1-Hydroxybenzotriazole → 3-((R)-2-(2,2-dimethylhydrazinecarbonyl)pyrrolidine-1-carbonyl)-N-((2S,3R)-3-hydroxy-4-((5-isopropylpyridin-3-yl)methylamino)-1-phenylbutan-2-yl)benzamide

A flask containing (R)—N′,N′-dimethylpyrrolidine-2-carbohydrazide was evacuated and back-filling with Ar (×3), followed by the sequential addition of 1 mL anhydrous CH2Cl2 and DIPEA (0.22 ml, 0.16 g, 1.24 mmol, 8 eq). In a separate flask HOBT.H2O (0.023 g, 0.17 mmol, 1.1 eq) was added to a stirred solution of 3-((2S,3R)-3-hydroxy-4-((5-isopropylpyridin-3-yl)methylamino)-1-phenylbutan-2-ylcarbamoyl)benzoic acid (0.0714 g, 0.155 mmol, 1 eq) in 4 ml anhydrous CH2Cl2 at and 1 ml anhydrous DMF at 0° C. under Ar. After 30 min EDCI.HCl (0.032 g, 0.17 mmol, 1.1 eq) was added. After both solutions had stirred for at least 1 h the active ester was treated with the free-base amine. The reaction was stirred at 0° C. to room temperature overnight. The solvent was removed in vacuo and the residue partitioned between EtOAc/water. The layers were separated. The aqueous layer was saturated with NaCl and extracted with 10% MeOH in CHCl3 (×4). The combined organic fractions were dried over Na2SO4. The inorganics were filtered off, and the solvent removed in vacuo. Purification via flash chromatography yielded only crude product. The crude was stirred with water and filtered through Celite. The water was removed in vacuo. The resulting solid was dissolved in saturated aqueous NaHCO3 and filtered through Celite. The solution was extracted with 10% MeOH in CHCl3 (×2). The combined organics were dried over Na2SO4. The inorganics were filtered off, and the solvent removed in vacuo. The residue was stirred with water and filtered through cotton. The solvent was removed in vacuo yielding 0.0046 g (0.0077 mmol, 4.9% yield) of 3-((R)-2-(2,2-dimethylhydrazinecarbonyl)pyrrolidine-1-carbonyl)-N-((2S,3R)-3-hydroxy-4-((5-isopropylpyridin-3-yl)methylamino)-1-phenylbutan-2-yl)benzamide.

1. customwas evacuated and back-filling with Ar (×3)
2. customThe solvent was removed in vacuo
3. customthe residue partitioned between EtOAc/water
4. customThe layers were separated
5. extractionextracted with 10% MeOH in CHCl3 (×4)
6. dry with materialThe combined organic fractions were dried over Na2SO4
7. filtrationThe inorganics were filtered off
8. customthe solvent removed in vacuo
9. customPurification via flash chromatography
10. customyielded only crude product
11. filtrationfiltered through Celite
12. customThe water was removed in vacuo
13. dissolutionThe resulting solid was dissolved in saturated aqueous NaHCO3
14. filtrationfiltered through Celite
15. extractionThe solution was extracted with 10% MeOH in CHCl3 (×2)
16. dry with materialThe combined organics were dried over Na2SO4
17. filtrationThe inorganics were filtered off
18. customthe solvent removed in vacuo
19. stirringThe residue was stirred with water
20. filtrationfiltered through cotton
21. customThe solvent was removed in vacuo

ORDレコード

ord-08999874a9704a298f6e80f1099f5b04

出典データセット

uspto-grants-2012_10

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US08299267B2