1,4-Dioxane → (2S,4S)-4-{4-[6-amino-5-(5-chloro-8-fluoroisoquinolin-3-yl)-pyridin-3-yl]-pyrazol-1-yl}-pyrrolidine-2-carboxylic acid

HRID 1926322Notes

Reaction equation

HRID 1926322 reaction equation
[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:3]=1[CH:4]=[C:5]([C:13]1[C:14]([NH2:28])=[N:15][CH:16]=[C:17](B3OC(C)(C)C(C)(C)O3)[CH:18]=1)[N:6]=[CH:7]2.C[O:30][C:31]([C@@H:33]1[CH2:37][C@H:36]([N:38]2[CH:42]=[C:41](I)[CH:40]=[N:39]2)[CH2:35][N:34]1C(OCC1C=CC=CC=1)=O)=[O:32].[F-].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[NH2:28][C:14]1[N:15]=[CH:16][C:17]([C:41]2[CH:40]=[N:39][N:38]([C@@H:36]3[CH2:35][NH:34][C@H:33]([C:31]([OH:32])=[O:30])[CH2:37]3)[CH:42]=2)=[CH:18][C:13]=1[C:5]1[N:6]=[CH:7][C:8]2[C:3]([CH:4]=1)=[C:2]([Cl:1])[CH:11]=[CH:10][C:9]=2[F:12]

Participants

7

Reactant 4

HCID 312751,4-DioxaneHCID 522689Potassium FluorideHCID 67520517(2S,4S)-4-(4-iodopyrazol-1-yl)-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl esterHCID 67520645HCID 67520645, compound

Product 1

HCID 67521202(2S,4S)-4-{4-[6-amino-5-(5-chloro-8-fluoroisoquinolin-3-yl)-pyridin-3-yl]-pyrazol-1-yl}-pyrrolidine-2-carboxylic acid

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolvent

Conditions

Temperature
60 °C

Procedure

A mixture of 3-(5-chloro-8-fluoroisoquinolin-3-yl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine (100 mg, 0.250 mmol), (2S,4S)-4-(4-iodopyrazol-1-yl)-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester (137.0 mg, 0.300 mmol), Pd(PPh3)4 (29 mg, 0.025 mmol), potassium fluoride (43.6 mg, 0.751 mmol) and 4:1 dioxane:water (3 mL) was heated in the microwave reactor to 85° C. for 30 min. The material was concentrated in vacuo, then dry-loaded onto silica gel for column chromatography. The product was eluted with 2→5% MeOH/DCM, and the fractions containing the product were concentrated in vacuo. The material was dissolved in conc. HCl, transferred to a sealed tube and heated at 60° C. for 2 h. The solvent was removed in vacuo to afford the title compound as a brown solid. MS (ES+): m/z=453.09/455.10 (100/37) [MH+]. HPLC: tR=1.94 min (ZQ2, polar—5 min).

Workup

  1. concentrationThe material was concentrated in vacuo
  2. washThe product was eluted with 2→5% MeOH/DCM
  3. additionthe fractions containing the product
  4. concentrationwere concentrated in vacuo
  5. dissolutionThe material was dissolved in conc. HCl
  6. customtransferred to a sealed tube
  7. customThe solvent was removed in vacuo

Sources & evidence

ORD record
ord-79c349bc58134a99a97fd0bfb340aca1
Source dataset
uspto-grants-2012_05
Patent number
US08178668B2

Reaction notes

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