METHOD FOR PREPARING 3-CARBAMOYMETHYL-5-METHYLHEXANOIC ACID IN RECYCLING WAY

Abstract

The present invention provides a method for recycling 3-carbamoymethyl-5-methylhexanoic acid from 3-carbamoymethyl-5-methylhexanoic acid chiral resolving mother liquor. The method comprises the following steps: (a) distilling 3-carbamoymethyl-5-methylhexanoic acid chiral resolving mother liquor, adding aromatic hydrocarbon, heating to dissolve, keeping the temperature and stirring; (b) after completing the reaction in step (a), cooling the reaction solution to 30-60° C., then adding alkali liquor dropwise, keeping the temperature and reacting; and (c) after completing the reaction in step (b), cooling the reactant to 20-30° C., layering, adjusting the pH of the separated water layer to 1 to 2, performing extraction by using an organic solvent, distilling an organic phase under a reduced pressure, and crystallizing at 0±5° C. to obtain 3-carbamoymethyl-5-methylhexanoic acid. The method provided in the present invention is convenient to operate, and the recycled product is high in purity (≧99.8%) and yield.

Claims

1. A method for recycling 3-carbamoymethyl-5-methylhexanoic acid from 3-carbamoymethyl-5-methylhexanoic acid chiral resolving mother liquor, comprising following steps: (a) distilling the 3-carbamoymethyl-5-methylhexanoic acid chiral resolving mother liquor, then adding aromatic hydrocarbon, heating to dissolve, keeping the temperature and stirring; (b) after completing reaction in the above step (a), cooling reaction solution, then adding alkali liquor dropwise, keeping the temperature and reacting; and (c) after completing reaction in the above step (b), cooling to 20-30° C., layering, adjusting the pH of the separated water layer to 1-2, extracting with organic solvent, distilling the organic phase under reduced pressure, and then crystallizing at a temperature of 0±5° C. to obtain 3-carbamoymethyl-5-methylhexanoic acid.

2. The method according to claim 1, characterized in that the aromatic hydrocarbon added into 3-carbamoymethyl-5-methylhexanoic acid chiral resolving mother liquor after the distilling in step (a) is C.sub.6-C.sub.12 aromatic hydrocarbon;

3. The method according to claim 1, characterized in that temperature for heating to dissolve in step (a) is 80-150° C.

4. The method according to claim 1, characterized in that after the distilling in step (a), the ratio of the mass of 3-carbamoymethyl-5-methylhexanoic acid chiral resolving mother liquor to the volume of aromatic hydrocarbon solvent is 1:10-1:20 g/ml.

5. The method according to claim 1, characterized in that the temperature of the reaction in step (a) is 90-130° C.

6. The method according to claim 1, characterized in that the duration of the reaction in step (a) is 20-48 h.

7. The method according to claim 1, characterized in that the temperature of the reaction in step (b) is 90-130° C.

8. The method according to claim 1, characterized in that the duration of the reaction in step (b) is 20-48 h.

9. The method according to claim 1, characterized in that the alkali liquor in step (b) is aqueous solution of alkali metal hydroxide and/or aqueous solution of alkali metal carbonate, such as aqueous solution of sodium hydroxide, sodium carbonate, potassium carbonate, potassium hydroxide.

10. The method according to claim 1, characterized in that the alkali liquor in step (b) is added dropwise at a temperature of 30-50° C.

11. The method according to claim 1, characterized in that the final temperature of the cooling in step (b) is 40-50° C.

12. The method according to claim 1, characterized in that the cooling after distillation under reduced pressure in step (b) is carried out at a cooling rate of 1° C. per 5 minutes, and the crystallization time is controlled in the range of 3-5 hours.

13. The method according to claim 1, characterized in that the solvent for extracting in step (c) is organic solvent that is water-immiscible.

14. The method according to claim 1, characterized in that in the step (b), the mass ratio of the amount of the alkali liquor used to the content of the 3-carbamoymethyl-5-methylhexanoic acid in the 3-carbamoymethyl-5-methylhexanoic acid chiral resolving mother liquor is 1-3:1.

15. The method according to claim 1, characterized in that in the step (a), the 3-carbamoymethyl-5-methylhexanoic acid chiral resolving mother liquor is the mother liquor obtained by centrifuging and filtering after the resolution of 3-carbamoymethyl-5-methylhexanoic acid via a resolution agent of R-phenylethylamine.

