Dimethyl Sulfoxide → 1-(3,3-dimethyl-butylamino)-1H-pyrrole-2-carboxylic acid allyl ester

Temperature

-78 °C

Dimethylsulfoxide (6.80 mL, 95.7 mmol) was added over 5 min to a solution of oxalylchloride (23.9 mL, 47.8 mmol) in dichloromethane at −78° C. The resulting mixture was stirred at −78° C. for 5 min, then 3,3-dimethyl-butan-1-ol (5.22 mL, 43.1 mmol) was added. After stirring an additional 30 min at −78° C., triethylamine (23.3 mL, 167 mmol) was added and the reaction mixture warmed to 0° C. and stirred at that temperature for 45 min. The mixture was then transferred to a separatory funnel and was washed with 0.5 M aqueous hydrochloric acid. The organic layer was dried over sodium sulfate, filtered and was concentrated in vacuo to a volume of about 70 mL (water bath temperature=0° C.). Methanol (100 mL) was added followed sequentially by 1-amino-1H-pyrrole-2-carboxylic acid allyl ester (Example 1b, 7.16 g, 43.1 mmol), acetic acid (6 mL), and sodium cyanoborohydride (5.42 g, 86.3 mmol). The reaction mixture was stirred at 23° C. for 2 h, and then was partitioned between saturated aqueous sodium bicarbonate solution (400 mL) and a 1:1 mixture of ethyl acetate and hexanes (2×200 mL). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by flash column chromatography (Merck silica gel 60, 40-63 μm, 5-10% ethyl acetate in hexanes) afforded the desired product, 1-(3,3-dimethyl-butylamino)-1H-pyrrole-2-carboxylic acid allyl ester (4.04 g, 16.15 mmol, 37% yield) as a clear liquid. 1HNMR (400 MHz, CDCl3) δ: 0.91 (9H, s), 1.42-1.46 (2H, m), 2.98-3.04 (2H, m), 4.75-4.77 (2H, m), 5.26-5.28 (1H, m), 5.37-5.41 (1H, m), 5.96-5.99 (1H, m), 6.01-6.05 (1H, m), 6.27-6.30 (1H, m), 6.89-6.91 (1H, m), 6.96-6.98 (1H, m).

1. stirringAfter stirring an additional 30 min at −78° C.
2. temperaturethe reaction mixture warmed to 0° C.
3. stirringstirred at that temperature for 45 min
4. customThe mixture was then transferred to a separatory funnel
5. washwas washed with 0.5 M aqueous hydrochloric acid
6. dry with materialThe organic layer was dried over sodium sulfate
7. filtrationfiltered
8. concentrationwas concentrated in vacuo to a volume of about 70 mL (water bath temperature=0° C.)
9. additionMethanol (100 mL) was added
10. stirringThe reaction mixture was stirred at 23° C. for 2 h
11. customwas partitioned between saturated aqueous sodium bicarbonate solution (400 mL)
12. additiona 1:1 mixture of ethyl acetate and hexanes (2×200 mL)
13. dry with materialThe organic layers were dried over sodium sulfate
14. filtrationfiltered
15. concentrationconcentrated in vacuo
16. customPurification of the residue by flash column chromatography (Merck silica gel 60, 40-63 μm, 5-10% ethyl acetate in hexanes)

ORD record

ord-7cccc882014f4431be6a4d629cfe705a

Source dataset

uspto-grants-2008_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07462611B2