CN119431175A - Preparation method of 3-hydroxybutyric acid betaine salt - Google Patents
Preparation method of 3-hydroxybutyric acid betaine salt Download PDFInfo
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- CN119431175A CN119431175A CN202310975344.3A CN202310975344A CN119431175A CN 119431175 A CN119431175 A CN 119431175A CN 202310975344 A CN202310975344 A CN 202310975344A CN 119431175 A CN119431175 A CN 119431175A
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- Prior art keywords
- salt
- hydroxybutyric acid
- betaine
- hydroxybutyrate
- acid betaine
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- WHBMMWSBFZVSSR-UHFFFAOYSA-N R3HBA Natural products CC(O)CC(O)=O WHBMMWSBFZVSSR-UHFFFAOYSA-N 0.000 title claims abstract description 127
- -1 3-hydroxybutyric acid betaine salt Chemical class 0.000 title claims abstract description 41
- 238000002360 preparation method Methods 0.000 title abstract description 13
- 208000004930 Fatty Liver Diseases 0.000 claims abstract description 9
- 208000010706 fatty liver disease Diseases 0.000 claims abstract description 9
- 206010019708 Hepatic steatosis Diseases 0.000 claims abstract description 8
- 231100000240 steatosis hepatitis Toxicity 0.000 claims abstract description 8
- 229910021645 metal ion Inorganic materials 0.000 claims abstract description 5
- KWIUHFFTVRNATP-UHFFFAOYSA-N glycine betaine Chemical compound C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 claims description 113
- 229960003237 betaine Drugs 0.000 claims description 61
- 150000003839 salts Chemical class 0.000 claims description 30
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 23
- 238000003756 stirring Methods 0.000 claims description 19
- 239000013078 crystal Substances 0.000 claims description 17
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 14
- WHBMMWSBFZVSSR-UHFFFAOYSA-M 3-hydroxybutyrate Chemical compound CC(O)CC([O-])=O WHBMMWSBFZVSSR-UHFFFAOYSA-M 0.000 claims description 13
- LDHQCZJRKDOVOX-NSCUHMNNSA-N crotonic acid Chemical compound C\C=C\C(O)=O LDHQCZJRKDOVOX-NSCUHMNNSA-N 0.000 claims description 12
- 239000012535 impurity Substances 0.000 claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 12
- 239000007864 aqueous solution Substances 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 10
- 238000001816 cooling Methods 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- LDHQCZJRKDOVOX-UHFFFAOYSA-N trans-crotonic acid Natural products CC=CC(O)=O LDHQCZJRKDOVOX-UHFFFAOYSA-N 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 7
- 210000003734 kidney Anatomy 0.000 claims description 7
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims description 7
- 239000011734 sodium Substances 0.000 claims description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- 235000013305 food Nutrition 0.000 claims description 6
- 239000011575 calcium Substances 0.000 claims description 5
- 159000000007 calcium salts Chemical group 0.000 claims description 5
- 239000002131 composite material Substances 0.000 claims description 5
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 claims description 5
- 159000000003 magnesium salts Chemical class 0.000 claims description 5
- 229910052751 metal Inorganic materials 0.000 claims description 5
- 239000002184 metal Substances 0.000 claims description 5
- 229910052708 sodium Inorganic materials 0.000 claims description 5
- 239000000706 filtrate Substances 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- 159000000000 sodium salts Chemical group 0.000 claims description 4
- WHBMMWSBFZVSSR-GSVOUGTGSA-N (R)-3-hydroxybutyric acid Chemical compound C[C@@H](O)CC(O)=O WHBMMWSBFZVSSR-GSVOUGTGSA-N 0.000 claims description 3
- 229910052791 calcium Inorganic materials 0.000 claims description 3
- OXUQOKIBNYSTGF-UHFFFAOYSA-L calcium;3-hydroxybutanoate Chemical compound [Ca+2].CC(O)CC([O-])=O.CC(O)CC([O-])=O OXUQOKIBNYSTGF-UHFFFAOYSA-L 0.000 claims description 3
- 238000004821 distillation Methods 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- WHBMMWSBFZVSSR-VKHMYHEASA-N (S)-3-hydroxybutyric acid Chemical compound C[C@H](O)CC(O)=O WHBMMWSBFZVSSR-VKHMYHEASA-N 0.000 claims description 2
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 150000001340 alkali metals Chemical class 0.000 claims description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 2
- 150000001342 alkaline earth metals Chemical class 0.000 claims description 2
- 229910052749 magnesium Inorganic materials 0.000 claims description 2
- 239000011777 magnesium Substances 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 abstract description 4
- 239000002778 food additive Substances 0.000 abstract description 4
