CN111848432A - Preparation method of p-aminosalicylic acid - Google Patents
Preparation method of p-aminosalicylic acid Download PDFInfo
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- CN111848432A CN111848432A CN202010680904.9A CN202010680904A CN111848432A CN 111848432 A CN111848432 A CN 111848432A CN 202010680904 A CN202010680904 A CN 202010680904A CN 111848432 A CN111848432 A CN 111848432A
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- Prior art keywords
- aminosalicylic acid
- acid
- sodium
- organic solvent
- dihydrate
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- WUBBRNOQWQTFEX-UHFFFAOYSA-N 4-aminosalicylic acid Chemical compound NC1=CC=C(C(O)=O)C(O)=C1 WUBBRNOQWQTFEX-UHFFFAOYSA-N 0.000 title claims abstract description 86
- 229960004909 aminosalicylic acid Drugs 0.000 title claims abstract description 85
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 54
- 239000003960 organic solvent Substances 0.000 claims abstract description 40
- 238000001914 filtration Methods 0.000 claims abstract description 39
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 37
- 238000000034 method Methods 0.000 claims abstract description 31
- 238000001035 drying Methods 0.000 claims abstract description 29
- 239000002253 acid Substances 0.000 claims abstract description 25
- 238000005406 washing Methods 0.000 claims abstract description 22
- 239000008139 complexing agent Substances 0.000 claims abstract description 13
- 239000003963 antioxidant agent Substances 0.000 claims abstract description 12
- 230000003078 antioxidant effect Effects 0.000 claims abstract description 12
- 229940113720 aminosalicylate Drugs 0.000 claims abstract description 10
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound 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 claims abstract description 9
- 239000011734 sodium Substances 0.000 claims abstract description 9
- 229910052708 sodium Inorganic materials 0.000 claims abstract description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 36
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 26
- GMUQJDAYXZXBOT-UHFFFAOYSA-M sodium;4-amino-2-hydroxybenzoate;dihydrate Chemical compound O.O.[Na+].NC1=CC=C(C([O-])=O)C(O)=C1 GMUQJDAYXZXBOT-UHFFFAOYSA-M 0.000 claims description 25
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- 150000002148 esters Chemical class 0.000 claims description 16
- 235000010265 sodium sulphite Nutrition 0.000 claims description 13
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical group OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims description 12
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 7
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 claims description 6
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 claims description 5
- 229940090181 propyl acetate Drugs 0.000 claims description 5
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims description 5
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 claims description 4
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims description 4
- 235000018417 cysteine Nutrition 0.000 claims description 4
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims description 4
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 4
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 claims description 4
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 3
- 238000003756 stirring Methods 0.000 abstract description 36
- 239000002904 solvent Substances 0.000 abstract description 13
- 238000010438 heat treatment Methods 0.000 abstract description 12
- 239000012535 impurity Substances 0.000 abstract description 7
- 239000013078 crystal Substances 0.000 abstract description 6
- 150000007524 organic acids Chemical class 0.000 abstract description 4
- FNAZKAPRBSUSHL-UHFFFAOYSA-N O.O.[Na].Nc1ccc(C(O)=O)c(O)c1 Chemical compound O.O.[Na].Nc1ccc(C(O)=O)c(O)c1 FNAZKAPRBSUSHL-UHFFFAOYSA-N 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- 159000000000 sodium salts Chemical class 0.000 abstract description 2
- 238000000967 suction filtration Methods 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 26
- 238000006243 chemical reaction Methods 0.000 description 21
- 239000000047 product Substances 0.000 description 18
- 238000007599 discharging Methods 0.000 description 11
- 239000012071 phase Substances 0.000 description 8
- 239000007788 liquid Substances 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 230000009286 beneficial effect Effects 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 239000012452 mother liquor Substances 0.000 description 4
- 239000008213 purified water Substances 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 150000001335 aliphatic alkanes Chemical class 0.000 description 3
