CN102816077A - Application of urotropine as catalyst in aminomethylbenzoic acid synthesis - Google Patents
Application of urotropine as catalyst in aminomethylbenzoic acid synthesis Download PDFInfo
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- CN102816077A CN102816077A CN2012103541236A CN201210354123A CN102816077A CN 102816077 A CN102816077 A CN 102816077A CN 2012103541236 A CN2012103541236 A CN 2012103541236A CN 201210354123 A CN201210354123 A CN 201210354123A CN 102816077 A CN102816077 A CN 102816077A
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- CN
- China
- Prior art keywords
- urotropine
- acid
- catalyst
- ammonia
- 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.)
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- QCTBMLYLENLHLA-UHFFFAOYSA-N aminomethylbenzoic acid Chemical compound NCC1=CC=C(C(O)=O)C=C1 QCTBMLYLENLHLA-UHFFFAOYSA-N 0.000 title claims abstract description 23
- 229960003375 aminomethylbenzoic acid Drugs 0.000 title claims abstract description 22
- VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 title claims abstract description 20
- 239000003054 catalyst Substances 0.000 title abstract description 5
- 230000015572 biosynthetic process Effects 0.000 title abstract 2
- 238000003786 synthesis reaction Methods 0.000 title abstract 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims abstract description 47
- 229910021529 ammonia Inorganic materials 0.000 claims abstract description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000003756 stirring Methods 0.000 claims abstract description 10
- 238000001816 cooling Methods 0.000 claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims description 19
- 239000002253 acid Substances 0.000 claims description 11
- 125000005997 bromomethyl group Chemical group 0.000 claims description 9
- 238000002425 crystallisation Methods 0.000 claims description 8
- 230000008025 crystallization Effects 0.000 claims description 8
- YTEUDCIEJDRJTM-UHFFFAOYSA-N 2-(chloromethyl)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1CCl YTEUDCIEJDRJTM-UHFFFAOYSA-N 0.000 claims description 7
- ZWLPBLYKEWSWPD-UHFFFAOYSA-N o-toluic acid Chemical compound CC1=CC=CC=C1C(O)=O ZWLPBLYKEWSWPD-UHFFFAOYSA-N 0.000 claims description 4
- 238000000034 method Methods 0.000 abstract description 8
- 239000000047 product Substances 0.000 abstract description 7
- 238000009776 industrial production Methods 0.000 abstract description 4
- 238000003912 environmental pollution Methods 0.000 abstract description 3
- CQQSQBRPAJSTFB-UHFFFAOYSA-N 4-(bromomethyl)benzoic acid Chemical compound OC(=O)C1=CC=C(CBr)C=C1 CQQSQBRPAJSTFB-UHFFFAOYSA-N 0.000 abstract 1
- OITNBJHJJGMFBN-UHFFFAOYSA-N 4-(chloromethyl)benzoic acid Chemical compound OC(=O)C1=CC=C(CCl)C=C1 OITNBJHJJGMFBN-UHFFFAOYSA-N 0.000 abstract 1
- 239000012295 chemical reaction liquid Substances 0.000 abstract 1
- 238000001035 drying Methods 0.000 abstract 1
- 238000001704 evaporation Methods 0.000 abstract 1
- 239000000706 filtrate Substances 0.000 abstract 1
- 238000001914 filtration Methods 0.000 abstract 1
- 238000010438 heat treatment Methods 0.000 abstract 1
- 239000010413 mother solution Substances 0.000 abstract 1
- 239000000460 chlorine Substances 0.000 description 5
- 238000005576 amination reaction Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- -1 aminomethyl phenyl formic acid monohydrate Chemical compound 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000000701 coagulant Substances 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000020764 fibrinolysis Effects 0.000 description 1
- 230000023597 hemostasis Effects 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- GYDJEQRTZSCIOI-LJGSYFOKSA-N tranexamic acid Chemical compound NC[C@H]1CC[C@H](C(O)=O)CC1 GYDJEQRTZSCIOI-LJGSYFOKSA-N 0.000 description 1
- 229960000401 tranexamic acid Drugs 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to application of urotropine as a catalyst in aminomethylbenzoic acid synthesis. The method comprises the following steps: at the temperature of 10-30 DEG C, dissolving urotropine in water, stirring until the urotropine is completely dissolved, adding p-chloromethylbenzoic acid or p-bromomethylbenzoic acid, stirring uniformly, slowly introducing ammonia gas within 1 hour until the reaction liquid is completely clear, heating to 40-60 DEG C to react for 3-4 hours, evaporating under reduced pressure to remove ammonia until the pH value is 7-8, cooling to crystallize, filtering, and drying to obtain the aminomethylbenzoic acid, wherein the filtrate can be continuously used repeatedly more than six times. By using the urotropine as the catalyst for aminating aminomethylbenzoic acid, compared with the prior art, the invention can greatly enhance the product yield, wherein the first-use yield of the catalyst is 60%, and the product yield of the repeatedly used mother solution can reach 70-80%, thereby greatly lowering the industrial production cost and reducing the environmental pollution.
