Di-benzoyl-d-tartaric acid → dibenzoyl-D-tartrate

HRID 84952Notes

Reaction equation

HRID 84952 reaction equation
[C:1]([C@:9]([C:24]([OH:26])=[O:25])([OH:23])[C@:10]([C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([OH:14])[C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:27][C:28]1[CH:43]=[CH:42][C:31]2[C@@H:32]3[CH2:40][N:39]([CH3:41])[CH2:38][C@H:33]3[CH2:34][NH:35][C:36](=[O:37])[C:30]=2[CH:29]=1.C([C@](C([O-])=O)(O)[C@](C(=O)C1C=CC=CC=1)(O)C([O-])=O)(=O)C1C=CC=CC=1.CO>CO>[Cl:27][C:28]1[CH:43]=[CH:42][C:31]2[C@H:32]3[CH2:40][N:39]([CH3:41])[CH2:38][C@@H:33]3[CH2:34][NH:35][C:36](=[O:37])[C:30]=2[CH:29]=1.[C:15]([C@:10]([C:11]([O-:13])=[O:12])([OH:14])[C@:9]([C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([OH:23])[C:24]([O-:26])=[O:25])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1

Participants

6

Reactant 3

HCID 12362977Di-benzoyl-d-tartaric acidHCID 54673810trans-8-Chloro-2-methyl-1,2,3,3a,4,5-hexahydrobenzo[e]pyrrolo[3,4-c]azepin-6(10bh)-oneHCID 131731905dibenzoyl-D-tartrate methanol

Product 2

HCID 29414292dibenzoyl-D-tartrateHCID 54675190(3As,10bs)-8-chloro-2-methyl-1,2,3,3a,4,5-hexahydrobenzo[e]pyrrolo[3,4-c]azepin-6(10bh)-one

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent3×

Procedure

A 12 L, 4-neck, flask was fitted with a mechanical stirrer, temperature probe and then charged with dibenzoyl-D-tartaric acid (189.7 g) and methanol (5.5 kg) under an atmosphere of nitrogen. Example 53 (126.3 g) was dissolved in methanol (1.48 kg) in a separate flask. A portion of the solution (13.5%) of Example 53 in methanol was added over a period of 1 hour to the dibenzoyl-D-tartrate/methanol solution. The solution was then seeded (seed crystals are prepared as described below) with product (250 mg). The remainder of the Example 53 solution was added over 7.5 hours. A rinse of methanol (278 mL) was employed to wash any remaining starting material residue from the 2 L Erlenmeyer flask, and the resultant mixture was pumped into the reaction vessel over 1 hour. The reaction was allowed to proceed for 14 hours. The suspension was filtered, washed with tert-butyl methyl ether (0° C., 2 L) and dried under vacuum to provide the title compound as the dibenzoyl-D-tartrate. The product exhibited an ee of 98.2%, as judged by reverse phase chiral HPLC analysis [Method: Isocratic elution: 70% aqueous (with 5 mM phosphate buffer, pH 6.9): 30% acetonitrile for 15 minutes. Column: Chiralpak® AS-RH (4.6 mm×150 mm) Temperature 35° C. The wavelength that is used for calculations was 210 nm.]. The salt was freebased by the addition of ethyl acetate (1 L) and extraction with 15% aqueous K3PO4 (600 mL) twice. The combined basic aqueous layers were then extracted with ethyl acetate (500 mL). The combined organic layers were then extracted with 20% brine (500 mL) twice. The title compound was obtained by evaporation of the organic layer under vacuum (47.5 g). 1H NMR (500 MHz, DMSO-d6) δ ppm 8.12 (s, 1H), 7.81 (d, J=2.0 Hz, 1H), 7.49 (dd, J=2.5, 8.0 Hz, 1H), 7.18 (d, J=8.0 Hz, 1H), 3.26 (m, 1H), 3.20 (m, 1H), 3.11 (m, 1H), 3.08 (m, 1H), 2.84 (dd, J=9.0, 10.5 Hz, 1H), 2.62 (m, 2H), and 2.18 (m, 1H); MS (ESI+) m/z 251 [M+H]+.

Workup

  1. customA 12 L, 4-neck, flask was fitted with a mechanical stirrer
  2. additionThe remainder of the Example 53 solution was added over 7.5 hours
  3. washA rinse of methanol (278 mL)
  4. washto wash
  5. waitto proceed for 14 hours
  6. filtrationThe suspension was filtered
  7. washwashed with tert-butyl methyl ether (0° C., 2 L)
  8. customdried under vacuum

Sources & evidence

ORD record
ord-9532ec232d8e48b29b74d37a089ccd86
Source dataset
uspto-grants-2014_09
Patent number
US08846951B2

Reaction notes

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