Cesium fluoride → (1,1-dimethylethyl) 3-[[5-methyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alaninate

HRID 729746Notes

Reaction equation

HRID 729746 reaction equation
Br[C:2]1[C:7]([CH3:8])=[C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]3[N:24]=[C:23]4[C:18]([CH2:19][CH2:20][CH2:21][NH:22]4)=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)[N:5]=[CH:4][N:3]=1.[CH3:25][C:26]([O:29][C:30](=[O:45])[C@H:31]([CH2:43][NH2:44])[NH:32][C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])([CH3:28])[CH3:27].[F-].[Cs+]>O1CCOCC1.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[CH3:8][C:7]1[C:2]([NH:44][CH2:43][C@@H:31]([C:30]([O:29][C:26]([CH3:28])([CH3:27])[CH3:25])=[O:45])[NH:32][C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])=[N:3][CH:4]=[N:5][C:6]=1[N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[N:24]=[C:23]3[C:18]([CH2:19][CH2:20][CH2:21][NH:22]3)=[CH:17][CH:16]=2)[CH2:11][CH2:10]1

Participants

6

Reactant 3

HCID 25953Cesium fluoride2×HCID 10803731(S)-tert-Butyl 3-amino-2-(((benzyloxy)carbonyl)amino)propanoate2×HCID 578328314-Bromo-5-methyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-piperidinyl]-pyrimidine

Product 1

HCID 12094349(1,1-dimethylethyl) 3-[[5-methyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alaninateYield 37.4%

Reagents, catalysts & solvents 2

HCID 9832798Tris(dibenzylideneacetone) dipalladiumCatalystHCID 312751,4-DioxaneSolvent

Procedure

A mixture of 620 mg (1.6 mmoles) of 4-bromo-5-methyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-piperidinyl]-pyrimidine, 565 mg (1.92 mmoles) of (1,1-dimethylethyl)3-amino-N-[(phenylmethoxy)carbonyl]alaninate (prepared according to J. Med. Chem.(2001), 44(8), 1158-1176), 340 mg (2.25 mmoles) of caesium fluoride, 73 mg (0.08 mmoles) of tris(dibenzylideneacetone) dipalladium(0), 100 mg (0.16 mmoles) of S(−)2,2′-bis(diphenyl-phosphino)-1,1′-binaphthyl in 50 ml of dioxane is heated under reflux for 5 hours. After cooling down another 280 mg (0.96 mmoles) of (1,1-dimethylethyl)3-amino-N-[(phenylmethoxy)carbonyl]alaninate, 340 mg (2.25 mmoles) of caesium fluoride, 73 mg (0.08 mmoles) of tris(dibenzylideneacetone) dipalladium(0),and 100 mg (0.16 mmoles) of S(−)2,2′-bis(diphenyl-phosphino)-1,1′-binaphthyl are then added and the reaction mixture is heated under reflux for 5 hours. The reaction mixture is evaporated to dryness under reduced pressure (2 kPa) and the residue is taken up in ethyl acetate, water and a saturated solution of sodium bicarbonate. The organic phase is separated, dried over magnesium sulphate and the solvent is evaporated off under reduced pressure (2 kPa). The residue is chromatographed a first time on silicagel eluting with a gradient of ethyl acetate-methylene chloride-triethylamine-methanol from 50-50-0-0 to 50-50-2-2. The product obtained is chromatographed a second time on alumina eluting with a mixture of heptane-methylene chloride 50-50 then with ethyl acetate-diisopropyl ether 50-50. 360 mg (Yield=37%) of expected product is obtained in the form of an amorphous white solid.

Workup

  1. temperatureis heated
  2. temperatureunder reflux for 5 hours
  3. additionare then added
  4. temperaturethe reaction mixture is heated
  5. temperatureunder reflux for 5 hours
  6. customThe reaction mixture is evaporated to dryness under reduced pressure (2 kPa)
  7. customThe organic phase is separated
  8. dry with materialdried over magnesium sulphate
  9. customthe solvent is evaporated off under reduced pressure (2 kPa)
  10. customThe residue is chromatographed a first time
  11. washon silicagel eluting with a gradient of ethyl acetate-methylene chloride-triethylamine-methanol from 50-50-0-0 to 50-50-2-2
  12. customThe product obtained
  13. customis chromatographed a second time on alumina eluting
  14. additionwith a mixture of heptane-methylene chloride 50-50

Sources & evidence

ORD record
ord-d2989b773a784f50a34b642470575111
Source dataset
uspto-grants-2009_09
Patent number
US07582640B2

Reaction notes

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