- 229910052742 iron Inorganic materials 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- CWLKGDAVCFYWJK-UHFFFAOYSA-N 3-aminophenol Chemical compound NC1=CC=CC(O)=C1 CWLKGDAVCFYWJK-UHFFFAOYSA-N 0.000 description 2
- 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 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000003651 drinking water Substances 0.000 description 2
- 235000020188 drinking water Nutrition 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- -1 iron ions Chemical class 0.000 description 2
- 229960003350 isoniazid Drugs 0.000 description 2
- QRXWMOHMRWLFEY-UHFFFAOYSA-N isoniazide Chemical compound NNC(=O)C1=CC=NC=C1 QRXWMOHMRWLFEY-UHFFFAOYSA-N 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000004064 recycling Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 239000008215 water for injection Substances 0.000 description 2
- YUCTUWYCFFUCOR-UHFFFAOYSA-N 1,4-dihexoxy-1,4-dioxobutane-2-sulfonic acid;sodium Chemical compound [Na].CCCCCCOC(=O)CC(S(O)(=O)=O)C(=O)OCCCCCC YUCTUWYCFFUCOR-UHFFFAOYSA-N 0.000 description 1
- 229940018563 3-aminophenol Drugs 0.000 description 1
- QPCXTXXNVNTTQR-UHFFFAOYSA-N 3-phenylcyclohexa-3,5-diene-1,2-dione Chemical compound O=C1C(=O)C=CC=C1C1=CC=CC=C1 QPCXTXXNVNTTQR-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000002365 anti-tubercular Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 description 1
- 201000006674 extrapulmonary tuberculosis Diseases 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 208000008128 pulmonary tuberculosis Diseases 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Classifications
-
- 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
-
- 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
-
- 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
- C07C227/44—Stabilisation; Use of additives
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A method for preparing para-aminosalicylic acid, comprising: adding sodium para-aminosalicylate dihydrate to a mixed phase of water and an organic solvent, the organic solvent comprising a lower alcohol; and then adding an antioxidant and a complexing agent, stirring, adding an acid solution to adjust the pH value to 2.5-4.0, filtering, washing and drying. The preparation method of p-aminosalicylic acid takes p-aminosalicylic acid sodium dihydrate as a raw material, sodium salt is converted into organic acid by adding acid, water and a mixed organic solvent are taken as a solvent, so that the high-density crystal nodule and high-purity product can be generated, the suction filtration and drying time of the product is reduced, and the preparation efficiency of the product is improved; the p-aminosalicylic acid is prepared by a one-step method, the process steps are few, and the yield is high; heating is not needed in the whole process, and the amino salicylic acid is prevented from being heated and oxidized to generate impurities.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a preparation method of para-aminosalicylic acid.
Background
Paszidine, also known as isoniazid aminosalicylate, is used for the treatment of various pulmonary tuberculosis, endobronchial tuberculosis and extrapulmonary tuberculosis. The parazidine is an antituberculotic synthesized from para-aminosalicylic acid and isoniazid, and the para-aminosalicylic acid is an important intermediate for preparing the parazidine. In order to prepare p-aminosalicylic acid with high quality, the prior art generally prepares p-aminosalicylic acid and then refines the p-aminosalicylic acid.
Chinese patent CN104402749B neutralizes commercially available sodium p-aminosalicylate dihydrate with sulfuric acid to obtain p-aminosalicylic acid, and mixes the obtained p-aminosalicylic acid with organic solvent, refines and fully dissolves the p-aminosalicylic acid to obtain p-aminosalicylic acid. The organic solvent is preferably an ester solvent, or a combination of tetrahydrofuran and a chlorinated alkane solvent, or a combination of acetone and a chlorinated alkane solvent, or a combination of N, N-dimethylformamide and a chlorinated alkane solvent. Mixing p-aminosalicylic acid and an organic solvent, crystallizing by a temperature difference method, carrying out solid-liquid separation and drying to obtain the p-aminosalicylic acid with a new crystal form; wherein, the temperature difference crystallization needs to be heated and raised, the temperature of the reaction solution is controlled to be 50 +/-2 ℃, the temperature is reduced to-10 +/-2 ℃ after stirring, the solution is clear and filtered, and the solution is stirred and crystallized.
