Formaldehyde → HCID 69498082, compound

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).

1. customThe aqueous phase was separated
2. washthe organic phase was washed with a saturated solution of sodium hydrogencarbonate
3. washThe combined organic extracts were washed with brine
4. dry with materialdried with magnesium sulfate
5. concentrationconcentrated to dryness under reduced pressure
6. customThe 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. washeluting solvent
8. additionThe collected solution was treated with sodium hydrogencarbonate up to pH 8
9. extractionextracted 3 times with 200 mL of ethyl acetate
10. washThe combined organic extracts were washed twice with 100 mL of water
11. dry with materialdried with magnesium sulfate
12. concentrationconcentrated to dryness under reduced pressure
13. customThe residue was then dried in a dessicator under reduced pressure for 16 hours

ORD record

ord-8e49a5ed960648398aee7a6fe2345672

Source dataset

uspto-grants-2014_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08680132B2