Hydrochloric Acid → HCID 68678794, compound

HRID 1989080Notes

Reaction equation

HRID 1989080 reaction equation
[Na].C([O:4][C:5]([C:7]1[C:8]([N:15]([CH:23]2[CH2:28][CH:27]3[CH2:29][CH:24]2[CH2:25][CH2:26]3)[CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:9][C:10]([S:13][CH3:14])=[N:11][CH:12]=1)=O)C.CC(C)([O-])C.[Na+].Cl>C1(C)C=CC=CC=1.C(O)(C)(C)C>[CH2:21]([O:20][C:18]([CH:17]1[CH2:16][N:15]([CH:23]2[CH2:28][CH:27]3[CH2:29][CH:24]2[CH2:25][CH2:26]3)[C:8]2[N:9]=[C:10]([S:13][CH3:14])[N:11]=[CH:12][C:7]=2[C:5]1=[O:4])=[O:19])[CH3:22]

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 5360545SodiumHCID 23676156Sodium t-butoxideHCID 68676748HCID 68676748, compound

Product 1

HCID 68678794HCID 68678794, compoundYield 32.1%

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 6386tert-ButanolSolvent

Conditions

Temperature
90 °C

Procedure

3-(Bicyclo[2.2.1]hept-2-ylamino)-propionic acid ethyl ester (1.5 g, 7.1 mmol) and 4-chloro-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (1.6 g, 7.1 mmol) were combined in CH2Cl2 (20 mL) and triethylamine (1.0 g, 10 mmol) was added. After 16 h, water (10 mL) was added the organic layer was separated, dried (MgSO4), and concentrated. Chromatography (10-50% EtOAc/hexanes gradient) provided 1.8 g of 4-[bicyclo[2.2.1]hept-2-yl-(2-ethoxycarbonyl-ethyl)-amino]-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester. Sodium (30 wt % dispersion in paraffin wax, 0.55 g, 7.2 mmol) was added to t-butanol (5.0 mL) at rt. After 30 minutes, a solution of 4[bicyclo[2.2.1]hept-2-yl-(2-ethoxycarbonyl-ethyl)-amino]-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (1.8 g, 4.4 mmol) in 20 mL of toluene was added to the sodium t-butoxide solution and the resulting mixture was heated at 90° C. for 30 minutes. The reaction mixture was then cooled and the solution was adjusted to pH 7 using a 1N HCl solution. The solution was then extracted with EtOAc (2×20 mL) and the organic layer was dried (MgSO4), and concentrated. Recrystallization from i-PrOH provided 0.51 g of 8-bicyclo[2.2.1]hept-2-yl-2-methylsulfanyl-5-oxo-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester. 8-Bicyclo[2.2.1]hept-2-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (46 mg, 0.12 mmol) and 4-(4-methyl-piperazin-1-yl)-phenylamine (22 mg, 0.12 mmol) were combined in i-PrOH (2 mL) and heated to 90° C. After 3 h, the reaction mixture was concentrated and purified by preparative HPLC (C-18 column, 32 mL/min 5-100% MeCN/H2O gradient over 15 min) and lyophilized to provide 11.4 mg of 8-bicyclo[2.2.1]hept-2-yl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester. 1H NMR (400 MHz, CDCl3) δ (ppm): 9.21 (s, 1H), 8.59 (s, 1H), 7.52 (d, 2H, J=8.9 Hz), 6.87 (d, 2H, J=9.0 Hz), 4.31 (q, 2H, J=7.1 Hz), 3.52-3.62 (m, 4H), 3.28 (br s, 2H), 2.98 (br s, 2H), 2.82 (s, 3H), 2.14-2.53 (m, 5H), 1.58-1.75 (m, 4H), 1.22-1.42 (m, 5H).

Workup

  1. temperatureThe reaction mixture was then cooled
  2. extractionThe solution was then extracted with EtOAc (2×20 mL)
  3. dry with materialthe organic layer was dried (MgSO4)
  4. concentrationconcentrated
  5. customRecrystallization from i-PrOH

Sources & evidence

ORD record
ord-19a8079055f7416f9be47a85b5922df5
Source dataset
uspto-grants-2010_01
Patent number
US07642270B2

Reaction notes

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