Sodium Hydroxide → 4-(((3S,4S)-1-(tert-butoxycarbonyl)-4-methylpyrrolidin-3-yl)amino)-3-carbamoylpyrrolo[1,2-b]pyridazine-6-carboxylic acid

HRID 877794Notes

Reaction equation

HRID 877794 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([CH3:13])[C@H:10]([NH:14][C:15]2[C:16]3[N:17]([CH:24]=[C:25]([C:27]([O:29]CC)=[O:28])[CH:26]=3)[N:18]=[CH:19][C:20]=2[C:21](=[O:23])[NH2:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([CH3:13])[C@H:10]([NH:14][C:15]2[C:16]3[N:17]([CH:24]=[C:25]([C:27]([OH:29])=[O:28])[CH:26]=3)[N:18]=[CH:19][C:20]=2[C:21](=[O:23])[NH2:22])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]

Participants

4

Reactant 2

HCID 14798Sodium Hydroxide2×HCID 68291296ethyl 4-(((3S,4S)-1-(tert-butoxycarbonyl)-4-methylpyrrolidin-3-yl)amino)-3-carbamoylpyrrolo[1,2-b]pyridazine-6-carboxylate

Product 1

HCID 682909544-(((3S,4S)-1-(tert-butoxycarbonyl)-4-methylpyrrolidin-3-yl)amino)-3-carbamoylpyrrolo[1,2-b]pyridazine-6-carboxylic acidYield 100%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

A mixture of ethyl 4-(((3S,4S)-1-(tert-butoxycarbonyl)-4-methylpyrrolidin-3-yl)amino)-3-carbamoylpyrrolo[1,2-b]pyridazine-6-carboxylate (585 mg, 1.356 mmol) and NaOH, 1N (3.39 mL, 3.39 mmol) in THF (14 mL) was stirred at rt for 4 days. At the end of each day, additional NaOH, 1N (3.39 mL, 3.39 mmol) was added, for a total of three additions. The reaction mixture was partitioned between ˜70 ml of EtOAc and 50 ml of water. While stirring the biphasic mixture, the pH was adjusted to ˜2 with saturated KHSO4 solution. The layers were separated and the aqueous layer was extracted with DCM (50 ml). A precipitant began to form in the combined organic layer. The solid was very fine and the suspension was dried over Na2SO4. The supernate was decanted off and the sodium sulfate was thoroughly rinsed with hot EtOAc and hot MeOH. The decanted supernates were concentrated to afford 4-(((3S,4S)-1-(tert-butoxycarbonyl)-4-methylpyrrolidin-3-yl)amino)-3-carbamoylpyrrolo[1,2-b]pyridazine-6-carboxylic acid (545 mg, 1.351 mmol, 100% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ 12.51 (br. s., 1H), 11.23 (br. s., 1H), 8.32 (s, 1H), 8.07 (d, J=1.3 Hz, 1H), 7.19 (d, J=1.3 Hz, 1H), 4.76 (d, J=15.0 Hz, 1H), 3.83-3.51 (m, 2H), 3.40-3.34 (m, 1H), 3.09-2.87 (m, 1H), 2.58 (d, J=7.5 Hz, 1H), 1.37 (d, J=13.2 Hz, 9H), 1.13-0.86 (m, 3H). MS (ES+) m/z: 304.2 (M+H-Boc); LC retention time: 2.533 min (analytical HPLC Method O).

Workup

  1. customThe reaction mixture was partitioned between ˜70 ml of EtOAc and 50 ml of water
  2. stirringWhile stirring the biphasic mixture
  3. customThe layers were separated
  4. extractionthe aqueous layer was extracted with DCM (50 ml)
  5. customto form in the combined organic layer
  6. dry with materialthe suspension was dried over Na2SO4
  7. customThe supernate was decanted off
  8. washthe sodium sulfate was thoroughly rinsed with hot EtOAc and hot MeOH
  9. concentrationThe decanted supernates were concentrated

Sources & evidence

ORD record
ord-5400019e93674ba4b0ee778d1aeaa3a5
Source dataset
uspto-grants-2015_03
Patent number
US08987268B2

Reaction notes

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