Description
Technical field
The present invention relates to a kind of new Application of Catalyst in the Aminomethylbenzoic Acid amination building-up process, belong to the synthetic field of chemicals.
Background technology
Aminomethylbenzoic Acid full name paraaminomethyl benzoic acid is claimed Styptopur, right-carboxylic Bian amine again, chemical name is right-and aminomethyl phenyl formic acid monohydrate, English name Axinoxethyl benzoic acid Xonohydrate, chemical structural formula:
Molecular formula: C
8H
9NO
2H
2O, molecular weight 169.18 is coagulants, is applicable to that fibrinolysis is caused various hemorrhage.The still synthetic hemostasis of Aminomethylbenzoic Acid is wider, the raw material of the tranexamic acid of better effects if, referring to 2011 the 6th the 17th phases of volume of the practical medicine of China, 160-170 page or leaf.
The aminating synthetic route of Aminomethylbenzoic Acid has following two kinds at present, referring to 1977 the 8th the 7th phases of volume of medicine industry, 19-20 page or leaf.
1, to chlorine/bromo methyl acid under the condition that catalyzer carbonic acid ammonium exists, obtain Aminomethylbenzoic Acid with the ammoniacal liquor amination.
X=Cl wherein, Br
This goes on foot reaction yield 50%～55%.
2, to chlorine/bromo methyl acid under the condition that catalyzer carbonic acid hydrogen ammonium exists, obtain Aminomethylbenzoic Acid with the ammoniacal liquor amination.
This goes on foot reaction yield 35%～40%.
Though the employed catalyzer of these amination methods is cheap, be easy to get, and environmental pollution is less, and product yield is all lower, and industrial production cost is higher.
Summary of the invention
Problem to be solved by this invention is to above-mentioned prior art and propose urotropine as the application method of catalyzer in the synthetic ammonia toluic acid, and not only low in raw material cost is easy to get, pollutes little, and improves yield greatly, reduces industrial production cost.
Realize that the technical scheme that the object of the invention is taked is:
Under 10～30 ℃, urotropine is soluble in water, be stirred to dissolving fully, add to chloromethyl benzoic acid or to bromo methyl acid; Stir, slowly feed ammonia in 1 hour, molten fully clear to reaction solution; Be heated to 40～60 ℃ of reactions 3～4 hours then, remove ammonia under reduced pressure to pH7～8, cooling crystallization; Filter, oven dry promptly gets Aminomethylbenzoic Acid; Be 1:1.2～2.0:15～18:6～8 wherein to chloromethyl benzoic acid or to the mol ratio of bromo methyl acid, urotropine, water, ammonia.
Filtrating can be applied mechanically six times continuously at least.
The present invention can explain with the reactions formula:
Reaction product bullion Aminomethylbenzoic Acid can adopt method purifying well known in the prior art, water recrystallization method for example, and acid is dissolved alkali and is analysed method and alkali-soluble acid analysis method.
The present invention adopts urotropine as the aminating catalyzer of Aminomethylbenzoic Acid; Compared with prior art outstanding effect is: improve product yield; Wherein the first use of catalyzer yield is 60%; The mother liquid recycle product yield can reach 70%～80%, thereby greatly reduces industrial production cost, has reduced environmental pollution simultaneously.
Embodiment
In order to understand the present invention better, be described further in the face of the present invention down.But the scope that the present invention requires to protect is not limited to the scope that embodiment representes.The following stated is merely the present invention embodiment preferably, only is used to explain the present invention, can not therefore be interpreted as the restriction to claim of the present invention.
