CN118045039A - Preparation method of high-stability aminomethylbenzoic acid injection - Google Patents
Preparation method of high-stability aminomethylbenzoic acid injection Download PDFInfo
- Publication number
- CN118045039A CN118045039A CN202410179969.3A CN202410179969A CN118045039A CN 118045039 A CN118045039 A CN 118045039A CN 202410179969 A CN202410179969 A CN 202410179969A CN 118045039 A CN118045039 A CN 118045039A
- Authority
- CN
- China
- Prior art keywords
- purified water
- added
- hours
- potassium permanganate
- aminomethylbenzoic acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 229960003375 aminomethylbenzoic acid Drugs 0.000 title claims abstract description 89
- QCTBMLYLENLHLA-UHFFFAOYSA-N aminomethylbenzoic acid Chemical compound NCC1=CC=C(C(O)=O)C=C1 QCTBMLYLENLHLA-UHFFFAOYSA-N 0.000 title claims abstract description 88
- 239000007924 injection Substances 0.000 title claims abstract description 62
- 238000002347 injection Methods 0.000 title claims abstract description 62
- 238000002360 preparation method Methods 0.000 title claims abstract description 40
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 135
- 239000012286 potassium permanganate Substances 0.000 claims abstract description 101
- -1 p-iodobenzyl benzoic acid Chemical compound 0.000 claims abstract description 55
- 238000001914 filtration Methods 0.000 claims abstract description 50
- 239000007787 solid Substances 0.000 claims abstract description 45
- 238000006243 chemical reaction Methods 0.000 claims abstract description 28
- 239000000706 filtrate Substances 0.000 claims abstract description 28
- 125000000129 anionic group Chemical group 0.000 claims abstract description 25
- 238000000034 method Methods 0.000 claims abstract description 18
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 claims abstract description 7
- 229940124274 edetate disodium Drugs 0.000 claims abstract description 7
- 239000008213 purified water Substances 0.000 claims description 132
- 229940090044 injection Drugs 0.000 claims description 59
- 238000001816 cooling Methods 0.000 claims description 45
- 238000003756 stirring Methods 0.000 claims description 35
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 23
- 238000010438 heat treatment Methods 0.000 claims description 22
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 19
- 238000001035 drying Methods 0.000 claims description 18
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 17
- 229940093181 glucose injection Drugs 0.000 claims description 17
- 239000002504 physiological saline solution Substances 0.000 claims description 17
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 15
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 15
- 239000013078 crystal Substances 0.000 claims description 13
- 238000002156 mixing Methods 0.000 claims description 13
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 13
- 229910021529 ammonia Inorganic materials 0.000 claims description 11
- 230000001376 precipitating effect Effects 0.000 claims description 11
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- 239000000463 material Substances 0.000 claims description 6
- 239000012535 impurity Substances 0.000 abstract description 21
- 239000002244 precipitate Substances 0.000 abstract description 9
- 229910021645 metal ion Inorganic materials 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 16
- 241000289690 Xenarthra Species 0.000 description 16
- 230000000052 comparative effect Effects 0.000 description 12
- 238000001514 detection method Methods 0.000 description 12
- 239000000047 product Substances 0.000 description 10
- 238000004821 distillation Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 208000032843 Hemorrhage Diseases 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 230000000740 bleeding effect Effects 0.000 description 4
- 230000006866 deterioration Effects 0.000 description 4
- 238000005189 flocculation Methods 0.000 description 4
- 230000016615 flocculation Effects 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 3
- 230000001590 oxidative effect Effects 0.000 description 3
- SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 229960002684 aminocaproic acid Drugs 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 230000020764 fibrinolysis Effects 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 230000002439 hemostatic effect Effects 0.000 description 2
- 238000000643 oven drying Methods 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 238000007789 sealing Methods 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 1
- 208000000616 Hemoptysis Diseases 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 206010046274 Upper gastrointestinal haemorrhage Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 210000004100 adrenal gland Anatomy 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 229940030225 antihemorrhagics Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 1
- 208000034158 bleeding Diseases 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 208000024753 bloody sputum Diseases 0.000 description 1
- 239000013522 chelant Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000002845 discoloration Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 208000006750 hematuria Diseases 0.000 description 1
- 239000002874 hemostatic agent Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 208000008128 pulmonary tuberculosis Diseases 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A preparation method of high-stability aminomethylbenzoic acid injection belongs to the technical field of medicines, and comprises the preparation of p-iodobenzyl benzoic acid and the preparation of aminomethylbenzoic acid. According to the method, in the preparation process of the p-iodobenzyl benzoic acid, the addition proportion of the edetate disodium and the potassium permanganate is gradually reduced, so that impurities in a reaction system can be well removed, the reaction system is not affected, a large amount of impurities are not introduced in the later stage of the reaction, and the purity of the p-iodobenzyl benzoic acid is improved; in the preparation process of the aminomethylbenzoic acid, PAM anionic flocculant is added to be further complexed with metal ion impurities to generate solid precipitate, the solid precipitate is resuspended in hot water, the solid impurities can be removed well by hot filtration, filtrate is purified, high-purity aminomethylbenzoic acid is separated out at low temperature, and the injection has good storage stability, is not easy to oxidize and deteriorate, is not easy to flocculate and separate out, and has good economic and practical values.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a preparation method of high-stability aminomethylbenzoic acid injection.
