WO2023241117A1 - 一种易溶的胍基乙酸络合物的合成方法 - Google Patents
一种易溶的胍基乙酸络合物的合成方法 Download PDFInfo
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- WO2023241117A1 WO2023241117A1 PCT/CN2023/080184 CN2023080184W WO2023241117A1 WO 2023241117 A1 WO2023241117 A1 WO 2023241117A1 CN 2023080184 W CN2023080184 W CN 2023080184W WO 2023241117 A1 WO2023241117 A1 WO 2023241117A1
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- Prior art keywords
- guanidinoacetic acid
- guanidinoacetic
- solution
- acid complex
- acid
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- BPMFZUMJYQTVII-UHFFFAOYSA-N guanidinoacetic acid Chemical compound NC(=N)NCC(O)=O BPMFZUMJYQTVII-UHFFFAOYSA-N 0.000 title claims abstract description 236
- 238000001308 synthesis method Methods 0.000 title claims abstract description 13
- 239000000243 solution Substances 0.000 claims abstract description 30
- 229960000789 guanidine hydrochloride Drugs 0.000 claims abstract description 17
- PJJJBBJSCAKJQF-UHFFFAOYSA-N guanidinium chloride Chemical compound [Cl-].NC(N)=[NH2+] PJJJBBJSCAKJQF-UHFFFAOYSA-N 0.000 claims abstract description 17
- 239000000126 substance Substances 0.000 claims abstract description 16
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims abstract description 14
- 230000002378 acidificating effect Effects 0.000 claims abstract description 14
- 239000012670 alkaline solution Substances 0.000 claims abstract description 11
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 claims abstract description 11
- 229940106681 chloroacetic acid Drugs 0.000 claims abstract description 11
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims abstract description 7
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims abstract description 7
- 229960004198 guanidine Drugs 0.000 claims abstract description 7
- 239000011259 mixed solution Substances 0.000 claims abstract description 7
- 238000005292 vacuum distillation Methods 0.000 claims abstract description 6
- 238000002156 mixing Methods 0.000 claims abstract 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 13
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- 239000007788 liquid Substances 0.000 claims description 7
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 6
- 239000013078 crystal Substances 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 3
- 150000001450 anions Chemical class 0.000 claims description 2
- 238000004821 distillation Methods 0.000 claims description 2
- 230000005611 electricity Effects 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 abstract description 2
- 239000007790 solid phase Substances 0.000 abstract description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 39
- 238000004128 high performance liquid chromatography Methods 0.000 description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- 229910019142 PO4 Inorganic materials 0.000 description 13
- 235000015165 citric acid Nutrition 0.000 description 13
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 13
- 239000010452 phosphate Substances 0.000 description 13
- 238000003756 stirring Methods 0.000 description 12
- 238000001514 detection method Methods 0.000 description 11
- 238000001228 spectrum Methods 0.000 description 11
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 9
- WTICMVDMUBVSIA-UHFFFAOYSA-N 2-(diaminomethylideneamino)acetic acid;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound NC(=N)NCC(O)=O.OC(=O)CC(O)(C(O)=O)CC(O)=O WTICMVDMUBVSIA-UHFFFAOYSA-N 0.000 description 8
- 238000009395 breeding Methods 0.000 description 7
- 230000001488 breeding effect Effects 0.000 description 7
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 6
- 238000004364 calculation method Methods 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 239000003643 water by type Substances 0.000 description 6
- HBOGVDDPCCTYJI-UHFFFAOYSA-N 2-(diaminomethylideneamino)acetic acid;phosphoric acid Chemical compound OP(O)(O)=O.NC(=N)NCC(O)=O HBOGVDDPCCTYJI-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 239000003674 animal food additive Substances 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000014759 maintenance of location Effects 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 239000012047 saturated solution Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- HNSDLXPSAYFUHK-UHFFFAOYSA-N 1,4-bis(2-ethylhexyl) sulfosuccinate Chemical compound CCCCC(CC)COC(=O)CC(S(O)(=O)=O)C(=O)OCC(CC)CCCC HNSDLXPSAYFUHK-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000005341 cation exchange Methods 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 229940098779 methanesulfonic acid Drugs 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 244000144977 poultry Species 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 241000287828 Gallus gallus Species 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000006184 cosolvent Substances 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000012086 standard solution Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 230000037149 energy metabolism Effects 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000002778 food additive Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 230000008642 heat stress Effects 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 150000002484 inorganic compounds Chemical class 0.000 description 1
- 229910010272 inorganic material Inorganic materials 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 235000013372 meat Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000003307 slaughter Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C277/00—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C277/08—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups of substituted guanidines
-
- 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
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
Definitions
- the invention belongs to the technical field of chemical synthesis technology, and specifically relates to a synthesis method of guanidinoacetic acid complex.
