(2R,3R)-2,3-dihydroxy-2,3-bis(4-methylbenzoyl)butanedioic acid → 4-[(5S,9R)-3-(3,5-Dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-9-yl]-benzonitrile

HRID 130367

Reaction equation

HRID 130367 reaction equation
Cl.[Cl:2][C:3]1[CH:4]=[C:5]([N:10]2[C:14](=[O:15])[C@@:13]3([C@H:19]([C:20]4[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=4)[CH2:18][NH:17][CH2:16]3)[N:12]([CH3:28])[C:11]2=[O:29])[CH:6]=[C:7]([Cl:9])[CH:8]=1.C1(C)C=CC(C([C@](C(O)=O)(O)[C@](C(C2C=CC(C)=CC=2)=O)(O)C(O)=O)=O)=CC=1>ClCCl>[Cl:2][C:3]1[CH:4]=[C:5]([N:10]2[C:14](=[O:15])[C@@:13]3([C@H:19]([C:20]4[CH:21]=[CH:22][C:23]([C:24]#[N:25])=[CH:26][CH:27]=4)[CH2:18][NH:17][CH2:16]3)[N:12]([CH3:28])[C:11]2=[O:29])[CH:6]=[C:7]([Cl:9])[CH:8]=1

Participants

4

Reactant 2

HCID 22860073(2R,3R)-2,3-dihydroxy-2,3-bis(4-methylbenzoyl)butanedioic acidHCID 692187994-[(5S*,9R*)-3-(3,5-Dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-9-yl]-benzonitrile hydrochloric acid salt

Product 1

HCID 119947544-[(5S,9R)-3-(3,5-Dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-9-yl]-benzonitrileYield 51.2%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
35 °C

Procedure

To a suspension of 4-[(5S*,9R*)-3-(3,5-Dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-9-yl]-benzonitrile hydrochloric acid salt (1.00 kg, 2.21 mol) in dichloromethane (10.67 L) was added diispopropylethylamine (0.29 kg, 2.21 mol). The mixture was stirred to a clear solution, to which (+)-Di-p-toluoyl-D-tartaric acid (0.21 kg, 0.55 mol) was added. The resulting solution was warmed to 34-36° C. and seeded immediately. It was cooled to 20-25° C. in 1.5-2.0 hours. Crystallization occurred during cooling. TBME (2.75 L) was added in 0.5 hours. The suspension was stirred at 20-25° C. for 16 hours and then filtered. The filter cake was washed with dichloromethane/TBME (2/1, 1.00 L), TBME (1 L) and dried at maximum 35° C. to a constant weight. 4-[(5S,9R)-3-(3,5-Dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-9-yl]-benzonitrile semi (+)-DTTA salt (0.47 kg, 35%) was obtained as a white crystalline solid. mp=175-177° C. 1H NMR (DMSO-d6): 7.86 (2H, d, J=8.1 Hz), 7.81 (2H, d, J=8.3 Hz), 7.61 (1H, m), 7.28 (2H, d, J=8.1 Hz), 7.22 (2H, 8.5 Hz), 6.68 (2H, m), 5.71 (1H, s), 3.81(1H, m), 3.50 (4H, m), 3.06 (3H, s), 2.34 (3H, s). 13C NMR (DMSO-d6): 24 Carbons (171.45, 169.40, 165.04, 152.88, 143.61, 138.99, 133.88, 133.08, 132.16, 129.26, 129.20, 128.76, 127.84, 126.99, 124.51, 118.25, 110.78, 72.81, 73.38, 48.15, 47.51, 46.30, 24.90, 21.14). Anal. Calcd for C30H25Cl2N4O6+0.5 H2O: C, 58.40; H, 4.17; N, 9.08; Cl, 11.49. Found C, 58.58; H, 4.06; N, 8.94; Cl, 11.38; KF, 1.59.

Workup

  1. additionwas added diispopropylethylamine (0.29 kg, 2.21 mol)
  2. additionwas added
  3. temperatureIt was cooled to 20-25° C. in 1.5-2.0 hours
  4. customCrystallization
  5. temperatureduring cooling
  6. additionTBME (2.75 L) was added in 0.5 hours
  7. filtrationfiltered
  8. washThe filter cake was washed with dichloromethane/TBME (2/1, 1.00 L), TBME (1 L)
  9. customdried at maximum 35° C. to a constant weight

Sources & evidence

ORD record
ord-1fe8961c7b234081b9605612d49eb347
Source dataset
uspto-grants-2008_06
Patent number
US07381737B2

Linked notes

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