German patent DEM0028204 takes sodium p-aminosalicylate dihydrate as a starting material, dissolves the crystalline monosodium p-aminosalicylate dihydrate in distilled water, heats to 45 ℃, adds carbon, stirs and filters; adding isopropanol and adding a surfactant; adding formic acid while stirring, adjusting the pH value to 3.0-3.4, cooling, filtering, washing and vacuum drying.
It should be noted that the chemical properties of the para-aminosalicylic acid are unstable, and the para-aminosalicylic acid is sensitive to light, heat and oxygen, and when the temperature is higher than 40 ℃, the para-aminosalicylic acid is decarboxylated to generate m-aminophenol, and the para-aminosalicylic acid is further oxidized to generate a biphenyl quinone colored substance:
in the two patents, the preparation of the p-aminosalicylic acid needs heating, which can cause impurities to be generated, the purity of the p-aminosalicylic acid is reduced, the p-aminosalicylic acid can be prepared only by two or more steps, and the yield is reduced due to the increase of the steps.
Therefore, it is a technical problem to be solved in the art to provide a preparation method which has few process steps, does not need heating and can obtain high-purity p-aminosalicylic acid.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provide a preparation method of para-aminosalicylic acid.
The invention is realized by the following technical scheme: a method for preparing para-aminosalicylic acid, comprising:
adding sodium para-aminosalicylate dihydrate to a mixed phase of water and an organic solvent, the organic solvent comprising a lower alcohol; and adding an acid solution to adjust the pH value to 2.5-4.0, filtering, washing and drying.
Compared with the prior art, the preparation method of p-aminosalicylic acid takes p-aminosalicylic acid sodium dihydrate as a raw material, sodium salt is converted into organic acid by adding acid to generate a product, and simultaneously, low alcohol with high polarity is used as a solvent, so that the high-density crystal nodule product is favorably generated, and the drying and heating time is reduced; the p-aminosalicylic acid is prepared by a one-step method, the process steps are few, and the yield is high; heating is not needed in the whole process, and the amino salicylic acid is prevented from being heated and oxidized to generate impurities.
Further, the lower alcohol is selected from one or more of methanol, ethanol and isopropanol, and the lower alcohol with large polarity is used as a solvent to be beneficial to generating high-density crystal habit p-aminosalicylic acid.
Further, the organic solvent also includes esters. The organic solvent obtained by mixing the low-grade alcohol with large polarity and the ester with small polarity has a synergistic effect, so that the high-density crystal nodule product is favorably formed, the filtering and drying speed is improved, the drying and heating time is shortened, and the preparation of a high-purity product is favorably realized.
Further, the volume ratio of the lower alcohol to the esters in the organic solvent is (10-40): 1, the synergistic effect of the lower alcohol and the ester is favorably realized after the lower alcohol and the ester are mixed.
Furthermore, the esters are selected from one or more of ethyl acetate, methyl acetate, propyl acetate, methyl formate and ethyl formate, and esters with low polarity are selected as a solvent, so that organic impurities in the solution can be removed, and the purity is improved.
Furthermore, the preparation method of the p-aminosalicylic acid also comprises the step of adding an antioxidant and/or a complexing agent, which is beneficial to enhancing the stability of the product and improving the purity.
Further, the ratio of the volume of the organic solvent to the weight of the sodium p-aminosalicylate dihydrate is 1-22L: 1kg, is beneficial to generating a high-density crystal nodule product, is easy to dry, and has less impurities and high purity.
