Method for preparing 3-carbamoymethyl-5-methylhexanoic acid in recycling way

Patent metadata

Field	Value
Publication number	US-10131625-B2
Application number	US-201515521021-A
Country	US
Kind code	B2
Filing date	Oct 13, 2015
Priority date	Oct 24, 2014
Publication date	Nov 20, 2018
Grant date	Nov 20, 2018

Abstract

The present invention provides a method for recycling 3-carbamoylmethyl-5-methylhexanoic acid from 3-carba carbamoylmethyl moymethyl-5-methylhexanoic acid chiral resolving mother liquor. The method comprises the following steps: (a) distilling 3-carbamoylmethyl-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-carbamoylmethyl-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.

First claim

What is claimed is:

1. A method for recycling 3-carbamoylmethyl-5-methylhexanoic acid from 3-carbamoylmethyl-5-methylhexanoic acid chiral resolving mother liquor, comprising following steps:
(a) distilling the 3-carbamoylmethyl-5-methylhexanoic acid chiral resolving mother liquor to obtain residues, then adding C 6 -C 12 aromatic hydrocarbon, heating to dissolve the residues, keeping the temperature at 90-130° C. and stirring;
(b) after completing reaction in the above step (a), cooling reaction solution to 30-60° C., then adding alkali liquor dropwise, keeping the temperature at 90-130° C. 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-carbamoylmethyl-5-methylhexanoic acid.

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

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

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

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

6. 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.

7. 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.

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

9. 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.

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

11. 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-carbamoylmethyl-5-methylhexanoic acid in the 3-carbamoylmethyl-5-methylhexanoic acid chiral resolving mother liquor is 1-3:1.

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

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

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

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

16. 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%.

17. 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.

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

Assignees

• Zhejiang Huahai Pharm Co Ltd

Inventors

• Wang Shudong
• You Xuehai
• Zhang Wenling

Classifications

• C07C211/27

  having amino groups linked to the six-membered aromatic ring by saturated carbon chains · CPC title

• C01D1/04

  Hydroxides · CPC title

• C07C233/05

  having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms · CPC title

• Y02P20/582

  Recycling of unreacted starting or intermediate materials · CPC title

• C07C231/24 Primary

  Separation; Purification · CPC title