CN116003274A - Method for synthesizing catalyst-free 5-aminosalicylic acid - Google Patents
Method for synthesizing catalyst-free 5-aminosalicylic acid Download PDFInfo
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- CN116003274A CN116003274A CN202211721610.1A CN202211721610A CN116003274A CN 116003274 A CN116003274 A CN 116003274A CN 202211721610 A CN202211721610 A CN 202211721610A CN 116003274 A CN116003274 A CN 116003274A
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- aminosalicylic acid
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- hydrazine hydrate
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- KBOPZPXVLCULAV-UHFFFAOYSA-N mesalamine Chemical compound NC1=CC=C(O)C(C(O)=O)=C1 KBOPZPXVLCULAV-UHFFFAOYSA-N 0.000 title claims abstract description 33
- 229960004963 mesalazine Drugs 0.000 title claims abstract description 33
- 238000000034 method Methods 0.000 title claims abstract description 26
- 230000002194 synthesizing effect Effects 0.000 title claims description 11
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims abstract description 19
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims abstract description 19
- JHDYSXXPQIFFJZ-UHFFFAOYSA-N chembl1834961 Chemical compound C1=C(O)C(C(=O)O)=CC(N=NC=2C=CC=CC=2)=C1 JHDYSXXPQIFFJZ-UHFFFAOYSA-N 0.000 claims abstract description 17
- 238000006243 chemical reaction Methods 0.000 claims abstract description 16
- 238000001308 synthesis method Methods 0.000 claims abstract description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 239000002994 raw material Substances 0.000 claims description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 239000007810 chemical reaction solvent Substances 0.000 claims description 4
- 239000003638 chemical reducing agent Substances 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N Salicylic acid Natural products OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 abstract description 9
- 239000003054 catalyst Substances 0.000 abstract description 9
- 238000009776 industrial production Methods 0.000 abstract description 7
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 abstract description 6
- 229960004889 salicylic acid Drugs 0.000 abstract description 6
- 238000006396 nitration reaction Methods 0.000 abstract description 5
- 238000011282 treatment Methods 0.000 abstract description 5
- -1 benzene azo salicylic acid Chemical compound 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 238000000746 purification Methods 0.000 abstract description 4
- 229910052751 metal Inorganic materials 0.000 abstract description 3
- 239000002184 metal Substances 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 230000007613 environmental effect Effects 0.000 abstract description 2
- 229910001385 heavy metal Inorganic materials 0.000 abstract description 2
- 238000011084 recovery Methods 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- 239000002699 waste material Substances 0.000 abstract description 2
- 238000010438 heat treatment Methods 0.000 description 13
- 238000003756 stirring Methods 0.000 description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 5
- 239000012467 final product Substances 0.000 description 5
- 238000006722 reduction reaction Methods 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 206010009900 Colitis ulcerative Diseases 0.000 description 2
- 201000006704 Ulcerative Colitis Diseases 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 239000000975 dye Substances 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 230000000968 intestinal effect Effects 0.000 description 2
- 239000004973 liquid crystal related substance Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- XVMIKRZPDSXBTP-UHFFFAOYSA-N 1,3-dibromobutan-2-one Chemical compound CC(Br)C(=O)CBr XVMIKRZPDSXBTP-UHFFFAOYSA-N 0.000 description 1
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000003699 antiulcer agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000002983 circular dichroism Methods 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 238000006193 diazotization reaction Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000005227 gel permeation chromatography Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 210000002429 large intestine Anatomy 0.000 description 1
- 150000002617 leukotrienes Chemical class 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000011418 maintenance treatment Methods 0.000 description 1
- 238000001840 matrix-assisted laser desorption--ionisation time-of-flight mass spectrometry Methods 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
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Abstract
The invention belongs to the technical field of chemical medicines, and particularly relates to a catalyst-free synthesis method of 5-aminosalicylic acid. The invention provides a method for preparing 5-aminosalicylic acid by reducing phenylazo salicylic acid without a catalyst, which has the advantages of low cost, high yield, environmental friendliness and suitability for large-scale industrial production. Compared with the traditional nitration reduction method, the method for directly reducing the phenylazo salicylic acid by using hydrazine hydrate without a catalyst has the advantages of high selectivity, high yield and simple and convenient post-treatment and purification; compared with the conventional benzene azo salicylic acid reduction method in the current industrial production, the method does not need to use an expensive metal catalyst, avoids the problems of heavy metal residue risk, catalyst recovery treatment and the like, reduces the generation of three wastes, is more environment-friendly, reduces the production cost, performs normal-pressure reaction, and reduces the requirements of reaction equipment, thereby being suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of chemical medicines, and particularly relates to a catalyst-free synthesis method of 5-aminosalicylic acid.