Further, the ratio of the volume of the water to the weight of the sodium p-aminosalicylate dihydrate is 2-10L: 1kg, which is beneficial to dissolving the sodium para-aminosalicylate dihydrate in water.
Further, the complexing agent is EDTA and is used for enabling impurities in the solution to generate a complex so as to be separated from a reaction system of the p-aminosalicylic acid.
Further, the antioxidant is selected from one of sodium sulfite, sodium bisulfite and cysteine, and is used for preventing para-aminosalicylic acid from being oxidized.
For a better understanding and practice, the present invention is described in detail below with reference to the following examples.
Detailed Description
The invention can prepare the p-aminosalicylic acid by a one-step method, can complete the preparation at room temperature, and obtains the p-aminosalicylic acid with high purity and high yield. The following examples are intended to illustrate the details.
Example 1
A method for preparing para-aminosalicylic acid, comprising:
adding sodium para-aminosalicylate dihydrate to a mixed phase of water and an organic solvent, the organic solvent comprising a lower alcohol; and adding an acid solution to adjust the pH value to 2.5-4.0, filtering, washing and drying.
Specifically, the method comprises the following steps: sodium para-aminosalicylate dihydrate is added to a mixed phase of water and an organic solvent, including a lower alcohol. Preferably, adding an antioxidant and a complexing agent into the mixed phase, and stirring for 10-30 min. The obtained system can be a solid-liquid coexisting system or a clear liquid phase, and does not need to be completely dissolved. Adding an acid solution to adjust the pH value to 2.5-4.0; filtering, washing and drying to obtain the p-aminosalicylic acid.
The method comprises the following specific steps:
respectively measuring water and organic solvent, and mixing.
Wherein the water can be selected from drinking water, purified water or water for injection, and is preferably purified water. Wherein the ratio of water to sodium p-aminosalicylate dihydrate is 2-10L: 1 kg.
The organic solvent is lower alcohol, and the lower alcohol is preferably one or more of methanol, ethanol and isopropanol. The ratio of the organic solvent to the sodium p-aminosalicylate dihydrate is 1-22L: 1kg, preferably 2-10L: 1 kg.
Adding an antioxidant, wherein the antioxidant can be one selected from sodium sulfite, sodium bisulfite and cysteine. Because the para-aminosalicylic acid is commonly used as an intermediate for preparing the drug, the stability of the para-aminosalicylic acid is crucial to the synthesis of the drug, and the para-aminosalicylic acid is easily oxidized by light, heat, oxygen and the like, so that an antioxidant is required to be added to prevent the para-aminosalicylic acid from being oxidized.
Adding a complexing agent, wherein the complexing agent can be EDTA. The p-aminosalicylic acid is commonly used as an intermediate for preparing the drug, the purity of the p-aminosalicylic acid is crucial to the synthesis of the drug, and the addition of the complexing agent can avoid the interference of metal ions, for example, iron ions in an iron container from factory production are combined with the complexing agent to generate a complex, so that the iron ions are separated from a reaction system.
And dropwise adding an acid solution after stirring until the pH value is 2.5-4.0, wherein the acid can be inorganic acid or organic acid.
Obtaining white precipitate, filtering, washing and drying to obtain the p-aminosalicylic acid.
The organic solvent can be continuously used as the solvent for recycling after being filtered, the product is filtered to obtain mother liquor, the mother liquor is distilled or fractionated to obtain the recovered organic solvent, and the recovered organic solvent can be used for preparing the next batch of products, so that the recovery cost of the solvent is reduced, and the pollution is reduced.
Example 2
The invention provides a preparation method of p-aminosalicylic acid, wherein the method of the embodiment 2 is basically the same as the method of the embodiment 1, and the differences mainly lie in the types of organic solvents and the proportions of different types of organic solvents in the organic solvents.
Adding sodium para-aminosalicylate dihydrate into a mixed phase of water and an organic solvent, wherein the organic solvent comprises a lower alcohol and an ester; and adding an acid solution to adjust the pH value to 2.5-4.0, filtering, washing and drying.
