Reaktion #818415

Reaktionsgleichung

hydrochloric acid

Sodium triacetoxyborohydride

sodium hydroxide

2-(4-fluoro-benzylamino)-cyclopent-1-enecarboxylic acid ethyl ester

→

cis-2-(4-fluoro-benzylamino)-cyclopentanecarboxylic acid ethyl ester

Ausbeute 77.0%

desired product

2-(4-Fluoro-benzylamino)-cyclopentanecarboxylic acid ethyl ester

Lösungsmittel

actonitrile

acetic acid

Reaktionsbedingungen

Aufarbeitung

1. 1
   SonstigeThe mixture was transferred to a large Erlenmeyer flask
2. 2
   workup.ADDITIONcontaining a stirbar
3. 3
   Temperaturwas cooled to 0° C
4. 4
   workup.STIRRINGwith gentle stirring
5. 5
   Temperaturcontinued external cooling (large exotherm noted; melted ice was replenished)
6. 6
   Sonstigethe mixture was transferred to a separatory funnel
7. 7
   Sonstigethe phases were separated
8. 8
   ExtraktionThe aqueous phase was extracted with ethyl acetate (1×300 mL)
9. 9
   Waschenthe combined organic layers were washed with half-saturated aqueous sodium bicarbonate solution (1×200 mL)
10. 10
    Trocknendried over sodium sulfate
11. 11
    Filtrationfiltered
12. 12
    Einengenwere concentrated in vacuo
13. 13
    SonstigePurification of the residue by flash chromatography (Teledyne Isco RediSep Column; 15-40% ethyl acetate in hexanes)

Vorschrift

Sodium triacetoxyborohydride (62.1 g, 293 mmol) was suspended in a 1:1 mixture of glacial acetic acid and actonitrile (200 mL) at 0° C. The crude 2-(4-fluoro-benzylamino)-cyclopent-1-enecarboxylic acid ethyl ester was added via cannula over 15 min and the resulting orange/brown suspension was allowed to warm to 23° C. over 19 h. A 4.0 M aqueous hydrochloric acid solution (60 mL) was then carefully added and the mixture was stirred at 23° C. for 20 min. The mixture was transferred to a large Erlenmeyer flask containing a stirbar and was cooled to 0° C. Aqueous sodium hydroxide (98 g dissolved in 350 mL; approx. 8.0 M) was then added over 20 min with gentle stirring and continued external cooling (large exotherm noted; melted ice was replenished). After the exotherm subsided, the mixture was transferred to a separatory funnel and the phases were separated. The aqueous phase was extracted with ethyl acetate (1×300 mL) and the combined organic layers were washed with half-saturated aqueous sodium bicarbonate solution (1×200 mL), dried over sodium sulfate, filtered and were concentrated in vacuo. Purification of the residue by flash chromatography (Teledyne Isco RediSep Column; 15-40% ethyl acetate in hexanes) afforded the desired product, cis-2-(4-fluoro-benzylamino)-cyclopentanecarboxylic acid ethyl ester (19.9 g, 77% over two steps), as a pale yellow oil. 1H NMR (CDCl3) δ: 1.27 (3H, t, J=7.0), 1.55-1.71 (2H, m), 1.81-1.91 (4H, m), 1.98-2.06 (1H, m), 2.90-2.96 (1H, m), 3.26-3.31 (1H, m), 3.73 (1H, d, J=13.1), 3.77 (1H, d, J=13.2), 4.15 (2H, q, J=7.3), 6.94-7.00 (2H, m), 7.24-7.28 (2H, m). 13C NMR (CDCl3) δ: 14.8, 22.7, 27.9, 32.2, 48.0, 51.9, 60.5, 61.7, 115.2 (d, J=21.5), 129.6 (d, J=8.4), 136.5 (d, J=3.1), 161.9 (d, J=243.8), 174.7. Anal. calcd for C15H20FNO2: C, 67.90; H, 7.60; N, 5.28; Found: C, 67.92; H, 7.88; N, 5.55. Continued elution of the silica gel column with increasing amounts of ethyl acetate (up to 100% of eluent concentration) afforded trans-2-(4-fluoro-benzylamino)-cyclopentanecarboxylic acid ethyl ester (3.2 g, 12%) as a dark orange oil. 1H NMR (CDCl3) δ: 1.26 (3H, t, J=7.0), 1.40-1.49 (1H, m), 1.67-1.77 (2H, m), 1.82-1.91 (1H, m), 1.97-2.05 (2H, m), 2.58 (1H, q, J=7.9), 3.31 (1H, q, J=7.3), 3.72 (1H, d, J=13.2), 3.77 (1H, d, J=12.5), 4.14 (2H, q, J=7.0), 6.96-7.01 (2H, m), 7.24-7.29 (2H, m).

Quelle