Embodiment 1:
Under 10 ℃, urotropine 33.6g (0.24mol) and water 54.0g (3.0mol) are dropped in the reactor drum, be stirred to dissolving fully; Add subsequently to chloromethyl benzoic acid 34.2g (0.2mol), stir, feed ammonia to reaction solution and dissolve clear fully; Be heated to 40 ℃ of reactions 4 hours then, remove ammonia at last under reduced pressure to PH7～8, cooling crystallization; Filter, oven dry gets Aminomethylbenzoic Acid 21.1g (molar yield 62.4%).
Embodiment 2:
Under 22 ℃, urotropine 44.9g (0.32mol) and water 61.2g (3.4mol) are dropped in the reactor drum, be stirred to dissolving fully; Add subsequently to chloromethyl benzoic acid 34.2g (0.2mol), stir, feed ammonia to reaction solution and dissolve clear fully; Be heated to 50 ℃ of reactions 4 hours then, remove ammonia at last under reduced pressure to PH7～8, cooling crystallization; Filter, oven dry gets Aminomethylbenzoic Acid 22.3g (molar yield 65.9%).
Embodiment 3:
Under 30 ℃, urotropine 56.1g (0.40mol) and water 64.8g (3.6mol) are dropped in the reactor drum, be stirred to dissolving fully; Add subsequently to chloromethyl benzoic acid 34.2g (0.2mol), stir, feed ammonia to reaction solution and dissolve clear fully; Be heated to 60 ℃ of reactions 3 hours then, remove ammonia at last under reduced pressure to PH7～8, cooling crystallization; Filter, oven dry gets Aminomethylbenzoic Acid 21.8g (molar yield 64.4%).
Applying mechanically the first six time result sees the following form:
Embodiment 4:
Under 10 ℃, urotropine 33.6g (0.24mol) and water 57.6g (3.2mol) are dropped in the reactor drum, be stirred to dissolving fully; Add subsequently to bromo methyl acid 43.0g (0.2mol), stir, feed ammonia to reaction solution and dissolve clear fully; Be heated to 50 ℃ of reactions 4 hours then, remove ammonia at last under reduced pressure to PH7～8, cooling crystallization; Filter, oven dry gets Aminomethylbenzoic Acid 21.0g (molar yield 62.1%).
Embodiment 5:
Under 18 ℃, urotropine 56.1g (0.40mol) and water 54.0g (3.0mol) are dropped in the reactor drum, be stirred to dissolving fully; Add subsequently to bromo methyl acid 34.2g (0.2mol), stir, feed ammonia to reaction solution and dissolve clear fully; Be heated to 55 ℃ of reactions 3 hours then, remove ammonia at last under reduced pressure to PH7～8, cooling crystallization; Filter, oven dry gets Aminomethylbenzoic Acid 22.0g (molar yield 65.0%).
Embodiment 6:
Under 30 ℃, urotropine 42.1g (0.30mol) and water 64.8g (3.6mol) are dropped in the reactor drum, be stirred to dissolving fully; Add subsequently to bromo methyl acid 34.2g (0.2mol), stir, feed ammonia to reaction solution and dissolve clear fully; Be heated to 60 ℃ of reactions 4 hours then, remove ammonia at last under reduced pressure to PH7～8, cooling crystallization; Filter, oven dry gets Aminomethylbenzoic Acid 23.0g (molar yield 68.0%).
Product to the synthetic gained of above-mentioned each embodiment carries out chemical analysis, and the physics value that obtains is following, confirms that thus synthetic product is an Aminomethylbenzoic Acid.
ESI-MS（m/z）：152.0706[M+H]
+。
IR (KBr method, cm
-1): 3000-2208,2860,1638,1588,1541,1415,1179,
1098,796。
13C-NMR (DMSO-TMS, (δ) ppm): 130.832 (season C), 129.598 (uncle C), 129.265 (uncle C), 138.919 (season C), 167.150 (season C), 42.005 (secondary C).
1H-NMR（DMSO-TMS,(δ)ppm）：8.6780（s，br，3H）,
7.934-7.913(m,2H),7.623-7.602(m,2H),4.093-4.052(like?q,2H)。
Claims (2)
1. urotropine is as the application of catalyzer at the synthetic ammonia toluic acid, and its concrete grammar is: under 10～30 ℃ that urotropine is soluble in water, be stirred to dissolving fully; Adding stirs to chloromethyl benzoic acid or to bromo methyl acid, slowly feeds ammonia in 1 hour, and is molten fully clear to reaction solution; Be heated to 40～60 ℃ of reactions 3～4 hours then, remove ammonia under reduced pressure to pH7～8, cooling crystallization; Filter, oven dry promptly gets Aminomethylbenzoic Acid; Be 1:1.2～2.0:15～18:6～8 wherein to chloromethyl benzoic acid or to the mol ratio of bromo methyl acid, urotropine, water, ammonia.