Specifically, the method comprises the following steps: sodium para-aminosalicylate dihydrate is added to a mixed phase of water and an organic solvent, including lower alcohols and esters. Preferably, adding an antioxidant and a complexing agent into the mixed phase, and stirring for 10-30 min. The obtained system can be a solid-liquid coexisting system or a clear liquid phase, and does not need to be completely dissolved. Adding an acid solution to adjust the pH value to 2.5-4.0; filtering, washing and drying to obtain the p-aminosalicylic acid.
The method comprises the following specific steps:
respectively measuring water and organic solvent, and mixing.
Wherein the water can be selected from drinking water, purified water or water for injection, and is preferably purified water. Wherein the ratio of water to sodium p-aminosalicylate dihydrate is 2-10L: 1 kg.
The organic solvent is lower alcohol and esters, and the lower alcohol is preferably one or more of methanol, ethanol and isopropanol; the esters are preferably selected from one or a mixture of any several of ethyl acetate, methyl acetate, propyl acetate, methyl formate or ethyl formate which are mixed in any proportion. In the organic solvent, the ratio of lower alcohol to ester is 10-40L: 1L of the compound. The ratio of the organic solvent to the sodium p-aminosalicylate dihydrate is 1-22L: 1kg, preferably 2-5L: 1 kg.
Adding an antioxidant and a complexing agent, wherein the antioxidant can be one selected from sodium sulfite, sodium bisulfite and cysteine; the complexing agent may be EDTA.
And dropwise adding an acid solution until the pH value is 2.5-4.0, wherein the acid can be inorganic acid or organic acid.
Obtaining white precipitate, filtering, washing and drying to obtain the p-aminosalicylic acid.
The organic solvent can be continuously used as the solvent for recycling after being filtered, the product is filtered to obtain mother liquor, the mother liquor is distilled or fractionated to obtain the recovered organic solvent, and the recovered organic solvent can be used for preparing the next batch of products, so that the recovery cost of the solvent is reduced, and the pollution is reduced.
Example 3
A clean reaction flask was charged with 200mL of water, 200mL of ethanol, and 20mL of ethyl acetate, stirred, and 100g of sodium p-aminosalicylate dihydrate, about 0.5g of EDTA, and about 0.5g of sodium sulfite were added and dissolved with stirring. And dropwise adding an acid solution, adjusting the pH value to 3.5, and stirring for 5-10 minutes. The pH was again measured and controlled to 3.0. Filtering, washing, filtering, drying to obtain the p-aminosalicylic acid, wherein the purity of the obtained p-aminosalicylic acid is 99.9 percent, and the yield is 95.2 percent.
Example 4
200mL of water, 200mL of recovered ethanol, and 10mL of recovered ethyl acetate were put into a clean reaction flask, stirred, and 100g of sodium p-aminosalicylate dihydrate, about 0.3g of EDTA, and about 0.5g of sodium sulfite were added and dissolved by stirring. And dropwise adding an acid solution, adjusting the pH value to 3.1, and stirring for 5-10 minutes. The pH was again measured and controlled to 3.1. Discharging, filtering, washing, filtering, drying to obtain the p-aminosalicylic acid, wherein the purity of the obtained p-aminosalicylic acid is 99.8 percent, and the yield is 94.9 percent.
Wherein, the ethanol recovery and the ethyl acetate recovery refer to the ethanol and the ethyl acetate recovered and utilized in the previous preparation of the sodium para-aminosalicylate.
Example 5
A clean reaction flask was charged with 300mL of water, 100m of methanol and 10mL of ethyl formate, stirred, charged with 100g of sodium p-aminosalicylate dihydrate and about 0.5g of sodium sulfite, and dissolved by stirring. And dropwise adding an acid solution, adjusting the pH value to 3.2, and stirring for 5-10 minutes. The pH was again measured and controlled to 2.8. Discharging, filtering, washing, filtering, drying to obtain the p-aminosalicylic acid, wherein the purity of the obtained p-aminosalicylic acid is 99.9 percent, and the yield is 95.6 percent.
