Ethyl chloroacetate → HCID 16724470, compound

Temperature

25 °C

Following the procedure of (Vol. 8, No. 6, 2004, Organic Research & Development) with modification, this compound was synthesised as follows: Ethyl chloroacetate (44.8 ml, 421 mmol) and anhydrous ethanol (30 ml) were cooled to 10-12° C. A solution of sodium ethoxide in ethanol (21% w/w, 165 ml) was added over 25 min at 12-16° C. under N2. After addition was complete the reaction mixture was warmed to 25° C. and stirred for 1 h. The mixture was then cooled to 10° C. and solid NaOEt (33.3 g, 488 mmol) was then added portion-wise over 0.5 h at 10-14° C. Ethanol (20 ml) was then added followed by the addition of diethyl carbonate (31 ml, 256 mmol). The slurry was then cooled to 0-5° C. and then 3-thiophene carboxaldehyde (20.2 g, 179.5 mmol) was added over a period of 1 h. After addition was complete the mixture was stirred at 40° C. in an oil bath for 15 h. The slurry was then cooled to 10-15° C. and then water (40 ml) was added followed by the addition of aqueous NaOH (55 ml of a 10 M solution). The resulting slurry was then stirred at pH 14 for 3 h at 20° C. The mixture was then diluted with water (60 ml) and then placed under reduced pressure at 45° C. to remove most of the ethanol and some water. The resulting thick slurry was then cooled to 4° C. in an ice-bath and then treated with conc. HCl (115 ml) drop-wise. The resulting slurry was then stirred at room temperature for 1.5 h and then extracted with EtOAc (2×200 ml) and the organic layer washed with water, brine and then dried (sodium sulphate). Evaporation of the solvent under reduced pressure afforded a deep-brown residue. This was dissolved in 5 M NaOH (250 ml) and this solution was washed with EtOAc (100 ml). The basic aqueous was then cooled to 4° C. and acidified with conc. HCl (11 M) to pH 4-6. The product was extracted with diethyl ether (3×200 ml), washed with brine, dried (sodium sulphate) and the solvent removed under reduced pressure. The residue was then filtered through a pad of silica (eluent hexane:EtOAc 90:10). The solvent was removed under reduced pressure and then the residue recrystallised from Et2O/hexane to afford the title compound as yellow crystals (79%). M.p. 88-89° C. 1H NMR (CDCl3, 250 MHz) δ 11.16 (1H, br s, COOH), 7.73-7.75 (1H, dd, j=0.5 Hz, Ar), 7.44-7.47 (1H, dd, J=1 Hz, Ar), 7.25-7.28 (1H, m, Ar), 7.18 (1H, s, CH═C), 3.96-4.05 (2H, q, J=7 Hz, CH2CH3), 1.35 (3H, t, J=7 Hz, CH2CH3),). Found: C, 54.64; H, 5.08; Calculated for C9H10SO3 C, 54.54; H, 5.08. M/z [(Cl) 222 (M)+ 30%, 223 (M+H)+ 50%, 240 (M+NH4)+ 100%; Found: 223.09705; required for C12H15O4 223.09155]. M/z [(Cl) 198 (M)+ 22%, 199 (M+H)+ 50%, 216 (M+NH4)+ 100%].

1. custom6, 2004, Organic Research & Development) with modification, this compound was synthesised
2. additionAfter addition
3. temperatureThe mixture was then cooled to 10° C.
4. temperatureThe slurry was then cooled to 0-5° C.
5. additionAfter addition
6. stirringwas stirred at 40° C. in an oil bath for 15 h
7. temperatureThe slurry was then cooled to 10-15° C.
8. stirringThe resulting slurry was then stirred at pH 14 for 3 h at 20° C
9. customplaced under reduced pressure at 45° C.
10. customto remove most of the ethanol
11. temperatureThe resulting thick slurry was then cooled to 4° C. in an ice-bath
12. additiontreated with conc. HCl (115 ml) drop-wise
13. stirringThe resulting slurry was then stirred at room temperature for 1.5 h
14. extractionextracted with EtOAc (2×200 ml)
15. washthe organic layer washed with water, brine
16. dry with materialdried (sodium sulphate)
17. customEvaporation of the solvent under reduced pressure
18. customafforded a deep-brown residue
19. washthis solution was washed with EtOAc (100 ml)
20. temperatureThe basic aqueous was then cooled to 4° C.
21. extractionThe product was extracted with diethyl ether (3×200 ml)
22. washwashed with brine
23. dry with materialdried (sodium sulphate)
24. customthe solvent removed under reduced pressure
25. filtrationThe residue was then filtered through a pad of silica (eluent hexane:EtOAc 90:10)
26. customThe solvent was removed under reduced pressure
27. customthe residue recrystallised from Et2O/hexane

ORD record

ord-39237556e1894b999f6e7a6b550293d3

Source dataset

uspto-grants-2011_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07906669B2