反応 #1279209

反応方程式

sodium cyanoborohydride

formaldehyde

(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro [indole-3,3′-pyrrolidine]-5′-carboxylic acid (trans-4-hydroxy-cyclohexyl)-amide

ethyl acetate

→

(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-1′-methyl-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-hydroxy-cyclohexyl)-amide

収率 33.1%

溶媒

water

acetonitrile

反応条件

後処理

1. 1
   その他The aqueous phase was separated
2. 2
   洗浄the organic phase was washed with a saturated solution of sodium hydrogencarbonate
3. 3
   洗浄The combined organic extracts were washed with brine
4. 4
   乾燥dried with magnesium sulfate
5. 5
   濃縮concentrated to dryness under reduced pressure
6. 6
   その他The residue (0.52 g) was purified by chiral HPLC chromatography on a Kromasil C18 column (1100 g batch 4680, 10 m, 7.65×35 cm)
7. 7
   洗浄eluting solvent
8. 8
   workup.ADDITIONThe collected solution was treated with sodium hydrogencarbonate up to pH 8
9. 9
   抽出extracted 3 times with 200 mL of ethyl acetate
10. 10
    洗浄The combined organic extracts were washed twice with 100 mL of water
11. 11
    乾燥dried with magnesium sulfate
12. 12
    濃縮concentrated to dryness under reduced pressure
13. 13
    その他The residue was then dried in a dessicator under reduced pressure for 16 hours

実験手順

To a suspension of 0.50 g (0.89 mmol) of (2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro [indole-3,3′-pyrrolidine]-5′-carboxylic acid (trans-4-hydroxy-cyclohexyl)-amide in 18.0 mL of acetonitrile under argon, were added 0.89 mL (0.97 mmol) of a 36.5% solution of formaldehyde in water, followed by 65 mg (0.98 mmol) of sodium cyanoborohydride. The resulting solution was stirred at room temperature for 2 hours, upon which it was poured into 50 mL of ethyl acetate. The aqueous phase was separated and the organic phase was washed with a saturated solution of sodium hydrogencarbonate. The latter aqueous phase was reextracted with ethyl acetate. The combined organic extracts were washed with brine, dried with magnesium sulfate and then concentrated to dryness under reduced pressure. The residue (0.52 g) was purified by chiral HPLC chromatography on a Kromasil C18 column (1100 g batch 4680, 10 m, 7.65×35 cm), eluting solvent: acetonitrile/water 40/60 v/v+0.1% trifluoroacetic acid; flow: 250 mL/min. The collected solution was treated with sodium hydrogencarbonate up to pH 8 and then extracted 3 times with 200 mL of ethyl acetate. The combined organic extracts were washed twice with 100 mL of water, dried with magnesium sulfate and then concentrated to dryness under reduced pressure. The residue was then dried in a dessicator under reduced pressure for 16 hours. 0.17 g of (2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-1′-methyl-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-hydroxy-cyclohexyl)-amide was obtained as a white solid. mp: 188° C. (Kofler); LC-MS: tR (min)=0.85-0.97 (mixture of isomers); [M+H]+: m/z 576; [M−H]−: m/z 574 (method A); 1H NMR (400 MHz, CHLOROFORM-d): 0.73 (d, J=15.6 Hz, 1 H); 0.79 (s, 9 H); 1.15 to 1.48 (m, 4 H); 1.85 to 2.12 (m, 5 H); 2.75 (s, 3 H); 3.60 to 3.77 (m, 3 H); 4.17 (d, J=9.8 Hz, 1 H); 4.33 (d broad, J=9.8 Hz, 1 H); 6.69 (d, J=1.5 Hz, 1 H); 6.99 (t, J=7.8 Hz, 1 H); 7.05 (dd, J=1.5 and 8.3 Hz, 1 H); 7.10 to 7.25 (m, 3 H); 7.37 (m broad, 1 H); 7.56 (t, J=7.8 Hz, 1 H).

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