Example 6
1000mL of water, 500mL of ethanol, and 50mL of ethyl acetate were put into a clean reaction flask, stirred, and 100g of sodium p-aminosalicylate dihydrate, about 0.3g of EDTA, and about 0.2g of sodium sulfite were added and dissolved by stirring. Dropwise adding an acid solution, adjusting the pH value to 3.0, stirring for 5-10 minutes, measuring the pH value again, and controlling the pH value to 2.5. Discharging, filtering, washing, filtering, drying to obtain the product with the purity of 99.2 percent and the yield of 93.2 percent.
Example 7
200mL of water, 500mL of ethanol and 12.5mL of ethyl acetate were put into a clean reaction flask, stirred, and 100g of sodium p-aminosalicylate dihydrate, about 0.5g of EDTA and about 0.3g of sodium sulfite were added and dissolved by stirring. Dropwise adding an acid solution, adjusting the pH value to 3.5, stirring for 5-10 minutes, measuring the pH value again, and controlling the pH value to 3.2. Discharging, filtering, washing, filtering, drying to obtain the product with the purity of 99.8 percent and the yield of 92.1 percent.
Example 8
1000mL of water, 2000mL of ethanol and 100mL of ethyl acetate were put into a clean reaction flask, stirred, and 100g of sodium p-aminosalicylate dihydrate, about 0.1g of EDTA and about 0.2g of sodium sulfite were added and dissolved by stirring. Dropwise adding an acid solution, adjusting the pH value to 3.3, stirring for 5-10 minutes, measuring the pH value again, and controlling the pH value to 3.1. Discharging, filtering, washing, filtering, drying to obtain the product with the purity of 99.5 percent and the yield of 91.6 percent.
Example 9
1000mL of water, 2000mL of ethanol, and 200mL of ethyl acetate were put into a clean reaction flask, stirred, and 100g of sodium p-aminosalicylate dihydrate, about 0.3g of EDTA, and about 0.2g of sodium sulfite were added and dissolved by stirring. Dropwise adding an acid solution, adjusting the pH value to 3.0, stirring for 5-10 minutes, measuring the pH value again, and controlling the pH value to 2.5. Discharging, filtering, washing, filtering, drying to obtain the product with the purity of 99.8 percent and the yield of 90.2 percent.
Example 10
400mL of water, 200mL of isopropyl alcohol, and 20mL of propyl acetate were put into a clean reaction flask, stirred, 100g of sodium p-aminosalicylate dihydrate and about 0.5g of EDTA were added, and dissolved by stirring. And dropwise adding an acid solution, adjusting the pH value to 4.0, and stirring for 5-10 minutes. The pH was again measured and controlled to 4.0. Discharging, filtering, washing, filtering, drying to obtain the p-aminosalicylic acid, wherein the purity of the obtained p-aminosalicylic acid is 99.8 percent, and the yield is 95.1 percent.
Example 11
300L of water and 100L of methanol were put into a clean reaction flask, stirred, and 100kg of sodium p-aminosalicylate dihydrate, about 0.5kg of EDTA, and about 0.5kg of sodium sulfite were put into the flask, and stirred. And dropwise adding an acid solution, adjusting the pH value to 3.2, and stirring for 5-10 minutes. The pH was re-measured and controlled at 2.8. Discharging, filtering, washing, filtering, drying to obtain the product with the purity of 99.93 percent and the yield of 95.6 percent.
Example 12
200L of water and 200L of ethanol were added to a clean reaction flask, followed by stirring, 100kg of sodium p-aminosalicylate dihydrate and about 0.5kg of sodium sulfite were added, and the mixture was stirred. And dropwise adding an acid solution, adjusting the pH value to 3.5, and stirring for 5-10 minutes. The pH was re-measured and controlled at 3.0. Discharging, filtering, washing, filtering, drying to obtain the product with the purity of 99.91 percent and the yield of 95.2 percent.