2. urotropine according to claim 1 is characterized in that as the application of catalyzer at the synthetic ammonia toluic acid: filtrating can be applied mechanically six times continuously at least.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012103541236A CN102816077A (en) | 2012-09-21 | 2012-09-21 | Application of urotropine as catalyst in aminomethylbenzoic acid synthesis |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012103541236A CN102816077A (en) | 2012-09-21 | 2012-09-21 | Application of urotropine as catalyst in aminomethylbenzoic acid synthesis |
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|---|---|
| CN102816077A true CN102816077A (en) | 2012-12-12 |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104447757A (en) * | 2014-11-17 | 2015-03-25 | 合肥华方医药科技有限公司 | Method for synthesizing epinastine |
| CN105037186A (en) * | 2015-06-17 | 2015-11-11 | 苏州敬业医药化工有限公司 | Preparation method of aminomethylbenzoic acid |
| CN111790444A (en) * | 2020-06-18 | 2020-10-20 | 安徽禾宸化学科技有限公司 | Ionic resin-based catalyst and method for catalytically synthesizing aminobenzoic acid by using same |
| CN112409196A (en) * | 2020-11-26 | 2021-02-26 | 白云山东泰商丘药业有限公司 | Preparation process of aminomethylbenzoic acid based on Delbin reaction |
| CN113354550A (en) * | 2021-05-28 | 2021-09-07 | 吉林大学 | Novel preparation method of aminomethylbenzoic acid |
| CN114057592A (en) * | 2020-08-05 | 2022-02-18 | 沈阳化工研究院有限公司 | Method for preparing 4-aminomethylbenzoic acid |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1368415A (en) * | 1973-05-11 | 1974-09-25 | Asahi Chemical Ind | Process for the preparation of p-aminomethylbenzoic acid |
| GB2084146A (en) * | 1980-09-17 | 1982-04-07 | Kureha Chemical Ind Co Ltd | Process for preparing 4-aminomethylbenzoic acid |
| CN102241600A (en) * | 2011-05-13 | 2011-11-16 | 嘉兴市博源生物化工科技有限公司 | Preparation method of 2-amino butyric acid |
-
2012
- 2012-09-21 CN CN2012103541236A patent/CN102816077A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1368415A (en) * | 1973-05-11 | 1974-09-25 | Asahi Chemical Ind | Process for the preparation of p-aminomethylbenzoic acid |
| GB2084146A (en) * | 1980-09-17 | 1982-04-07 | Kureha Chemical Ind Co Ltd | Process for preparing 4-aminomethylbenzoic acid |
| CN102241600A (en) * | 2011-05-13 | 2011-11-16 | 嘉兴市博源生物化工科技有限公司 | Preparation method of 2-amino butyric acid |
Non-Patent Citations (1)
| Title |
|---|
| 叶连克: "止血芳酸生产经验", 《医药工业》 * |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104447757A (en) * | 2014-11-17 | 2015-03-25 | 合肥华方医药科技有限公司 | Method for synthesizing epinastine |
| CN105037186A (en) * | 2015-06-17 | 2015-11-11 | 苏州敬业医药化工有限公司 | Preparation method of aminomethylbenzoic acid |
| CN111790444A (en) * | 2020-06-18 | 2020-10-20 | 安徽禾宸化学科技有限公司 | Ionic resin-based catalyst and method for catalytically synthesizing aminobenzoic acid by using same |
| CN114057592A (en) * | 2020-08-05 | 2022-02-18 | 沈阳化工研究院有限公司 | Method for preparing 4-aminomethylbenzoic acid |
| CN114057592B (en) * | 2020-08-05 | 2023-08-22 | 沈阳化工研究院有限公司 | A method for preparing 4-aminomethylbenzoic acid |
| CN112409196A (en) * | 2020-11-26 | 2021-02-26 | 白云山东泰商丘药业有限公司 | Preparation process of aminomethylbenzoic acid based on Delbin reaction |
| CN113354550A (en) * | 2021-05-28 | 2021-09-07 | 吉林大学 | Novel preparation method of aminomethylbenzoic acid |
| CN113354550B (en) * | 2021-05-28 | 2023-04-11 | 吉林大学 | Preparation method of aminomethylbenzoic acid |
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