Background
The aminomethylbenzoic acid is a hemostatic with good effect, is normally white or white-like phosphorus tablet crystal, is para-aminomethylbenzoic acid monohydrate, has no odor and is slightly bitter. The hemostatic mechanism of the aminotoluene acid is the same as that of the aminocaproic acid, adverse reaction is rare, thrombus is not easy to form, excretion is slow, and the fibrinolysis resistance activity is 5 times stronger than that of the aminocaproic acid, so that the hemostatic agent has better general blood seepage effect. Is mainly used for bleeding caused by excessive fibrinolysis, such as abnormal bleeding during surgery, lung, liver, pancreas, prostate, thyroid gland, adrenal gland, etc., and bleeding in obstetrics and gynecology, puerperal and pulmonary tuberculosis hemoptysis, bloody sputum, hematuria, prostatic hyperplasia bleeding, upper gastrointestinal bleeding, etc.
The use of the aminomethylbenzoic acid is generally divided into oral administration and injection, wherein the oral administration is carried out for 3 times per day by 0.25 g-0.5 g each time; injecting 0.1-0.3 g/10-20 ml glucose injection or physiological saline injection for 1-2 times per day;
Compared with injection, the oral administration has large dosage and slow drug effect, so that the aminomethylbenzoic acid injection is generally adopted; however, at present, because of the low purity of the aminomethylbenzoic acid produced and its own characteristics, and the dissolution characteristics of slightly cold water, hot water and almost insoluble ethanol, the aminomethylbenzoic acid injection has poor storage stability, is susceptible to oxidative deterioration due to impurities, and has unstable solubility, resulting in easy flocculation precipitation.
Disclosure of Invention
Aims at solving the problems that the existing aminomethylbenzoic acid injection has poor storage stability, is easily affected by impurities to generate oxidative deterioration and has unstable solubility to cause easy flocculation and precipitation. The invention provides a preparation method of high-stability aminomethylbenzoic acid injection, which is characterized in that disodium edentate is added to match with potassium permanganate to reduce the adding proportion step by step, so that impurities in a reaction system can be well removed, the reaction system is not affected, a large amount of impurities are not introduced in the later stage of the reaction, and the purity of p-iodobenzyl benzoic acid is improved; the PAM anionic flocculant is added to be further complexed with metal ion impurities to generate solid precipitate, the solid precipitate is resuspended in purified water at 80-90 ℃, the solid impurities can be removed well by hot filtration, the filtrate is purified, high-purity aminomethylbenzoic acid is separated out, and the injection has good storage stability, is not easy to oxidize and deteriorate and is not easy to flocculate and separate out. The specific technical scheme is as follows:
a preparation method of high-stability aminomethylbenzoic acid injection comprises the following steps:
S1: heating purified water to 90-95 ℃, adding tetrabutylammonium bromide, p-methyl iodobenzyl and potassium permanganate, stirring and reacting for 6-8 hours, adding edetate disodium, continuously stirring and reacting for 4-6 hours, accumulating and reacting for 12 hours, cooling to room temperature, filtering, concentrating filtrate at 90-95 ℃ until turbidity appears, cooling to 5-10 ℃, precipitating, filtering, drying solids to obtain p-iodobenzyl benzoic acid;
S2: adding p-iodobenzyl benzoic acid, ammonia water, PAM anionic flocculant and active carbon into purified water, uniformly mixing, heating to 55-60 ℃ for reaction for 2-3 h, distilling under negative pressure to remove ammonia, cooling to 3-5 ℃, and filtering to obtain solid; re-suspending the solid in purified water at 80-90 deg.c, stirring for 1-3 hr, hot filtering at 80-90 deg.c to obtain filtrate, cooling to 3-5 deg.c, standing to separate out crystal to obtain wet aminomethylbenzoic acid material, stoving to obtain aminomethylbenzoic acid with purity over 99.96%;
s3: the injection is prepared by mixing the aminomethylbenzoic acid with glucose injection or physiological saline injection with the concentration of 0.1 g-0.3 g/10 ml-20 ml.
In the S1 of the preparation method, the adding amount of the tetrabutylammonium bromide is 20g/L of purified water to 30g/L of purified water.
In the S1 of the preparation method, the adding amount of the p-methyl iodobenzyl is 260g/L of purified water to 300g/L of purified water.
In the S1 of the preparation method, the addition amount of the potassium permanganate is 800g/L purified water to 900g/L purified water; the potassium permanganate is added 6 times, 1 time is added every 2 hours, 25% of the total amount of potassium permanganate is initially added, 25% of the total amount of potassium permanganate is added in 2 hours, 20% of the total amount of potassium permanganate is added in 4 hours, 15% of the total amount of potassium permanganate is added in 6 hours, 10% of the total amount of potassium permanganate is added in 8 hours, and 5% of the total amount of potassium permanganate is added in 8 hours.
In the S1 of the preparation method, the addition amount of the edetate disodium is 2g/L of purified water to 5g/L of purified water.
In the above preparation method S1, the purity of the p-iodobenzyl benzoic acid is 99.83% or more.
In the S2 of the preparation method, the adding amount of the p-iodobenzyl benzoic acid is 450g/L of purified water to 480g/L of purified water.
In the S2 of the preparation method, the addition amount of the ammonia water is equal to the volume of the purified water; the concentration of the ammonia water is 20% -25%.
In the S2 of the preparation method, the addition amount of the PAM anionic flocculant is 5g/L purified water-8 g/L purified water.
