CN104557566A - Preparation method for 4-nitrobenzene ethylamine hydrobromide - Google Patents
Preparation method for 4-nitrobenzene ethylamine hydrobromide Download PDFInfo
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- CN104557566A CN104557566A CN201410814732.4A CN201410814732A CN104557566A CN 104557566 A CN104557566 A CN 104557566A CN 201410814732 A CN201410814732 A CN 201410814732A CN 104557566 A CN104557566 A CN 104557566A
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- kilogram
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- ethylamine hydrobromide
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- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- JSUDVBHWPFYYJB-UHFFFAOYSA-N ethanamine nitrobenzene hydrobromide Chemical compound Br.C(C)N.[N+](=O)([O-])C1=CC=CC=C1 JSUDVBHWPFYYJB-UHFFFAOYSA-N 0.000 title abstract 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 22
- 238000006243 chemical reaction Methods 0.000 claims abstract description 22
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims abstract description 18
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 claims abstract description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 10
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 5
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000012535 impurity Substances 0.000 claims abstract description 4
- 229910017604 nitric acid Inorganic materials 0.000 claims abstract description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- PNZDZRMOBIIQTC-UHFFFAOYSA-N ethanamine;hydron;bromide Chemical compound Br.CCN PNZDZRMOBIIQTC-UHFFFAOYSA-N 0.000 claims description 10
- 239000013078 crystal Substances 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 9
- 238000002425 crystallisation Methods 0.000 claims description 7
- 230000008025 crystallization Effects 0.000 claims description 7
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 6
- 210000003298 dental enamel Anatomy 0.000 claims description 6
- 230000008014 freezing Effects 0.000 claims description 6
- 238000007710 freezing Methods 0.000 claims description 6
- 238000001514 detection method Methods 0.000 claims description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 238000000605 extraction Methods 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 3
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 3
- 239000012046 mixed solvent Substances 0.000 claims description 3
- 239000012074 organic phase Substances 0.000 claims description 3
- 239000011541 reaction mixture Substances 0.000 claims description 3
- 238000009776 industrial production Methods 0.000 abstract description 2
- 239000011259 mixed solution Substances 0.000 abstract description 2
- 238000002156 mixing Methods 0.000 abstract description 2
- 239000000203 mixture Substances 0.000 abstract description 2
- 238000006396 nitration reaction Methods 0.000 abstract description 2
- 239000002904 solvent Substances 0.000 abstract description 2
- 235000019441 ethanol Nutrition 0.000 abstract 1
- ODLMAHJVESYWTB-UHFFFAOYSA-N ethylmethylbenzene Natural products CCCC1=CC=CC=C1 ODLMAHJVESYWTB-UHFFFAOYSA-N 0.000 abstract 1
- 239000003814 drug Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 230000027939 micturition Effects 0.000 description 1
- ZODDGFAZWTZOSI-UHFFFAOYSA-N nitric acid;sulfuric acid Chemical compound O[N+]([O-])=O.OS(O)(=O)=O ZODDGFAZWTZOSI-UHFFFAOYSA-N 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a preparation method for 4-nitrobenzene ethylamine hydrobromide. The preparation method adopts a mixed solution of Beta-phenylethylamine and acetic oxide for dripping into a mixture system of nitric acid and sulfuric acid, alleviates the drastic heating-up reaction caused by the regular nitration reaction, and improves the industrial production operability of reactions of the type; by adopting a ternary solvent system formed by mixing water, ethyl alcohol and methyl benzene, a high-standard product, with the content being over 99.8%, the individual impurity amount being less than 0.1% and the isomer being less than 0.05%, is crystallized out.
Description
Technical field
The present invention relates generally to field of medicaments, particularly relates to a kind of preparation method of 4-oil of mirbane ethylamine hydrobromide.
Background technology
4-oil of mirbane ethylamine hydrobromide is the medicine intermediate being used for the treatment of the medicines such as arrythmias, cardiovascular and frequent micturition, it is a kind of important fine-chemical intermediate, have been widely used at pharmaceutical industries tool, the report of current related methods of synthesis is less, and is all not too applicable to suitability for industrialized production.
