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

HRID 1783446

반응식

HRID 1783446 반응식
[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]

참가 물질

6

반응물 3

HCID 962Water2회HCID 10964447(S)-1,1,1-trifluoropropan-2-amine3회HCID 589101014,6-Dichloro-2-(pyrazin-2-yl)-5-(2,4,6-trifluorophenyl)pyrimidine5회

생성물 1

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

시약·촉매·용매 2

HCID 3776Isopropanol용매2회HCID 13387N-methyl-2-pyrrolidone용매6회

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온도
110 °C

실험 절차

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-trifluoro-phenyl)-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.

후처리

  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

출처 및 근거

ORD 기록
ord-4b2392e773864b249106f5bc0b76f0ef
출처 데이터셋
uspto-grants-2009_03
특허 번호
US07501423B2

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