- Guanidinoacetic acid also known as guanidinoacetic acid and N-imidylglycine, has a molecular formula of C 3 N 7 N 3 O 2 and a molecular weight of 117. It is a white or slightly yellow crystalline powder, soluble in water, and extremely microscopic. Soluble in ethanol and ether. Guanidinoacetic acid is mainly used as an intermediate in pharmaceutical organic synthesis, and can also be used as a food and feed additive. It plays an important role in improving production performance, improving meat quality, and promoting energy metabolism. In addition, it can also prevent bacterial infection, enhance animal immune function, and reduce Effects of heat stress on animals, thereby reducing animal mortality in high temperature environments.
- the current guanidinoacetic acid feed additive is mainly added at the feed end, so the application scenarios are narrowed and the difficulty of promotion is greatly increased. .
- Automatic drinking water dosing equipment is a common water supply system in modern intensive breeding farms. It is very convenient and quick to add water-soluble additives.
- guanidinoacetic acid Although there are many publicly reported synthesis methods of guanidinoacetic acid, the solubility of guanidinoacetic acid in water is relatively low. The water solubility of guanidinoacetic acid at 20°C is 3.6 g/L, which greatly limits its scope of use. , so the research and development of water-soluble guanidinoacetic acid is urgent. In terms of physical properties, guanidinoacetic acid is a weakly polar organic compound, while water is a highly polar inorganic compound. Based on this, how to improve the solubility of guanidinoacetic acid and make its addition methods more diversified has become a key research topic for technicians in this field at this stage.
- citric acid acts as an acidic cosolvent.
- aqueous solution storing guanidinoacetic acid in a citric acid solution is not conducive to long-term storage stability, and storage and transportation are very inconvenient.
- guanidinoacetic acid must be added and used in the form of a solution, such as as a feed additive. , will cause a large amount of aqueous solution to be added at the same time, which is not conducive to the control of the water content in the added object.
- the present invention provides a new synthesis method of guanidinoacetic acid complex, which changes the traditional crystallization method of guanidinoacetic acid and crystallizes guanidinoacetic acid in the form of complexes with other acids. came out, and successfully obtained a guanidinoacetic acid complex with higher solubility.
- This guanidinoacetic acid complex can be stored in a stable solid phase, and compared with the storage method of acidic solutions such as ordinary citric acid, , which can double the solubility of guanidinoacetic acid relative to the unit acidic cosolvent content.
- a method for synthesizing an easily soluble guanidinoacetic acid complex including the following steps: Step S1: Add guanidine hydrochloride to alkaline solution A to generate free guanidine, and obtain solution B; Step S2: Add chloroacetic acid dropwise In solution B, mixed liquid C is obtained; Step S3: Mix acidic substance D and mixed liquid C, and distill under reduced pressure to obtain guanidinoacetic acid complex.
- the step S1 is a neutralization reaction to generate free guanidine.
- This step is generally carried out at normal temperature, which can be controlled below 20°C, preferably below 15°C.
- the molar ratio of alkaline solution A and guanidine hydrochloride is generally controlled as follows.
- the alkaline solution A can be a sodium hydroxide solution or a sodium carbonate solution.
- concentration (mass percentage) of the sodium hydroxide solution is 5%-40%, and the preferred concentration is 20%.
- the mass ratio of sodium hydroxide:guanidine hydrochloride is (150-250): (430-530), and the preferred mass ratio is 200:480.
- the concentration (mass percentage) of the sodium carbonate solution is 5%-30%, and the preferred concentration is 15%.
- the mass ratio of sodium carbonate: guanidine hydrochloride is (200-300): (430-530), and the preferred mass ratio is 265:480.
- step S2 The reaction in step S2 will generate HCl gas and obtain intermediate guanidinoacetic acid. Therefore, chloroacetic acid needs to be added dropwise to solution B and maintained with gentle stirring.
- the stirring speed is preferably 20-50 rpm, preferably 30 rpm. points, which can promote the full release of HCl gas.
- This reaction is an exothermic reaction, and the temperature should be controlled between 35°C and 50°C, preferably 40°C.
- the reaction time is not less than 20 hours, preferably 24 hours.
- the amount of chloroacetic acid added is 1: (1 ⁇ 0.2) based on the molar ratio of guanidine hydrochloride: chloroacetic acid.
