CN114315651A - Preparation method of p-guanidinobenzoic acid hydrochloride - Google Patents
Preparation method of p-guanidinobenzoic acid hydrochloride Download PDFInfo
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- CN114315651A CN114315651A CN202111637339.9A CN202111637339A CN114315651A CN 114315651 A CN114315651 A CN 114315651A CN 202111637339 A CN202111637339 A CN 202111637339A CN 114315651 A CN114315651 A CN 114315651A
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- acid hydrochloride
- hydrochloride
- guanidinobenzoic acid
- preparation
- reaction
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- YETFLAUJROGBMC-UHFFFAOYSA-N (4-carboxyphenyl)-(diaminomethylidene)azanium;chloride Chemical compound Cl.NC(N)=NC1=CC=C(C(O)=O)C=C1 YETFLAUJROGBMC-UHFFFAOYSA-N 0.000 title claims abstract description 30
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 29
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 claims abstract description 26
- -1 pyrazole formamidine hydrochloride Chemical compound 0.000 claims abstract description 13
- 238000010992 reflux Methods 0.000 claims abstract description 13
- 229960004050 aminobenzoic acid Drugs 0.000 claims abstract description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 45
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 4
- 238000009776 industrial production Methods 0.000 abstract description 6
- 239000002994 raw material Substances 0.000 abstract description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- 238000012565 NMR experiment Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- KBCPMQUSOLSAQO-UHFFFAOYSA-N (4-carboxyphenyl)azanium;chloride Chemical compound Cl.NC1=CC=C(C(O)=O)C=C1 KBCPMQUSOLSAQO-UHFFFAOYSA-N 0.000 description 1
- GWEATQMXNIFWCP-UHFFFAOYSA-N 1H-pyrazole-5-carboximidamide hydrochloride Chemical compound Cl.NC(=N)C=1C=CNN=1 GWEATQMXNIFWCP-UHFFFAOYSA-N 0.000 description 1
- 208000009663 Acute Necrotizing Pancreatitis Diseases 0.000 description 1
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 description 1
- 206010033645 Pancreatitis Diseases 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 201000003229 acute pancreatitis Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- XASIMHXSUQUHLV-UHFFFAOYSA-N camostat Chemical compound C1=CC(CC(=O)OCC(=O)N(C)C)=CC=C1OC(=O)C1=CC=C(N=C(N)N)C=C1 XASIMHXSUQUHLV-UHFFFAOYSA-N 0.000 description 1
- 229960000772 camostat Drugs 0.000 description 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- MQQNFDZXWVTQEH-UHFFFAOYSA-N nafamostat Chemical compound C1=CC(N=C(N)N)=CC=C1C(=O)OC1=CC=C(C=C(C=C2)C(N)=N)C2=C1 MQQNFDZXWVTQEH-UHFFFAOYSA-N 0.000 description 1
- 229950009865 nafamostat Drugs 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a preparation method of p-guanidinobenzoic acid hydrochloride, which comprises the following steps: and carrying out reflux reaction on p-aminobenzoic acid and pyrazole formamidine hydrochloride to generate the p-guanidinobenzoic acid hydrochloride. The preparation method provided by the embodiment of the invention comprises the following steps: short route, high safety of raw materials, strong experimental operability and suitability for industrial production.
Description
Technical Field
The invention relates to the technical field of chemical synthesis, in particular to a preparation method of p-guanidinobenzoic acid hydrochloride.
Background
The p-guanidinobenzoic acid hydrochloride is an important drug intermediate, is used for synthesizing non-peptide protease inhibitors, such as anti-pancreatitis drugs of camostat, nafamostat and the like, and is mainly used for treating acute necrotizing pancreatitis.
At present, the preparation method of p-guanidinobenzoic acid hydrochloride comprises the following steps:
firstly, isocyanate and methyl iodide are adopted, however, the post-treatment of the route is complicated, and the danger of using raw materials is high;
secondly, a cyanamide method, however, the method is difficult to treat three wastes and is not environment-friendly;
and thirdly, a thiourea and peracetic acid method has a larger risk due to the use of a strong oxidant.
The three routes have great limitations in industrial production, and a preparation method which is short in synthesis route, high in raw material safety, strong in experimental operability and suitable for industrial production needs to be provided urgently.
Disclosure of Invention
In view of this, the preparation method of p-guanidinobenzoic acid hydrochloride provided by the invention has the advantages of short reaction steps, high raw material safety, strong experiment operability and suitability for industrial production.
In order to solve the technical problems, the invention adopts the following technical scheme:
the preparation method of p-guanidinobenzoic acid hydrochloride according to the embodiment of the invention comprises the following steps:
and carrying out reflux reaction on p-aminobenzoic acid and pyrazole formamidine hydrochloride to generate the p-guanidinobenzoic acid hydrochloride.