Background
5-aminosalicylic acid is an important pharmaceutical and dye intermediate. 5-aminosalicylic acid is used as antiulcer agent, and has antiinflammatory effect on colon and large intestine, and is mainly used for treating acute episode and remission stage of mild and moderate ulcerative colitis, and long-term maintenance treatment of ulcerative colitis; by acting on intestinal inflammatory mucosa, inhibiting prostaglandin synthesis and formation of inflammatory mediator leukotriene, which cause inflammation, thereby having remarkable anti-inflammatory effect on intestinal wall; the 5-aminosalicylic acid can perform various reactions due to three active reactive groups of amino, hydroxyl and carboxyl on the ring, and can be used for preparing various active dyes with excellent quality.
The current industrialized production methods of 5-aminosalicylic acid mainly comprise two methods:
1. salicylic acid nitration reduction method: the process for preparing 5-nitro salicylic acid by using salicylic acid as a starting material through nitration reaction and then reducing to obtain 5-amino salicylic acid has poor nitration reaction selectivity, complicated post-treatment, separation and purification and low yield.
2. Benzene azo salicylic acid reduction method: the common method for industrial production mainly uses aniline as a starting material, diazotization is carried out, then the aniline is coupled with salicylic acid, and the prepared phenylazo salicylic acid is hydrogenated or hydrazine hydrate is reduced under the action of a metal catalyst.
Disclosure of Invention
The invention provides a method for preparing 5-aminosalicylic acid by reducing phenylazo salicylic acid without a catalyst, which has the advantages of low cost, high yield, environmental friendliness and suitability for large-scale industrial production.
The technical scheme adopted by the invention is as follows:
and (3) carrying out reduction reaction on the phenylazosalicylic acid (I) and hydrazine hydrate in a reaction solvent at a certain temperature to obtain the 5-aminosalicylic acid (II).
Wherein, the liquid crystal display device comprises a liquid crystal display device,
the molar ratio of the phenylazosalicylic acid to the hydrazine hydrate serving as the reaction raw material is 1 (1-10), preferably 1: (2-5), further preferably 1:4.
the solvent is any one or mixture of more than one of water, ethanol, methanol, tetrahydrofuran, toluene, acetonitrile and ethyl acetate, and ethanol is preferred.
The reaction temperature of the reaction is 60-120 ℃, preferably 80 ℃.
The reducing agent is hydrazine hydrate (50% -100%), preferably 85% -100%.
The pH is 2-12, preferably pH 8.
The reaction time is 2 to 8 hours, preferably 6 hours.
The end products prepared in the present invention may be purified by purification methods including, but not limited to, extraction, recrystallization, precipitation, distillation, dialysis, or tangential flow permeation. Characterization of the structure, molecular weight, etc. of the final product can be confirmed by characterization methods including, but not limited to, nuclear magnetism, electrophoresis, ultraviolet-visible spectrophotometry, FTIR, AFM, GPC, HPLC, MALDI-TOF, circular dichroism, etc. The structure is preferably that of 1 HNMR confirms that its molecular weight is preferably confirmed by LC-MS (ESI).
Compared with the prior art, the invention has the following beneficial effects:
compared with the traditional nitration reduction method, the method for directly reducing the phenylazo salicylic acid by using hydrazine hydrate without a catalyst has the advantages of high selectivity, high yield and simple and convenient post-treatment and purification; compared with the conventional benzene azo salicylic acid reduction method in the current industrial production, the method does not need to use an expensive metal catalyst, avoids the problems of heavy metal residue risk, catalyst recovery treatment and the like, reduces the generation of three wastes, is more environment-friendly, reduces the production cost, performs normal-pressure reaction, and reduces the requirements of reaction equipment, thereby being suitable for industrial production.