- the intermediate guanidinoacetic acid and the acidic substance D are complexed and crystallized through vacuum distillation, and as the solvent continues to evaporate at a certain temperature, they are successfully precipitated from the solution in the form of a guanidinoacetic acid complex.
- the vacuum distillation is carried out at -0.08 ⁇ 0.1MPa, and the reaction temperature is above 55°C, preferably (80 ⁇ 5)°C.
- the acidic substance D In order to obtain a guanidinoacetic acid complex with better solubility, the acidic substance D needs to be present in excess.
- the molar ratio of the acidic substance D to guanidinoacetic acid (or guanidinoacetic acid) is (1-5):1, Preferably (1.2-3): 1.
- the acidic substance D may be an organic acid or an inorganic acid, including one or more of phosphoric acid, citric acid, formic acid, acetic acid, malic acid, lactic acid, etc.
- the acidic substance D can be phosphoric acid.
- the mass ratio of phosphoric acid:guanidine hydrochloride is (50-100):(43-53), and the preferred mass ratio is 85:48.
- the acidic substance D can be citric acid.
- the mass ratio of citric acid:guanidine hydrochloride is (100-200):(43-53), and the preferred mass ratio is 150:48.
- step S3 the mixed liquid C obtained in step S2 may not be used, and the existing guanidinoacetic acid product may be directly used in proportion to form a solution equivalent to the mixed liquid C under the same conditions and put into use.
- the guanidinoacetic acid in the mixed liquid C The concentration can be 0.5 ⁇ 8mol/L.
- step S3 After the step S3 obtains the crystallization of the guanidinoacetic acid complex, it also includes the step of drying the crystallization of the guanidinoacetic acid complex obtained after distillation under reduced pressure.
- the drying temperature is preferably 80-98°C.
- the present invention adopts a new guanidinoacetic acid crystallization preparation method.
- the solubility of the obtained guanidinoacetic acid complex is greatly improved compared to the existing guanidinoacetic acid products, and can be conveniently stored and transported in solid form for long periods of time, and can be reconstituted. Finally, it can retain the structure of guanidinoacetic acid standard and retain basically the same activity and function of guanidinoacetic acid.
- Figure 1 is a preparation flow chart of the present invention.
- Figure 2 is the HPLC spectrum of guanidinoacetic acid and its salts. Among them, 2a is the HPLC spectrum of the soluble guanidinoacetic acid phosphate sample; 2b is the HPLC spectrum of the guanidinoacetic acid standard (purity 99%).
- Figure 3 is the standard curve of the guanidinoacetic acid standard.
- Figure 4 is the concentration curve of guanidinoacetic acid ⁇ phosphate.
- Figure 5 is the HPLC spectrum of the solubility detection of guanidinoacetic acid ⁇ phosphate.
- Figure 6 is the HPLC spectrum of the guanidinoacetic acid ⁇ citrate sample.
- Figure 7 is the concentration curve of guanidinoacetic acid ⁇ citrate.
- Figure 8 is the HPLC spectrum of the solubility detection of guanidinoacetic acid ⁇ citrate.
- Example 1 1. Preparation of guanidinoacetic acid ⁇ phosphate.
- HPLC determination HPLC detection conditions: chromatography system: waters 2695; UV detector: waters 2996; chromatographic column: Dionex IonPacTM CS16 cation exchange column (5*250mm); mobile phase: methanesulfonic acid 50mM and water; flow rate: 1mL/min ; Column temperature: 35°C; Sample volume: 10 ⁇ L; Detection time: 40 min.
- Figure 2a is the HPLC spectrum of the soluble guanidinoacetic acid ⁇ phosphate sample
- Figure 2b is the HPLC spectrum of the guanidinoacetic acid standard. It can be seen from the figure that the soluble guanidinoacetic acid ⁇ phosphate sample obtained by the present invention has the same HPLC spectrum as the guanidinoacetic acid standard substance, indicating that the soluble guanidinoacetic acid ⁇ phosphate sample can retain the structure of the guanidinoacetic acid standard substance. Furthermore, calculations from the figure show that the content of guanidinoacetic acid in this example of guanidinoacetic acid phosphate reaches 53.77%.
- the specific calculation method is as follows.
- guanidinoacetic acid ⁇ phosphate sample Use pure water to prepare the guanidinoacetic acid ⁇ phosphate sample into a test solution of 0.5 ⁇ 200 ⁇ g/mL, and perform HPLC detection.
- the HPLC peak area is known from the spectrum, listed in Table 1.
