Lithium hydroxide, monohydrate → HCID 71283622, compound

HRID 1752394Notes

Reaction equation

HRID 1752394 reaction equation
[C:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)[N:7]=[C:6]([N:24]2[CH2:28][CH2:27][CH2:26][C@H:25]2[C:29]([O:31]C)=[O:30])[CH:5]=1)(=[O:3])[NH2:2].[OH:33][Li].O>C1COCC1.O>[C:29]([C@@H:25]1[CH2:26][CH2:27][CH2:28][N:24]1[C:6]1[N:7]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[N:9]=[C:4]([C:1]([OH:33])=[O:3])[CH:5]=1)([OH:31])=[O:30].[C:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16][C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)=[CH:14][CH:15]=2)[N:7]=[C:6]([N:24]2[CH2:28][CH2:27][CH2:26][C@H:25]2[C:29]([OH:31])=[O:30])[CH:5]=1)(=[O:3])[NH2:2]

Participants

5

Reactant 2

HCID 168937Lithium hydroxide, monohydrateHCID 71283744HCID 71283744, compound

Product 2

HCID 71283592HCID 71283592, compoundYield 29%HCID 71283622HCID 71283622, compoundYield 40%

Reagents, catalysts & solvents 1

HCID 21881883Oxolane--water (1/1)Solvent

Procedure

To a mixture of the (S)-methyl 1-(6-carbamoyl-2-(4-(4-fluorophenoxy)phenyl)pyrimidin-4-yl)pyrrolidine-2-carboxylate (0.439 g, 1.01 mmol) in 5:1 THF/water (10 mL) was added LiOH.H2O (0.084 g, 2.00 mmol). After stirring 3 days the reaction was quenched with 1N aqueous HCl (2.00 mL). The mixture was evaporated in vacuo then chromatographed using reverse-phase HPCL with a 40-100% acetonitrile in water (+0.1% TFA) gradient. The first product to elute was the (S)-6-(2-carboxypyrrolidin-1-yl)-2-(4-(4-fluorophenoxy)phenyl)pyrimidine-4-carboxylic acid (A) followed by the (S)-1-(6-carbamoyl-2-(4-(4-fluorophenoxy)phenyl)pyrimidin-4-yl)pyrrolidine-2-carboxylic acid (B). Separately, product fractions for each product were pooled and concentrated to give solid suspensions. The solid precipitates were filtered, rinsed with water, and dried under vacuum at 50° C. to give (S)-6-(2-carboxypyrrolidin-1-yl)-2-(4-(4-fluorophenoxy)phenyl)pyrimidine-4-carboxylic acid (A) as a light tan powder (0.170 g, 0.402 mmol, 40% yield) and (S)-1-(6-carbamoyl-2-(4-(4-fluorophenoxy)phenyl)pyrimidin-4-yl)pyrrolidine-2-carboxylic acid (B) as an off-white powder (0.125 g, 0.296 g, 29% yield). (S)-6-(2-carboxypyrrolidin-1-yl)-2-(4-(4-fluorophenoxy)phenyl)pyrimidine-4-carboxylic acid (A): 1H NMR (400 MHz, DMSO-d6): Exists as a ˜80:20 ratio of rotamers: 13.71-12.30 (2H, br m), 8.43 (0.4H, d, J=8.8 Hz), 8.37 (1.6H, d, J=8.8 Hz), 7.32-7.24 (2H, m), 7.20-7.13 (2H, m), 7.09-6.99 (2.8H, m), 6.79 (0.2H, s), 4.62-4.55 (1H, m), 3.87-3.48 (2H, m), 2.38-2.29 (1H, m), 2.24-1.98 (3H, m). LC/MS: m/z=424.1 [M+H]+. (S)-1-(6-carbamoyl-2-(4-(4-fluorophenoxy)phenyl)pyrimidin-4-yl)pyrrolidine-2-carboxylic acid (B): 1H NMR (400 MHz, DMSO-d6): Exists as a 80:20 ratio of rotamers: 13.05 (0.2H, br s), 12.60 (0.8H, br s), 8.57 (0.4H, d, J=8.8 Hz), 8.51 (1.6H, d, J=8.8 Hz), 8.35 (1H, s), 7.81 (1H, s), 7.32-7.24 (2H, m), 7.20-7.13 (2H, m), 7.08-6.97 (2.8H, m), 6.79 (0.2H, s), 4.62-4.52 (1H, m), 3.86-3.72 (0.4H, m), 3.66-3.55 (1.6H, m), 2.40-2.28 (1H, m), 2.22-1.95 (3H, m). LC/MS: m/z=423.1 [M+H]+.

Workup

  1. customwas quenched with 1N aqueous HCl (2.00 mL)
  2. customThe mixture was evaporated in vacuo
  3. customthen chromatographed
  4. washThe first product to elute
  5. concentrationconcentrated
  6. customto give solid suspensions
  7. customThe solid precipitates
  8. filtrationwere filtered
  9. washrinsed with water
  10. customdried under vacuum at 50° C.

Sources & evidence

ORD record
ord-80fcbf436b05465b8ff95858a7dc857e
Source dataset
uspto-grants-2015_10
Patent number
US09163008B2

Reaction notes

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