تفاعل #710524

معادلة التفاعل

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

المردود 33.1%

المذيبات

water

acetonitrile

ظروف التفاعل

المعالجة

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

الإجراء التجريبي

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 μm, 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:

المصدر