Sodium Carbonate → Nav1.7 blocker 1

HRID 1752407

反応式

HRID 1752407 の反応式
Cl[C:2]1[N:7]=[C:6]([C:8]([NH2:10])=[O:9])[CH:5]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH:12]2[CH2:17][OH:18])[N:3]=1.[F:19][C:20]1[CH:41]=[CH:40][C:23]([O:24][C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][CH:26]=2)=[CH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:19][C:20]1[CH:41]=[CH:40][C:23]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:2]3[N:7]=[C:6]([C:8]([NH2:10])=[O:9])[CH:5]=[C:4]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH:12]4[CH2:17][OH:18])[N:3]=3)=[CH:27][CH:26]=2)=[CH:22][CH:21]=1

参加物

6

反応物 3

HCID 10340Sodium CarbonateHCID 666684382-[4-(4-Fluorophenoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneHCID 894227662-Chloro-6-(3-(hydroxymethyl)morpholino)pyrimidine-4-carboxamide

生成物 1

HCID 71283649Nav1.7 blocker 1収率 49.2%

試薬・触媒・溶媒 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)触媒HCID 312751,4-Dioxane溶媒

反応条件

温度
100 °C

実験手順

To a mixture of the 2-chloro-6-(3-(hydroxymethyl)morpholino)pyrimidine-4-carboxamide (0.501 g, 1.84 mmol) in dioxane (10 mL) was added 2-(4-(4-fluorophenoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.637 g, 2.03 mmol), 2M aqueous Na2CO3 (1.8 mL, 3.6 mmol), and PdCl2(dppf) (0.078 g, 0.096 mmol). The reaction vessel was flushed with argon, sealed, and heated at 100° C. overnight. After cooling, the reaction mixture was evaporated in vacuo and the residue chromatographed over silica gel with 25-75% acetone in hexanes. The product fractions that were less than 97% isomerically pure were evaporated in vacuo and the resulting solid triturated with 3 mL acetone, filtered and rinsed with 1 mL acetone. This solid was then combined with the fractions from the chromatography that were greater than 97% isomerically pure. This combined material was triturated with 5 mL acetone, filtered, and rinsed once with 5 mL acetone. The solid was dried under vacuum at 40° C. to yield 2-(4-(4-fluorophenoxy)phenyl)-6-(3-(hydroxymethyl)morpholino)pyrimidine-4-carboxamide as an off-white powder (0.384 g, 0.905 mmol, 49% yield). 1H NMR (400 MHz, DMSO-d6): 8.54 (2H, d, J=8.8 Hz), 8.35 (1H, s), 7.80 (1H, s), 7.31-7.24 (2H, m), 7.22 (1H, s), 7.19-7.13 (2H, m), 7.04 (2H, d, J=9.0 Hz), 4.99 (1H, t, J=5.7 Hz), 4.60 (1H, very broad s), 4.14 (1H, very broad s), 4.04 (1H, d, J=11.4 Hz), 3.94 (1H, dd, J=11.6 Hz, 3.5 Hz), 3.76-3.68 (1H, m), 3.59-3.43 (3H, m), 3.25-3.13 (1H, m). LC/MS: m/z=425.1 [M+H]+.

後処理

  1. customThe reaction vessel was flushed with argon
  2. customsealed
  3. temperatureAfter cooling
  4. customthe reaction mixture was evaporated in vacuo
  5. customthe residue chromatographed over silica gel with 25-75% acetone in hexanes
  6. customisomerically pure were evaporated in vacuo
  7. customthe resulting solid triturated with 3 mL acetone
  8. filtrationfiltered
  9. washrinsed with 1 mL acetone
  10. customThis combined material was triturated with 5 mL acetone
  11. filtrationfiltered
  12. washrinsed once with 5 mL acetone
  13. customThe solid was dried under vacuum at 40° C.

出典と根拠

ORDレコード
ord-6550a59411974d3e8df4ffbb46573e0b
出典データセット
uspto-grants-2015_10
特許番号
US09163008B2

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