In the S2 of the preparation method, the addition amount of the activated carbon is 3g/L of purified water to 8g/L of purified water.
Compared with the prior art, the preparation method of the high-stability aminomethylbenzoic acid injection has the beneficial effects that:
1. The method is designed to add disodium edentate in the preparation process of the p-iodobenzyl benzoic acid, has a washing effect on raw materials and reaction process products, has wide coordination performance, can form stable chelate with metal ion impurities, can remove the impurities after filtration, improves the purity of filtrate, further improves the crystallization purity of the p-iodobenzyl benzoic acid, and is used for preparing high-purity aminomethylbenzoic acid subsequently. In addition, the unexpected finding is that adding disodium edentate in stirring reaction for 6-8 hours has the best purifying effect, the purity of p-iodobenzyl benzoic acid can reach more than 99.83%, and adding disodium edentate with the adding amount of 2-5 g/L purified water can not influence the reaction system while ensuring impurity removal.
2. According to the method, PAM anionic flocculant is added in the process of preparing the aminomethylbenzoic acid, so that the PAM anionic flocculant can be further complexed with metal ion impurities to generate solid precipitate, the solid precipitate is resuspended in purified water at 80-90 ℃, the solid impurities can be well removed by hot filtration at 80-90 ℃, the filtrate is purified, and the high-purity aminomethylbenzoic acid is separated out at 3-5 ℃, and the purity can reach more than 99.96%. Surprisingly, it has been found that the addition of PAM anionic flocculant during the reaction to produce aminomethylbenzoic acid has a better purification effect than the addition of PAM anionic flocculant by aminomethylbenzoic acid dissolution and recrystallization.
3. In the process of preparing the aminomethylbenzoic acid, the method can be added with activated carbon to decolorize the reaction solution, so that the reaction solution of the aminomethylbenzoic acid is further purified.
4. The method is characterized in that the potassium permanganate is added for 6 times, 1 time is added every 2 hours, 25% of the total amount of the potassium permanganate is initially added, 25% of the total amount of the potassium permanganate is added in 2 hours, 20% of the total amount of the potassium permanganate is added in 4 hours, 15% of the total amount of the potassium permanganate is added in 6 hours, 10% of the total amount of the potassium permanganate is added in 8 hours, and 5% of the total amount of the potassium permanganate is added in 8 hours. The design of the adding proportion can be matched with edetate disodium to purify the reaction system for removing impurities, the smooth operation of the reaction system is not affected, and a large amount of impurities are not introduced in the later reaction stage.
In conclusion, in the preparation process of the p-iodobenzyl benzoic acid, the addition ratio of the edetate disodium to the potassium permanganate is gradually reduced, so that impurities in a reaction system can be well removed, the reaction system is not affected, a large amount of impurities are not introduced in the later stage of the reaction, and the purity of the p-iodobenzyl benzoic acid is improved to more than 99.83%. In the preparation process of the aminomethylbenzoic acid, PAM anionic flocculant is added to be further complexed with metal ion impurities to generate solid precipitate, the solid precipitate is resuspended in purified water at 80-90 ℃, the solid impurities can be well removed by hot filtration at 80-90 ℃, the filtrate is purified, and the high-purity aminomethylbenzoic acid is separated out at 3-5 ℃, and the purity can reach more than 99.96%; the injection prepared by the method has good storage stability, is not easy to oxidize and deteriorate, is not easy to flocculate and precipitate, and has good economic and practical values.
Detailed Description
The invention will be further illustrated with reference to specific examples, but the invention is not limited to these examples.
Example 1
A preparation method of high-stability aminomethylbenzoic acid injection comprises the following steps:
S1: heating purified water to 92 ℃, adding 25g/L of tetrabutylammonium bromide of the purified water, 280g/L of p-methyl iodobenzyl and 850g/L of potassium permanganate of the purified water, stirring and reacting for 6 hours, adding 3g/L of disodium edentate of the purified water, continuously stirring and reacting for 6 hours, accumulating and reacting for 12 hours, cooling to room temperature, filtering, concentrating filtrate at 92 ℃ until turbidity appears, cooling to 6 ℃, precipitating, filtering, drying solid to obtain p-iodobenzyl benzoic acid, and detecting to obtain the purity of 99.85%;
Wherein, the potassium permanganate is added for 6 times, 1 time is added every 2 hours, 25% of the total amount of potassium permanganate is added initially, 25% of the total amount of potassium permanganate is added in 2 hours, 20% of the total amount of potassium permanganate is added in 4 hours, 15% of the total amount of potassium permanganate is added in 6 hours, 10% of the total amount of potassium permanganate is added in 8 hours, and 5% of the total amount of potassium permanganate is added in 8 hours.
S2: adding 460g/L of p-iodobenzyl benzoic acid of the purified water, ammonia water with the same volume as the purified water and the concentration of 24%, 6g/L of PAM anionic flocculant of the purified water and 6g/L of activated carbon of the purified water into the purified water, uniformly mixing, heating to 58 ℃ for reaction for 2.5 hours, carrying out negative pressure distillation to remove ammonia, cooling to 4 ℃, filtering, and taking solid; re-suspending the solid in purified water at 85 ℃, stirring for 2 hours, thermally filtering at 85 ℃, taking filtrate, cooling to 4 ℃, standing until crystals are separated out, obtaining wet aminomethylbenzoic acid, drying, and obtaining the aminomethylbenzoic acid with the purity of 99.98 percent after detection;
S3: the aminomethylbenzoic acid and glucose injection or physiological saline injection are prepared into 0.1g over-high
Injection of 0.3g/10 ml-20 ml.