16. The method according to claim 1, characterized in that the aromatic hydrocarbon added into 3-carbamoymethyl-5-methylhexanoic acid chiral resolving mother liquor after the distilling in step (a) is benzene, toluene, xylene, or p-xylene.

17. The method according to claim 1, characterized in that the temperature for heating to dissolve in step (a) is 100-120° C.

18. The method according to claim 1, characterized in that after the distilling in step (a), the ratio of the mass of 3-carbamoymethyl-5-methylhexanoic acid chiral resolving mother liquor to the volume of aromatic hydrocarbon solvent is 1:13-1:18 g/ml.

19. The method according to claim 1, characterized in that the concentration of the mass percentage of the alkali liquor in step (b) is 20-30%.

20. The method according to claim 1, characterized in that the solvent for extracting in step (c) is selected from n-hexane, cyclohexane, n-heptane, toluene, ethyl acetate or ethyl ether.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0030] To make the objects, technical solutions, and advantages of the present invention much more dearly, hereinafter the present invention will be further described in detail by referring to the examples. It is obvious that the described examples are only parts of examples of the present invention, rather than all of the examples. Based on the examples in the present invention, any other examples that obtained without creative work by the ordinary skilled in the art are within the protection scope of the present invention.

Definition:

[0031] The aromatic hydrocarbon used in the present invention refers to hydrocarbons containing benzene ring structure in the molecule, in particular to C.sub.6-C.sub.12 aromatic hydrocarbons, and includes but not limited to, benzene, toluene, xylene, p-xylene, o-xylene, m-xylene, ethylbenzene, isopropyl benzene, naphthalene and the like.

[0032] The xylene used in the present invention means the mixture of three isomers of o-xylene, m-xylene and p-xylene.

Reference Example: Obtaining 3-carbamoymethyl-5-methylhexanoic acid Mother Liquor

[0033] 2139.0 g of trichloromethane and 26.7 g of ethanol were pumped into a 3 L reaction kettle in order under the temperature of 15-25° C., and 142.0 g of 3-carbamoymethyl-5-methylhexanoic acid was added under stirring by a solid feeder. The feeder was washed with 300.0 g of trichloromethane. The kettle was heated to 55-60° C. within 1-2 hours. 50.0 g of R(+)-α-phenethylamine was added dropwise at 55-60° C. during about 3-4 hours, and stirred continuously for 0.5-1 hour at 55-60° C. 16.7 g of R(+)-α-phenethylamine was added dropwise at 55-60° C. during about 2-3 hours, and stirred continuously for 1-2 hours at 55-60° C. after completion of the dropping. The kettle was cooled to 28-32° C. at a cooling rate of 10-20° C./hour. The stir was continued for 1-2 hours at 28-32° C. The reaction product was filtered at 28-32° C., the wet filter cake was washed twice with 184.0 g of trichloromethane, and the filtrates were combined, and reserved for later use.

Example 1: Recycling 3-carbamoymethyl-5-methylhexanoic acid from 3-carbamoymethyl-5-methylhexanoic acid chiral Resolving Mother Liquor

[0034] The filtrate (about 1.7 L) obtained in the above reference example was pumped in, and concentrated to 300-500 mL under reduced pressure while controlling the temperature to 30-40° C. The concentrate was cooled to 15-25° C., and 200 mL of water was added. The reactant was concentrated under reduced pressure while controlling the temperature to 30-40° C. until no obvious distillate flowed out, 700 mL of toluene was added, and the temperature was raised to 110-120° C. within 1-2 hours with stirring, and water was removed at the same time. HPLC detection was conducted every 4 hours from the 24.sup.th hour until the amount of 3-carbamoymethyl-5-methylhexanoic acid was <1%. The temperature was cooled to 40-50° C. within 1-2 hours, 284.0 g of water and 284.0 g of 10% aqueous solution of MOH were added dropwise at 40-50° C., and the temperature was controlled at 35-55° C. The reactant was stirred at 40-50° C. for 3-4 hours, then cooled to 20-30° C., and stood to layer for 1-2 hours. The liquids were separated, after the water phase was separated, 140.0 g of water was added into the organic phase, stirred for 0.5-1 hour and stood and layered for 1-2 hours. The liquids were separated. After separation the water phases were combined. 167.0 g of toluene was added into the water phase, stirred for 0.5-1 hour and stood to layer for 0.5-1 hour, The liquids were separated. 167.0 g of toluene was added into the water phase, stirred for 0.5-1 hour and stood to layer for 0.5-1 hour. The water phase was separated. 100.0 g of concentrated hydrochloric acid was added into the water phase dropwise to adjust the pH to 1.5-2 (took the amount of concentrated hydrochloric acid added as the practical dosage), and the temperature was controlled at 0-10° C. It was stirred for 1-2 hours at 0-5° C. 600 mL of ethyl acetate was added, and stirred for 20-30 minutes and stood to layer for 30 minutes. Then 300 mL of ethyl acetate was added into the water phase, stirred for 20-30 minutes and stood to layer for 30 minutes. The organic phases were combined and distilled to 240 ml. under a reduced pressure at 40-50° C., and cooled slowly to 0±5° C., filtered, and dried. 3-carbamoymethyl-5-methylhexanoic acid was recycled once (about 67.9 g of white solid, with the yield of 72.5%, and the purity of 99.81%).

