Toluene → Isopropyl Acetate

HRID 902210Notes

Reaction equation

HRID 902210 reaction equation
[O-:1][CH2:2][CH3:3].[Na+].[CH2:5]([N:7]([CH2:10][CH3:11])[CH2:8][CH3:9])C.[CH2:12]1[CH2:16][O:15]C[CH2:13]1.[C:17]1([CH3:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[C:24](#[N:26])[CH3:25]>C(Cl)Cl.C(OCC)(=O)C.CN(C=O)C>[CH:10]([N:7]([CH:12]([CH3:16])[CH3:13])[CH2:8][CH3:9])([CH3:11])[CH3:2].[CH2:21]1[CH2:20][CH2:19][N:7]2[C:23](=[N:26][CH2:24][CH2:25][CH2:5]2)[CH2:17][CH2:22]1.[C:2]([O:15][CH:17]([CH3:23])[CH3:18])(=[O:1])[CH3:3]

Participants

11

Reactant 5

HCID 1140TolueneHCID 6342AcetonitrileHCID 8028TetrahydrofuranHCID 8471TriethylamineHCID 2723922Sodium ethoxide

Product 3

HCID 7915Isopropyl AcetateHCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 81531Diisopropylethylamine

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

A preferred process is shown in Scheme XV. Nitro vinyl compound (88) is reacted with beta-keto ester 89 in the presence of a base such as sodium ethoxide and the like or a trialkylamine such as triethylamine or diisopropylethylamine and the like or an amidine such as DBU and the like in an inert solvent such as THF, toluene, DMF, acetonitrile, ethyl acetate, isopropyl acetate or methylene chloride and the like at a temperature of from about 0° C. to about 100° C. for a period of time from about 15 minutes to overnight to give compound 90. Reduction of the nitro group followed by cyclization was effected for example by catalytic hydrogenation with a hydrogen pressure of from about atmospheric pressure to 300 p.s.i. over from about 1 hour to about 1 day of compound 90 in an inert solvent such as THF, ethyl acetate, toluene, ethanol, isopropanol, DMF or acetonitrile and the like, using a hydrogenation catalyst such as Raney nickel, palladium on carbon, a platinum catalyst, such as platinum oxide, platinum on carbon or platinum on alumina and the like, or a rhodium catalyst, such as rhodium on carbon or rhodium on alumina and the like, and the like affords intermediate nitrone 91a or a mixture of nitrone 91a and imine 91b. The reaction mixture comprising the nitrone or nitrone/imine mixture is treated with an acid such as trifluoroacetic acid or acetic acid or sulfuric acid or phosphoric acid or methanesulfonic acid and the like, and the hydrogenation is continued to give pyrrolidine compound 92 as the cis,cis-isomer. Epimerization at C-3 is effected by treatment of compound 92 with a base such as sodium ethoxide, potassium t-butoxide, lithium t-butoxide or potassium t-amyloxide and the like or a trialkylamine such as triethylamine or diisopropylethylamine and the like or an amidine such as DBU and the like in an inert solvent such as ethanol, ethyl acetate, isopropyl acetate, THF, toluene or DMF and the like at a temperature of from about −20° C. to about 120° C. to give the trans,trans compound 93. Compound 93 itself can optionally be resolved into enantiomers prior to reacting with X—R3. The substantially pure (i.e., at least 95% of the desired isomer) optically active (+)-isomer of compound 93 is obtained by treatment of a mixture of the (+)-isomer and the (−)-isomer of 93 with S-(+)-mandelic acid, D-tartaric acid or D-dibenzoyl tartaric acid and the like in a solvent such as acetonitrile, ethyl acetate, isopropyl acetate, ethanol or isopropanol and the like. The (+)-isomer of 93 selectively crystallizes as the salt, leaving the (−)-isomer of 93 in solution. Alternatively, the substantially pure (i.e., at least 95% of the desired isomer) optically active-(−)-isomer of compound 93 can be selectively crystallized by reaction of a mixture of the (+)-isomer and the (−)-isomer of 93 with L-tartaric acid, L-dibenzoyl tartaric acid or L-pyroglutamic acid and the like, leaving the desired (+)-isomer of compound 93 in solution.

Sources & evidence

ORD record
ord-ba31bf524bb74a6faf88776014ab0ab6
Source dataset
uspto-grants-2008_04
Patent number
US07365093B2

Reaction notes

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