Water → 4-amino-5-chloro-2-methoxy-N-[(2S,4S)-2-hydroxymethyl-4-pyrrolidinyl]benzamide monohydrochloride

11.74 g of 4-acetylamino-5-chloro-2-methoxy-N-[(2S,4S)-1-acetyl-2-hydroxymethyl-4-pyrrolidinyl]benzamide was dissolved in ethyl alcohol (60 ml), and sodium hydroxide (2.7 g) was added thereto. The mixture was heated at reflux for 8.5 hours. After addition of water (20 ml), the mixture was stirred at room temperature for 1 hour to filter insolubles off, and washed sufficiently with water (50 ml). The filtrate was concentrated under reduced pressure, n-butyl alcohol (50 ml) and a saturated brine solution (20 ml) were added to the resulting residue, and the layers were separated, followed by re-extraction with n-butyl alcohol (30 ml). The extract was concentrated under reduced pressure, methyl alcohol (50 ml) was added to the residue to dissolve it, and 18% (w/w) hydrochloric acid-containing methyl alcohol (6.5 g) was gradually added to adjust to a pH 6. After ice-cooling, precipitated crystals were filtered, and washed with a small amount of methyl alcohol. The resulting crystals were recrystallized from ethyl alcohol to obtain 5.5 g of the objective 4-amino-5-chloro-2-methoxy-N-[(2S,4S)-2-hydroxymethyl-4-pyrrolidinyl]benzamide monohydrochloride. mp 219-222° C., [α]D20: +4.20 (c=1.00, EtOH)

1. temperatureThe mixture was heated
2. temperatureat reflux for 8.5 hours
3. filtrationto filter insolubles off, and
4. washwashed sufficiently with water (50 ml)
5. concentrationThe filtrate was concentrated under reduced pressure, n-butyl alcohol (50 ml)
6. additiona saturated brine solution (20 ml) were added to the resulting residue
7. customthe layers were separated
8. extractionfollowed by re-extraction with n-butyl alcohol (30 ml)
9. concentrationThe extract was concentrated under reduced pressure, methyl alcohol (50 ml)
10. additionwas added to the residue
11. dissolutionto dissolve it, and 18% (w/w) hydrochloric acid-
12. additioncontaining methyl alcohol (6.5 g)
13. additionwas gradually added
14. temperatureAfter ice-cooling
15. customprecipitated crystals
16. filtrationwere filtered
17. washwashed with a small amount of methyl alcohol
18. customThe resulting crystals were recrystallized from ethyl alcohol

ORD record

ord-215f385f87524e668736f5d8c4bf1521

Source dataset

uspto-grants-2009_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07485665B2