- Solubility test Prepare a saturated solution of guanidinoacetic acid and phosphate: add 100 g of guanidinoacetic acid and phosphate sample to 100 mL of water, stir and dissolve at 20°C for 30 minutes, take the upper saturated solution, dilute it 1000 times, and perform HPLC Measurement, the results are shown in Figure 5, and the peak area results are shown in Table 2. The method is the same as the second one.
- the sample concentration is 320.48 ⁇ g/mL.
- the solution concentration is 320.48 mg/ml.
- the solubility of the soluble guanidinoacetic acid complex produced by the method provided by the invention is 32.05 g/100 mL (25°C).
- the content of guanidinoacetic acid in guanidinoacetic acid ⁇ phosphate is 53.77%. Therefore, the solubility of guanidinoacetic acid in guanidinoacetic acid ⁇ phosphate is 17.23g/100 ml, and the solubility of guanidinoacetic acid standard is 0.36g/100 mL ( 20°C), the method provided by the invention increases the solubility of guanidinoacetic acid 49 times.
- Example 2 1. Preparation of guanidinoacetic acid ⁇ citrate.
- HPLC determination Chromatography system: waters 2695; UV detector: waters 2996; Chromatographic column: Dionex IonPacTM CS16 cation exchange column (5*250mm); Mobile phase: methanesulfonic acid 50mM and water; flow rate: 1mL/min; column temperature: 35°C; sample volume: 10 ⁇ L; detection time: 40 min.
- the sample concentration is 284.90 ⁇ g/mL, multiplied by the dilution factor of 1000, the solution concentration is 284.90 mg/ml.
- the solubility of soluble guanidinoacetic acid citrate produced by the method provided by the invention is 28.49 g/100 mL. (20°C).
- the content of guanidinoacetic acid in guanidinoacetic acid citrate is 30.75%. Therefore, the solubility of guanidinoacetic acid in guanidinoacetic acid citrate is 8.76 g/100 ml, and the solubility of guanidinoacetic acid standard is 0.36 g/100 mL (20°C), the method provided by the invention improves the solubility of guanidinoacetic acid 24 times.
- the solubility of guanidinoacetic acid citrate is 28.49 g/100 mL and the guanidinoacetic acid content is 30.75%.
