Реакция #710524

Уравнение реакции

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

Выход 33.1%

Растворители

water

acetonitrile

Условия реакции

Обработка

1. 1
   ДругоеThe aqueous phase was separated
2. 2
   Промывкаthe organic phase was washed with a saturated solution of sodium hydrogencarbonate
3. 3
   ПромывкаThe combined organic extracts were washed with brine
4. 4
   Сушкаdried with magnesium sulfate
5. 5
   Концентрированиеconcentrated to dryness under reduced pressure
6. 6
   ДругоеThe 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
   Промывкаeluting solvent
8. 8
   workup.ADDITIONThe collected solution was treated with sodium hydrogencarbonate up to pH 8
9. 9
   Экстракцияextracted 3 times with 200 mL of ethyl acetate
10. 10
    ПромывкаThe combined organic extracts were washed twice with 100 mL of water
11. 11
    Сушкаdried with magnesium sulfate
12. 12
    Концентрированиеconcentrated to dryness under reduced pressure
13. 13
    ДругоеThe residue was then dried in a dessicator under reduced pressure for 16 hours

Методика

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:

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