Hydrochloric Acid → (S)-2-((S)-2-(6-(2,5-dioxo-2H-pyrrol-1(5H)-yl)hexanamido)-3-methylbutanamido)propanoic acid

Maleimidocaproyl N-hydroxysuccinimide (1.619 g, 5.25 mmol, 1.05 eq.) and H-Val-Ala-OH (0.941 g, 5 mmol, 1 eq.) were placed in a 25 mL recovery flask with a stir bar and the flask was flushed with nitrogen. DMF (4.7 mL) was added and the resulting white slurry was stirred. DIPEA (0.87 mL, 5 mmol, 1 eq) was added and the mixture was allowed to stir at room temperature overnight. The mixture was cooled in an ice/water bath and 2M HCl (3 mL, 6 mmol) was added dropwise. The viscous mixture was transferred to a separatory funnel and the reaction vessel rinsed with sat. NaCl (7 mL), EtOAc (10 mL), sat NaCl (10 mL) and EtOAc (5 mL). After separation of the aqueous phase, it was extracted with additional EtOAc (2×15 mL). The combined organic extracts were washed with sat NaCl (4×15 mL), until the washings were pH ˜3.5. The organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure to give crude 5 as a white solid (2.172 g, 114% crude yield). Crude 5 was suspended in warm CH2Cl2 (35 mL) and filtered to remove a fine white solid. The solids were rinsed with additional CH2Cl2 (3 mL). Toluene (5 mL) was added and the mixture was cooled in an ice/water bath, which resulted in a thick slurry. The solids were collected by filtration, washed with a cold mixture of CH2Cl2 (12 mL) and toluene (2 mL) and dried by pulling air through the sample overnight to give 5 as a white solid (1.327 g, 70% yield). TLC: Rf=0.26, 10% MeOH in CH2Cl2. 1H NMR (CDCl3) (ppm) 0.95 (d, J=17 Hz, 3H), 0.98 (d, J=17 Hz, 3H), 1.30 (m, 2H), 1.40 (d, J=17 Hz, 3H), 1.61 (m, 4H), 2.06 (m, 1H), 2.25 (dt, J=4, 19 Hz, 2H), 3.35 (s, 1H), 3.49 (t, J=17 Hz, 2H), 4.20 (d, J=18 Hz, 1H), 4.38 (m, 1H), 6.80 (s, 2H). Analytical HPLC (0.1% formic acid): tR 9.05 min. LC-MS: tR 11.17 min, m/z (ES+) found 381.9 (M+H)+, m/z (ES−) found 379.9 (M−H)−.

1. customthe flask was flushed with nitrogen
2. additionDMF (4.7 mL) was added
3. stirringto stir at room temperature overnight
4. temperatureThe mixture was cooled in an ice/water bath
5. customThe viscous mixture was transferred to a separatory funnel
6. washthe reaction vessel rinsed with sat. NaCl (7 mL), EtOAc (10 mL)
7. customAfter separation of the aqueous phase, it
8. extractionwas extracted with additional EtOAc (2×15 mL)
9. washThe combined organic extracts were washed with sat NaCl (4×15 mL), until the washings
10. dry with materialThe organic extracts were dried over Na2SO4
11. filtrationfiltered
12. concentrationconcentrated under reduced pressure

ORD record

ord-d100243123d34b869e9b2980274c9b55

Source dataset

uspto-grants-2016_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09387259B2