- the concentration of citric acid is 1.0mol/L, which corresponds to the solubility of guanidinoacetic acid is 8.76 g/ 100 ml, compared with the solubility of guanidinoacetic acid stored in the form of citric acid solution (citric acid concentration 4.0 mol/L corresponds to the solubility of guanidinoacetic acid 8.2 g/100 ml), the form of guanidinoacetic acid citrate of the present invention can be improved The solubility is more than 4 times.
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Abstract
一种易溶的胍基乙酸络合物的合成方法，首先将盐酸胍加入碱性溶液A中，生成游离的胍，获得溶液B；然后将氯乙酸滴加入溶液B中，获得混合液C；最后将酸性物质D与混合液C混合，减压蒸馏，获得胍基乙酸络合物。将胍基乙酸以酸性物质D的络合盐的形式结晶出来，获得了一种溶解度较高、且能够以固相形式进行保存的胍基乙酸络合物。
Description
本发明属于化学合成工艺技术领域，具体涉及一种胍基乙酸络合物的合成方法。
胍基乙酸（GAA），又称为胍乙酸和N-咪基甘氨酸，分子式为C
3N
7N
3O
2，分子量为117，为白色或微黄色结晶性粉末，可溶于水，极微溶于乙醇和乙醚。胍基乙酸主要用于医药有机合成中间体，也可作为食品和饲料添加剂，对提高生产性能、改善肉质和促进能量代谢等方面具有重要作用，此外还可以防止细菌感染，增强动物免疫功能，减低热应激对动物的影响，从而减少动物在高温环境下的死亡率。
现代化、集约化、规模化畜禽养殖模式是我国畜牧业发展的必然趋势。在这种饲养模式下，全价料使用方便高效的优点显得尤为突出，是规模化养殖使用最普遍的饲料类型。对于肉禽养殖来说，全价料的普遍使用及大型肉禽饲料厂的集中都不利于胍基乙酸饲料添加剂的推广使用。对于生猪养殖来说，饲料加工、养殖、屠宰一条龙模式使得各部门分工明确，饲料供应和养殖环节独立，目前的胍基乙酸饲料添加剂主要在饲料端添加，故应用场景缩小、推广难度大大增加。自动饮水加药设备是现代化集约化养殖场常见的供水系统，用于水溶性添加剂的添加非常而方便快捷。
尽管胍基乙酸已公开报道的合成方法非常多，然而这些方法所获得的胍基乙酸，在水中的溶解度都比较低，胍基乙酸20℃下水溶性为3.6 g/L，大大制约了其使用范围，因此水溶性胍基乙酸的研发迫在眉睫。从物理性质而言，胍基乙酸是一种极性较弱的有机化合物，而水则是极性很强的无机化合物。基于此，如何提高胍基乙酸的溶解度，使其添加方式更为多元化，成为现阶段该领域技术人员的重点研究内容。
有研究发现通过向水溶液中添加柠檬酸，制成柠檬酸溶液，然后再将胍基乙酸溶解于该柠檬酸的溶液中，可以提高胍基乙酸的溶解度，此时柠檬酸作为一种酸性助溶剂存在于水溶液中。但一方面，将胍基乙酸在柠檬酸溶液中保存十分不利于长期保存的稳定性，存储和运输都十分不便；另一方面，应用时以溶液形式添加和使用胍基乙酸，如作为饲料添加剂，将导致大量水溶液同时被添加，不利于添加对象中含水量的控制。
针对现有技术的不足，本发明提供了一种新的胍基乙酸络合物合成方法，改变了传统的胍基乙酸的结晶方式，将胍基乙酸以和其他酸的络合物的形式结晶出来，成功获得了一种溶解度较高的胍基乙酸络合物，这种胍基乙酸络合物能够以稳定的固相形式进行保存，并且相对于普通柠檬酸等酸性溶液的保存方式而言，相对于单位酸性助溶剂的含量下能够成倍提高胍基乙酸的溶解度。
本发明所采取的技术方案如下。
一种易溶的胍基乙酸络合物的合成方法，包括下述步骤：步骤S1：将盐酸胍加入碱性溶液A中，生成游离的胍，获得溶液B；步骤S2：将氯乙酸滴加入溶液B中，获得混合液C；步骤S3：将酸性物质D与混合液C混合，减压蒸馏，获得胍基乙酸络合物。
所述步骤S1是中和反应，生成游离胍。该步骤一般在常温下进行，可以控制在20℃以下，优选是15℃以下。为更好的获得充分游离状态下的胍，一般控制碱性溶液A、盐酸胍的摩尔比为，碱性溶液A以可电离的碱性阴离子单位电价计：盐酸胍=（1±0.3）：1。