Summary of the invention
The object of the invention is just to provide a kind of preparation method of 4-oil of mirbane ethylamine hydrobromide.
The present invention is achieved by the following technical solutions:
A preparation method for 4-oil of mirbane ethylamine hydrobromide, comprises the following steps:
(1) in 500L enamel reaction still, add 120-128 kilogram of β-phenylethylamine and 145-150 kilogram of diacetyl oxide, at 40-50 DEG C, stir 4-5h, for subsequent use;
(2) nitric acid adding 340-350 kilogram of 62-64% in 1000L enamel reaction still stirs, 490-500 kilogram of 70% sulfuric acid is dripped at 30-35 DEG C, then temperature control drips the reaction mixture of 2-phenylethylamine and acetic anhydride in (1) at 25-35 DEG C, after dropwising, stirring at room temperature reaction 2-3h, terminates reaction;
(3) in reaction solution, slowly adding 30%NaOH alkali lye to PH is between 6-7, adds 295-300 kilogram of toluene extraction, uses anhydrous sodium sulfate drying organic phase, be concentrated into thickness;
(4) add 40% Hydrogen bromide 275-280 kilogram again, back flow reaction 2-3h at 102-106 DEG C, after at-2 DEG C of freezing crystallization 4.8-5h, get rid of and consider to obtain crystal 80-100 kilogram;
(5) in crystal obtained above, add volume ratio water: ethanol: toluene is the ternary mixed solvent system 100-120 kilogram of 1:6.8-7:2, heating for dissolving, after at-2 DEG C of freezing crystallization 4.8-5h, get rid of and consider to obtain crystal 70-90 kilogram, HPLC detection level more than 99.8%, single impurity is less than 0.1%, and wherein isomer 2-oil of mirbane ethylamine hydrobromide content is less than 0.05%.
Advantage of the present invention is:
The present invention's β-phenylethylamine and acetic anhydride mixed solution is counter drips in nitric acid-sulfuric acid mixture system, has relaxed conventional nitration and has reacted the violent temperature reaction brought, improve the industrial production operability of the type reaction;
With water, ethanol: the ternary solvent system of toluene mixing, crystallization goes out content more than 99.8%, is singly assortedly less than 0.1%, the high standard product that isomer is less than 0.05%.
Embodiment
Embodiment 1
A preparation method for 4-oil of mirbane ethylamine hydrobromide, is characterized in that comprising the following steps:
(1) in 500L enamel reaction still, add 128 kilograms of β-phenylethylamines and 150 kilograms of diacetyl oxides, at 50 DEG C, stir 5h, for subsequent use;
(2) nitric acid adding 350 kilogram 64% in 1000L enamel reaction still stirs, 490-500 kilogram of 70% sulfuric acid is dripped at 35 DEG C, then temperature control drips the reaction mixture of 2-phenylethylamine and acetic anhydride in (1) at 35 DEG C, after dropwising, stirring at room temperature reaction 2-3h, terminates reaction;
(3) in reaction solution, slowly adding 30%NaOH alkali lye to PH is between 6-7, adds 300 kilograms of toluene extractions, uses anhydrous sodium sulfate drying organic phase, be concentrated into thickness;
(4) add 40% Hydrogen bromide 280 kilograms again, back flow reaction 3h at 106 DEG C, after at-2 DEG C of freezing crystallization 4.8h, get rid of and consider to obtain 100 kilograms, crystal;
(5) in crystal obtained above, add volume ratio water: ethanol: toluene is the ternary mixed solvent system 120 kg of 1:7:2, heating for dissolving, after at-2 DEG C of freezing crystallization 5h, get rid of and consider to obtain 87 kilograms, crystal, HPLC detection level more than 99.8%, single impurity is less than 0.1%, and wherein isomer 2-oil of mirbane ethylamine hydrobromide content is less than 0.05%.