Example 2
A preparation method of high-stability aminomethylbenzoic acid injection comprises the following steps:
S1: heating purified water to 90 ℃, adding 30g/L of tetrabutylammonium bromide of the purified water, 260g/L of p-methyl iodobenzyl and 900g/L of potassium permanganate of the purified water, stirring and reacting for 6 hours, adding 3.5g/L of disodium edentate of the purified water, continuously stirring and reacting for 6 hours, accumulating and reacting for 12 hours, cooling to room temperature, filtering, concentrating filtrate at 95 ℃ until turbidity appears, cooling to 5 ℃, precipitating, filtering, drying the solid to obtain p-iodobenzyl benzoic acid, and detecting to obtain the product with the purity of 99.83%;
Wherein, the potassium permanganate is added for 6 times, 1 time is added every 2 hours, 25% of the total amount of potassium permanganate is added initially, 25% of the total amount of potassium permanganate is added in 2 hours, 20% of the total amount of potassium permanganate is added in 4 hours, 15% of the total amount of potassium permanganate is added in 6 hours, 10% of the total amount of potassium permanganate is added in 8 hours, and 5% of the total amount of potassium permanganate is added in 8 hours.
S2: adding 480g/L p-iodobenzyl benzoic acid of purified water, ammonia water with the same volume as the purified water and the concentration of 20%, 8g/L PAM anionic flocculant of the purified water and 3g/L active carbon of the purified water into the purified water, uniformly mixing, heating to 60 ℃ for reaction for 2 hours, carrying out negative pressure distillation to remove ammonia, cooling to 5 ℃, filtering, and taking solid; suspending the solid in purified water at 80deg.C again, stirring for 3 hr, hot filtering at 80deg.C, collecting filtrate, cooling to 5deg.C, standing until crystals are separated out to obtain wet material of aminomethylbenzoic acid, oven drying to obtain aminomethylbenzoic acid, and detecting to obtain product with purity of 99.96%;
S3: the aminomethylbenzoic acid and glucose injection or physiological saline injection are prepared into 0.1g over-high
Injection of 0.3g/10 ml-20 ml.
Example 3
A preparation method of high-stability aminomethylbenzoic acid injection comprises the following steps:
S1: heating purified water to 90 ℃, adding 20g/L of tetrabutylammonium bromide of the purified water, 260g/L of p-methyl iodobenzyl of the purified water and 800g/L of potassium permanganate of the purified water, stirring and reacting for 8 hours, adding 2g/L of disodium edentate of the purified water, continuously stirring and reacting for 4 hours, accumulating and reacting for 12 hours, cooling to room temperature, filtering, concentrating filtrate at 90 ℃ until turbidity appears, cooling to 5 ℃, precipitating, filtering, drying solid to obtain p-iodobenzyl benzoic acid, and detecting to obtain the purity of 99.84%;
Wherein, the potassium permanganate is added for 6 times, 1 time is added every 2 hours, 25% of the total amount of potassium permanganate is added initially, 25% of the total amount of potassium permanganate is added in 2 hours, 20% of the total amount of potassium permanganate is added in 4 hours, 15% of the total amount of potassium permanganate is added in 6 hours, 10% of the total amount of potassium permanganate is added in 8 hours, and 5% of the total amount of potassium permanganate is added in 8 hours.
S2: adding 450g/L of p-iodobenzyl benzoic acid of the purified water, ammonia water with the same volume as the purified water and the concentration of 20%, 5g/L of PAM anionic flocculant of the purified water and 3g/L of active carbon of the purified water into the purified water, uniformly mixing, heating to 55 ℃ for reaction for 2 hours, distilling under negative pressure to remove ammonia, cooling to 3 ℃, filtering, and taking solid; re-suspending the solid in purified water at 80 ℃, stirring for 1h, thermally filtering at 80 ℃, taking filtrate, cooling to 3 ℃, standing until crystals are separated out to obtain wet aminomethylbenzoic acid, drying to obtain the aminomethylbenzoic acid, and detecting to obtain the product with the purity of 99.96%;
S3: the aminomethylbenzoic acid and glucose injection or physiological saline injection are prepared into 0.1g over-high
Injection of 0.3g/10 ml-20 ml.
Example 4
A preparation method of high-stability aminomethylbenzoic acid injection comprises the following steps:
S1: heating purified water to 95 ℃, adding 20g/L of tetrabutylammonium bromide of the purified water, 300g/L of p-methyl iodobenzyl and 800g/L of potassium permanganate of the purified water, stirring and reacting for 6 hours, adding 5g/L of disodium edentate of the purified water, continuously stirring and reacting for 6 hours, accumulating and reacting for 12 hours, cooling to room temperature, filtering, concentrating filtrate at 90 ℃ until turbidity appears, cooling to 10 ℃, precipitating, filtering, drying solid to obtain p-iodobenzyl benzoic acid, and detecting to obtain the purity of 99.84%;
Wherein, the potassium permanganate is added for 6 times, 1 time is added every 2 hours, 25% of the total amount of potassium permanganate is added initially, 25% of the total amount of potassium permanganate is added in 2 hours, 20% of the total amount of potassium permanganate is added in 4 hours, 15% of the total amount of potassium permanganate is added in 6 hours, 10% of the total amount of potassium permanganate is added in 8 hours, and 5% of the total amount of potassium permanganate is added in 8 hours.
