Synthesis of 4-[3-(2,6-dimethylbenzyloxy)phenyl]-4-oxobutanoic acid

1. A method for producing a crude preparation of 4-[3-(2,6-Dimethylbenzyloxy)phenyl]-4-oxobutanoic acid ethyl ester, comprising:

(a) to a first solution in a reaction vessel, adding dropwise a second solution while maintaining the solution in the reaction vessel under an inert gas at a temperature below −50° C. under stirring conditions,

wherein the first solution consists essentially of one equivalent of 1-[3-(2,6-Dimethylbenzyloxy)-phenyl]-ethanone dissolved in tetrahydrofuran and 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, the first solution being cooled to a temperature between −35° C. and −75° C. and having a total water content of from 0.1 to 0.6 equivalents; and the second solution consists essentially of from 1.1 to 1.3 equivalents of lithium bis(trimethylsilyl)amide dissolved in tetrahydrofuran;

(b) stirring the solution resulting from step (a) at a temperature between −35° C. and −75° C. for about 30 minutes;

(c) to the solution from step (b), adding dropwise from 1 to 2 equivalents of ethyl bromoacetate while maintaining the temperature of the solution in the reaction vessel between −35° C. and −75° C.;

(d) allowing the temperature of the solution from step (c) to warm to a temperature in a range from −40° C. to 0° C. and maintaining the solution at a temperature in said range for a sufficient time for completion of alkylation;

(e) adding water or an aqueous salt solution to the solution from step (d) to quench;

(f) to the organic solution from step (e), adding an organic solvent;

(g) to the solution from step (f), separating the aqueous layer from the organic layer and discarding the aqueous layer;

(h) washing the organic layer from the preceding step with a saturated aqueous sodium chloride solution;

(i) concentrating the organic layer from step (h) to an oil,

thereby yielding crude 4-[3-(2,6-Dimethylbenzyloxy)phenyl]-4-oxobutanoic acid ethyl ester.

2. The method of claim 1 , wherein the temperature recited in one or more of steps (a), (b) and (c) is below −50° C.

3. The method of claim 1 , where in step (a) the first solution has a total water content of 0.36 equivalents.

4. The method of claim 1 , where in step (a) the number of equivalents of lithium bis(trimethylsilyl)amide in the second solution is from 1.15 to 1.2.

5. The method of claim 4 , wherein the number of equivalents of lithium bis(trimethylsilyl)amide in the second solution is 1.17.

6. The method of claim 1 , where in step (c) the number of equivalents of ethyl bromoacetate is from 1.2 to 1.6.

7. The method of claim 6 , wherein the number of equivalents of ethyl bromoacetate is from 1.25 to 1.56.

8. The method of claim 1 , where in step (d) the solution is maintained at a temperature of −25° C. for about ten minutes.

9. The method of claim 1 , where in step (e) the aqueous salt solution is aqueous 10% ammonium chloride.

10. The method of claim 1 , where in step (f) the organic solvent is selected from the group consisting of ethyl acetate, ethyl formate, propyl acetate, toluene, and methyl tert-butyl ether.

11. The method of claim 1 , further comprising between steps (h) and (i), washing the organic layer from step (h) twice with water or a 4% aqueous solution of either sodium chloride or ammonium chloride.

12. A method for producing a crude preparation of 4-[3-(2,6-Dimethylbenzyloxy)phenyl]-4-oxobutanoic acid, comprising:

(a) under stirring conditions in a reaction vessel, dissolving the 4-[3-(2,6-Dimethylbenzyloxy)phenyl]-4-oxobutanoic acid ethyl ester produced by the process of claim 1 in ethanol;

(b) to the solution from step (a), adding 2 equivalents of sodium hydroxide solution compared to the amount of the ethyl ester and maintaining the solution in the reaction vessel at 55° C. for thirty minutes;

(c) to the mixture from step (b), adding water and removing the ethanol by evaporation;

(d) to the solution from step (c), adding water;

(e) washing the solution from step (d) with methyl t-butyl ether;

(f) acidifying the solution from step (e) with concentrated hydrochloric acid and ethyl acetate to a pH of between 1 and about 3;

(g) to the solution from step (f), separating the aqueous layer from the organic layer and discarding the aqueous layer;

(h) washing the organic layer from step (g) with water;

(i) concentrating the organic layer from step (h) to a solid,

thereby yielding crude 4-[3-(2,6-Dimethylbenzyloxy)phenyl]-4-oxobutanoic acid.

13. The method of claim 12 , where in step (f) the pH is between 2 and 3.

14. A method for producing purified 4-[3-(2,6-Dimethylbenzyloxy)phenyl]-4-oxobutanoic acid, comprising:

(a) in a reaction vessel, dissolving the crude 4-[3-(2,6-Dimethylbenzyloxy)phenyl]-4-oxobutanoic acid produced by the process of claim 12 in ethanol and heating the resulting solution to 65° C.;

(b) to the solution from the preceding step, adding water dropwise while maintaining the solution at a temperature of from 45° C. to 60° C., wherein the ratio of water added to the amount of ethanol from step (a) is about 4:6;

(c) allowing the solution from step (b) to cool slowly under stirring conditions to produce a solid; and

(d) isolating the solid from step (c),

thereby yielding purified 4-[3-(2,6-Dimethylbenzyloxy)phenyl]-4-oxobutanoic acid.

15. The method of claim 14 , further comprising between steps (a) and (b), filtering the solution from step (a) through a medium glass frit.

16. The method of claim 14 , where in step (b) the temperature is from 50° C. to 60° C.

17. The method of claim 16 , wherein the temperature is from 50° C. to 55° C.

18. The method of claim 17 , wherein the temperature is about 55° C.

19. The method of claim 14 , where in step (c) the solution is allowed to cool slowly to room temperature.

20. The method of claim 14 , further comprising after step (d),

(e) washing the solid from step (d) with 1:1 water/ethanol;

(f) dissolving the solid from step (e) in ethanol to produce a solution;

(g) to the solution from step (f), adding water dropwise while maintaining the solution at 55° C.;

(h) allowing the solution from step (g) to cool slowly to room temperature under stirring conditions to produce a solid;

(i) isolating the solid from step (h) and washing the solid with 1:1 water/ethanol;

(j) drying the solid from step (i),

thereby yielding further purified 4-[3-(2,6-Dimethylbenzyloxy)phenyl]-4-oxobutanoic acid.