Example 2: Recycling 3-carbamoymethyl-5-methylhexanoic acid from 3-carbamoymethyl-5-methylhexanoic acid chiral Resolving Mother Liquor

[0035] The filtrate (about 1.7 L) obtained in the above reference example was pumped in, and concentrated to 300-500 mL under reduced pressure while controlling the temperature to 30-40° C. The concentrate was cooled to 15-25° C., and 200 mL of water was added. The reactant was concentrated under reduced pressure while controlling the temperature to 30-40° C. until no obvious distillate flowed out. 700 mL of xylene was added, and the temperature was raised to 110-120° C. within 1-2 hours with stirring, and water was removed at the same time. HPLC detection was conducted every 4 hours from the 24.sup.th hour until the amount of 3-carbamoymethyl-5-methylhexanoic acid was <1%. The temperature was cooled to 40-50° C. within 1-2 hours. 284.0 g of water and 284.0 g of 10% aqueous solution of NaOH were added dropwise at 40-50° C., and the temperature was controlled at 35-55° C. The reactant was stirred at 40-50° C. for 3-4 hours, then cooled to 20-30° C., and stood to layer for 1-2 hours. The liquids were separated, after the water phase was separated, 140.0 g of water was added into the organic phase, stirred for 0.5-1 hour and stood and layered for 1-2 hours. The liquids were separated. After separation the water phases were combined. 167.0 g of toluene was added into the water phase, stirred for 0.5-1 hour and stood to layer for 0.5-1 hour. The liquids were separated. 167.0 g of toluene was added into the water phase, stirred for 0.5-1 hour and stood to layer for 0.5-1 hour. The water phase was separated. 100.0 g of concentrated hydrochloric acid was added into the water phase dropwise to adjust the pH to 1.5-2 (took the amount of concentrated hydrochloric acid added as the practical dosage), and the temperature was controlled at 0-10° C. It was stirred for 1-2 hours at 0-5° C. 600 mL of n-heptane was added, and stirred for 20-30 minutes and stood to layer for 30 minutes. Then 300 mL of n-heptane was added into the water phase, stirred for 20-30 minutes and stood to layer for 30 minutes. The organic phases were combined and distilled to 240 mL under a reduced pressure at 60-70° C., and cooled slowly to 0±5° C., filtered, and dried. 3-carbamoymethyl-5-methylhexanoic acid was recycled once (about 67.3 g of white solid, with the yield of 71.8%, and the purity of 99.79%).

Example 3: Recycling 3-carbamoymethyl-5-methylhexanoic acid from 3-carbamoymethyl-5-methylhexanoic acid chiral Resolving Mother Liquor