S2: adding 450g/L of p-iodobenzyl benzoic acid of the purified water, ammonia water with the same volume as the purified water and the concentration of 25%, 5g/L of PAM anionic flocculant of the purified water and 8g/L of activated carbon of the purified water into the purified water, uniformly mixing, heating to 55 ℃ for reaction for 3 hours, distilling under negative pressure to remove ammonia, cooling to 3 ℃, filtering, and taking solid; suspending the solid in purified water at 90 ℃ again, stirring for 1h, performing hot filtration at 90 ℃, taking filtrate, cooling to 3 ℃, standing until crystals are separated out to obtain wet aminomethylbenzoic acid, drying to obtain the aminomethylbenzoic acid, and detecting to obtain the product with the purity of 99.96%;
S3: the aminomethylbenzoic acid and glucose injection or physiological saline injection are prepared into 0.1g over-high
Injection of 0.3g/10 ml-20 ml.
Example 5
A preparation method of high-stability aminomethylbenzoic acid injection comprises the following steps:
s1: heating purified water to 95 ℃, adding 30g/L of tetrabutylammonium bromide of the purified water, 300g/L of p-methyl iodobenzyl and 900g/L of potassium permanganate of the purified water, stirring and reacting for 8 hours, adding 4g/L of disodium edentate of the purified water, continuously stirring and reacting for 4 hours, accumulating and reacting for 12 hours, cooling to room temperature, filtering, concentrating filtrate at 95 ℃ until turbidity appears, cooling to 10 ℃, precipitating, filtering, drying solid to obtain p-iodobenzyl benzoic acid, and detecting to obtain the purity of 99.86%;
Wherein, the potassium permanganate is added for 6 times, 1 time is added every 2 hours, 25% of the total amount of potassium permanganate is added initially, 25% of the total amount of potassium permanganate is added in 2 hours, 20% of the total amount of potassium permanganate is added in 4 hours, 15% of the total amount of potassium permanganate is added in 6 hours, 10% of the total amount of potassium permanganate is added in 8 hours, and 5% of the total amount of potassium permanganate is added in 8 hours.
S2: adding 480g/L p-iodobenzyl benzoic acid of the purified water, ammonia water with the same volume as the purified water and the concentration of 25%, 8g/L PAM anionic flocculant of the purified water and 8g/L active carbon of the purified water into the purified water, uniformly mixing, heating to 60 ℃ for reaction for 3 hours, carrying out negative pressure distillation to remove ammonia, cooling to 5 ℃, filtering, and taking solid; suspending the solid in purified water at 90 ℃ again, stirring for 3h, thermally filtering at 90 ℃, taking filtrate, cooling to 5 ℃, standing until crystals are separated out to obtain wet aminomethylbenzoic acid, drying to obtain the aminomethylbenzoic acid, and detecting to obtain the product with the purity of 99.99%;
S3: the aminomethylbenzoic acid and glucose injection or physiological saline injection are prepared into 0.1g over-high
Injection of 0.3g/10 ml-20 ml.
Example 6
A preparation method of high-stability aminomethylbenzoic acid injection comprises the following steps:
S1: heating purified water to 91 ℃, adding 22g/L of tetrabutylammonium bromide of the purified water, 270g/L of p-methyl iodobenzyl of the purified water and 820g/L of potassium permanganate of the purified water, stirring and reacting for 6 hours, adding 4.5g/L of disodium edentate of the purified water, continuously stirring and reacting for 6 hours, accumulating and reacting for 12 hours, cooling to room temperature, filtering, concentrating filtrate at 91 ℃ until turbidity appears, cooling to 6 ℃, precipitating, filtering, drying the solid to obtain p-iodobenzyl benzoic acid, and detecting to obtain the product with the purity of 99.83 percent;
Wherein, the potassium permanganate is added for 6 times, 1 time is added every 2 hours, 25% of the total amount of potassium permanganate is added initially, 25% of the total amount of potassium permanganate is added in 2 hours, 20% of the total amount of potassium permanganate is added in 4 hours, 15% of the total amount of potassium permanganate is added in 6 hours, 10% of the total amount of potassium permanganate is added in 8 hours, and 5% of the total amount of potassium permanganate is added in 8 hours.
S2: adding 460g/L of p-iodobenzyl benzoic acid of the purified water, ammonia water with the same volume as the purified water and the concentration of 22%, 6g/L of PAM anionic flocculant of the purified water and 4g/L of active carbon of the purified water into the purified water, uniformly mixing, heating to 56 ℃ for reaction for 2 hours, carrying out negative pressure distillation to remove ammonia, cooling to 3.5 ℃, and filtering to obtain solid; suspending the solid in purified water at 82 deg.C again, stirring for 1.5h, hot filtering at 82 deg.C, collecting filtrate, cooling to 3.5 deg.C, standing until crystals are separated out to obtain wet material of aminomethylbenzoic acid, oven drying to obtain aminomethylbenzoic acid, and detecting to obtain the product with purity of 99.97%;
S3: the aminomethylbenzoic acid and glucose injection or physiological saline injection are prepared into 0.1g over-high
Injection of 0.3g/10 ml-20 ml.