- 235000013373 food additive Nutrition 0.000 abstract description 4
- 239000000047 product Substances 0.000 description 11
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- 238000002425 crystallisation Methods 0.000 description 9
- 230000008025 crystallization Effects 0.000 description 9
- 229940079593 drug Drugs 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- 239000000126 substance Substances 0.000 description 5
- 239000008367 deionised water Substances 0.000 description 4
- 229910021641 deionized water Inorganic materials 0.000 description 4
- 210000004185 liver Anatomy 0.000 description 4
- 238000000967 suction filtration Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 241000287828 Gallus gallus Species 0.000 description 3
- 235000013330 chicken meat Nutrition 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 235000020939 nutritional additive Nutrition 0.000 description 3
- PHIQHXFUZVPYII-ZCFIWIBFSA-N (R)-carnitine Chemical compound C[N+](C)(C)C[C@H](O)CC([O-])=O PHIQHXFUZVPYII-ZCFIWIBFSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 229960004203 carnitine Drugs 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000012847 fine chemical Substances 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 230000001766 physiological effect Effects 0.000 description 2
- NBPUSGBJDWCHKC-UHFFFAOYSA-M sodium 3-hydroxybutyrate Chemical compound [Na+].CC(O)CC([O-])=O NBPUSGBJDWCHKC-UHFFFAOYSA-M 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 208000007082 Alcoholic Fatty Liver Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 206010016262 Fatty liver alcoholic Diseases 0.000 description 1
- 229920002527 Glycogen Polymers 0.000 description 1
- 208000007976 Ketosis Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 238000005411 Van der Waals force Methods 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 210000000577 adipose tissue Anatomy 0.000 description 1
- 208000026594 alcoholic fatty liver disease Diseases 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910001413 alkali metal ion Inorganic materials 0.000 description 1
- 229910001420 alkaline earth metal ion Inorganic materials 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- RLYNGYDVXRKEOO-SQQVDAMQSA-N but-2-enoic acid;(e)-but-2-enoic acid Chemical compound CC=CC(O)=O.C\C=C\C(O)=O RLYNGYDVXRKEOO-SQQVDAMQSA-N 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 229940096919 glycogen Drugs 0.000 description 1
- 235000013402 health food Nutrition 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 230000004140 ketosis Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000012317 liver biopsy Methods 0.000 description 1
- 150000004668 long chain fatty acids Chemical class 0.000 description 1
- ZIMQIJFHENOQDO-UHFFFAOYSA-L magnesium;3-hydroxybutanoate Chemical compound [Mg+2].CC(O)CC([O-])=O.CC(O)CC([O-])=O ZIMQIJFHENOQDO-UHFFFAOYSA-L 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- CINYGFCEISABSR-UHFFFAOYSA-M potassium;3-hydroxybutanoate Chemical compound [K+].CC(O)CC([O-])=O CINYGFCEISABSR-UHFFFAOYSA-M 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 150000003385 sodium Chemical class 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
- C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
- C07C229/12—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of acyclic carbon skeletons
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/38—Separation; Purification; Stabilisation; Use of additives
- C07C227/40—Separation; Purification
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/01—Saturated compounds having only one carboxyl group and containing hydroxy or O-metal groups
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- Chemical & Material Sciences (AREA)
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- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
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- Veterinary Medicine (AREA)
- Gastroenterology & Hepatology (AREA)
- Urology & Nephrology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a 3-hydroxybutyric acid betaine salt, which has the following molecular structure: Wherein M n+ is a metal ion selected from Na +、K+、Mg2+ and Ca 2+;n+ is a charge number representing 1-2 positive charges. The 3-hydroxybutyric acid betaine salt is used as food additive and pharmaceutical active ingredient for reducing or preventing fatty liver. The invention also discloses a preparation method of the 3-hydroxybutyric acid betaine salt.
Description
Technical Field
The invention belongs to the field of nutritional additives, and particularly relates to a 3-hydroxybutyric acid betaine salt, a preparation method and application thereof.