Performance Detection:
Claims (1)
1. a preparation method for 4-oil of mirbane ethylamine hydrobromide, is characterized in that comprising the following steps:
(1) in 500L enamel reaction still, add 120-128 kilogram of β-phenylethylamine and 145-150 kilogram of diacetyl oxide, at 40-50 DEG C, stir 4-5h, for subsequent use;
(2) nitric acid adding 340-350 kilogram of 62-64% in 1000L enamel reaction still stirs, 490-500 kilogram of 70% sulfuric acid is dripped at 30-35 DEG C, then temperature control drips the reaction mixture of 2-phenylethylamine and acetic anhydride in (1) at 25-35 DEG C, after dropwising, stirring at room temperature reaction 2-3h, terminates reaction;
(3) in reaction solution, slowly adding 30%NaOH alkali lye to PH is between 6-7, adds 295-300 kilogram of toluene extraction, uses anhydrous sodium sulfate drying organic phase, be concentrated into thickness;
(4) add 40% Hydrogen bromide 275-280 kilogram again, back flow reaction 2-3h at 102-106 DEG C, after at-2 DEG C of freezing crystallization 4.8-5h, get rid of and consider to obtain crystal 80-100 kilogram;
(5) in crystal obtained above, add volume ratio water: ethanol: toluene is the ternary mixed solvent system 100-120 kilogram of 1:6.8-7:2, heating for dissolving, after at-2 DEG C of freezing crystallization 4.8-5h, get rid of and consider to obtain crystal 70-90 kilogram, HPLC detection level more than 99.8%, single impurity is less than 0.1%, and wherein isomer 2-oil of mirbane ethylamine hydrobromide content is less than 0.05%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410814732.4A CN104557566A (en) | 2014-12-23 | 2014-12-23 | Preparation method for 4-nitrobenzene ethylamine hydrobromide |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410814732.4A CN104557566A (en) | 2014-12-23 | 2014-12-23 | Preparation method for 4-nitrobenzene ethylamine hydrobromide |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104557566A true CN104557566A (en) | 2015-04-29 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410814732.4A Pending CN104557566A (en) | 2014-12-23 | 2014-12-23 | Preparation method for 4-nitrobenzene ethylamine hydrobromide |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019081972A1 (en) | 2017-08-09 | 2019-05-02 | Saneca Pharmaceuticals A.S. | A method for preparing mandelic acid 4-nitrophenyl ethylamide from 4-nitrobenzyl cyanide |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1156142A (en) * | 1995-12-06 | 1997-08-06 | 中国药科大学 | Process for preparing mesylamido-phenethylamine derivative |
| CN1287999A (en) * | 1999-11-24 | 2001-03-21 | 中国药科大学 | Method for preparing intermediate of methylsalfonamido phenethylamine derivative |
| CN1400207A (en) * | 2001-07-30 | 2003-03-05 | 中国科学院上海药物研究所 | Sulfonamide phenylalkylamine compound, its preparation method and application |
| CN1417206A (en) * | 2001-11-08 | 2003-05-14 | 中国药科大学 | Alkyl sulfonamide phenyl alkylamide compound and its prepn and medicinal use |
| CN104151170A (en) * | 2013-05-15 | 2014-11-19 | 天津希恩思生化科技有限公司 | 4-nitrophenethylamine hydrochloride and preparation method thereof |
-
2014
- 2014-12-23 CN CN201410814732.4A patent/CN104557566A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1156142A (en) * | 1995-12-06 | 1997-08-06 | 中国药科大学 | Process for preparing mesylamido-phenethylamine derivative |
| CN1287999A (en) * | 1999-11-24 | 2001-03-21 | 中国药科大学 | Method for preparing intermediate of methylsalfonamido phenethylamine derivative |
| CN1400207A (en) * | 2001-07-30 | 2003-03-05 | 中国科学院上海药物研究所 | Sulfonamide phenylalkylamine compound, its preparation method and application |
| CN1417206A (en) * | 2001-11-08 | 2003-05-14 | 中国药科大学 | Alkyl sulfonamide phenyl alkylamide compound and its prepn and medicinal use |
| CN104151170A (en) * | 2013-05-15 | 2014-11-19 | 天津希恩思生化科技有限公司 | 4-nitrophenethylamine hydrochloride and preparation method thereof |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019081972A1 (en) | 2017-08-09 | 2019-05-02 | Saneca Pharmaceuticals A.S. | A method for preparing mandelic acid 4-nitrophenyl ethylamide from 4-nitrobenzyl cyanide |
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Application publication date: 20150429 |
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