[0036] The filtrate (about 1.7L) obtained in the above reference example was pumped in, and concentrated to 300-500 mL under reduced pressure while controlling the temperature to 30-40° C. The concentrate was cooled to 15-25° C., and 200 mL of water was added. The reactant was concentrated under reduced pressure while controlling the temperature to 30-40° C. until no obvious distillate flowed out. 700 mL of p-xylene was added, and the temperature was raised to 110-120° C. within 1-2 hours with stirring, and water was removed at the same time. HPLC detection was conducted every 4 hours from the 24.sup.th hour until the amount of 3-carbamoymethyl-5-methylhexanoic acid was <1%. The temperature was cooled to 40-50° C. within 1-2 hours, 284.0 g of water and 284.0 g of 10% aqueous solution of NaOH were added dropwise at 40-50° C., and the temperature was controlled at 35-55° C. The reactant was stirred at 40-50° C. for 3-4 hours, then cooled to 20-30° C., and stood to layer for 1-2 hours. The liquids were separated, after the water phase was separated, 140.0 g of water was added into the organic phase, stirred for 0.5-1 hour and stood and layered for 1-2 hours. The liquids were separated. After separation the water phases were combined. 167.0 g of toluene was added into the water phase, stirred for 0.5-1 hour and stood to layer for 0,5-1 hour, The liquids were separated. 167.0 g of toluene was added into the water phase, stirred for 0.5-1 hour and stood to layer for 0.5-1 hour. The water phase was separated. 100.0 g of concentrated hydrochloric acid was added into the water phase dropwise to adjust the pH to 1.5-2 (took the amount of concentrated hydrochloric acid added as the practical dosage), and the temperature was controlled at 0-10° C. It was stirred for 1-2 hours at 0-5° C. 600 mL of cyclohexane was added, and stirred for 20-30 minutes and stood to layer for 30 minutes. Then 300 mL of cyclohexane was added into the water phase, stirred for 20-30 minutes and stood to layer for 30 minutes. The organic phases were combined and distilled to 240 mL under a reduced pressure at 40-50° C., and cooled slowly to 0±5° C., filtered, and dried. 3-carbamoymethyl-5-methylhexanoic acid was recycled once (about 66.9 g of white solid, with the yield of 70.5%, and the purity of 99.84%).

Example 4: Recycling 3-carbamoymethyl-5-methylhexanoic acid from 3-carbamoymethyl-5-methylhexanoic acid chiral Resolving Mother Liquor

[0037] The filtrate (about 1.7 L) obtained in the above reference example was pumped in, and concentrated to 300-500 mL under reduced pressure while controlling the temperature to 30-40° C. The concentrate was cooled to 15-25° C., and 200 mL of water was added. The reactant was concentrated under reduced pressure while controlling the temperature to 30-40° C. until no obvious distillate flowed out. 700 mL of p-xylene was added, and the temperature was raised to 110-120° C. within 1-2 hours with stirring, and water was removed at the same time. HPLC detection was conducted every 4 hours from the 24.sup.th hour until the amount of 3-carbamoymethyl-5-methylhexanoic acid was <1%. The temperature was cooled to 40-50° C. within 1-2 hours. 284.0 g of water and 284.0 g of 10% aqueous solution of NaOH were added dropwise at 40-50° C., and the temperature was controlled at 35-55° C. The reactant was stirred at 40-50° C. for 3-4 hours, then cooled to 20-30° C., and stood to layer for 1-2 hours. The liquids were separated, after the water phase was separated, 140.0 g of water was added into the organic phase, stirred for 0.5-1 hour and stood and layered for 1-2 hours. The liquids were separated. After separation the water phases were combined. 167.0 g of toluene was added into the water phase, stirred for 0.5-1 hour and stood to layer for 0.5-1 hour. The liquids were separated. 167.0 g of toluene was added into the water phase, stirred for 0.5-1 hour and stood to layer for 0.5-1 hour. The water phase was separated. 100.0 g of concentrated hydrochloric acid was added into the water phase dropwise to adjust the pH to 1.5-2 (took the amount of concentrated hydrochloric acid added as the practical dosage), and the temperature was controlled at 0-10° C. It was stirred for 1-2 hours at 0-5° C. 600 mL of ethyl acetate was added, and stirred for 20-30 minutes and stood to layer for 30 minutes. Then 300 mL of ethyl acetate was added into the water phase, stirred for 20-30 minutes and stood to layer for 30 minutes. The organic phases were combined and distilled to 240 mL under a reduced pressure at 40-50° C., and cooled slowly to 0±5° C., filtered, and dried. 3-carbamoymethyl-5-methylhexanoic acid was recycled once (about 75.1 g of white solid, with the yield of 80.1%, and the purity of 99.81%). The above examples are only the preferable examples of the present invention, not intending to limit the present invention. Any modification, equivalent substitution, improvement and the like made within the spirit and principle of the present invention should be included in the protection scope of the present invention.