β-Hydroxy-β-methylbutyric (HMB) acid purification method

Abstract

The present invention relates generally to the field of chemical synthesis. Specifically, the present invention relates to a method for purification of -hydroxyl--methyl butyrate comprising (1) neutralizing a crude -hydroxyl--methyl butyrate; (2) cooling and crystallizing the crude -hydroxyl--methyl butyrate solution to create a -hydroxyl--methyl butyrate salt; (3) dissolving and acidifying the salt; and (4) extracting the resultant high purity -hydroxyl--methyl butyrate. Additionally, the present invention relates to a method of obtaining high purity -hydroxyl--methyl butyrate at normal temperature and vacuum conditions.

Claims

1. A method for purifying -hydroxyl--methyl butyrate, comprising: (a) neutralizing a crude -hydroxyl--methyl butyrate with a base; (b) crystallizing, centrifuging, and drying the crude -hydroxyl--methyl butyrate to obtain a crystallized product containing a salt of -hydroxyl--methyl butyrate; (c) adding an inorganic acid to the salt of -hydroxyl--methyl butyrate product for dissolution and acidification; and (d) extracting -hydroxyl--methyl butyrate from the dissolved and acidified salt of -hydroxyl--methyl butyrate to obtain -hydroxyl--methyl butyrate; wherein the purity of the -hydroxyl--methyl butyrate is about 97 percent or greater.

2. The method of claim 1, wherein in step (a), the neutralizing comprises: (a) dissolving the crude -hydroxyl--methyl butyrate; (b) adding a base at 20-60 C. until the pH reaches 6-8; (c) adding diatomite and maintaining the temperature at 40-75 C.; (d) filtering and recovering a filtrate; and (e) slowly cooling the filtrate to 10 to 20 C. to obtain a -hydroxyl--methyl butyrate crystal.

3. The method of claim 2, wherein the crude -hydroxyl--methyl butyrate is dissolved in an aqueous solvent.

4. The method of claim 1, wherein in step (c), the dissolution and acidification comprises: (a) adding the salt of -hydroxyl--methyl butyrate product into pure water in a weight ratio of 1:1-5; and (b) dropping an inorganic acid at 0-40 C. until the pH reaches 1-3.5.

5. The method of claim 1, wherein the base is a metal salt having low solubility.

6. The method of claim 1, wherein the inorganic acid is selected from the group consisting of hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid.

7. The method of claim 1, wherein in step (c), an organic solvent is used to extract -hydroxyl--methyl butyrate from the dissolved and acidified product to obtain an organic solvent extract, and further wherein the organic solvent is removed to produce -hydroxyl--methyl butyrate of high purity.

8. The method of claim 7, wherein the organic solvent is a water-immiscible solvent, selected from the group consisting of: methyl acetate, ethyl acetate, butyl acetate, n-butanol, methyl ethyl ketone, methyl isobutyl ketone, dichloromethane, and dichloroethane.

9. The method of claim 7, wherein the organic solvent is removed by vacuum distillation.

10. The method of claim 1, wherein before step (a), the method further comprises: (a) reacting diacetone alcohol with hypochlorite to produce a product containing a salt of -hydroxyl--methyl butyrate; (b) reacting the product containing the salt of -hydroxyl--methyl butyrate obtained in step (a) with an inorganic acid to obtain a crude -hydroxyl--methyl butyrate.

11. The method of claim 3, wherein the aqueous solvent is selected from the group consisting of water and ethanol.

12. The method of claim 5 wherein, the base is selected from the group consisting of calcium hydroxide and magnesium hydroxide.

13. The method of claim 1, wherein the method has less strain on equipment when compared to conventional production methods.

Description

EXAMPLE 1

Production of Crude HMB

(1) 1. Starting Materials and Auxiliary Materials

(2) Starting materials and auxiliary materials used in the production of crude HMB are shown in Table 1.