Example 13
400mL of water, 200mL of isopropyl alcohol, and 20mL of propyl acetate were put into a clean reaction flask, stirred, and 100g of sodium p-aminosalicylate dihydrate was added and dissolved with stirring. And dropwise adding an acid solution, adjusting the pH value to 4.0, and stirring for 5-10 minutes. The pH was again measured and controlled to 4.0. Discharging, filtering, washing, filtering, drying to obtain the p-aminosalicylic acid, wherein the purity of the obtained p-aminosalicylic acid is 99.3 percent, and the yield is 93.9 percent.
Example 14
200L of water and 200L of ethanol were added to a clean reaction flask, followed by stirring, 100kg of sodium p-aminosalicylate dihydrate was added thereto, and the mixture was stirred. And dropwise adding an acid solution, adjusting the pH value to 3.5, and stirring for 5-10 minutes. The pH was re-measured and controlled at 3.0. Discharging, filtering, washing, filtering, drying to obtain the product with the purity of 99.24 percent and the yield of 94.8 percent.
Comparative example 1
The p-aminosalicylic acid is prepared according to Chinese patent CN104402749B, and the method comprises the following specific steps:
adding 100g of sodium p-aminosalicylate dihydrate into a clean reaction bottle, neutralizing with sulfuric acid to obtain p-aminosalicylic acid, drying for later use, wherein the purity is 95.6 percent, and the yield is 94.8 percent;
adding 250ml of ethyl acetate into a clean reaction bottle, stirring, protecting a reaction system with nitrogen, adding 56g of p-aminosalicylic acid, heating, controlling the temperature of the reaction solution to be 50 +/-2 ℃, and stirring the solution to be clear. Filtering, cooling to-10 + -2 deg.C, stirring for 8 hr, filtering, and drying to obtain final product with purity of 99.3% and yield of 86.1%; the overall yield of the two steps is 82.3%.
Comparative example 2
The preparation of para-aminosalicylic acid according to German patent DEM0028204 comprises the following steps:
adding 250mL of water into a clean reaction bottle, stirring, adding 138g of sodium p-aminosalicylate dihydrate and 1g of activated carbon, heating to 45 ℃, stirring for 15 minutes, and filtering the activated carbon to obtain water-phase feed liquid. Adding 50mL of isopropanol and 0.5 g of surfactant (dihexyl sulfosuccinate sodium) into the aqueous phase feed liquid, controlling the temperature of the aqueous phase feed liquid to 25 ℃, slowly adding 95mL of 85% formic acid, stirring, crystallizing, filtering, and drying to obtain the p-aminosalicylic acid with the purity of 98.2% and the yield of 91.3%.
TABLE 1 comparison of preparation methods for para-aminosalicylic acid
Table 1 is a comparison of the preparation of four para-aminosalicylic acids. As can be seen from table 1, the prior art generally requires a two-step preparation process, and the preparation process requires heating, which is not favorable for improving purity and stabilizing the product, and impurities are generated in the heating process of the aminosalicylic acid; the method can prepare the p-aminosalicylic acid with the purity of 99.9% in one step, the whole process is finished at room temperature without heating, the p-aminosalicylic acid is prevented from being oxidized when the temperature is increased, the p-aminosalicylic acid with high purity and high yield is obtained, and the organic solvent can be recovered.
The preparation method of p-aminosalicylic acid provided by the invention can be applied to the preparation of p-aminosalicylic acid in the production of a medicine, namely, paszidine. Compared with the prior art, the invention takes the lower alcohol and the esters as the solvent, or takes the lower alcohol as the solvent, prepares the p-aminosalicylic acid by one step, can complete the reaction at room temperature, does not need heating, avoids the p-aminosalicylic acid from being oxidized when the temperature is raised, has less process steps, is simple to operate, and obtains the p-aminosalicylic acid with high purity and high yield.