Drawings
Fig. 1: structural formula of final product 5-aminosalicylic acid
Fig. 2: HPLC profile of the final product 5-aminosalicylic acid
Fig. 3: final product 5-aminosalicylic acid 13 CNMR spectra
Fig. 4: final product 5-aminosalicylic acid 1 HNMR spectrogram
Detailed Description
Example 1
To a 50ml three-necked flask, phenylazosalicylic acid (10.0 g), ethanol (12.7 ml) and 85% hydrazine hydrate (4.16 g) were sequentially added, the temperature was raised to 45 ℃ and then 85% hydrazine hydrate (4.16 g) was added dropwise, after the completion of the dropwise addition, the temperature was raised to 80 ℃ and the reaction was carried out for 8 hours, 15ml of water was added, the aniline was distilled off under reduced pressure at 80-90 ℃ and activated carbon was added, the pH was adjusted to 2.5-3 by heating and decolorizing hydrochloric acid with stirring, the temperature was lowered, the stirring and suction filtration were carried out, and 5-aminosalicylic acid (5.40 g yield 85.44%) was obtained. 1 HNMR(400MHz,DMSO)δ7.37(s,1H),7.36(s,1H),7.02(d,J＝2.8Hz,1H),7.00(d,J＝2.8Hz,1H),6.75(s,1H),6.73(s,1H). 13 CNMR(400MHz,DMSO)δ171.933,156.668,131.993,124.700,118.673,117.206,115.922.HPLC:>95％purity.
Example 2
Adding phenylazosalicylic acid (10.0 g), ethyl acetate (11.1 ml) and hydrazine hydrate (4.16 g) dropwise after heating to 45 ℃ into a 50ml three-port bottle, heating to 80 ℃ after the dropwise addition, reacting for 8 hours, adding 15ml of water, distilling at 80-90 ℃ under reduced pressure, adding active carbon, heating, stirring, decoloring, adjusting the PH to 2.5-3, cooling, stirring, and suction filtering to obtain 5-aminosalicylic acid (5.22 g yield 82.59%)
Example 3
Adding phenylazosalicylic acid (10.0 g), ethanol (12.7 ml) and hydrazine hydrate (6.24 g) dropwise after heating to 45 ℃ into a 50ml three-port bottle, heating to 80 ℃ after the dropwise addition, reacting for 8 hours, adding 15ml of water, distilling at 80-90 ℃ under reduced pressure, adding active carbon, heating, stirring, decoloring, adjusting the PH to 2.5-3, cooling, stirring, and suction filtering to obtain 5-aminosalicylic acid (5.69 g yield 90.13%)
Example 4
Adding phenylazosalicylic acid (10.0 g), ethanol (12.7 ml) and hydrazine hydrate (6.24 g) dropwise after heating to 45 ℃ into a 50ml three-port bottle, heating to 80 ℃ after the dropwise addition, reacting for 6 hours, adding 15ml of water, distilling at 80-90 ℃ under reduced pressure, adding active carbon, heating, stirring, decoloring, adjusting the PH to 2.5-3, cooling, stirring, and suction filtering to obtain 5-aminosalicylic acid (5.34 g yield 84.49%)
Example 5
Adding phenylazosalicylic acid (10.0 g), ethanol (12.7 ml) and hydrazine hydrate (8.32 g) dropwise after heating to 45 ℃ into a 50ml three-port bottle, heating to 95 ℃ after the dropwise addition, reacting for 8 hours, adding 15ml of water, distilling at 80-90 ℃ under reduced pressure, adding active carbon, heating, stirring, decoloring, adjusting the PH to 2.5-3, cooling, stirring, and suction filtering to obtain 5-aminosalicylic acid (5.83 g yield 92.24%)
Example 6
To a 500ml three-necked flask were added phenylazosalicylic acid (100.0 g), ethanol (120.7 ml) and hydrazine hydrate (83.2 g) dropwise added at 45℃and heated to 95℃after the completion of the dropwise addition, and after the completion of the dropwise addition, 15ml of water was added, the mixture was reacted for 6 hours, and distilled under reduced pressure at 80-90℃with active carbon, and then heated, stirred and decolorized hydrochloric acid was added to adjust the pH to 2.5-3, cooled, stirred and suction filtered to obtain 5-aminosalicylic acid (59.23 g yield 93.71%).
