Water → 6-Chloro-2-pyrazin-2-yl-N-[(1S)-2,2,2-trifluoro-1-methylethyl]-5-(2,4,6-trifluorophenyl)pyrimidin-4-amine

HRID 1295680Notes

Reaction equation

HRID 1295680 reaction equation
[Cl:1][C:2]1[C:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([F:15])=[CH:10][C:9]=2[F:16])=[C:6](Cl)[N:5]=[C:4]([C:18]2[CH:23]=[N:22][CH:21]=[CH:20][N:19]=2)[N:3]=1.[F:24][C:25]([F:30])([F:29])[C@@H:26]([NH2:28])[CH3:27].O>C(O)(C)C.CN1C(=O)CCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:18]2[CH:23]=[N:22][CH:21]=[CH:20][N:19]=2)[N:5]=[C:6]([NH:28][C@@H:26]([CH3:27])[C:25]([F:30])([F:29])[F:24])[C:7]=1[C:8]1[C:9]([F:16])=[CH:10][C:11]([F:15])=[CH:12][C:13]=1[F:14]

Participants

6

Reactant 3

HCID 962Water2×HCID 10964447(S)-1,1,1-trifluoropropan-2-amine3×HCID 589101014,6-Dichloro-2-(pyrazin-2-yl)-5-(2,4,6-trifluorophenyl)pyrimidine5×

Product 1

HCID 112819276-Chloro-2-pyrazin-2-yl-N-[(1S)-2,2,2-trifluoro-1-methylethyl]-5-(2,4,6-trifluorophenyl)pyrimidin-4-amineYield 92%

Reagents, catalysts & solvents 2

HCID 3776IsopropanolSolvent2×HCID 13387N-methyl-2-pyrrolidoneSolvent6×

Conditions

Temperature
110 °C

Procedure

In scheme 1, step d, a solution of 4,6-dichloro-2-pyrazin-2-yl-5-(2,4,6-trifluoro-phenyl)-pyrimidine 5 in an aprotic solvent, preferably 1-methyl-2-pyrrolidinone (NMP) in a ratio of 1–10 mL NMP/g of 4,6-dichloro-2-pyrazin-2-yl-5-(2,4,6-trifluoro-phenyl)-pyrimidine 5, preferably 1–5 mL NMP/g of 4,6-dichloro-2-pyrazin-2-yl-5-(2,4,6-trifluoro-phenyl)-pyrimidine 5, most preferably 1 mL NMP/g of 4,6-dichloro-2-pyrazin-2-yl-5-(2,4,6-trifluoro-phenyl)-pyrimidine 5 is added (S)-2,2,2-trifluoro-1-methyl-ethylamine 6 in a mole ratio of 4,6-dichloro-2-pyrazin-2-yl-5-(2,4,6-trifluoro-phenyl)-pyrimidine 5 to (S)-2,2,2-trifluoro-1-methyl-ethylamine 6 is 1:2–1:3 (mole/mole) preferably 1:2.5 (mole/mole) with stirring for over 24–48 h, preferably about 24 hours in a temperature range of about 90–125° C., more preferably at about 110° C. for about 24 hours. In an optional embodiment of the invention, the reaction is sealed to prevent loss of (S)-2,2,2-trifluoro-1-methyl-ethylamine 6. The reaction mixture is diluted with isopropyl alcohol (IPA), IPA to NMP (V/V) of about 1:1–1:5 preferable at about 1:3, then water is added with stirring at about 10–20° C. in a ratio of NMP to water (v/v) of about 1:1–1:5 (v/v), preferably at about 1:3 (v/v) with about 30 minutes of additional stirring and collecting, without the need of chromatography, the solid product, washing with water and drying to give 6-chloro-2-pyrazin-2-yl-N-[(1S)-2,2,2-trifluoro-1-methylethyl]-5-(2,4,6-trifluorophenyl)pyrimidin-4-amine 7. In a preferred embodiment of the invention, 4,6-dichloro-2-pyrazin-2-yl-5-(2,4,6-trifluorophenyl)-pyrimidine in 1-methyl-2-pyrrolidinone (NMP) is treated with (S)-2,2,2-trifluoro-1-methyl-ethylamine at about 110° C. for about 24 h and the reaction mixture diluted with IPA, then water 1:3 (v/v) is added slowly forming a precipitated product. The precipitated product is filtered, washed with water, and dried to give a solid product in 92% yield, having a 96% HPLC purity and an enantiomeric excess of >99%. The product 6-chloro-2-pyrazin-2-yl-N-[(1S)-2,2,2-trifluoro-1-methylethyl]-5-(2,4,6-trifluorophenyl)pyrimidin-4-amine 7 is collected without the need for chromatography.

Workup

  1. customIn an optional embodiment of the invention, the reaction is sealed
  2. stirringof additional stirring
  3. customcollecting, without the need of chromatography
  4. washthe solid product, washing with water
  5. customdrying

Sources & evidence

ORD record
ord-e83678eb26bd4adb94a8442c60f70939
Source dataset
uspto-grants-2007_07
Patent number
US07244736B2

Reaction notes

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