优选的，所述碱性溶液A可以为氢氧化钠溶液或碳酸钠溶液。所述氢氧化钠溶液浓度（质量百分比）为5%-40%，优选浓度为20%。氢氧化钠：盐酸胍的质量比为（150-250）：（430-530），优选质量比为200：480。所述碳酸钠溶液浓度（质量百分比）为5%-30%，优选浓度为15%。碳酸钠：盐酸胍的质量比为（200-300）：（430-530），优选质量比为265：480。
所述步骤S2反应会产生HCl气体，获得中间态的胍基乙酸，因而氯乙酸需要滴加到溶液B中，保持温和搅拌，搅拌速度以20-50 转/分为宜，优选为30转/分，可以促进HCl气体充分释放。该反应为放热反应，应控制温度为35℃-50℃，优选为40℃。反应时间为不小于20小时，优选为24小时。该反应中，氯乙酸的添加量，以盐酸胍：氯乙酸的摩尔比计为1：（1±0.2），质量比可为盐酸胍：氯乙酸=（430-530）：（400-550）。
所述步骤S3反应，中间态的胍基乙酸与酸性物质D通过减压蒸馏得以络合结晶，并在一定温度下随着溶剂持续蒸发，成功以胍基乙酸络合物的形式自溶液中析出。所述减压蒸馏在-0.08~0.1MPa下进行，反应温度为55℃以上，优选为（80±5）℃。
为获得溶解性较好的胍基乙酸络合物，酸性物质D需要在过量情况下存在,所述酸性物质D与胍基乙酸（或盐酸胍）的摩尔比为（1-5）：1，优选为（1.2-3）：1。酸性物质D可以为有机酸或无机酸，包括磷酸、柠檬酸、甲酸、乙酸、苹果酸、乳酸等中的一种或多种。
优选的，所述酸性物质D可为磷酸，此时磷酸：盐酸胍的质量比为（50-100）：（43-53），优选质量比为85：48。
优选的，所述酸性物质D可为柠檬酸，此时柠檬酸：盐酸胍的质量比为（100-200）：（43-53），优选质量比为150：48。
所述步骤S3也可以不采用步骤S2获得的混合液C，另行直接采用现有的胍基乙酸产品按比例配置成同等条件下与混合液C相当的溶液投入使用，混合液C中胍基乙酸的浓度可以为0.5~8mol/L。
所述步骤S3获得胍基乙酸络合物的结晶物后，还包括对减压蒸馏后获得的胍基乙酸络合物结晶物进行干燥的步骤，干燥温度优选为80-98℃。
本发明采用全新的胍基乙酸结晶制备方法，获得的胍基乙酸络合物相对于现有的胍基乙酸产品可溶性具有极大的提升，能够以固体形式进行方便的长期储存和运输，复溶后能够保留胍基乙酸标准品结构，并保留胍基乙酸基本相同的活性和功能。
下面通过附图和实施例，对本发明实施例的技术方案做进一步详细描述。
图1为本发明制备流程图。
图2是胍基乙酸及其盐的HPLC谱图。其中，2a是可溶胍基乙酸·磷酸盐样品的HPLC谱图；2b是胍基乙酸标准品（纯度99%）的HPLC谱图。
图3是胍基乙酸标准品的标准曲线。
图4是胍基乙酸·磷酸盐的浓度曲线。
图5是胍基乙酸·磷酸盐溶解度检测的HPLC谱图。
图6是胍基乙酸·柠檬酸盐样品的HPLC谱图。
图7是胍基乙酸·柠檬酸盐的浓度曲线。
图8是胍基乙酸·柠檬酸盐溶解度检测的HPLC谱图。
下面通过附图和具体的实施例，对本发明进行进一步的说明，但应当理解为这些实施例仅仅是用于更详细说明之用，而不应理解为用以任何形式限制本发明，即并不意于限制本发明的保护范围。
实施例1：一、制备胍基乙酸·磷酸盐。
200 ml 水中加入 100 g NaOH（或132.5 g Na
2CO
3）搅拌溶解，降温至 15℃以下，获得碱性溶液A。缓慢加入240 g盐酸胍，搅拌溶解至透明，即可得到游离胍溶液B。200 ml水中加入 250 g氯乙酸室温下搅拌至溶解，滴加到溶液B中，保持温度40℃，温和搅拌24小时，获得混合液C。此时往混合液C中缓慢加入500 ml 磷酸（85%，w/v）。升温至80℃进行-0.08MPa减压蒸馏，获得白色结晶，过滤取结晶。85℃干燥得到胍基乙酸·磷酸盐产物。
二、胍基乙酸·磷酸盐中胍基乙酸的含量检测。
HPLC测定： HPLC检测条件：色谱系统：waters 2695；紫外检测器：waters 2996；色谱柱：Dionex IonPacTM CS16阳离子交换柱（5*250mm）；流动相：甲磺酸50mM和水；流速：1mL/min；柱温：35℃；上样量：10 μL ；检测时间：40 min。
结果如图2所示，胍基乙酸的保留时间为13.157 min。图2a是可溶胍基乙酸·磷酸盐样品的HPLC谱图；图2b是胍基乙酸标准品的HPLC谱图。由图可知，本发明获得的可溶胍基乙酸·磷酸盐样品与胍基乙酸标准品具有相同的HPLC谱图，说明可溶胍基乙酸·磷酸盐样品能够保留胍基乙酸标准品结构。进一步，由图计算可知本例胍基乙酸·磷酸盐中，胍基乙酸的含量达53.77 %。
具体计算方法如下。
1.1 HPLC检测条件 色谱系统：waters 2695 紫外检测器：waters 2996 色谱柱：Dionex IonPacTM CS16阳离子交换柱（5*250mm） 流动相：甲磺酸50mM和水 流速：1mL/min 柱温：35℃ 上样量：10 μL 检测时间：40 min。