Further, the molar ratio of p-aminobenzoic acid to pyrazole formamidine hydrochloride is 1: (0.8-1.5).
Preferably, the molar ratio of p-aminobenzoic acid to pyrazole formamidine hydrochloride is 1: 1.2.
Further, the solvent used in the reflux reaction is any one of acetonitrile, toluene, dichloromethane, acetone and chlorobenzene.
Further, the solvent is acetonitrile, the reaction temperature is 70-90 ℃, and the reaction time is 2-6 hours.
Preferably, the reaction temperature is about 80-85 ℃ and the reaction time is 3-4 hours.
Further, after the reflux reaction was completed, the solvent was distilled off under reduced pressure, and water was added thereto to precipitate the p-guanidinobenzoic acid hydrochloride.
Further, the p-guanidinobenzoic acid hydrochloride is washed by water and dried to refine the p-guanidinobenzoic acid hydrochloride.
The technical scheme of the invention at least has one of the following beneficial effects:
the preparation method provided by the embodiment of the invention comprises the following steps: short route, high safety of raw materials, strong experimental operability and suitability for industrial production.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. It is to be understood that the embodiments described are only a few embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the described embodiments of the invention, are within the scope of the invention.
The preparation method of p-guanidinobenzoic acid hydrochloride according to an embodiment of the present invention will be described first in detail.
The preparation method of p-guanidinobenzoic acid hydrochloride according to the embodiment of the invention comprises the following steps:
and carrying out reflux reaction on p-aminobenzoic acid and pyrazole formamidine hydrochloride to generate the p-guanidinobenzoic acid hydrochloride.
That is, the method for preparing p-guanidinobenzoic acid hydrochloride of the present invention selects p-aminobenzoic acid and pyrazole formamidine hydrochloride as raw materials, and generates reflux reaction to the p-aminobenzoic acid hydrochloride.
The specific reaction process is shown as the following formula:
the molar ratio of p-aminobenzoic acid to pyrazole formamidine hydrochloride can be set to, for example, 1: (0.8-1.5). Among them, it is preferable to use an excess amount of pyrazole carboxamidine hydrochloride to promote the reaction and increase the yield. Preferably, the molar ratio of p-aminobenzoic acid to pyrazole formamidine hydrochloride is 1: 1.2.
The solvent used in the reflux reaction may be, for example, any one of acetonitrile, toluene, dichloromethane, acetone, and chlorobenzene. Among them, acetonitrile is preferred because of its high chemical stability, being not easily oxidized and reduced, and being infinitely miscible with water and the like and being easily removed.
Further, the solvent is acetonitrile, the reaction temperature is set to 70 to 90 ℃ and the reaction time is set to 2 to 6 hours, for example. That is, when acetonitrile is used as a reflux solvent, the reaction temperature can be set to about the boiling point of acetonitrile, and the reaction temperature is not high and operability is high.
Further, after the reflux reaction was completed, the solvent was distilled off under reduced pressure, and water was added thereto to precipitate the p-guanidinobenzoic acid hydrochloride.
Further, the p-guanidinobenzoic acid hydrochloride is washed by water and dried to refine the p-guanidinobenzoic acid hydrochloride. That is, after precipitating by adding water, the precipitated p-guanidinobenzoic acid hydrochloride is washed with water and dried to be refined.
The method for producing p-guanidinobenzoic acid hydrochloride of the present invention is further illustrated by the following specific examples.
Example 1:
a250 mL reaction flask was charged with P-aminobenzoic acid (30g, 0.219mol, 1.0eq) and pyrazole formamidine hydrochloride (38.48g, 0.263mol, 1.2eq) and acetonitrile (90mL, 3P), heated to 82 ℃ and refluxed for 3 hours to complete the reaction.
The reaction solution was concentrated to remove acetonitrile by evaporation, 90mL of water was added, the mixture was stirred to precipitate a solid, the filtrate was filtered, the filter cake was washed once with water, the filter cake was collected and air-dried at 70 ℃ to obtain 42.27g of p-guanidinobenzoic acid hydrochloride with a yield of 89.5%.
The reactants were subjected to nmr experiments to confirm the product structure, and the data are as follows:
1H NMR (model: AVANCE III HD 400M, CDCl3, 400MHz) with a delta of 12.98(s, 1H), 10.51(s, 1H), 7.98-7.96(d, 2H), 7.82(s, 4H), 7.34-7.32(d, 2H), and the results were consistent with the structure.
Example 2:
A1L reaction flask was charged with P-aminobenzoic acid (182g, 1.327mol, 1.0eq) and pyrazole formamidine hydrochloride (233.43g, 1.593mol, 1.2eq) and acetonitrile (550mL, 3P), and the reaction was completed by heating to 82 ℃ and refluxing for 3 hours.
