Reaction #1178460

Reaction equation

(2-chloroethoxy)acetyl chloride

benzyl (4-aminocyclohexyl)carbamate

triethylamine

→

4-(4-aminocyclohexyl)morpholin-3-one

Solvents

tetrahydrofuran

Conditions

Workup

1. 1
   OtherThe reaction mixture is then evaporated under reduced pressure
2. 2
   Extractionthe aqueous solution is extracted three times with 20 ml of ethyl acetate each time
3. 3
   DryingAfter the combined organic phases have been dried over sodium sulfate
4. 4
   workup.ADDITION2.3 g of caesium carbonate are added to the resultant solution
5. 5
   workup.WAITThe reaction mixture is then left
6. 6
   workup.STIRRINGto stir at room temperature for 48 hours
7. 7
   Otherevaporated under reduced pressure
8. 8
   Extractionthe aqueous solution is extracted four times with 20 ml of ethyl acetate each time
9. 9
   DryingAfter the combined organic phases have been dried over sodium sulfate
10. 10
    workup.ADDITION0.3 g of 5% palladium/carbon is added to the resultant solution
11. 11
    FiltrationThe catalyst is subsequently filtered off
12. 12
    Otherthe filtrate is evaporated to dryness under reduced pressure

Procedure

13-9.1 6.32 g (40.3 mmol) of (2-chloroethoxy)acetyl chloride are added to the solution of 10 g (40.3 mmol) of benzyl (4-aminocyclohexyl)carbamate and 6.2 ml of triethylamine (TEA) in 300 ml of tetrahydrofuran, and the mixture is subsequently stirred at room temperature for 20 hours. The reaction mixture is then evaporated under reduced pressure, the residue is taken up in 20 ml of water, and the aqueous solution is extracted three times with 20 ml of ethyl acetate each time. After the combined organic phases have been dried over sodium sulfate and the solvent has been stripped off, the residue is taken up in 20 ml of acetonitrile, and 2.3 g of caesium carbonate are added to the resultant solution. The reaction mixture is then left to stir at room temperature for 48 hours and then evaporated under reduced pressure, the residue is taken up in 20 ml of water, and the aqueous solution is extracted four times with 20 ml of ethyl acetate each time. After the combined organic phases have been dried over sodium sulfate and the solvent has been stripped off, the residue is taken up in 50 ml of tetrahydrofuran, 0.3 g of 5% palladium/carbon is added to the resultant solution, and the mixture is hydrogenated until the take-up of hydrogen ceases. The catalyst is subsequently filtered off, and the filtrate is evaporated to dryness under reduced pressure, giving 1.5 g of 4-(4-aminocyclohexyl)morpholin-3-one as a colourless oil; ESI 199. 13-9.2 Analogously to Example 7.3, reaction of cis-N′-BOC-4-hydroxy-D-proline and 4-chlorophenyl isocyanate gives the compound (2R,4R)-1-(4-chlorophenylcarbamoyl)-4-hydroxypyrrolidine-2-carboxylic acid; ESI 285; m.p. 132°. 13-9.3 Analogously to Example 7.1, reaction of the amine 13-9.1 and the acid 13-9.2 gives the compound 1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl)cyclohexan-1-yl]}-(2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxamide, ESI 465; m.p. 245°.

Source