Sodium Carbonate → 2-[4-(4-Fluorophenoxy)phenyl]pyrimidine-4-carboxamide

HRID 1752414노트

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HRID 1752414 반응식
NC(=O)[C@@H](O)CN[C:6]1[N:11]=[C:10](Cl)[N:9]=[C:8]([C:13]([NH2:15])=[O:14])[CH:7]=1.[F:18][C:19]1[CH:40]=[CH:39][C:22]([O:23][C:24]2[CH:29]=[CH:28][C:27](B3OC(C)(C)C(C)(C)O3)=[CH:26][CH:25]=2)=[CH:21][CH:20]=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:18][C:19]1[CH:40]=[CH:39][C:22]([O:23][C:24]2[CH:29]=[CH:28][C:27]([C:10]3[N:9]=[C:8]([C:13]([NH2:15])=[O:14])[CH:7]=[CH:6][N:11]=3)=[CH:26][CH:25]=2)=[CH:21][CH:20]=1

참가 물질

6

반응물 3

HCID 10340Sodium CarbonateHCID 666684382-[4-(4-Fluorophenoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneHCID 89422640(S)-6-((3-amino-2-hydroxy-3-oxopropyl)amino)-2-chloropyrimidine-4-carboxamide

생성물 1

HCID 98362702-[4-(4-Fluorophenoxy)phenyl]pyrimidine-4-carboxamide수율 20%

시약·촉매·용매 2

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

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온도
100 °C

실험 절차

To a mixture of the (S)-6-((3-amino-2-hydroxy-3-oxopropyl)amino)-2-chloropyrimidine-4-carboxamide (0.372 g, 1.43 mmol) in dioxane (10 mL) was added 2-(4-(4-fluorophenoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.494 g, 1.57 mmol), 2M aqueous Na2CO3 (1.45 mL, 2.90 mmol), and PdCl2(dppf) (0.063 g, 0.077 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 triturated with 25 mL acetone. The insoluble solid was filtered off and washed successively with water, MeOH, 1N aqueous HCl, water, and MeOH. The solid was then dissolved in 3 mL DMSO with warming and diluted with 15 mL MeOH. Upon standing the solution deposited a solid that was filtered and rinsed twice with 5 mL MeOH and once with 2:1 acetonitrile/DMSO. The remaining solid was purified by reverse-phase chromatography using a 40-70% acetonitrile in water (+0.1% TFA) gradient. The product fractions were pooled and lyophilized to give (S)-6-(3-amino-2-hydroxy-3-oxopropyl)amino)-2-(4-(4-fluorophenoxy)phenyl)pyrimidine-4-carboxamide as a cream-colored powder (0.115 g, 0.280 mmol, 20% yield). 1H NMR (400 MHz, DMSO-d6): 8.54 (2H, d, J=8.1 Hz), 8.26 (1H, s), 7.91-7.84 (1H, m), 7.73 (1H, s), 7.33-7.23 (4H, m), 7.19-7.13 (2H, m), 7.08-7.01 (3H, m), 5.78 (1H, br s), 4.14-4.07 (1H, m), 3.92-3.83 (1H, m), 3.53-3.45 (1H, m). LC/MS: m/z=412.0 [M+H]+.

후처리

  1. customThe reaction vessel was flushed with argon
  2. customsealed
  3. temperatureAfter cooling
  4. customthe reaction mixture was evaporated in vacuo
  5. customthe residue triturated with 25 mL acetone
  6. filtrationThe insoluble solid was filtered off
  7. washwashed successively with water, MeOH, 1N aqueous HCl, water, and MeOH
  8. dissolutionThe solid was then dissolved in 3 mL DMSO
  9. temperaturewith warming
  10. additiondiluted with 15 mL MeOH
  11. filtrationthat was filtered
  12. washrinsed twice with 5 mL MeOH and once with 2:1 acetonitrile/DMSO
  13. customThe remaining solid was purified by reverse-phase chromatography

출처 및 근거

ORD 기록
ord-82ebf84037d2453098d8b6f7da40d45c
출처 데이터셋
uspto-grants-2015_10
특허 번호
US09163008B2

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