Claims (10)
1. A catalyst-free synthesis method of 5-aminosalicylic acid, which uses phenylazosalicylic acid as initial raw material and hydrazine hydrate as reducer, reacts in reaction solvent to obtain 5-aminosalicylic acid
2. The method for synthesizing 5-aminosalicylic acid according to claim 1, wherein the molar ratio of the phenylazosalicylic acid serving as the reaction raw material to hydrazine hydrate is 1:1-10, and the reducing agent is 50% -100% of hydrazine hydrate.
3. The method for synthesizing 5-aminosalicylic acid according to claim 2, wherein the molar ratio of the phenylazosalicylic acid serving as the reaction raw material to the hydrazine hydrate is 1:2-5, and the reducing agent is 85% -100% of the hydrazine hydrate.
4. The method for synthesizing 5-aminosalicylic acid according to claim 3, wherein the molar ratio of the reaction raw material phenylazosalicylic acid to hydrazine hydrate is 1:4.
5. the method for synthesizing 5-aminosalicylic acid according to claim 1, wherein the reaction solvent is any one or a mixture of a plurality of water, ethanol, methanol, tetrahydrofuran, toluene, acetonitrile and ethyl acetate in any proportion.
6. The method for synthesizing 5-aminosalicylic acid according to claim 5, wherein the reaction solvent is ethanol.
7. The method for synthesizing 5-aminosalicylic acid according to claim 1, wherein the reaction temperature of the reaction is 60 to 120 ℃.
8. The method for synthesizing 5-aminosalicylic acid according to claim 7, wherein the reaction temperature of the reaction is 80 ℃.
9. The method for synthesizing 5-aminosalicylic acid according to claim 1, wherein the pH is 2-12 and the reaction time is 2-8 hours.
10. The method for synthesizing 5-aminosalicylic acid according to claim 9, wherein the PH is 8 and the reaction time is 6 hours.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202211721610.1A CN116003274A (en) | 2022-12-30 | 2022-12-30 | Method for synthesizing catalyst-free 5-aminosalicylic acid |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4001266A (en) * | 1973-11-27 | 1977-01-04 | Ciba-Geigy Corporation | Process for the manufacture of 2-(2-hydroxyphenyl)benztriazoles |
| CN1215720A (en) * | 1998-09-02 | 1999-05-05 | 华东理工大学 | Process for production of 3,5-dimethyl aniline |
| CN103508904A (en) * | 2013-10-24 | 2014-01-15 | 滨海白云化工有限公司 | Preparation method for 5-chloro-2-methyl-1,4-phenylenediamine |
| CN107382855A (en) * | 2017-06-28 | 2017-11-24 | 浙江荣耀生物科技股份有限公司 | A kind of synthetic method of deccox |
-
2022
- 2022-12-30 CN CN202211721610.1A patent/CN116003274A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4001266A (en) * | 1973-11-27 | 1977-01-04 | Ciba-Geigy Corporation | Process for the manufacture of 2-(2-hydroxyphenyl)benztriazoles |
| CN1215720A (en) * | 1998-09-02 | 1999-05-05 | 华东理工大学 | Process for production of 3,5-dimethyl aniline |
| CN103508904A (en) * | 2013-10-24 | 2014-01-15 | 滨海白云化工有限公司 | Preparation method for 5-chloro-2-methyl-1,4-phenylenediamine |
| CN107382855A (en) * | 2017-06-28 | 2017-11-24 | 浙江荣耀生物科技股份有限公司 | A kind of synthetic method of deccox |
Non-Patent Citations (2)
| Title |
|---|
| M. A. PASHA等: ""Uncatalyzed Reductive Fission of Azoarenes to Aminoarene(s) by Hydrazine Hydrate"", 《SYNTHETIC COMMUNICATIONS》, vol. 35, no. 7, 21 August 2006 (2006-08-21), pages 898 - 899 * |
| 戴国华, 费炜, 徐子鹏: "马沙拉嗪的催化转移氢化还原法合成", 《中国医药工业杂志》, vol. 29, no. 10, 21 October 1998 (1998-10-21), pages 443 * |
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