Sodium Carbonate → HCID 72548394, compound

HRID 2206433Notes

Reaction equation

HRID 2206433 reaction equation
[Cl:1][C:2]1[C:3]([F:46])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:43]=[CH:42][C:34]([C:35]([O:37][CH2:38][C:39](O)=[O:40])=[O:36])=[CH:33][C:32]=2[O:44][CH3:45])=[O:29])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH2:81][C@@H:82]([CH2:93][CH2:94][C:95]([O:97][CH2:98][C:99]1[CH:104]=[CH:103][CH:102]=[CH:101][CH:100]=1)=[O:96])[C:83]([O:85][CH2:86][C:87]1[CH:92]=[CH:91][CH:90]=[CH:89][CH:88]=1)=[O:84].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[CH2:86]([O:85][C:83](=[O:84])[C@@H:82]([NH:81][C:39](=[O:40])[CH2:38][O:37][C:35](=[O:36])[C:34]1[CH:42]=[CH:43][C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:46])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]2)=[O:29])=[C:32]([O:44][CH3:45])[CH:33]=1)[CH2:93][CH2:94][C:95]([O:97][CH2:98][C:99]1[CH:104]=[CH:103][CH:102]=[CH:101][CH:100]=1)=[O:96])[C:87]1[CH:88]=[CH:89][CH:90]=[CH:91][CH:92]=1

Participants

7

Reactant 5

HCID 10340Sodium CarbonateHCID 81531Diisopropylethylamine2×HCID 199613(S)-Dibenzyl 2-aminopentanedioate hydrochlorideHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 72548393HCID 72548393, compound

Product 1

HCID 72548394HCID 72548394, compoundYield 33%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

In a 20 mL round-bottomed flask, 2-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoyloxy)-acetic acid (Example 69, 133 mg, 197 μmol), HATU (75.0 mg, 197 μmol) and Hunig's base (51.0 mg, 68.9 μL, 394 μmol) were combined with dry tetrahydrofuran (1 mL) to give an off-white suspension at room temperature. The mixture was stirred for 30 min and a solution of (S)-dibenzyl 2-aminopentanedioate hydrochloride (108 mg, 296 μmol) and Hunig's base (2 eq.) in dry tetrahydrofuran (1 mL) was added. After 1 h, the reaction mix was directly purified with reverse phase high-performance liquid chromatography to isolate the desired fraction, which was neutralized with saturated aqueous sodium carbonate solution, extracted with methylene chloride. The methylene chloride layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to give (S)-2-[2-(4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoyloxy)-acetylamino]-pentanedioic acid dibenzyl ester (63 mg, 33% yield). LCMS (ES+) m/z calcd. for C52H51Cl2F2N4O9 [(M+H)+]: 983. found: 983.

Workup

  1. customto give an off-white suspension at room temperature
  2. waitAfter 1 h
  3. additionthe reaction mix
  4. customwas directly purified with reverse phase high-performance liquid chromatography
  5. customto isolate the desired fraction, which
  6. extractionextracted with methylene chloride
  7. washThe methylene chloride layer was washed with water and brine
  8. dry with materialdried over anhydrous sodium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated

Sources & evidence

ORD record
ord-ec2f52d8374a4990be11fa1b8f11e8ca
Source dataset
uspto-grants-2016_06
Patent number
US09371280B2

Reaction notes

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