Background
3-Hydroxybutyric acid is one of three ketone bodies generated by fat metabolism in a human body, has multiple physiological functions, and can help the human body to efficiently generate energy under the condition of no glucose. 3-hydroxybutyric acid is produced in the liver by fat metabolism, and by blood circulation, transports corresponding tissues and organs, and oxidizes in cell mitochondria to generate energy, i.e., it can increase the consumption of fat in the body. K-Clark discloses in patent document CN 110869012A that 3-hydroxybutyric acid and salts/esters thereof have therapeutic effects on liver fat-related diseases, and can be used for treating healthy subjects and subjects suffering from liver fat-related diseases. The patent document CN 109734575A discloses that 3-hydroxybutyric acid and salts thereof can be used as nutritional additives or medicines, and have great health care and medicinal values.
It was found that when running on ketone bodies, the mechanical efficiency of the heart increased by 30%, blood flow increased by 75%, burning fatty acids increased free radicals, and 3-hydroxybutyric acid destroyed them. During ketosis exercise, the burning of intramuscular fat increases 20-fold, even with muscle glycogen available. This means that the cells ignore the normally preferred glucose reserves, but burn more fat.
Betaine is a nutritional additive, can be used in pharmaceutical industry, has effects of resisting fatty liver and protecting kidney, and can also be used in health food and skin caring food. Abdelmalek et al (2009) conducted a randomized control study on 55 non-alcoholic fatty liver disease patients, of which 34 patients were treated and a liver biopsy was performed, and found that the degree of liver steatosis was improved in the oral betaine group compared to the control group, saunderson (1990) test demonstrated that betaine was added to the diet of growing chickens, the body fat of chickens was decreased, the protein content was increased, xu Zirong et al (1998) reported that betaine increased the free carnitine content in the liver of chickens, and that carnitine contributed to the beta-oxidation of long chain fatty acids, xu Zhongna et al (2006) studied on rats fully confirmed the therapeutic effect of betaine on alcoholic fatty liver.
Disclosure of Invention
As manufacturers of 3-hydroxybutyric acid and betaine related fine chemicals, based on their correlation and the same properties in terms of physiological activity as food additives and pharmaceutical active ingredients, a feasible exploration route for compounding the two into salts was conceived, and experiments verified that composite salt crystals with stable properties were obtained. Specifically, the invention comprises the following technical scheme.
In a first aspect, the present invention provides a betaine salt of 3-hydroxybutyric acid having the following molecular structure:
Wherein n is a natural number 1 or 2;M is an alkali metal or alkaline earth metal selected from the group consisting of Na, K, mg and Ca, i.e., M n+ is a metal ion selected from the group consisting of Na +、K+、Mg2+ and Ca 2+;n+ is a charge number representing 1-2 positive charges,
The 3-hydroxybutyric acid is selected from D-3-hydroxybutyric acid, L-3-hydroxybutyric acid and DL-3-hydroxybutyric acid, namely racemic 3-hydroxybutyric acid.
In one embodiment, the equivalent ratio of betaine to 3-hydroxybutyrate in the 3-hydroxybutyrate betaine salt is 1:0.3-3, such as 1:0.5-2 or 1:0.8-1.5.
Preferably, the equivalent ratio of betaine to 3-hydroxybutyrate in the 3-hydroxybutyrate betaine salt is about 1:1.
It is to be understood that the term "about" or "about" when used herein in describing a numerical feature means that the number represented may have an error range or float range of + -10%, + -9%, + -8%, + -7%, + -6% or + -5%.
Preferably, the crotonic acid content as an impurity in the 3-hydroxybutyric acid betaine salt is not more than 0.2wt%, preferably 0.18wt% or less.
In a second aspect the present invention provides a process for the preparation of the above-mentioned 3-hydroxybutyric acid betaine salt,
When the salt is a sodium, potassium or magnesium salt, comprising the steps of:
(1) Dissolving a predetermined equivalence ratio, e.g., an equivalence ratio (1:1), of betaine and a metal salt of 3-hydroxybutyric acid in water to obtain an aqueous solution;
(2) Heating and stirring the aqueous solution, and continuing stirring and reacting for 1-5 hours after the system is dissolved;
(3) Filtering while the system is hot to remove insoluble impurities in the system;
(4) Concentrating the filtrate from step (3), for example, concentrating by distillation under reduced pressure, substantially removing water to form a complex salt;
(5) Adding an organic solvent into the composite salt obtained in the step (4) until crystals are precipitated (crystallization);
(6) Cooling by standing, for example, cooling to below 10deg.C until crystals are substantially completely precipitated (growing crystals);
(7) Filtering, drying the filter cake to obtain 3-hydroxybutyric acid betaine salt crystal, and
When the salt is a calcium salt, the method comprises the steps of:
(1) Dissolving betaine and calcium 3-hydroxybutyrate in a preset equivalent ratio in water to obtain an aqueous solution;
(2) Heating and stirring the aqueous solution, and continuing stirring and reacting for 1-5 hours after the system is dissolved;
(3) Filtering while the system is hot to remove insoluble impurities in the system;
(4) Concentrating the filtrate in the step (3) until crystals are precipitated (crystallization);
(6) Standing and cooling until the crystal is basically completely precipitated (crystal growth);
(7) Filtering and drying to obtain the 3-hydroxybutyric acid betaine calcium salt.