(3) TABLE-US-00001 TABLE 1 Starting and auxiliary materials for production of crude HMB Name of the starting and auxiliary materials Quality Ratio Hypochlorite Industrial grade 1000 kg 4-Methyl-4-Hydroxyl-2-Pentanone Industrial grade reaction status (diacetone alcohol) dependent Hydrochloric acid Food grade pH dependent Ethyl acetate Food grade 1000 kg

(4) 2. Operational Process and Processing Parameters

(5) 2.1 Oxidative Synthesis (it is a Strong Exothermic Reaction)

(6) Sodium hypochlorite was pumped into a reaction kettle and diacetone alcohol (DIA) was slowly added. The addition velocity was controlled to maintain the reaction temperature of the materials in the kettle in the range of 10 to 20 C. during the course of the reaction. DIA was added until the addition significantly decreased the temperature of the kettle, indicating that the reaction was no longer taking place.

(7) 2.2 Acidification

(8) The reaction product obtained through oxidative synthesis was pumped into another reaction kettle. The temperature was adjusted to about 20 C. Hydrochloric acid was added to adjust the pH to between 2 and 3.5. After the acid addition, the mixture was allowed to stand for 30 minutes. The chloroform by-product was removed from the bottom of the kettle.

(9) 2.3 Removal of Water by Evaporation

(10) The reaction product obtained in by acidification was pumped into another reaction kettle and placed under vacuum until the volume of the product was reduced to approximately half of its initial volume. The product was cooled to about 60 C., discharged from the kettle, and filtered to remove the sodium chloride byproduct. The filtrates were combined and added to the reaction kettle.

(11) 2.4 Extraction

(12) The filtrate was extracted by ethyl acetate three times. Before each extraction, the pH of the filtrate was adjusted to between 2 and 3.5 using hydrochloric acid. After each addition of ethyl acetate, the resultant mixture was thoroughly stirred and then allowed to stand and separate. The ethyl acetate layer was collected.

(13) 2.5 Removal of Ethyl Acetate

(14) The extracted ethyl acetate layers were combined and pumped into a reaction kettle. Ethyl acetate was removed by vacuum distillation. The resultant product was cooled to less than 60 C. and discharged from the kettle to obtain the crude HMB.

EXAMPLE 2

Production of High Purity HMB

(15) Starting auxiliary materials used for refining the crude HMB are shown in Table 2.

(16) TABLE-US-00002 TABLE 2 Staring and auxiliary materials for HMB purification step Name of the starting and Addition amount auxiliary materials Quality (for each batch) Crude HMB Produced by the subject 40 kg invention Ethanol Food grade 200 kg Calcium hydroxide Food grade pH dependent Diatomite Food grade 2 kg Hydrochloric acid Food grade pH dependent Ethyl acetate Food grade 600 kg

(17) 2. Operational Process and Processing Parameters

(18) 2.1 Neutralization and Crystallization

(19) Ethanol was added into a reaction kettle. The crude HMB prepared according to the method in Example 1 was added into the kettle, stirred, and heated within the range of 40 to 60 C. After the reaction was stable, calcium hydroxide was added to adjust the pH to between 6.5 and 7.5. Next, Diatomite was added at constant temperature. The reaction product was filtered into a crystallization kettle and slowly cooled to between 0 and 10 C.

(20) 2.2 Centrifugation

(21) The reaction product obtained in the neutralization and crystallization step was added into a centrifuge having a laid filter cloth and centrifuged to obtain a wet product.

(22) 2.3 Drying

(23) The wet product obtained from the centrifugation step was placed on a tray and put into an oven for drying at a temperature between 60 and 80 C. An HMB-Ca salt was obtained by drying drying. The drying step can be omitted if loss of solvent isn't acceptable.

(24) 2.4 Dissolution and Acidification

(25) The HMB-Ca salt obtained in the dissolution and acidification step was weighed and pure water was added in a weight ratio of 3:1 (water:HMB-Ca). Hydrochloric acid was added at a temperature between 20 to 30 C. until the pH reached 2-3. The mixture was stirred to dissolve the HMB-Ca salt.

(26) 2.5 Extraction

(27) The above dissolved and acidified solution was extracted by ethyl acetate three times. For each addition of ethyl acetate, the resultant mixture was thoroughly stirred and then allowed to stand and separate at 2030 C. The ethyl acetate layers were collected.

