Sodium Carbonate → (S)-3-((6-carbamoyl-2-(4-(4-fluorophenoxy)phenyl)pyrimidin-4-yl)amino)-2-hydroxypropanoic acid

HRID 1752415Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1752415
[C:1]([C:4]1[N:9]=[C:8](Cl)[N:7]=[C:6]([NH:11][CH2:12][C@H:13]([OH:18])[C:14]([O:16]C)=[O:15])[CH:5]=1)(=[O:3])[NH2:2].[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]>[C:1]([C:4]1[N:9]=[C:8]([C:28]2[CH:27]=[CH:26][C:25]([O:24][C:23]3[CH:22]=[CH:21][C:20]([F:19])=[CH:41][CH:40]=3)=[CH:30][CH:29]=2)[N:7]=[C:6]([NH:11][CH2:12][C@H:13]([OH:18])[C:14]([OH:16])=[O:15])[CH:5]=1)(=[O:3])[NH2:2]

Komponenten

6

Edukt 3

HCID 10340Sodium CarbonateHCID 666684382-[4-(4-Fluorophenoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneHCID 89422638(S)-methyl 3-((6-carbamoyl-2-chloropyrimidin-4-yl)amino)-2-hydroxypropanoate

Produkt 1

HCID 71283948(S)-3-((6-carbamoyl-2-(4-(4-fluorophenoxy)phenyl)pyrimidin-4-yl)amino)-2-hydroxypropanoic acidAusbeute 9 %

Reagenzien, Katalysatoren, Lösungsmittel 2

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

Reaktionsbedingungen

Temperatur
100 °C

Versuchsvorschrift

To a mixture of the (S)-methyl 3-((6-carbamoyl-2-chloropyrimidin-4-yl)amino)-2-hydroxypropanoate (0.408 g, 1.49 mmol) in dioxane (10 mL) was added 2-(4-(4-fluorophenoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.517 g, 1.65 mmol), 2M aqueous Na2CO3 (1.50 mL, 3.00 mmol) and PdCl2(dppf) (0.066 g, 0.081 mmol). The reaction vessel was flushed with argon, sealed and heated at 100° C. overnight. After cooling, the reaction mixture was diluted with acetone and decanted. Water was added to the insoluble residue to make a suspension. The solid was filtered, washed successively with water, acetone, 1N aqueous HCl then MeOH. The solid was dried under vacuum at 40° C. to give the product (S)-3-((6-carbamoyl-2-(4-(4-fluorophenoxy)phenyl)pyrimidin-4-yl)amino)-2-hydroxypropanoic acid as a light tan powder (0.053 g, 0.13 mmol, 9% yield). 1H NMR (400 MHz, DMSO-d6): 12.61 (1H, s), 8.53 (2H, d, J=8.3 Hz), 8.27 (1H, s), 7.99-7.93 (1H, s), 7.73 (1H, s), 7.31-7.24 (2H, m), 7.19-7.13 (2H, m), 7.08-7.01 (3H, m), 5.60 (1H, s), 4.26 (1H, s), 3.90-3.80 (1H, s), 3.64-3.54 (1H, m). LC/MS: m/z=413.1 [M+H]+.

Aufarbeitung

  1. customThe reaction vessel was flushed with argon
  2. customsealed
  3. temperatureAfter cooling
  4. additionthe reaction mixture was diluted with acetone
  5. customdecanted
  6. additionWater was added to the insoluble residue
  7. filtrationThe solid was filtered
  8. washwashed successively with water, acetone, 1N aqueous HCl
  9. customThe solid was dried under vacuum at 40° C.

Quellen und Nachweise

ORD-Eintrag
ord-936cbf557c7245b6a31b3aa1d36b2fd4
Quelldatensatz
uspto-grants-2015_10
Patentnummer
US09163008B2

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