Acetic Acid → 1-Ethyl 7-methyl 3-oxoheptanedioate

Temperature

-78 °C

A five liter round bottom flask was fitted with a mechanical stirrer, thermometer and a one liter additional funnel. The addition funnel was in turn fitted with a septum into which was introduced a N2 line, an equalizing line and a liquid reagent inlet line. The equalizing line was further connected with tubing to a straight vacuum adapter and this adapter was fitted between the addition funnel and the flask. The flask was charged with N2 and then with 976 ml. (2.05 moles=2.25 equiv.) n-butyllithium in 800 ml. of anhydrous tetrahydrofuran (THF), and the mixture cooled to -78° C. in a dry ice/acetone bath. To this was added 408 ml. (2.05 moles) of dicyclohexylamine in 375 ml. THF dropwise over 45 minutes (temperature kept below -67° C.). After equilibrating to -78° C., 201 ml. (2.05 moles) of ethyl acetate in 100 ml. THF was added dropwise over 45 minutes (temperture kept below -67° C.). The mixture was allowed to stir at -78° C. for 15 minutes and then 150 g. (0.91 mole) of methyl 4-(chloroformyl)butyrate in 200 ml. THF was added dropwise over 30 minutes (temperature kept below -70° C.). After stirring for 1 hour at -78° C., 231 ml. (2.05 moles) of glacial acetic acid was added dropwise over 25 minutes, after which the dry ice/acetone bath was removed, and the reaction allowed to warm to 0° C., diluted with one liter Et2O, and the white inorganics filtered. The solids were washed well with ether. The combined filtrate and washes were evaporated in vacuo and the residue was partitioned between one liter ether and one liter water. The ether was separated, washed in sequence 2x with 500 ml. 0.5N HCl, 1x with 500 ml. H2O, 1x with 500 ml. saturated NaHCO3, 1x with 500 ml. H2O and 1x with 500 ml. brine, dried over MgSO4, filtered and evaporated in vacuo to yield 108.5 g. (55.1%) of title product as a gold colored mobile liquid. Nmr (CDCl3): 4.1 (q, 2H), 3.6 (s, 3H), 3.4 (s, 2H), 1.7-2.7 (m, 6H), 1.25 (t, 3H). M/e: 216 (m+).

1. customA five liter round bottom flask was fitted with a mechanical stirrer
2. customfitted with a septum into which
3. customwas fitted between the addition funnel
4. additionTo this was added 408 ml
5. customAfter equilibrating to -78° C.
6. stirringAfter stirring for 1 hour at -78° C.
7. customafter which the dry ice/acetone bath was removed
8. temperatureto warm to 0° C.
9. additiondiluted with one liter Et2O
10. filtrationthe white inorganics filtered
11. washThe solids were washed well with ether
12. customThe combined filtrate and washes were evaporated in vacuo
13. customthe residue was partitioned between one liter ether and one liter water
14. customThe ether was separated
15. washwashed in sequence 2x with 500 ml
16. dry with materialbrine, dried over MgSO4
17. filtrationfiltered
18. customevaporated in vacuo
19. customto yield 108.5 g

ORD record

ord-c7baa9156c074659a66c7be987d20eaf

Source dataset

uspto-grants-1990_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US04920221