CN102417462A - Preparation method of 4-hydroxy-3-ethoxybenzylamine hydrochloride - Google Patents
Preparation method of 4-hydroxy-3-ethoxybenzylamine hydrochloride Download PDFInfo
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- CN102417462A CN102417462A CN201110254274XA CN201110254274A CN102417462A CN 102417462 A CN102417462 A CN 102417462A CN 201110254274X A CN201110254274X A CN 201110254274XA CN 201110254274 A CN201110254274 A CN 201110254274A CN 102417462 A CN102417462 A CN 102417462A
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- Prior art keywords
- vanirone
- mol
- hydroxyl
- amine hydrochlorate
- amination reagent
- 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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- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- USHFIWRLIIZZCA-UHFFFAOYSA-N 4-(aminomethyl)-2-ethoxyphenol;hydrochloride Chemical compound Cl.CCOC1=CC(CN)=CC=C1O USHFIWRLIIZZCA-UHFFFAOYSA-N 0.000 title abstract 3
- 238000000034 method Methods 0.000 claims abstract description 16
- 238000005576 amination reaction Methods 0.000 claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 11
- 239000000047 product Substances 0.000 claims abstract description 11
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 10
- 229910000564 Raney nickel Inorganic materials 0.000 claims abstract description 9
- 239000003054 catalyst Substances 0.000 claims abstract description 9
- 239000007810 chemical reaction solvent Substances 0.000 claims abstract description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 29
- -1 4-hydroxyl-3-ethoxy benzylidene Chemical group 0.000 claims description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 9
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical group N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 8
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 238000002156 mixing Methods 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 239000013078 crystal Substances 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 229910021529 ammonia Inorganic materials 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 239000012141 concentrate Substances 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 230000006837 decompression Effects 0.000 claims description 2
- 239000000706 filtrate Substances 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 7
- 230000035484 reaction time Effects 0.000 abstract description 6
- 238000005984 hydrogenation reaction Methods 0.000 abstract description 3
- 238000006722 reduction reaction Methods 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 2
- CBOQJANXLMLOSS-UHFFFAOYSA-N ethyl vanillin Chemical compound CCOC1=CC(C=O)=CC=C1O CBOQJANXLMLOSS-UHFFFAOYSA-N 0.000 abstract 4
- 229940073505 ethyl vanillin Drugs 0.000 abstract 2
- 239000007868 Raney catalyst Substances 0.000 abstract 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 abstract 1
- 239000012043 crude product Substances 0.000 abstract 1
- 238000007038 hydrochlorination reaction Methods 0.000 abstract 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000009835 boiling Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 230000008676 import Effects 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000012805 post-processing Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
Landscapes
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of 4-hydroxy-3-ethoxybenzylamine hydrochloride. Taking ethyl vanillin as a raw material and Raney nickel as a hydrogenation catalyst, carrying out reduction reaction with an amination reagent in a C1-C3 mono-alcohol reaction solvent to generate ethyl vanillin amine, carrying out hydrochlorination to obtain a crude product, and further purifying to obtain the target product, namely 4-hydroxy-3-ethoxybenzylamine hydrochloride. The method has the advantages of reasonable process route, low raw material cost, mild reaction conditions, short reaction time, simple equipment requirement, safe and simple operation, and suitability for large-scale industrial production.
Description
Technical field
The present invention relates to the preparation method of 4-hydroxyl-3-ethoxy benzylidene amine hydrochlorate; Being specifically related to a kind of is raw material with the vanirone; Ammonia or ammoniacal liquor are amination reagent; Alcohols is a solvent, and Raney's nickel is that hydrogenation catalyst carries out amination reduction reaction generation vanirone amine, prepares the method for 4-hydroxyl-3-ethoxy benzylidene amine hydrochlorate again through the salt acidifying.
Background technology
4-hydroxyl-3-ethoxy benzylidene amine hydrochlorate is commonly called as the vanirone amine hydrochlorate, is a kind of important medicine and fine-chemical intermediate, especially can be used as the midbody of synthetic antimicrobial antiphlogistic drug and the sweeting agent of preparation food service industry etc., and its structural formula is following:
In the prior art, English Patent GB2168976A discloses following synthetic route:
This technology needs just can make title product 4-hydroxyl-3-ethoxy benzylidene amine hydrochlorate through two-step reaction, the first step reaction 16 hours, and yield only about 70%, the second step reaction needs spends the night, and yield is merely about 80%.And this method raw materials cost is high, long reaction time, and total recovery has only 56%, and is high to the requirement of equipment, so industrial prospect is undesirable.
Summary of the invention
Technical problem to be solved by this invention is to provide the preparation method of a kind of 4-hydroxyl-3-ethoxy benzylidene amine hydrochlorate, with the synthesis route length, the long reaction time that overcome in the prior art preparation 4-hydroxyl-3-ethoxy benzylidene amine hydrochlorate, shortcoming such as total recovery is low, raw materials cost is higher.The inventive method economical rationality, operating environment is safer in suitability for industrialized production.