The metal salt of 3-hydroxybutyric acid used in the above step (1) is generally a base-neutralized reaction product of 3-hydroxybutyric acid.
The organic solvent in the step (5) is generally an organic solvent approved for use by food and drug administration, such as the national food and drug administration or the FDA, and is selected from ethanol, isopropanol, isoamyl alcohol, acetone, ethyl acetate or a mixture of two or more thereof, for ensuring the safety of the product. Preferably, the organic solvent is acetone or ethyl acetate.
Preferably, the stirring reaction temperature in the above step (2) is controlled below 65 ℃, for example in the range of 55 ℃ to 60 ℃, to avoid the production of by-product crotonic acid from 3-hydroxybutyric acid.
Preferably, the above method further comprises a step (8) of recovering the organic solvent by distillation or rectification.
It is to be understood that the term "substantially" as used herein refers to a majority or substantial portion of a particular condition, such as 80% or more, 85% or more, 90% or more, 92% or more, 95% or more, or 98% or more of the total.
In a third aspect, the present invention provides the use of the above-described 3-hydroxybutyric acid betaine salt as a food additive and a pharmaceutical active ingredient in foods and medicines.
In particular, the above food is used for reducing or preventing fatty liver or protecting kidney, and the medicine is used for treating fatty liver or protecting kidney.
The sodium/potassium/magnesium/calcium salt of 3-hydroxybutyrate betaine of the invention has a stable crystal structure and a low impurity content, and thus can be sold and used as a compound as a fine chemical, for example, as a food additive and a pharmaceutically active ingredient for preparing foods and medicines having the function of preventing, alleviating or treating fatty liver, or protecting kidneys.
Drawings
FIG. 1 is a process flow diagram of one embodiment of the present invention for preparing betaine sodium salt of 3-hydroxybutyric acid.
FIG. 2 is an HPLC chart of the sodium salt of betaine 3-hydroxybutyrate prepared from example 1.
Detailed Description
The design idea of the invention is that the multifunctional 3-hydroxybutyric acid and betaine are provided for the organism together, so that better effects are exerted on the aspects of fat consumption and the like of the human body. The adopted technical scheme is that the 3-hydroxybutyric acid and betaine are made into compound salt, and the two components are combined into a whole, so that the compound salt is taken as a nutrition additive, and has important significance for improving the physique of a human body and promoting the health of the human body. No product for preparing the two substances into composite salt is known in the market at present.
Betaine is an alkaloid, the chemical name is N, N, N-trimethylglycine, the chemical structure is similar to that of amino acid, and the betaine is an inner salt, and belongs to quaternary ammonium alkali substances. The complex salts therefore require metal ions that match the 3-hydroxybutyrate. In order to ensure edible safety, alkali metal ions and alkaline earth metal ions Na +、K+、Mg2+ and Ca 2+ are selected as metal ions. Namely, the metal salt of 3-hydroxybutyric acid as a reaction material includes sodium salt, potassium salt, magnesium salt and calcium salt. Correspondingly, the 3-hydroxybutyric acid betaine compound salt can be 3-hydroxybutyric acid betaine sodium salt, 3-hydroxybutyric acid betaine potassium salt, 3-hydroxybutyric acid betaine magnesium salt and 3-hydroxybutyric acid betaine calcium salt.
Herein, the term "3-hydroxybutyric acid betaine salt" and "3-hydroxybutyric acid betaine complex salt" mean the same meaning and may be used interchangeably. For convenience of description, it may be simply referred to as "complex salt".
The compound salt at least maintains the respective physiological activity functions of 3-hydroxybutyric acid and betaine, including fatty liver alleviation, kidney protection and the like. The complex salt can be recovered into free 3-hydroxybutyric acid and betaine after being dissolved in water.
