Dichloromethane → HCID 72950693, compound

HRID 1526793Notes

Reaction equation

HRID 1526793 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:15]([NH:22][C:23](=[O:43])[CH2:24][NH:25][C:26](=[O:42])[C:27]2[CH:32]=[C:31]([NH:33][C:34]3[NH:35][CH2:36][CH:37]([OH:40])[CH2:38][N:39]=3)[CH:30]=[C:29]([OH:41])[CH:28]=2)[CH2:16][C:17]([O:19]CC)=[O:18])[CH:5]=[C:6]([C:8]([OH:14])([CH3:13])[C:9]([F:12])([F:11])[F:10])[CH:7]=1.O.[OH-].[Li+].ClCCl>C(#N)C.O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:15]([NH:22][C:23](=[O:43])[CH2:24][NH:25][C:26](=[O:42])[C:27]2[CH:32]=[C:31]([NH:33][C:34]3[NH:39][CH2:38][CH:37]([OH:40])[CH2:36][N:35]=3)[CH:30]=[C:29]([OH:41])[CH:28]=2)[CH2:16][C:17]([OH:19])=[O:18])[CH:5]=[C:6]([C:8]([OH:14])([CH3:13])[C:9]([F:12])([F:10])[F:11])[CH:7]=1

Participants

6

Reactant 3

HCID 6344DichloromethaneHCID 168937Lithium hydroxide, monohydrateHCID 86709960HCID 86709960, compound

Product 1

HCID 72950693HCID 72950693, compound

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 18373917Acetonitrile--water (1/1)Solvent

Procedure

To a suspension of (3S)-ethyl 3-(3-chloro-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)-3-(2-(3-hydroxy-5-((5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-yl)amino)benzamido)acetamido)propanoate (from step 2 above) (0.968 mmol, crude residue) in a mixture of acetonitrile/water (1:1) (8 mL) was added lithium hydroxide monohydrate (203.1 mg, 4.84 mmol) and the reaction mixture was stirred at room temperature overnight (15 h). The solvent was evaporated in vacuo to afford a yellow-orange viscous residue. The residue was dissolved in water (25 mL) and stirred with dichloromethane (50 mL). The DCM layer was removed and discarded after analyzed by LC-MS. The aqueous layer was neutralized with TFA (1 mL in 3 mL ACN) and evaporated in vacuo to afford a pale viscous residue. The crude residue was purified by reverse-phase preparative HPLC on a Biotage 40+M (100 g) C18HS column and a gradient 10-60% acetonitrile in water containing 0.05% TFA to afford the desired product, after lyophilization, as a colorless lyophilized powder (439.2 mg). LC-MS analysis of the solid shows the desired product: (3S)-3-(3-chloro-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)-3-(2-(3-hydroxy-5-((5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-yl)amino)benzamido)acetamido)propanoic acid's mass: m/z 602 (35ClM+H) and m/z 604 (37ClM+H); Calcd for C25H27ClF3N5O7: 601.96. 1H NMR (400 MHz, DMSO-d6): δ 1.69 (s, 3H), 2.72 (d, J=7.0 Hz, 2H), 3.16 (d, J=12.8 Hz, 2H), 3.33 (d, J=12.7 Hz, 2H), 3.87 (d, J=5.3 Hz, 2H), 4.08 (s, 1H), 5.21 (appq, 1H), 5.45 (brs, 1H), 6.74 (brs, 1H), 6.79 (brs, 1H), 7.12 (dt/m, 2H), 7.41 (s, 1H), 7.49 (brs, 2H), 8.14 (brs, 2H), 8.58 (dd/m, 1H), 8.63 (brt, 1H), 9.67 (brs, 1H), 10.03 (brs, 1H), 12.40 (brs, 1H). 1H NMR spectrum of the sample was consistent with the structure of the desired titled product.

Workup

  1. customThe solvent was evaporated in vacuo
  2. customto afford a yellow-orange viscous residue
  3. customThe DCM layer was removed
  4. customevaporated in vacuo
  5. customto afford a pale viscous residue
  6. customThe crude residue was purified by reverse-phase preparative HPLC on a Biotage 40+M (100 g) C18HS column

Sources & evidence

ORD record
ord-f74c8ad240544301875a62481edd5a5e
Source dataset
uspto-grants-2015_07
Patent number
US09085606B2

Reaction notes

Loading…