2:11][N:12]2[CH2:17][CH:16]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[N:29]=[CH:28][CH:27]=[CH:26][N:25]=4)=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)[CH2:6]1)=O.[OH-].[Na+].Cl.[CH:37]1([C:40]2[CH:45]=[C:44]([C:46]3[C:54]4[C:49](=[CH:50][CH:51]=[C:52]([NH2:55])[CH:53]=4)[N:48]([C:56]([C:69]4[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=4)([C:63]4[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=4)[C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)[N:47]=3)[CH:43]=[CH:42][N:41]=2)[CH2:39][CH2:38]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C)C=O.ClCCl.CO.ClCCl>[CH:37]1([C:40]2[CH:45]=[C:44]([C:46]3[C:54]4[C:49](=[CH:50][CH:51]=[C:52]([NH:55][C:31]([C:5]5([CH2:3][O:2][CH3:1])[CH2:9][CH2:8][N:7]([C:10](=[O:30])[CH2:11][N:12]6[CH2:17][CH:16]=[C:15]([C:18]7[CH:19]=[CH:20][C:21]([C:24]8[N:29]=[CH:28][CH:27]=[CH:26][N:25]=8)=[CH:22][CH:23]=7)[CH2:14][CH2:13]6)[CH2:6]5)=[O:32])[CH:53]=4)[N:48]([C:56]([C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)([C:69]4[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=4)[C:63]4[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=4)[N:47]=3)[CH:43]=[CH:42][N:41]=2)[CH2:38][CH2:39]1

Participants

9

Reactant 6

HCID 313Hydrochloric AcidHCID 8471TriethylamineHCID 14798Sodium HydroxideHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 576858383-(2-Cyclopropyl-pyridin-4-yl)-1-trityl-1H-indazol-5-ylamineHCID 674196363-Methoxymethyl-1-{2-[4-(4-pyrimidin-2-yl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-acetyl}-pyrrolidine-3-carboxylic acid methyl ester

Product 1

HCID 765923933-Methoxymethyl-1-{2-[4-(4-pyrimidin-2-yl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-acetyl}-pyrrolidine-3-carboxylic acid [3-(2-cyclopropyl-pyridin-4-yl)-1-trityl-1H-indazol-5-yl]-amideYield 56.4%

Reagents, catalysts & solvents 2

HCID 21226129Dichloromethane methanolSolventHCID 22350042dichloromethane N,N-dimethylformamideSolvent

Procedure

3-Methoxymethyl-1-{2-[4-(4-pyrimidin-2-yl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-acetyl}-pyrrolidine-3-carboxylic acid methyl ester (500 mg, 1.11 mmol) was added to a solution of 10 ml of 50% methanol/dichloromethane. 5 mL of 1N NaOH was added and the reaction mixture stirred for 18 hrs. 5.5 ml of 1N HCl was added and the reaction mixture evaporated to dryness. To the crude reaction mixture was added 3-(2-Cyclopropyl-pyridin-4-yl)-1-trityl-1H-indazol-5-ylamine (601 mg, 1.22 mmol), HATU (464 mg, 6.66 mmol), triethylamine (0.93 ml, 6.66 mmol) and 10 ml of 50% N,N-dimethylformamide/dichloromethane. The reaction mixture was stirred for 18 hrs. followed by washing with brine and extracted with ethylacetate 3×. After evaporation of the organic layers, the crude reaction mixture was chromatographed on silica gel using 1-3% 2N NH3/methanol/dichlormethane as the eluent to obtain 570 mg of title product.

Workup

  1. customthe reaction mixture evaporated to dryness
  2. customTo the crude reaction mixture
  3. stirringThe reaction mixture was stirred for 18 hrs
  4. washby washing with brine
  5. extractionextracted with ethylacetate 3×
  6. customAfter evaporation of the organic layers
  7. customthe crude reaction mixture
  8. customwas chromatographed on silica gel using 1-3% 2N NH3/methanol/dichlormethane as the eluent

Sources & evidence

ORD record
ord-95d80d1b366246fbbccf42a0b0835560
Source dataset
uspto-grants-2013_10
Patent number
US08546404B2

Reaction notes

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