Trifluoroacetic acid → Methanol isopropylamine ethyl acetate

To a suspension of 4-(t-butoxycarbonylamino)-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]cyclohexylcarboxamide (from Part B mother liquors) suspended in 15 mL of methylene chloride was added 5 mL of trifluoroacetic acid at room temperature. The reaction mixture was stirred for 2 h then concentrated in vacuo to remove volatiles. The residue was diluted with water, basified with aqueous NaOH solution then the resulting aqueous solution was extracted with ethyl acetate. The combined organic extracts were dried (sodium sulfate) to give a crude cis/trans product. The crude material was purified by flash chromatography (Merck silica, 25×3 cm, 1:9 isopropylamine/ethyl acetate then 1:2:7 methanol/iso-propylamine/ethyl acetate) to afford 0.74 g of the cis isomer as a yellow solid and 0.50 g of the trans isomer as a brown solid. The cis isomer was dissolved in methanol then 0.34 mL of 5N aqueous HCl was added. The solution was concentrated in vacuo, washed with ether, diluted with water and lyophilized to afford 0.80 g of cis-4-amino-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]cyclohexylcarboxamide hydrochloride as a yellow solid. MS: 395 [M+H]+; HPLC-HI 98% at 3.17 min (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). The trans isomer was dissolved in methanol then 0.24 mL of 5N aqueous HCl was added. The solution was concentrated in vacuo, washed with ether, diluted with water and lyophilized to afford 0.54 g of trans-4-amino-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]cyclohexylcarboxamide hydrochloride as an orange solid. MS: 395 [M+H]+; HPLC-HI 96% at 3.22 min (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).

1. concentrationthen concentrated in vacuo
2. customto remove volatiles
3. additionThe residue was diluted with water
4. extractionthe resulting aqueous solution was extracted with ethyl acetate
5. dry with materialThe combined organic extracts were dried (sodium sulfate)
6. customto give a crude cis/trans product
7. customThe crude material was purified by flash chromatography (Merck silica, 25×3 cm, 1:9 isopropylamine/ethyl acetate

ORDレコード

ord-37ace2591c3545bab306d94b7aca1b7a

出典データセット

uspto-grants-2003_02

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US06515004B1