1.2 胍基乙酸标准曲线的绘制：将胍基乙酸标准品（Sigma，纯度99%）用纯水配成0.5~200 μg/mL的标准溶液，进行HPLC检测，以浓度（μg/mL）为横坐标，峰面积为纵坐标绘制标准曲线，如图3所示。
胍基乙酸浓度x（μg/mL）为：x=峰面积÷9405.5。
1.3 胍基乙酸·磷酸盐样品纯度测定：将胍基乙酸·磷酸盐样品用纯水配成0.5~200 μg/mL的待测溶液，进行HPLC检测，HPLC峰面积自谱图得知，列于表1。以浓度（μg/mL）为横坐标，峰面积为纵坐标绘制浓度曲线，如图4所示。
表1
从HPLC检测结果可知，本发明所合成的样品，其保留时间和峰形与sigma的胍基乙酸标准品一致，确认本发明所合成的化合物为胍基乙酸络合物，本样品所得曲线为：样品浓度x（μg/mL）：x=峰面积÷5108.8。
纯度计算（%）：样品所绘制浓度曲线的斜率÷标准曲线斜率*99%（标准品纯度） =5108.8 ÷9405.5 *99%=53.77%，可得胍基乙酸·磷酸盐中，胍基乙酸含量为53.77%（w/w）。
三、溶解度检测：配置胍基乙酸·磷酸盐的饱和溶液：100 mL水中加入100 g 胍基乙酸·磷酸盐样品，在20℃下搅拌溶解30 min，取上层饱和溶液，稀释1000倍，进行HPLC测定，结果如图5，峰面积结果如表2所示。方法同二。
表2
根据样品浓度曲线计算，样品浓度x（μg/mL）x=峰面积÷5108.8
根据色谱图计算，样品浓度为 320.48μg/mL，乘以稀释倍数1000，得出，溶液浓度为320.48 mg/ml。
结果显示，本发明提供的方法生产可溶性胍基乙酸络合物的溶解度为32.05 g/100 mL（25℃）。胍基乙酸·磷酸盐中胍基乙酸含量为53.77%，因此，胍基乙酸·磷酸盐中胍基乙酸的溶解度为17.23g/100 ml，胍基乙酸标准品的溶解度为0.36g/100 mL（20℃），本发明提供的方法提高了胍基乙酸的溶解度49倍。
实施例2：一、制备胍基乙酸·柠檬酸盐。
600 ml 水中加入 40 g NaOH（或53 g Na
2CO
3）搅拌溶解，降温至 15℃以下，获得碱性溶液A。缓慢加入96g 盐酸胍，搅拌溶解至透明，即可得到游离胍溶液B。400 ml 水中加入 95.5 g 氯乙酸室温下搅拌至溶解，滴加到溶液B中，保持温度40℃，温和搅拌24小时，获得混合液C。此时往混合液C中缓慢加入300 g柠檬酸。升温至80℃进行-0.09MPa减压蒸馏，获得白色结晶，过滤取结晶。80℃干燥得到胍基乙酸·柠檬酸盐产物。
二、胍基乙酸·柠檬酸盐中胍基乙酸的含量检测。
HPLC测定： 色谱系统：waters 2695；紫外检测器：waters 2996；色谱柱：Dionex IonPacTM CS16阳离子交换柱（5*250mm）；流动相：甲磺酸50mM和水；流速：1mL/min；柱温：35℃；上样量：10 μL ；检测时间：40 min。
结果如图6所示，胍基乙酸的保留时间为13.057 min。由图对比图2b的标准品可知，本发明获得的可溶性胍基乙酸·柠檬酸盐样品与胍基乙酸标准品具有相同的HPLC谱图，说明可溶胍基乙酸·柠檬酸盐样品也能够保留胍基乙酸标准品结构。进一步，由图计算可知本例胍基乙酸·柠檬酸盐中，胍基乙酸的含量达30.75%。
具体计算方法同实施例1二。胍基乙酸·柠檬酸盐样品HPLC峰面积列于表3。以浓度（μg/mL）为横坐标，峰面积为纵坐标绘制浓度曲线，如图7所示。
表3
从HPLC检测结果可知，本发明所合成的样品，其保留时间和峰形与sigma的胍基乙酸标准品一致，确认本发明所合成的化合物为胍基乙酸络合物，本样品所得曲线为：样品浓度x（μg/mL）：x=峰面积÷2921.8。
纯度计算（%）：样品所绘制浓度曲线的斜率÷标准曲线斜率*99%（标准品纯度） =2921.8 ÷9405.5 *99%=30.75%，可得胍基乙酸·柠檬酸盐中，胍基乙酸含量为30.75%（w/w）。
三、溶解度检测。
配置胍基乙酸·柠檬酸盐的饱和溶液：100 mL水中加入100 g 胍基乙酸络合物样品，在20℃下搅拌溶解30 min，取上层饱和溶液稀释1000倍，进行HPLC测定，结果如图8，峰面积结果如表4所示。方法同二。
表4
根据样品浓度曲线计算，样品浓度x（μg/mL）x=峰面积÷2921.8
样品浓度为 284.90 μg/mL，乘以稀释倍数1000，得出，溶液浓度为284.90 mg/ml。
结果显示，本发明提供的方法生产可溶性胍基乙酸·柠檬酸盐的溶解度为28.49 g/100 mL。（20℃）。胍基乙酸·柠檬酸盐中胍基乙酸含量为30.75%，因此，胍基乙酸·柠檬酸盐中胍基乙酸的溶解度为8.76 g/100 ml，胍基乙酸标准品的溶解度为0.36 g/100 mL（20℃），本发明提供的方法提高了胍基乙酸的溶解度24倍。同时，由胍基乙酸·柠檬酸盐的溶解度28.49 g/100 mL和其中胍基乙酸含量为30.75%可知，其中柠檬酸的浓度为1.0mol/L，对应其中胍基乙酸的溶解度为8.76 g/100 ml，相对于以柠檬酸溶液形式保存胍基乙酸的溶解度（柠檬酸浓度4.0mol/L对应胍基乙酸的溶解度8.2 g/100 ml），以本发明胍基乙酸·柠檬酸盐形式能够提升溶解度4倍以上。
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (9)
- 一种易溶的胍基乙酸络合物的合成方法，包括将含有胍基乙酸的混合液C与酸性物质D混合，减压蒸馏获得胍基乙酸络合物的过程；所述酸性物质D为磷酸；所述减压蒸馏在-0.08~0.1MPa和（80±5）℃下进行；所述混合液C由下述方法获得：步骤S1：将盐酸胍加入碱性溶液A中，生成游离的胍，获得溶液B；步骤S2：将氯乙酸滴加入溶液B中，获得混合液C；所述步骤S1中，所述碱性溶液A为氢氧化钠溶液或碳酸钠溶液。
- 根据权利要求1所述的易溶的胍基乙酸络合物的合成方法，其特征在于，所述混合液C中胍基乙酸的浓度为0.5~8mol/L。
- 根据权利要求1所述的易溶的胍基乙酸络合物的合成方法，其特征在于，所述酸性物质D与胍基乙酸的摩尔比为（1-5）：1。
- 根据权利要求1所述的易溶的胍基乙酸络合物的合成方法，其特征在于，磷酸：盐酸胍的质量比为（50-100）：（43-53）。
- 根据权利要求1所述的易溶的胍基乙酸络合物的合成方法，其特征在于，所述步骤S1中，控制温度在20℃以下；所述步骤S1中，碱性溶液A、盐酸胍的摩尔比为，碱性溶液A以可电离的碱性阴离子单位电价计：盐酸胍=（1±0.3）：1。
- 根据权利要求1所述的易溶的胍基乙酸络合物的合成方法，其特征在于，所述步骤S1中，所述氢氧化钠溶液质量浓度为5%-40%，所述碳酸钠溶液质量浓度为5%-30%。
- 根据权利要求1所述的易溶的胍基乙酸络合物的合成方法，其特征在于，所述步骤S2中，控制温度为35℃-50℃；反应时间为不小于20小时；氯乙酸的添加量，以盐酸胍：氯乙酸的摩尔比计，为1：（1±0.2）。
- 根据权利要求7所述的易溶的胍基乙酸络合物的合成方法，其特征在于，所述步骤S2中，控制温度为40℃；反应时间为24小时。
- 根据权利要求1所述的易溶的胍基乙酸络合物的合成方法，其特征在于，还包括对减压蒸馏后获得的胍基乙酸络合物结晶物进行干燥的步骤，干燥温度为80-98℃。
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| CN104605161A (zh) * | 2015-01-23 | 2015-05-13 | 长沙兴嘉生物工程股份有限公司 | 胍基乙酸配合物的制备方法及其应用 |
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| CN1247536C (zh) * | 2002-06-14 | 2006-03-29 | 方建文 | 盐酸胍制备方法 |
| JP4602249B2 (ja) * | 2003-05-19 | 2010-12-22 | 生化学工業株式会社 | カルバ糖アミン誘導体の酸付加塩 |
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| JPS56111695A (en) * | 1980-02-12 | 1981-09-03 | Nippon Oil & Fats Co Ltd | Non-oil sensitizing treatment liquid for offset printing |
| CN1964633A (zh) * | 2004-06-09 | 2007-05-16 | 底古萨股份公司 | 作为饲料添加剂的胍基乙酸 |
| CN101132786A (zh) * | 2005-03-04 | 2008-02-27 | 澳泽化学特罗斯特贝格有限公司 | 胍基乙酸的盐、加成化合物和络合化合物 |
| CN101525305A (zh) * | 2009-04-17 | 2009-09-09 | 北京君德同创农牧科技有限公司 | 胍基乙酸及其盐的合成方法 |
| CN102850241A (zh) * | 2011-06-27 | 2013-01-02 | 天津天成制药有限公司 | 胍基乙酸硝酸盐的制备方法 |
| CN104605161A (zh) * | 2015-01-23 | 2015-05-13 | 长沙兴嘉生物工程股份有限公司 | 胍基乙酸配合物的制备方法及其应用 |
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