The present invention is not limited to the above-described embodiments, and various modifications and variations of the present invention are intended to be included within the scope of the claims and the equivalent technology of the present invention if they do not depart from the spirit and scope of the present invention.
Claims (10)
1. A preparation method of p-aminosalicylic acid is characterized by comprising the following steps: adding sodium para-aminosalicylate dihydrate to a mixed phase of water and an organic solvent, the organic solvent comprising a lower alcohol; and adding an acid solution to adjust the pH value to 2.5-4.0, filtering, washing and drying.
2. The process for producing para-aminosalicylic acid as claimed in claim 1, wherein: the lower alcohol is selected from one or more of methanol, ethanol and isopropanol.
3. The process for producing para-aminosalicylic acid as claimed in claim 2, wherein: the organic solvent also includes esters.
4. The process for producing para-aminosalicylic acid as claimed in claim 3, wherein: in the organic solvent, the volume ratio of the lower alcohol to the esters is (10-40): 1.
5. the process for producing para-aminosalicylic acid as claimed in claim 4, wherein: the esters are selected from one or more of ethyl acetate, methyl acetate, propyl acetate, methyl formate and ethyl formate.
6. The process for producing para-aminosalicylic acid as claimed in claim 5, wherein: the preparation method of the p-aminosalicylic acid also comprises the step of adding an antioxidant and/or a complexing agent.
7. The process for producing para-aminosalicylic acid as claimed in any one of claims 1 to 6, wherein: the ratio of the volume of the organic solvent to the weight of the sodium p-aminosalicylate dihydrate is 1-22L: 1 kg.
8. The process for producing para-aminosalicylic acid as claimed in claim 7, wherein: the ratio of the volume of the water to the weight of the sodium p-aminosalicylate dihydrate is 2-10L: 1 kg.
9. The process for producing para-aminosalicylic acid as claimed in claim 8, wherein: the complexing agent is EDTA.
10. The process for producing para-aminosalicylic acid as claimed in claim 9, wherein: the antioxidant is selected from one of sodium sulfite, sodium bisulfite and cysteine.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB786917A (en) * | 1954-09-13 | 1957-11-27 | Miles Lab | Para-aminosalicylic acids |
| CN1526700A (en) * | 2003-03-03 | 2004-09-08 | 鲁南制药股份有限公司 | Synthesis of Important intermediate for mosapride citrate |
| CN102344412A (en) * | 2010-07-30 | 2012-02-08 | 重庆华邦胜凯制药有限公司 | Preparation method of isoniazid para-aminosalicylate |
-
2020
- 2020-07-15 CN CN202010680904.9A patent/CN111848432A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB786917A (en) * | 1954-09-13 | 1957-11-27 | Miles Lab | Para-aminosalicylic acids |
| CN1526700A (en) * | 2003-03-03 | 2004-09-08 | 鲁南制药股份有限公司 | Synthesis of Important intermediate for mosapride citrate |
| CN102344412A (en) * | 2010-07-30 | 2012-02-08 | 重庆华邦胜凯制药有限公司 | Preparation method of isoniazid para-aminosalicylate |
Non-Patent Citations (5)
| Title |
|---|
| SURYANARAYAN CHERUKUVADA ET AL.: "4‑Aminosalicylic Acid Adducts", 《CRYSTAL GROWTH & DESIGN》 * |
| 刘世任 主编: "《药剂学知识新编》", 30 November 2016, 西安交通大学出版社 * |
| 刘国杰 主编: "《药剂学(第二版)》", 31 May 1985, 人民卫生出版社 * |
| 常忆凌 主编: "《药剂学》", 30 June 2008, 中国医药科技出版社 * |
| 邵伟 等: "对氨基水杨酸缓释微丸的制备和溶出曲线对比", 《山东化工》 * |
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