Example 7
A preparation method of high-stability aminomethylbenzoic acid injection comprises the following steps:
S1: heating purified water to 94 ℃, adding 28g/L of tetrabutylammonium bromide of the purified water, 280g/L of p-methyl iodobenzyl and 880g/L of potassium permanganate of the purified water, stirring and reacting for 8 hours, adding 2.5g/L of disodium edentate of the purified water, continuously stirring and reacting for 4 hours, accumulating and reacting for 12 hours, cooling to room temperature, filtering, concentrating filtrate at 94 ℃ until turbidity appears, cooling to 8 ℃, precipitating, filtering, drying the solid to obtain p-iodobenzyl benzoic acid, and detecting to obtain the product with the purity of 99.85 percent;
Wherein, the potassium permanganate is added for 6 times, 1 time is added every 2 hours, 25% of the total amount of potassium permanganate is added initially, 25% of the total amount of potassium permanganate is added in 2 hours, 20% of the total amount of potassium permanganate is added in 4 hours, 15% of the total amount of potassium permanganate is added in 6 hours, 10% of the total amount of potassium permanganate is added in 8 hours, and 5% of the total amount of potassium permanganate is added in 8 hours.
S2: adding 470g/L of p-iodobenzyl benzoic acid of the purified water, ammonia water with the same volume as the purified water and the concentration of 25%, 7g/L of PAM anionic flocculant of the purified water and 7g/L of active carbon of the purified water into the purified water, uniformly mixing, heating to 59 ℃ for reaction for 3 hours, distilling under negative pressure to remove ammonia, cooling to 4.5 ℃, filtering, and taking solid; suspending the solid in 88 ℃ purified water again, stirring for 2.5h, carrying out hot filtration at 88 ℃, taking filtrate, cooling to 4.5 ℃, standing until crystals are separated out, obtaining wet material of the aminomethylbenzoic acid, drying, obtaining the aminomethylbenzoic acid, and detecting to obtain the purity of 99.98%;
S3: the aminomethylbenzoic acid and glucose injection or physiological saline injection are prepared into 0.1g over-high
Injection of 0.3g/10 ml-20 ml.
Example 8
A preparation method of high-stability aminomethylbenzoic acid injection comprises the following steps:
S1: heating purified water to 91 ℃, adding 28g/L of tetrabutylammonium bromide of the purified water, 265g/L of p-methyl iodobenzyl and 870g/L of potassium permanganate of the purified water, stirring and reacting for 6 hours, adding 3g/L of disodium edentate of the purified water, continuously stirring and reacting for 6 hours, accumulating and reacting for 12 hours, cooling to room temperature, filtering, concentrating filtrate at 94 ℃ until turbidity appears, cooling to 7 ℃, precipitating, filtering, drying solid to obtain p-iodobenzyl benzoic acid, and detecting to obtain the purity of 99.84%;
Wherein, the potassium permanganate is added for 6 times, 1 time is added every 2 hours, 25% of the total amount of potassium permanganate is added initially, 25% of the total amount of potassium permanganate is added in 2 hours, 20% of the total amount of potassium permanganate is added in 4 hours, 15% of the total amount of potassium permanganate is added in 6 hours, 10% of the total amount of potassium permanganate is added in 8 hours, and 5% of the total amount of potassium permanganate is added in 8 hours.
S2: adding 455g/L p-iodobenzyl benzoic acid of purified water, ammonia water with the same volume as the purified water and the concentration of 23%, 6g/L PAM anionic flocculant of the purified water and 7g/L active carbon of the purified water into the purified water, uniformly mixing, heating to 56 ℃ for reaction for 2.5 hours, carrying out negative pressure distillation to remove ammonia, cooling to 3 ℃, filtering, and taking solid; suspending the solid in purified water at 90 ℃ again, stirring for 1h, performing hot filtration at 90 ℃, taking filtrate, cooling to 4 ℃, standing until crystals are separated out, obtaining wet aminomethylbenzoic acid, drying, and obtaining the aminomethylbenzoic acid, wherein the purity is 99.97% after detection;
S3: the aminomethylbenzoic acid and glucose injection or physiological saline injection are prepared into 0.1g over-high
Injection of 0.3g/10 ml-20 ml.
Example 9
A preparation method of high-stability aminomethylbenzoic acid injection comprises the following steps:
S1: heating purified water to 95 ℃, adding 29g/L of tetrabutylammonium bromide of the purified water, 275g/L of p-methyl iodobenzyl and 860g/L of potassium permanganate of the purified water, stirring and reacting for 8 hours, adding 2.5g/L of disodium edentate of the purified water, continuing stirring and reacting for 4 hours, accumulating and reacting for 12 hours, cooling to room temperature, filtering, concentrating filtrate at 95 ℃ until turbidity appears, cooling to 5 ℃, precipitating, filtering, drying the solid to obtain p-iodobenzyl benzoic acid, and detecting to obtain the product with the purity of 99.85%;
Wherein, the potassium permanganate is added for 6 times, 1 time is added every 2 hours, 25% of the total amount of potassium permanganate is added initially, 25% of the total amount of potassium permanganate is added in 2 hours, 20% of the total amount of potassium permanganate is added in 4 hours, 15% of the total amount of potassium permanganate is added in 6 hours, 10% of the total amount of potassium permanganate is added in 8 hours, and 5% of the total amount of potassium permanganate is added in 8 hours.