The reaction solution was concentrated to remove acetonitrile, 550mL of water was added, the mixture was stirred to precipitate a solid, the filtrate was filtered, the filter cake was washed with water once, the filter cake was collected and air-dried at 70 ℃ to obtain 261.26g of p-guanidinobenzoic acid hydrochloride with a yield of 91.3%.
The reactants were subjected to nmr experiments to confirm the product structure, and the data are as follows:
1H NMR (model: AVANCE III HD 400M, CDCl3, 400MHz): delta-12.98 (s, 1H), 10.50(s, 1H), 7.99-7.96(d, 2H), 7.82(s, 4H), 7.34-7.32(d, 2H), and the results were consistent with the structure.
Example 3:
A5L reaction flask was charged with P-aminobenzoic acid (1kg, 7.29mol, 1.0eq) and pyrazole formamidine hydrochloride (1.28g, 8.75mol, 1.2eq) and acetonitrile (3L, 3P), heated to 82 ℃ and refluxed for 3.5 hours to complete the reaction.
The reaction solution was concentrated to evaporate acetonitrile, 3L of water was added, the solid was precipitated by stirring, filtered, the filter cake was washed once with water, the filter cake was collected and air-dried at 70 ℃ to obtain 1.43kg of p-guanidinobenzoic acid hydrochloride with a yield of 91%.
The reactants were subjected to nmr experiments to confirm the product structure, and the data are as follows:
1H NMR (model: AVANCE III HD 400M, CDCl3, 400MHz) with a delta of 12.98(s, 1H), 10.50(s, 1H), 7.98-7.96(d, 2H), 7.82(s, 4H), 7.34-7.32(d, 2H), and the results were consistent with the structure.
The examples show that the synthetic route is suitable for large-scale industrial production, and has high yield and high purity.
While the foregoing is directed to the preferred embodiment of the present invention, it will be understood by those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the invention as defined in the appended claims.
Claims (6)
1. A preparation method of p-guanidinobenzoic acid hydrochloride is characterized by comprising the following steps:
and carrying out reflux reaction on p-aminobenzoic acid and pyrazole formamidine hydrochloride to generate the p-guanidinobenzoic acid hydrochloride.
2. The process according to claim 1, wherein the molar ratio of para-aminobenzoic acid to pyrazole formamidine hydrochloride is 1: (0.8-1.5).
3. The method according to claim 1, wherein the solvent used in the reflux reaction is any one of acetonitrile, toluene, dichloromethane, acetone, and chlorobenzene.
4. The method according to claim 3, wherein the solvent is acetonitrile, the reaction temperature is 70 to 90 ℃, and the reaction time is 2 to 6 hours.
5. The process according to claim 1, wherein after the reflux reaction is completed, the solvent is distilled off under reduced pressure, and water is added to the distilled solvent to precipitate the p-guanidinobenzoic acid hydrochloride.
6. The method according to claim 5, wherein the p-guanidinobenzoic acid hydrochloride is washed with water and dried to refine the p-guanidinobenzoic acid hydrochloride.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202111637339.9A CN114315651A (en) | 2021-12-29 | 2021-12-29 | Preparation method of p-guanidinobenzoic acid hydrochloride |
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| CN202111637339.9A CN114315651A (en) | 2021-12-29 | 2021-12-29 | Preparation method of p-guanidinobenzoic acid hydrochloride |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1118346A (en) * | 1994-04-27 | 1996-03-13 | 弗·哈夫曼-拉罗切有限公司 | Process for the manufacture of guanidines |
| US5618843A (en) * | 1993-07-22 | 1997-04-08 | Eli Lilly And Company | Glycoprotein IIb/IIIa antagonists |
| WO2000041469A2 (en) * | 1999-01-15 | 2000-07-20 | Bayer Aktiengesellschaft | β-PHENYLALANINE DERIVATIVES AS INTEGRIN ANTAGONISTS |
| CN1438217A (en) * | 2003-03-20 | 2003-08-27 | 中国人民解放军第二军医大学 | Bearing-resisting compound and preparing method |
-
2021
- 2021-12-29 CN CN202111637339.9A patent/CN114315651A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5618843A (en) * | 1993-07-22 | 1997-04-08 | Eli Lilly And Company | Glycoprotein IIb/IIIa antagonists |
| CN1118346A (en) * | 1994-04-27 | 1996-03-13 | 弗·哈夫曼-拉罗切有限公司 | Process for the manufacture of guanidines |
| WO2000041469A2 (en) * | 1999-01-15 | 2000-07-20 | Bayer Aktiengesellschaft | β-PHENYLALANINE DERIVATIVES AS INTEGRIN ANTAGONISTS |
| CN1438217A (en) * | 2003-03-20 | 2003-08-27 | 中国人民解放军第二军医大学 | Bearing-resisting compound and preparing method |
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Application publication date: 20220412 |