Citric Acid → Benzyl[2-[2-(1-aminocyclopropyl)phenoxy]ethyl]methylcarbamate

A nitrogen-sparged solution of lithium iodide (80.78 g, 0.60 mol), dry isopropanol (45.5 mL, 0.60 mol) and 2,2′-bipyridine (0.83 g, 5.28 mmol) in dry 2-Me-THF (868 mL) was stirred at ambient temperature under an inert atmosphere. The mixture was briefly heated to 50° C. (batch temperature) to fully dissolve the lithium iodide. After cooling to −10° C. (jacket temperature), methyllithium (3.18 M in diethoxymethane, 180 mL, 572.4 mmol) was added by syringe pump over 15 min. After the addition was complete, the jacket temperature had increased to 10° C. The addition of further methyllithium (3.18 M in diethoxymethane, 11.6 mL, 36.9 mmol) in small aliquots was sufficient to induce a permanent colour change to lilac. The reaction mixture was then cooled to 0° C. (batch temperature) and a portion of the previously prepared solution of MeTi(OiPr)3 (301 mL, 0.99 M in diethoxymethane/2-Me-THF, 297.5 mmol) was added over 25 min. At the end of the addition, the reaction solution was warmed to 20° C. (batch temperature) and benzyl[2-(2-cyanophenoxy)ethyl]methylcarbamate (Preparation 4a, 98.5% w/w, 75.04 g, 238.2 mmol) was charged. Neat diethylzinc (30.5 mL, 298 mmol) was then added by syringe pump over 85 min, during which time the reaction mixture was diluted with further 2-Me-THF (122 mL). After an overnight hold at ambient temperature, the mixture was cooled to 0° C. and discharged into a vigorously stirred ice-cold solution of citric acid (230.97 g, 1190 mmol) and trifluoroacetic acid (27.14 g, 238.0 mmol) in water (1000 mL). This produced a yellow organic fraction and an indigo aqueous fraction. The phases were separated and the organic phase warmed to 20° C. (batch temperature) and washed with aq. sodium hydroxide (2 M, 200 mL). The initial indigo aqueous fraction was re-extracted with 2-Me-THF (100 mL). The organic fractions were combined and concentrated in vacuo to ˜750 mL. The residual solution was then extracted with aq. citric acid (0.1 M, 8×100 mL). Aq. sodium hydroxide (46/48% w/w, 50.76 g, 600 mmol) was added to the combined citric acid extracts at 6° C. (batch temperature) to afford a solution of pH 10. Further aq. sodium hydroxide (46/48% w/w, ˜2 mL) was then added to basify the solution to pH>10. The basic aqueous phase was extracted with isopropyl acetate (2×200 mL, 1×100 mL); each organic extract was washed with brine (50 mL). The combined organic phase was filtered through a 0.45 μm membrane to leave a solution of benzyl [2-[2-(1-aminocyclopropyl)phenoxy]ethyl]methylcarbamate (12.74% w/w, 364.05 g, 136.2 mmol) which was concentrated in vacuo to leave benzyl [2-[2-(1-aminocyclopropyl)phenoxy]ethyl]methylcarbamate as an oil.

1. temperatureThe mixture was briefly heated to 50° C. (batch temperature)
2. additionwas added by syringe pump over 15 min
3. additionAfter the addition
4. temperaturethe jacket temperature had increased to 10° C
5. temperatureThe reaction mixture was then cooled to 0° C. (batch temperature)
6. additionAt the end of the addition
7. additionwas charged
8. temperaturethe mixture was cooled to 0° C.
9. customThis produced a yellow organic fraction
10. customThe phases were separated
11. temperaturethe organic phase warmed to 20° C. (batch temperature)
12. washwashed with aq. sodium hydroxide (2 M, 200 mL)
13. extractionThe initial indigo aqueous fraction was re-extracted with 2-Me-THF (100 mL)
14. concentrationconcentrated in vacuo to ˜750 mL
15. extractionThe residual solution was then extracted with aq. citric acid (0.1 M, 8×100 mL)
16. customextracts at 6° C.
17. customto afford a solution of pH 10
18. extractionThe basic aqueous phase was extracted with isopropyl acetate (2×200 mL, 1×100 mL)
19. extractioneach organic extract
20. washwas washed with brine (50 mL)
21. filtrationThe combined organic phase was filtered through a 0.45 μm membrane

ORD record

ord-2bda57ce861b4f00922ffad4e570c3e6

Source dataset

uspto-grants-2015_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08969350B2