Sodium Hydroxide → (1R,2S,5R)-2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-5-(isopropyl(methyl)amino)cyclohexanecarboxylic acid

Temperature

24 °C

Example 1, Alternative Preparation, Step 3: Cyclohexanone 5 (206 g) was dissolved in dichloromethane (1.1 L) and charged to a hydrogenator. Titanium tetraisopropoxide (218.2 g) and N-isopropyl N-methylamine (63.64 g) were added and the mixture was stirred at ambient temperature (23 to 25° C.) for at least 5 h. Platinum catalyst (5% Pt/S/C, 15 g, approx. 7.5% relative to 5) was added and hydrogenation was performed at ˜30 psig for at least 6 h, yielding a mixture of ethyl (1R,2S,5R)-2-((S)-3-benzyloxycarbonylamino-2-oxo-pyrrolidin-1-yl)-5-(isopropyl-methyl-amino)-cyclohexanecarboxylate 6 and its 5-epi-isomer (˜7%). The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to approx. ˜600 mL. Wet ethyl acetate (˜3% water, 2.0 L) was added with vigorous agitation over a period of at least 1.5 h. Stirring was continued for at least an additional 6 h. The slurry was filtered. Filter cake was washed with ethyl acetate (1.0 L) and discarded. The combined filtrate and washings were concentrated to ˜400 mL. Toluene (2.0 L) was added and the solution was washed with 2M aqueous hydrochloric acid (2×400 mL). The aqueous layer was warmed to 50° to 60° C. for approx. 20 h or hydrolysis of 6 was deemed complete (HPLC). Aqueous sodium hydroxide solution was added to adjust to pH ˜10, and mixture was extracted with toluene (3×600 mL). The organic phase was discarded and pH was readjusted to ˜6 by addition of aqueous hydrochloric acid. The aqueous phase was concentrated to ˜600 mL under reduced pressure and extracted with methylene chloride (at least 3×2.0 L). The combined methylene chloride layers were evaporated under reduced pressure and continuously replaced with THF to obtain a solution of (1R,2S,5R)-2-((S)-3-benzyloxycarbonylamino-2-oxo-pyrrolidin-1-yl)-5-(isopropyl-methyl-amino)-cyclohexane carboxylic acid 7 (˜148 g) in THF (˜4 L). Seed crystals of 8 were added, followed by 25% solution of sodium methoxide in methanol (81.24 g) below 25° C. The slurry was held for at least additional 16 h with agitation. The product was isolated by filtration and the cake was washed with THF (4×200 mL) and dried to a constant weight in vacuo below 30° C. Dry (1R,2S,5R)-2-((S)-3-benzyloxycarbonyl-amino-2-oxo-pyrrolidin-1-yl)-5-(isopropyl-methyl-amino)-cyclohexane-carboxylate sodium salt 8 was obtained (139 g, ˜60% yield from 5).

1. customExample 1, Alternative Preparation, Step 3
2. additioncharged to a hydrogenator
3. waithydrogenation was performed at ˜30 psig for at least 6 h
4. customyielding
5. customThe catalyst was removed by filtration
6. concentrationthe filtrate was concentrated under reduced pressure to approx. ˜600 mL
7. additionWet ethyl acetate (˜3% water, 2.0 L) was added with vigorous agitation over a period of at least 1.5 h
8. stirringStirring
9. customleast an additional 6 h
10. filtrationThe slurry was filtered
11. filtrationFilter cake
12. washwas washed with ethyl acetate (1.0 L)
13. concentrationThe combined filtrate and washings were concentrated to ˜400 mL
14. additionToluene (2.0 L) was added
15. washthe solution was washed with 2M aqueous hydrochloric acid (2×400 mL)
16. temperatureThe aqueous layer was warmed to 50° to 60° C. for approx. 20 h
17. customhydrolysis of 6
18. extractionwas extracted with toluene (3×600 mL)
19. additionpH was readjusted to ˜6 by addition of aqueous hydrochloric acid
20. concentrationThe aqueous phase was concentrated to ˜600 mL under reduced pressure
21. extractionextracted with methylene chloride (at least 3×2.0 L)
22. customThe combined methylene chloride layers were evaporated under reduced pressure

ORD record

ord-5baa7cbc72a547148a5f8854209acb2b

Source dataset

uspto-grants-2010_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07671062B2