Technical conceive of the present invention is such: be raw material with the vanirone; Raney's nickel is a hydrogenation catalyst; In C1～C3 unit alcohol reaction solvent, carry out reduction reaction with amination reagent, salt acidifying then generates the vanirone amine hydrochlorate; From reaction product, collect the vanirone amine hydrochlorate of separating out at last, promptly obtain title product of the present invention.
The preparation method of 4-hydroxyl of the present invention-3-ethoxy benzylidene amine hydrochlorate comprises the steps:
Vanirone, Raney's nickel catalyst, amination reagent are added in the C1-C3 unit alcohol reaction solvent,, react under 0-100 ℃ the condition at hydrogen pressure 0.1-2.0Mp; Reaction solution is through cooling off, remove by filter catalyzer; Filtrate decompression concentrates, and adds the acidifying of mixing solutions salt, promptly gets bullion 4-hydroxyl-3-ethoxy benzylidene amine hydrochlorate; Through being further purified, promptly get title product.
Wherein, among the above-mentioned preparation method, described amination reagent is ammonia or ammoniacal liquor, preferred 18-30wt% ammoniacal liquor.The mol ratio of described vanirone and amination reagent is 1: 4-10, mol/mol.
Described C1～C3 unit alcohol is methyl alcohol, ethanol, propyl alcohol or Virahol, and the mass ratio of described vanirone and C1～C3 unit alcohol is 1: 2-6, g/g.
Described mixing solutions is that the mass ratio according to 37wt% hydrochloric acid, 95wt% ethanol and water is 1: 1: 0.4-0.6 prepares, and the mol ratio of hydrochloric acid is 1 in described vanirone and the mixing solutions: 1-2, mol/mol.
The mass ratio of described vanirone and Raney's nickel catalyst is 5-20: 1, and g/g.
Said purification process is following: thick product 4-hydroxyl-3-ethoxy benzylidene amine hydrochlorate is cooled to 0-10 ℃, separate out crystal through filtration, ethanol drip washing, drain and dry, promptly get title product, its purity >=99% (HPLC), total recovery >=87%.
Reaction formula of the present invention is following:
Compared with prior art; Operational path of the present invention is reasonable, raw materials cost reduces, reaction conditions is gentle, the reaction times is short, only needs 5～20h, and simple to equipment requirements; Simple and safe operation; And purity >=99% (HPLC) of title product 4-hydroxyl-3-ethoxy benzylidene amine hydrochlorate, total recovery >=87% is suitable for large-scale industrial production.
Embodiment
Through embodiment the present invention is further described below, but embodiment does not limit protection scope of the present invention.
Embodiment 1
In the autoclave pressure that whisking appliance, TM are housed, add 250g (7.8mol) methyl alcohol respectively, 83.1g (0.5mol) vanirone, 5.0g Raney's nickel catalyst; Stirring feeds 51.0g (3.0mol) ammonia after going out air with nitrogen replacement down, imports hydrogen again, heat temperature raising; Keep 80 ± 5 ℃ of temperature of reaction; Hydrogen pressure 0.4Mp reacts, and no longer absorbs until hydrogen, and the reaction times is 5h.
Reaction solution is cooled to room temperature, removes by filter catalyzer, and filtrating is with adding by 66.5g 37wt% hydrochloric acid 66.5g 95wt% ethanol behind the Rotary Evaporators concentrating under reduced pressure; 38.0g the mixing solutions of water preparation is heated to the boiling that refluxes, and carries out the salt acidifying under stirring, and is cooled to 0-10 ℃ subsequently; The crystal of separating out is through filtering, and ethanol drip washing is drained, drying; Obtain white crystal product 4-hydroxyl-3-ethoxy benzylidene amine hydrochlorate 91.5g, yield 87.7%, purity 99.2% (HPLC).Whole post-processing operation process is 2h.
Embodiment 2
In the autoclave pressure that whisking appliance, TM are housed, add 200g (3.33mol) Virahol respectively, 83.1g (0.5mol) vanirone, 8.0g Raney's nickel catalyst and 560g (4.0mol) 25wt% ammoniacal liquor; Stirring imports hydrogen after going out air with nitrogen replacement down; Heat temperature raising keeps 50 ± 5 ℃ of temperature of reaction, and hydrogen pressure 0.6Mp reacts; No longer absorb until hydrogen, the reaction times is 5h.
Reaction solution is cooled to room temperature, removes by filter catalyzer, and filtrating is with adding by 70g 37wt% hydrochloric acid 70g 95wt% ethanol behind the Rotary Evaporators concentrating under reduced pressure; The mixing solutions of 30g water preparation is heated to the boiling that refluxes, and carries out the salt acidifying under stirring, and is cooled to 0-10 ℃ subsequently; The crystal of separating out is through filtering, and ethanol drip washing is drained, drying; Obtain white crystal product 4-hydroxyl-3-ethoxy benzylidene amine hydrochlorate 89.4g, yield 89.8%, purity 99.6% (HPLC).Whole post-processing operation process is 2h.