(28) 2.6 Removal of Solvent

(29) The extracts obtained from the extraction stage were combined. Ethyl acetate was removed by vacuum distillation. The distillation temperature was maintained between 40 and 70 C. and the vacuum was maintained at at least 0.09 Mpa. The vacuum pressure was maintained until the temperature reached between 65 and 70 C. and no bubbles were produced within the kettle. At this time, the distillation was stopped. The resultant high purity HMB was cooled to 50 C. and discharged from the kettle.

(30) The product obtained through this process yielded HMB with a purity of 99.6 percent and a desirable color.

EXAMPLE 3

Alternate Production of High Purity HMB

(31) The starting and auxiliary materials, operational process, and processing parameters used are the same as those used in Example 2, except that the neutralization and crystallization were carried out in the manner described below.

(32) The crude HMB was pumped into a reaction kettle. Then, 120 kg of deionized water was added. Calcium hydroxide was added at a temperature between 30 and 50 C. to adjust the pH to between 6.5 and 7.5. Diatomite was added and the temperature was increased to between 65 and 70 C. and the temperature was maintained for 10 minutes. The reaction product was filtered to a reaction kettle and slowly cooled to between 0 and 10 C.

(33) Centrifugation, drying, dissolution and acidification, extraction and removal of solvent were identical to the process described in Example 2. The product obtained through this process yielded HMB with a purity of 99.6 percent and a desirable color.

EXAMPLE 4

Study on Availability of Starting and Auxiliary Materials

(34) Production was performed with materials, operational conditions, and processing parameters similar to those used in Example 2. Differences are listed in Table 3.

(35) TABLE-US-00003 TABLE 3 Variations on HMB purity process Purity of Variation Starting HMB No. Materials Process product 1 In step 2.1, calcium hydroxide was placed During neutralization, the pH was kept for 1.5 99.2% by magnesium hydroxide for neutralization hours. Other processing conditions were the same as Example 2 2 In Step 2.4, hydrochloric acid was replaced Other processing conditions were the same as 99.5% by sulfuric acid for acidification Example 2 3 In Step 2.4, hydrochloric acid was replaced Other processing conditions were the same as 98.8% by nitric acid for acidification Example 2 4 In Step 2.4, hydrochloric acid was replaced Other processing conditions were the same as 98.7% by phosphoric acid for acidification Example 2 5 It step 2.5, ethyl acetate was replaced by Other processing conditions were the same as 99.5% methyl acetate for extraction Example 2 6 It step 2.5, ethyl acetate was replaced by Other processing conditions were the same as 99.2% methyl ethyl ketone for extraction Example 2 7 It step 2.5, ethyl acetate was replaced by Other processing conditions were the same as 98.9% methyl ethyl ketone for extraction Example 2, except that the posterior period of removal of solvent was maintained for 4 hours 8 It step 2.5, ethyl acetate was replaced Other processing conditions were the same as 99.3% by butyl acetate for extraction Example 2, except that the posterior period of removal of solvent was maintained for 4 hours 9 In step 2.5, n-butanol was Other processing conditions were the same as 99.4% used for extraction Example 2, except that the posterior period of removal of solvent was maintained for 4 hours 10 It step 2.5, ethyl acetate was replaced Other processing conditions were the same as 99.1% by iso-butanol for extraction Example 2, except that the posterior period of removal of solvent was maintained for 4 hours 11 In step 2.5, dichloromethane Other processing conditions were the same as 98.4% was used for extraction Example 2, except that the posterior period of removal of solvent was maintained for 4 hours 12 It step 2.5, ethyl acetate was replaced by Other processing conditions were the same as 98.6% dichloroethane for extraction Example 2, except that the posterior period of removal of solvent was maintained for 4 hours

(36) The contents of HMB in the final products were listed in Table 3. It can be found that products having high purity and excellent color could be obtained by suitable replacement of the starting materials.

(37) All references cited in the subject invention are incorporated herein by reference, as each of the references is individually cited for reference. Additionally, it should be understood that various modifications or amendments could be made to the present invention by the skilled artisan after reading the above contents. All these equivalences fall within the scope as defined in the claims of the subject application.