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

HRID 1752415Notes

Reaction equation

HRID 1752415 reaction equation
[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]

Participants

6

Reactant 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

Product 1

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

Reagents, catalysts & solvents 2

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

Conditions

Temperature
100 °C

Procedure

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]+.

Workup

  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.

Sources & evidence

ORD record
ord-936cbf557c7245b6a31b3aa1d36b2fd4
Source dataset
uspto-grants-2015_10
Patent number
US09163008B2

Reaction notes

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