Should be noted that at last; Above embodiment is only unrestricted in order to technical scheme of the present invention to be described; Although with reference to preferred embodiment the present invention is specified, those of ordinary skill in the art should be appreciated that and can make amendment or be equal to replacement the technical scheme of invention; And not breaking away from the spirit and the scope of technical scheme of the present invention, it all should be encompassed in the claim scope of the present invention.
Claims (10)
1. the preparation method of 4-hydroxyl-3-ethoxy benzylidene amine hydrochlorate is characterized in that, comprises the steps:
Vanirone, Raney's nickel catalyst, amination reagent are added in the C1-C3 unit alcohol reaction solvent,, react under the 0-100 ℃ of condition at hydrogen pressure 0.1-2.0Mp; Reaction solution is through cooling off, remove by filter catalyzer; Filtrate decompression concentrates, and adds the acidifying of mixing solutions salt, promptly gets bullion 4-hydroxyl-3-ethoxy benzylidene amine hydrochlorate; Purified, promptly get title product.
2. method according to claim 1 is characterized in that, described amination reagent is ammonia or ammoniacal liquor.
3. method according to claim 2 is characterized in that, the preferred 18-30wt% ammoniacal liquor of described amination reagent.
4. according to claim 1,2 or 3 described methods, it is characterized in that the mol ratio of described vanirone and amination reagent is 1: 4-10, mol/mol.
5. method according to claim 1 is characterized in that, described C1～C3 unit alcohol is methyl alcohol, ethanol, propyl alcohol or Virahol.
6. according to claim 1 or 5 described methods, it is characterized in that the mass ratio of described vanirone and C1～C3 unit alcohol is 1: 2-6, g/g.
7. method according to claim 1 is characterized in that, described mixing solutions is 1: 1 according to the mass ratio of 37wt% hydrochloric acid, 95wt% ethanol and water: 0.4-0.6 prepares.
8. according to claim 1 or 7 described methods, it is characterized in that the mol ratio of hydrochloric acid is 1 in described vanirone and the mixing solutions: 1-2, mol/mol.
9. method according to claim 1 is characterized in that, the mass ratio of described vanirone and Raney's nickel catalyst is 5-20: 1, and g/g.
10. method according to claim 1 is characterized in that, said purification process is following: bullion 4-hydroxyl-3-ethoxy benzylidene amine hydrochlorate is cooled to 0-10 ℃, separates out crystal, through filtrations, ethanol drip washing, drain and the drying, promptly get title product.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110254274XA CN102417462A (en) | 2011-08-30 | 2011-08-30 | Preparation method of 4-hydroxy-3-ethoxybenzylamine hydrochloride |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110254274XA CN102417462A (en) | 2011-08-30 | 2011-08-30 | Preparation method of 4-hydroxy-3-ethoxybenzylamine hydrochloride |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102417462A true CN102417462A (en) | 2012-04-18 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201110254274XA Pending CN102417462A (en) | 2011-08-30 | 2011-08-30 | Preparation method of 4-hydroxy-3-ethoxybenzylamine hydrochloride |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4388250A (en) * | 1982-03-15 | 1983-06-14 | Rhone Poulenc Inc. | Process for the preparation of p-hydroxy-benzyl-nitriles and corresponding amines |
| GB2168976A (en) * | 1984-12-20 | 1986-07-02 | Procter & Gamble | Amides and compositions thereof having anti-inflammatory activity |
| US20030065223A1 (en) * | 2001-09-28 | 2003-04-03 | Boehringer Ingelheim Pharma Kg | Process for preparing vanillylamine hydrochloride |
| CN1704397A (en) * | 2004-05-25 | 2005-12-07 | 张炳庚 | Method for preparing p-fluorobenzylamine by using nano nickel as catalyst |
| CN101538212A (en) * | 2009-02-05 | 2009-09-23 | 上海华谊（集团）公司 | Method for preparing 4-hydroxy-3-methoxybenzylamine hydrochloride |
-
2011
- 2011-08-30 CN CN201110254274XA patent/CN102417462A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4388250A (en) * | 1982-03-15 | 1983-06-14 | Rhone Poulenc Inc. | Process for the preparation of p-hydroxy-benzyl-nitriles and corresponding amines |
| GB2168976A (en) * | 1984-12-20 | 1986-07-02 | Procter & Gamble | Amides and compositions thereof having anti-inflammatory activity |
| US20030065223A1 (en) * | 2001-09-28 | 2003-04-03 | Boehringer Ingelheim Pharma Kg | Process for preparing vanillylamine hydrochloride |
| CN1704397A (en) * | 2004-05-25 | 2005-12-07 | 张炳庚 | Method for preparing p-fluorobenzylamine by using nano nickel as catalyst |
| CN101538212A (en) * | 2009-02-05 | 2009-09-23 | 上海华谊（集团）公司 | Method for preparing 4-hydroxy-3-methoxybenzylamine hydrochloride |
Non-Patent Citations (1)
| Title |
|---|
| 史鲁秋等: "3,4-二甲氧基苄胺的合成", 《药学进展》 * |
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Application publication date: 20120418 |