In one embodiment, the equivalent ratio of betaine to 3-hydroxybutyrate in the complex salt may be 1:0.3 to 3, for example, about 1:1. Those skilled in the art will readily appreciate that the ratio of the two components betaine and 3-hydroxybutyric acid may be adjusted depending on the specific application due to their different efficacy.
Experiments have shown that the physical stability of a complex salt that does not contain a crystallization mother liquor, such as crystallization water, is higher than that of a complex salt that does contain a crystallization mother liquor, such as crystallization water. Therefore, in the process for preparing a complex salt, when betaine and 3-hydroxybutyrate are subjected to a synthesis reaction in an aqueous solution, after being bound together by ionic bond, hydrogen bond, van der Waals force, etc., crystallization is not performed in the aqueous solution so as not to contain crystal water, but to remove water, and cooled organic solvents such as acetone are used for crystallization, and the resulting complex salt does not contain organic solvents such as acetone components.
It should be understood that in order to ensure the edible safety of the complex salt, the organic solvent is an organic solvent approved for use by the national food and drug administration and the FDA, and may be selected from ethanol, isopropanol, isoamyl alcohol, acetone, ethyl acetate, or a mixture of two or more thereof in any ratio, for example.
FIG. 1 shows a process flow diagram of one embodiment of the present invention for preparing a betaine salt of 3-hydroxybutyric acid.
In order to ensure the edible safety of the compound salt, the generation of impurities in the preparation process of the compound salt is controlled as much as possible. The impurity in the compound salt is mainly crotonic acid (butenoic acid) which is a byproduct generated by 3-hydroxybutyric acid, so that the synthetic reaction temperature of the compound salt is controlled below 65 ℃, and the crotonic acid content in the finished product of the 3-hydroxybutyric acid betaine salt is effectively controlled below 0.2 wt%.
Examples
The invention is further illustrated by the following examples. It is to be understood that these examples are for illustrative purposes only and are not limiting of the invention. Various changes and modifications may be made by one skilled in the art in light of the teachings of this invention, and are intended to fall within the scope of this invention. For example, those skilled in the art use metal salts of chiral 3-hydroxybutyric acid, such as D-3-hydroxybutyric acid, with betaines to prepare complex salts, and the synthesis process is similar to the process conditions described below for the calcium, magnesium, sodium, and potassium salts of racemic 3-hydroxybutyric acid.
The amounts, amounts and concentrations of various substances are referred to herein, wherein the percentages refer to percentages by mass unless otherwise specified.
In the examples herein, if no specific description is made regarding the operating temperature, this temperature is generally referred to as room temperature (15-35 ℃).
HPLC detection method of the components in the betaine salt of 3-hydroxybutyric acid in examples:
instrument liquid chromatograph Agilent1260;
chromatographic column: agilent ZORBAX SB-Aq 4.6mm×250mm×5 μm or equivalent;
Mobile phase: 0.1% aqueous perchloric acid solution: acetonitrile=95:5 (v/v);
The flow rate is 1.0ml/min;
The column temperature is 30 ℃,
A differential refraction detector with a detection wavelength of 214nm;
the sample injection volume is 10 μl, and the component content is calculated by area normalization.
Wherein, the retention time of betaine is 2.599min, the retention time of 3-hydroxybutyric acid is 4.864min, and the retention time of crotonic acid is 15.181min.
EXAMPLE 1 preparation of the sodium salt of betaine 3-hydroxybutyrate
The process for salifying the sodium 3-hydroxybutyrate and the betaine comprises the following steps:
1. 25.00g (0.198 mol) of sodium 3-hydroxybutyrate and 23.23g (0.198 mol) betaine were weighed into a three-necked flask, and 100ml of deionized water was added thereto and stirred.
2. The electric heater was started and slowly warmed to 55 ℃.
3. After the system in the flask is dissolved, the reaction is continued for 3 hours under stirring within the range of 55-60 ℃.
4. Filtering while hot to remove insoluble impurities in the system.
5. Starting a vacuum pump, decompressing and concentrating the reaction system until the reaction system is sticky, and stopping concentration.
6. 150Ml of acetone was slowly added dropwise, at which point white crystals began to precipitate.
7. Cooling to below 10deg.C, and stirring for 1 hr.
8. Suction filtration and baking of the wet product in an oven at 80 ℃ for 4 hours, and obtaining 47.1g of white crystalline 3-hydroxybutyric acid betaine sodium salt with the yield of 97.8%.