S2: adding 450g/L p-iodobenzyl benzoic acid of purified water, ammonia water with the same volume as the purified water and the concentration of 25%, 7.5g/L PAM anionic flocculant of the purified water and 6g/L active carbon of the purified water into the purified water, uniformly mixing, heating to 60 ℃ for reacting for 2.5 hours, carrying out negative pressure distillation to remove ammonia, cooling to 4 ℃, filtering, and taking solid; re-suspending the solid in purified water at 85 ℃, stirring for 2 hours, thermally filtering at 85 ℃, taking filtrate, cooling to 4 ℃, standing until crystals are separated out, obtaining wet aminomethylbenzoic acid, drying, and obtaining the aminomethylbenzoic acid with the purity of 99.98 percent after detection;
S3: the aminomethylbenzoic acid and glucose injection or physiological saline injection are prepared into 0.1g over-high
Injection of 0.3g/10 ml-20 ml.
The aminomethylbenzoic acid obtained in examples 1 to 9 was prepared into a glucose injection of 0.1g/10ml and a physiological saline injection of 0.1g/10m l, respectively, as test samples of examples.
Preparation of comparative example 1
S1, disodium edentate is not added, other step parameters are the same as in example 1, p-iodobenzyl benzoic acid is obtained, and after detection, the purity is 96.82%;
the procedure of example 1 was followed to obtain aminomethylbenzoic acid having a purity of 97.12% after detection.
The aminomethylbenzoic acid obtained in comparative example 1 was prepared into a glucose injection of 0.1g/10ml and a physiological saline injection of 0.1g/10ml, respectively, and used as a test sample in comparative example.
Preparation of comparative example 2
S1, the step parameters are the same as in example 1, so that p-iodobenzyl benzoic acid is obtained, and the purity is 99.85% after detection;
S2, PAM anionic flocculant is not added, other step parameters are the same as in example 1, and the aminomethylbenzoic acid is obtained, and after detection, the purity is 99.88%.
The aminomethylbenzoic acid obtained in comparative example 2 was prepared into a glucose injection solution of 0.1g/10ml and a physiological saline injection solution of 0.1g/10ml, respectively, as comparative example test samples.
Preparation of comparative example 3
S1, disodium edentate is not added, other step parameters are the same as in example 1, p-iodobenzyl benzoic acid is obtained, and after detection, the purity is 96.82%;
s2, PAM anionic flocculant is not added, other step parameters are the same as in example 1, and the aminomethylbenzoic acid is obtained, and after detection, the purity is 96.94%.
The aminomethylbenzoic acid obtained in comparative example 3 was prepared into a glucose injection of 0.1g/10ml and a physiological saline injection of 0.1g/10ml, respectively, as comparative example test samples.
Preparation of comparative example 4
In S1, potassium permanganate is added in 6 times, 1 time every 2 hours, and the equivalent amount of each time is 142g. Other parameters were the same as in example 1; the p-iodobenzyl benzoic acid is obtained, and the purity is 98.13% after detection;
the step parameters of S2 were the same as in example 1 to give aminomethylbenzoic acid, which was detected to have a purity of 98.74%.
Preparation of comparative example 5
S1, the step parameters are the same as in example 1, so that p-iodobenzyl benzoic acid is obtained, and the purity is 99.85% after detection;
S2, PAM anionic flocculant is not added, and other parameters are the same as in example 1. After the preparation of the aminomethyl acid is finished, redissolving the aminomethyl acid in purified water at 85 ℃, adding PAM anionic flocculant of 6g/L purified water, stirring for 2 hours, hot filtering at 85 ℃, taking filtrate, cooling to 4 ℃, standing until crystals are separated out, and obtaining wet aminomethyl acid material with the purity of 99.86 percent after detection.
The storage stability test was performed on the example sample and the comparative sample, respectively:
Placing a physiological saline injection sample with the concentration of 0.1g/10ml in a glass bottle for sealing storage at the temperature of 38-40 ℃ for 30 months, measuring oxidative deterioration, and recording flocculation phenomenon; placing a glucose injection sample of 0.1g/10ml in a glass bottle for sealing storage at 38-40 ℃ for 26 months, measuring discoloration, oxidation and deterioration, and recording flocculation; the results are shown in Table 1 below.
TABLE 1 storage stability test results
From the above results, it is understood that the addition of disodium edentate in the preparation process of examples 1 to 9 can improve the purity of p-iodobenzyl benzoic acid, and the addition of PAM anionic flocculant can improve the purity of aminomethylbenzoic acid, and the prepared aminomethylbenzoic acid has high stability and is not easy to oxidize and deteriorate.
Claims (10)
1. The preparation method of the high-stability aminomethylbenzoic acid injection is characterized by comprising the following steps:
S1: heating purified water to 90-95 ℃, adding tetrabutylammonium bromide, p-methyl iodobenzyl and potassium permanganate, stirring and reacting for 6-8 hours, adding edetate disodium, continuously stirring and reacting for 4-6 hours, accumulating and reacting for 12 hours, cooling to room temperature, filtering, concentrating filtrate at 90-95 ℃ until turbidity appears, cooling to 5-10 ℃, precipitating, filtering, drying solids to obtain p-iodobenzyl benzoic acid;
S2: adding p-iodobenzyl benzoic acid, ammonia water, PAM anionic flocculant and active carbon into purified water, uniformly mixing, heating to 55-60 ℃ for reaction for 2-3 h, distilling under negative pressure to remove ammonia, cooling to 3-5 ℃, and filtering to obtain solid; re-suspending the solid in purified water at 80-90 deg.c, stirring for 1-3 hr, hot filtering at 80-90 deg.c to obtain filtrate, cooling to 3-5 deg.c, standing to separate out crystal to obtain wet aminomethylbenzoic acid material, stoving to obtain aminomethylbenzoic acid with purity over 99.96%;
s3: the injection is prepared by mixing the aminomethylbenzoic acid with glucose injection or physiological saline injection with the concentration of 0.1 g-0.3 g/10 ml-20 ml.
