2-Amino-4-chloro-6-methylpyrimidine → 4-Chloro-5-iodo-6-methylpyrimidin-2-amine

HRID 518270Notes

Reaction equation

HRID 518270 reaction equation
N[C@H](C1[N:5](C2C=CC=CC=2)[C:6](=O)[C:7]2[C:12]([CH:13]=1)=CC=C[C:8]=2[Cl:14])C.COC1C=C(B(O)O)C=CN=1.[NH2:33][C:34]1[N:39]=[C:38]([Cl:40])[CH:37]=[C:36]([CH3:41])[N:35]=1.C1C(=O)N([I:49])C(=O)C1>C(#N)C.CO>[NH2:39][C:34]1[N:35]=[C:8]([Cl:14])[C:7]([C:6]#[N:5])=[C:12]([CH3:13])[N:33]=1.[Cl:40][C:38]1[C:37]([I:49])=[C:36]([CH3:41])[N:35]=[C:34]([NH2:33])[N:39]=1

Participants

8

Reactant 4

HCID 218102-Amino-4-chloro-6-methylpyrimidineHCID 120273N-IodosuccinimideHCID 23546919(2-Methoxypyridin-4-yl)boronic acidHCID 66607319(S)-3-(1-aminoethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one

Product 2

HCID 116447204-Chloro-5-iodo-6-methylpyrimidin-2-amineHCID 754124462-Amino-4-chloro-6-methyl-5-pyrimidinecarbonitrile

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6342AcetonitrileSolvent

Conditions

Temperature
60 °C

Procedure

Compound 362 was prepared from compound 1 and 2-methoxypyridin-4-ylboronic acid in analogous fashion to Example 2. Compound 363 was prepared as follows: 2-amino-4-chloro-6-methylpyrimidine (5.00 g, 34.8 mmol) was suspended in ACN (50 mL) and MeOH (70 mL). The mixture was charged with NIS (11.75 g, 52.2 mmol) at room temperature and the mixture was heated to 60° C. for 5 h. The mixture was cooled to room temperature and 80% of the volatiles were removed. The suspension was diluted with Et2O (100 mL) and the solids were filtered to obtain 10 g of 4-chloro-5-iodo-6-methylpyrimidin-2-amine. A solution of iodide (500 mg, 1.855 mmol) in DMF (40 mL) was charged with CuCN (332 mg, 3.71 mmol), Pd(PPh3)4 (1072 mg, 0.928 mmol) and CuI (247 mg, 1.299 mmol). The mixture was degassed for 10 min, then heated to 80° C. for 90 min. The mixture was cooled to room temperature and the material was partitioned between water and EA, then filtered on celite. The organic layer of the filtrate was washed several times with brine, dried and concentrated. The filtrate was pre-adsorbed on SiO2 and purified on ISCO 40 g (EA/hex) to give 2-amino-4-chloro-6-methylpyrimidine-5-carbonitrile 363. Compound 363 was coupled to compound 362 according to Method G to afford compound 364. ESI-MS m/z: 504.3 [M+H]+.

Workup

  1. temperatureThe mixture was cooled to room temperature
  2. custom80% of the volatiles were removed
  3. additionThe suspension was diluted with Et2O (100 mL)
  4. filtrationthe solids were filtered

Sources & evidence

ORD record
ord-0a85543566714ea29e38f0f2cc1845bf
Source dataset
uspto-grants-2015_08
Patent number
US09115141B2

Reaction notes

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