9. The purity of the product and crotonate was determined by HPLC, see Table 1, and the chromatogram shown in FIG. 2.
Table 1 purity of each component in 3-hydroxybutyric acid betaine sodium salt measured by HPLC
| 3-Hydroxybutyric acid | 42.123% |
| Betaine (betaine) | 57.828% |
| Crotonic acid | 0.049% |
EXAMPLE 2 preparation of the potassium salt of 3-hydroxybutyric acid betaine
The preparation process of the 3-hydroxybutyric acid betaine potassium salt comprises the following steps:
1. 28.17g (0.198 mol) of potassium 3-hydroxybutyrate and 23.23g (0.198 mol) betaine were weighed into a three-necked flask, followed by adding 120ml of deionized water thereto and stirring.
2. The electric heater was started and slowly warmed to 55 ℃.
3. After the system in the flask is dissolved, the reaction is continued for 3 hours under stirring within the range of 55-60 ℃.
4. Filtering while hot to remove insoluble impurities in the system.
5. Starting a vacuum pump, decompressing and concentrating the reaction system until the reaction system is sticky, and stopping concentration.
6. 150Ml of acetone was slowly added dropwise, at which point white crystals began to precipitate.
7. Cooling to below 10deg.C, and stirring for 1 hr.
8. Suction filtration, drying the wet product in an oven at 80 ℃ for 4 hours to obtain 48.8g of white crystalline 3-hydroxybutyric acid betaine potassium salt with the yield of 95 percent.
9. The purity of the product and crotonate was determined by HPLC and is shown in table 2.
Table 2 purity of each component in the potassium salt of 3-hydroxybutyric acid betaine measured by HPLC
EXAMPLE 3 preparation of magnesium salt of betaine 3-hydroxybutyrate
The preparation process of the 3-hydroxybutyric acid betaine magnesium salt comprises the following steps:
1. 22.9g (0.099 mol) of magnesium 3-hydroxybutyrate and 23.23g (0.198 mol) of betaine were weighed into a three-necked flask, followed by 250ml of deionized water and stirred.
2. The electric heater was started and slowly warmed to 55 ℃.
3. After the system in the flask is dissolved, the reaction is continued for 3 hours under stirring within the range of 55-60 ℃.
4. Filtering while hot to remove insoluble impurities in the system.
5. The vacuum pump was started, the reaction system was concentrated under reduced pressure until turbidity appeared, and the concentration was stopped.
6. 100Ml of ethyl acetate was slowly added dropwise, at which time a large amount of white crystals precipitated.
7. Cooling to below 10deg.C, and stirring for 1 hr.
8. Suction filtration, drying the wet product in an oven at 80 ℃ for 4 hours to obtain 44.2g of white crystalline 3-hydroxybutyric acid betaine magnesium salt with the yield of 96 percent.
9. The purity of the product and crotonate was determined by HPLC and is shown in table 3.
Table 3 purity of each component in magnesium salt of 3-hydroxybutyrate betaine measured by HPLC
| 3-Hydroxybutyric acid | 42.432% |
| Betaine (betaine) | 57.385% |
| Crotonic acid | 0.183% |
EXAMPLE 4 preparation of the calcium salt of 3-hydroxybutyric acid betaine
The preparation process of the 3-hydroxybutyric acid betaine calcium salt comprises the following steps:
1. 24.4g (0.099 mol) of calcium 3-hydroxybutyrate and 23.23g (0.198 mol) of betaine were weighed into a three-necked flask, and 380ml of deionized water was added thereto and stirred.
2. The electric heater was started and slowly warmed to 55 ℃.
3. After the system in the flask is dissolved, the reaction is continued for 3 hours under stirring within the range of 55-60 ℃.
4. Filtering while hot to remove insoluble impurities in the system.
5. Starting a vacuum pump, decompressing and concentrating the reaction system until a large amount of crystallization occurs, and stopping concentration.
6. Cooling to below 10deg.C, and stirring for 1 hr.
7. Suction filtration, drying the wet product in an oven at 80 ℃ for 4 hours to obtain 43.1g of white crystalline 3-hydroxybutyric acid betaine calcium salt with the yield of 91 percent.
9. The purity of the product and crotonate was determined by HPLC and is shown in table 4.
Table 4 purity of each component in calcium salt of 3-hydroxybutyrate betaine measured by HPLC
| 3-Hydroxybutyric acid | 42.143% |
| Betaine (betaine) | 57.815% |
| Crotonic acid | 0042% |
The above embodiments are only for illustrating the technical solution of the present invention, but not for limiting the same, and various modifications and variations of the present invention will be apparent to those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
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