2. The method for preparing high-stability aminomethylbenzoic acid injection according to claim 1, wherein in S1, the added amount of tetrabutylammonium bromide is 20g/L purified water to 30g/L purified water.
3. The method for preparing high-stability aminomethylbenzoic acid injection according to claim 1, wherein in S1, the amount of p-methyl iodobenzyl added is 260g/L purified water to 300g/L purified water.
4. The method for preparing high-stability aminomethylbenzoic acid injection according to claim 1, wherein in S1, the potassium permanganate is added in an amount of 800g/L purified water to 900g/L purified water; the potassium permanganate is added 6 times, 1 time is added every 2 hours, 25% of the total amount of potassium permanganate is initially added, 25% of the total amount of potassium permanganate is added in 2 hours, 20% of the total amount of potassium permanganate is added in 4 hours, 15% of the total amount of potassium permanganate is added in 6 hours, 10% of the total amount of potassium permanganate is added in 8 hours, and 5% of the total amount of potassium permanganate is added in 8 hours.
5. The method for preparing high-stability aminomethylbenzoic acid injection according to claim 1, wherein in S1, the addition amount of edetate disodium is 2g/L purified water to 5g/L purified water.
6. The method for preparing high-stability aminomethylbenzoic acid injection according to claim 1, wherein in S1, the purity of p-iodobenzyl benzoic acid is 99.83% or more.
7. The method for preparing high-stability aminomethylbenzoic acid injection according to claim 1, wherein in S2, the amount of p-iodobenzyl benzoic acid added is 450g/L to 480g/L of purified water.
8. The method for preparing high-stability aminomethylbenzoic acid injection according to claim 1, wherein in S2, the addition amount of said aqueous ammonia is equal volume of purified water; the concentration of the ammonia water is 20% -25%.
9. The method for preparing high-stability aminomethylbenzoic acid injection according to claim 1, wherein in S2, said PAM anionic flocculant is added in an amount of 5g/L purified water to 8g/L purified water.
10. The method for preparing high-stability aminomethylbenzoic acid injection according to claim 1, wherein in S2, said activated carbon is added in an amount of 3g/L purified water to 8g/L purified water.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202410179969.3A CN118045039A (en) | 2024-02-18 | 2024-02-18 | Preparation method of high-stability aminomethylbenzoic acid injection |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202410179969.3A CN118045039A (en) | 2024-02-18 | 2024-02-18 | Preparation method of high-stability aminomethylbenzoic acid injection |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN118045039A true CN118045039A (en) | 2024-05-17 |
Family
ID=91051124
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202410179969.3A Pending CN118045039A (en) | 2024-02-18 | 2024-02-18 | Preparation method of high-stability aminomethylbenzoic acid injection |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN118045039A (en) |
-
2024
- 2024-02-18 CN CN202410179969.3A patent/CN118045039A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP2000169426A (en) | Purification of long-chain dicarboxylic acid | |
| CN112552196A (en) | Method for preparing aspirin-lysine | |
| Baron et al. | CLXXV.—The formation and reactions of imino-compounds. Part I. Condensation of ethyl cyanoacetate with its sodium derivative | |
| CN111087326A (en) | Method for refining guanidine nitrate | |
| CN118045039A (en) | Preparation method of high-stability aminomethylbenzoic acid injection | |
| CN107488129A (en) | A kind of method that L valines are purified in the valine compound from L | |
| US3761474A (en) | Purification of crude cyanuric acid | |
| EP0611369B1 (en) | Process for preparing (s) (+)-4,4'-(1-methyl-1,2-ethanediyl)-bis(2,6-piperazinedione) | |
| CN105566098A (en) | Method for combined production of high purity crystalline calcium acetate and waterless calcium acetate | |
| JPH10273326A (en) | Production of ferrous sulfate or iron polysulfate having high purity from waste hydrochloric acid containing ferrous compound | |
| JPS60217897A (en) | Method for separating and purifying lactic acid | |
| US3562012A (en) | Process for the preparation of pure lactulose from crude lactulosate syrups | |
| CN111943234A (en) | Method for preparing medicinal sterile sodium bicarbonate granules with large particle size | |
| CN101509022A (en) | Method for improving extract yield of L-tryptophane | |
| CN109265460A (en) | A kind of purification process of folic acid | |
| Bogert et al. | 3-AMINO-o-PHTHALIC ACID AND CERTAIN OF ITS DERIVATIVES. | |
| JP3080801B2 (en) | Taurine purification method | |
| CN115403529B (en) | Purification method of 2, 5-pyrazine dicarboxylic acid byproduct | |
| JPS62440A (en) | Separation of dihydroxybenzoic acid isomer | |
| CN114604893A (en) | Preparation method of ammonium metavanadate | |
| CN117624042A (en) | Refining method of high-purity milrinone | |
| JPS5945898A (en) | Purification of l-tryptophan | |
| JPS6236093A (en) | Manufacture of liquid fertilizer | |
| CN110980781A (en) | Method for preparing high-purity magnesium sulfate | |
| RU2250197C1 (en) | Method of recovering strontium-containing concentrate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |