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Thionyl Chloride → 6-fluoro-N-(1-(3-fluorobenzyl)-1H-indazol-5-yl)pyrido[3,4-d]-pyrimidin-4-amine

HRID 511788
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HRID 511788 반응식
[F:1][C:2]1[N:12]=[CH:11][C:5]2[NH:6][C:7](=O)[N:8]=[CH:9][C:4]=2[CH:3]=1.S(Cl)(Cl)=O.[F:17][C:18]1[CH:19]=[C:20]([CH:32]=[CH:33][CH:34]=1)[CH2:21][N:22]1[C:30]2[C:25](=[CH:26][C:27]([NH2:31])=[CH:28][CH:29]=2)[CH:24]=[N:23]1>CN(C=O)C.CC(N(C)C)=O>[F:1][C:2]1[N:12]=[CH:11][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:31][C:27]3[CH:26]=[C:25]4[C:30](=[CH:29][CH:28]=3)[N:22]([CH2:21][C:20]3[CH:32]=[CH:33][CH:34]=[C:18]([F:17])[CH:19]=3)[N:23]=[CH:24]4)[C:4]=2[CH:3]=1
참가 물질실험 절차후처리출처 및 근거반응 노트

참가 물질

6

반응물 3

HCID 24386Thionyl ChlorideHCID 71470731-(3-Fluorobenzyl)-1H-indazol-5-amineHCID 668235116-Fluoropyrido[3,4-d]pyrimidinone

생성물 1

HCID 681586436-fluoro-N-(1-(3-fluorobenzyl)-1H-indazol-5-yl)pyrido[3,4-d]-pyrimidin-4-amine수율 80.1%

시약·촉매·용매 2

HCID 6228Dimethylformamide촉매
HCID 31374
Dimethylacetamide
용매

실험 절차

A heterogeneous mixture of 6-fluoropyrido[3,4-d]pyrimidin-4(3H)-one (200) (1.65 g, 10.0 mmol), thionyl chloride (30 mL) and a catalytic amount of DMF (2 drops) was stirred under reflux for 5 h to give a homogeneous mixture. It was evaporated under reduced pressure at 45° C. (bath temperature) to give a light brown solid. To this solid was added a solution of 1-(3-fluorobenzyl)-1H-indazol-5-amine (PCT Int. Appl., 2005058245, 30 Jun. 2005) (2.65 g, 11.0 mmol) in dry DMA (15 mL). The residue of 1-(3-fluorobenzyl)-1H-indazol-5-amine was washed down with more DMA (2×2 mL). The reaction mixture was stirred at room temperature for 65 h. It was poured into water (200 mL). The pH was adjusted to ca. 9 using an aqueous solution of Na2CO3 at room temperature. Petroleum ether (200 mL) was added and stirred at room temperature for 2 h. The petroleum ether layer was decanted. It was repeated once more with petroleum ether (200 mL). The solid was collected by filtration and washed with water (5×25 mL). It was suspended in acetone (80 mL) and stirred at room temperature for 20 min. Water (160 mL) was added and stirred further for 1.5 h. The solid was filtered, dried and finally purified by a silica column (MeOH/dichloromethane: gradient from 0-10%) to give 6-fluoro-N-(1-(3-fluorobenzyl)-1H-indazol-5-yl)pyrido[3,4-d]-pyrimidin-4-amine (202) (3.11 g, 80%) as a pale brown solid, mp 218-221° C.; 1H NMR δ [(CD3)2SO] 10.15 (s, 1H), 8.92 (s, 1H), 8.64 (s, 1H), 8.30 (d, J=1.3 Hz, 1H), 8.28 (br s, 14, 8.19 (poorly resolved d, J=0.7 Hz, 1H), 7.77 (d, J=9.0 Hz, 1H), 7.72 (dd, J=9.0, 1.8 Hz, 1H), 7.42-7.32 (m, 1H), 7.15-7.01 (m, 3H), 5.71 (s, 2H). Anal, Calcd for C21H14F2N6: C, 64.94; H, 3.63; N, 21.64. Found C, 65.21; H, 3.71; N, 21.63.

후처리

  1. temperatureunder reflux for 5 h
  2. customto give a homogeneous mixture
  3. customIt was evaporated under reduced pressure at 45° C. (bath temperature)
  4. customto give a light brown solid
  5. washThe residue of 1-(3-fluorobenzyl)-1H-indazol-5-amine was washed down with more DMA (2×2 mL)
  6. additionIt was poured into water (200 mL)
  7. customat room temperature
  8. additionPetroleum ether (200 mL) was added
  9. stirringstirred at room temperature for 2 h
  10. customThe petroleum ether layer was decanted
  11. filtrationThe solid was collected by filtration
  12. washwashed with water (5×25 mL)
  13. stirringstirred at room temperature for 20 min
  14. additionWater (160 mL) was added
  15. stirringstirred further for 1.5 h
  16. filtrationThe solid was filtered
  17. customdried
  18. customfinally purified by a silica column (MeOH/dichloromethane: gradient from 0-10%)

출처 및 근거

ORD 기록
ord-57d179354fa240cd89783533823f68a5
출처 데이터셋
uspto-grants-2015_08
DOI
10.6084/m9.figshare.5104873.v1
특허 번호
US09101632B2

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