Reaction #51187

Reaction equation

2-iodoethyl methyl ether

lithium diisopropylamide

1-(3-tert-butoxy-3-oxopropyl)cyclopentane carboxylic acid

→

crude title compound

Yield 81.0%

1-[2-(tert-butoxycarbonyl)-4-methoxybutyl]cyclopentanecarboxylic acid

Yield 81.0%

Solvents

n-heptane

1,2-dimethoxyethane

tetrahydrofuran n-heptane ethylbenzene

1,2-dimethoxyethane

1,2-dimethoxyethane

Conditions

Workup

1. 1
   WashThe header tank was washed with 1,2-dimethoxyethane (2.5 L)
2. 2
   workup.ADDITIONthis was added to the reaction
3. 3
   workup.STIRRINGto stir at −10° C. for 1.75 hours
4. 4
   workup.STIRRINGThe reaction was then stirred at this temperature for 4 hours
5. 5
   Temperaturebefore warming to 20° C. over a period of 4 hours
6. 6
   workup.STIRRINGAfter stirring at this temperature for 8 hours the reaction
7. 7
   Otherwas quenched by the addition of aqueous ammonium chloride (25 L of a 2.8 M solution), ethyl acetate (12.5 L)
8. 8
   workup.ADDITIONwas then added
9. 9
   workup.ADDITIONAqueous hydrochloric acid (10 L of 5 M solution) was then added
10. 10
    workup.STIRRINGwith stirring
11. 11
    workup.ADDITIONThe two phases were mixed
12. 12
    Otherseparated
13. 13
    ExtractionThe organic phase was then extracted three times with aqueous potassium carbonate solution (0.3 M solution
14. 14
    workup.STIRRINGadded n-heptane (15.6 L), and aqueous hydrochloric acid (14.5 L of a 5 M solution) with stirring until the pH of the aqueous layer
15. 15
    OtherThe layers were then separated
16. 16
    Extractionthe aqueous phase was extracted with n-heptane (15.6 L)
17. 17
    WashThe combined organic phases were then washed with saturated brine (3.1 L)
18. 18
    Concentrationwere then concentrated under vacuum

Procedure

To a solution of commercially supplied lithium diisopropylamide (9.63 kg of a 2M solution in tetrahydrofuran/n-heptane/ethylbenzene, 23.7 mol) in 1,2-dimethoxyethane (25 L) at −10° C. under an atmosphere of N2 was added a solution of 1-(3-tert-butoxy-3-oxopropyl)cyclopentane carboxylic acid (EP274234B1—see Example 35) (2.5 kg, 10.3 mol) in 1,2-dimethoxyethane (12.5 L) with stirring over a period of 4 hours whilst maintaining the reaction temperature at −10° C. The header tank was washed with 1,2-dimethoxyethane (2.5 L) and this was added to the reaction. The reaction mixture was then allowed to stir at −10° C. for 1.75 hours. To the resultant solution was added a solution of 2-iodoethyl methyl ether (2.73 kg, 14.4 mol) in 1,2-dimethoxyethane (10 L) over a period of 1.75 hours. The reaction was then stirred at this temperature for 4 hours before warming to 20° C. over a period of 4 hours. After stirring at this temperature for 8 hours the reaction was quenched by the addition of aqueous ammonium chloride (25 L of a 2.8 M solution), ethyl acetate (12.5 L) was then added. Aqueous hydrochloric acid (10 L of 5 M solution) was then added with stirring to adjust the pH to between 2 and 3. The two phases were mixed and then separated. The organic phase was then extracted three times with aqueous potassium carbonate solution (0.3 M solution; 37.5 L, 12.5 L and then 6.25 L). To the combined aqueous phases was then added n-heptane (15.6 L), and aqueous hydrochloric acid (14.5 L of a 5 M solution) with stirring until the pH of the aqueous layer was between 2 and 3. The layers were then separated and the aqueous phase was extracted with n-heptane (15.6 L). The combined organic phases were then washed with saturated brine (3.1 L) and were then concentrated under vacuum to give the crude title compound (2.50 kg, 8.32 mol, 81% yield) as a solution in n-heptane (21.8 kg total solution weight).

Source