O-Xylene → (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 2358202Notes

Reaction equation

HRID 2358202 reaction equation
Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][C@@H:10]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[NH:11][C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[C:3]=1[CH3:29].[NH:30]1[CH2:35][CH2:34][CH:33]([C:36]2[N:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][NH:43]3)=[CH:38][CH:37]=2)[CH2:32][CH2:31]1.C1(C)C(C)=CC=CC=1.C(=O)(O)[O-].[Na+]>C(N(C(C)C)CC)(C)C.O.C(OCC)(=O)C.CO.C(N(CC)CC)C.ClCCl.C(OCC)(=O)C>[NH:43]1[C:44]2[C:39](=[CH:38][CH:37]=[C:36]([CH:33]3[CH2:34][CH2:35][N:30]([C:2]4[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][C@@H:10]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[NH:11][C:12]([O:14][CH2:15][C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)=[O:13])[C:3]=4[CH3:29])[CH2:31][CH2:32]3)[N:45]=2)[CH2:40][CH2:41][CH2:42]1

Participants

9

Reactant 4

HCID 7237O-XyleneHCID 516892Sodium BicarbonateHCID 113903267-(4-Piperidinyl)-1,2,3,4-tetrahydro[1,8]naphthyridineHCID 12094347(1,1-Dimethylethyl)-3-[(6-chloro-5-methyl-4-pyrimidinyl)amino]-n-[(phenylmethoxy)carbonyl]alaninate

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 6%

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 8857Ethyl AcetateSolvent2×HCID 81531DiisopropylethylamineSolventHCID 22169411Ethyl acetate methanol triethylamine dichloromethaneSolvent

Conditions

Temperature
120 °C

Procedure

A mixture of 370 mg (0.88 mmoles) of (1,1-dimethylethyl) 3-[(6-chloro-5-methyl-4-pyrimidinyl)amino]-N-[(phenylmethoxy)carbonyl]alaninate and 1.0 g (1.79 mmoles) of 1,2,3,4-tetrahydro-7-(4-piperidinyl)-1,8-naphthyridine, tris (trifluoroacetate) (prepared according to Patents EP 1065207 or WO 0078317) in 1 ml of diisopropylethylamine is heated at 120° C. for 2 hours. Then 10 ml of xylene is added and the medium is taken to reflux for 4 hours. The reaction medium is taken up in a mixture of water, ethyl acetate and a saturated solution of sodium bicarbonate. The organic phase is decanted and the aqueous phase is reextracted with ethyl acetate. The combined organic phases are dried over magnesium sulphate and evaporated to dryness under vacuum and the residue is chromatographed on silicagel with a gradient of 100% ethyl acetate to a mixture of ethyl acetate-methanol-triethylamine-dichloromethane 50-10-10-50.32 mg (Yield=6%) of expected product is obtained and 200 mg (54%) of chlorinated starting product is recovered.

Workup

  1. temperatureto reflux for 4 hours
  2. customThe organic phase is decanted
  3. dry with materialThe combined organic phases are dried over magnesium sulphate
  4. customevaporated to dryness under vacuum

Sources & evidence

ORD record
ord-6b003734f3d34dfa960e0e65c9e99c6f
Source dataset
uspto-grants-2010_07
Patent number
US07763621B2

Reaction notes

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