Hexane → HCID 70526365, compound

HRID 903463Notes

Reaction equation

HRID 903463 reaction equation
[Br:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([CH2:8][CH:9]([CH3:20])[C:10]([N:12]2[CH2:19][CH2:18][CH2:17][C@H:13]2[C:14]([OH:16])=[O:15])=[O:11])=[O:7])=[CH:4][CH:3]=1.CCCCCC>C(OCC)(=O)C>[Br:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([CH2:8][CH:9]([CH3:20])[C:10]([N:12]2[CH2:19][CH2:18][CH2:17][C@@H:13]2[C:14]([OH:16])=[O:15])=[O:11])=[O:7])=[CH:4][CH:3]=1

Participants

4

Reactant 2

HCID 8058HexaneHCID 54569534HCID 54569534, compound2×

Product 1

HCID 70526365HCID 70526365, compound

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Procedure

The preceding compound, (72 g.) is converted to N-hydroxysuccinimide ester, m.p. 99°-104° C., as for Example 7 and the activated ester (94.6 g.) is coupled as for Example 9 with 44.9 g. of L-proline to give 70.7 g. of 1-[3-(4-bromobenzoyl)-2-methylpropionyl]-L-proline as a gum (mixture of diastereomers). The gum is dissolved in hot ethyl acetate (200 ml.) and hexane (250 ml.) added. Chilling gives 19.3 g. of solid which is recrystallized from ethyl acetate to give 10.3 g. of (S)-1-[3-(4-bromobenzoyl)-2-methylpropionyl]-L-proline, m.p. 165°-167° C. (isomer A). From the mother liquors additional isomer A is obtained and purified by chromatography on silica gel. From the column (R)-1-[3-(4-bromobenzoyl)-2-methylpropionyl]-L-proline (isomer B) is obtained. To a mixture of 10.2 g. of isomer A in 125 ml. of acetic acid is added 4.43 g. of bromine in 20 ml. of acetic acid. Anhydrous hydrogen bromide is added and the mixture stirred 3 hours. The mixture is concentrated to 1/3 volume and poured into ice and water. The mixture is extracted with dichloromethane and the extract washed with water, brine and dried (MgSO4). The solvent is removed under vacuum to give 12.7 g. of a glass (mixture of diastereomers). A mixture of 10.5 g. of the preceding glass in 150 ml. of acetonitrile is added dropwise to a mixture of sodium thioacetate (prepared from 2.9 ml. of thiolacetic acid and 1.4 g. of NaH (60% oil dispersion) in 150 ml. of acetonitrile. The mixture is stirred at room temperature for 18 hours, 30 ml. of acetic acid is added and the solvent is removed under vacuum. The residue is partitioned between dichloromethane and water. The dichloromethane layer is separated, washed with water, saline and dried (MgSO4). The solvent is removed and the residue chromatographed on a silica gel column with ethyl acetate-hexane-acetic acid (5:5:0.2) as solvent. The early fractions containing mainly one component are combined and chromatographed on silica gel to give 5.1 g. of solid. Crystallization from ethyl acetate-hexane gives 3.5 g. of [S-(R*,S*)]-1-[3-acetylthio-3-(4-bromobenzoyl)-2-methylpropionyl]-L-proline as white crystals, m.p. 136°-138° C.; [α]D +211°+1(c, 0.971, ethanol). The latter fractions from the column chromatography containing one component by thin layer chromatography are combined to give 1.2 g. of [S-(R*,R*)]-1-[3-acetylthio-3-(4-bromobenzoyl)-2-methylpropionyl]-L-proline as a white gla-s; [α]D -69±1(c, 0.983 ethanol).

Workup

  1. temperatureChilling
  2. customgives 19.3 g
  3. customof solid which is recrystallized from ethyl acetate
  4. customto give 10.3 g
  5. customFrom the mother liquors additional isomer A is obtained
  6. custompurified by chromatography on silica gel

Sources & evidence

ORD record
ord-3d0386279c094f6199e3c6d4b69c4b37
Source dataset
uspto-grants-1980_10
Patent number
US04226775

Reaction notes

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