CN101928247A - Method for synthesizing xylometazoline hydrochloride compound - Google Patents
Method for synthesizing xylometazoline hydrochloride compound Download PDFInfo
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Abstract
The invention relates to a method for synthesizing a xylometazoline hydrochloride compound. In the method, 1,3-dimethyl-5-butyl benzene is used as an initiative material, and the xylometazoline hydrochloride is obtained by chloromethylation, cyanation, cyclization and salification. The synthesis method has the advantages of simplicity, readily available raw materials, safe operation and high yield and is suitable for industrial production.
Description
Technical field
The invention belongs to the synthetic field of medicine, be specifically related to a kind of synthetic method of xylometazoline hydrochloride compound.
Background technology
Xylometazoline hydrochloride (Xylometazoline Hydrochloride, 1), chemistry is by name: 2-(the 4-tertiary butyl-2,6-dimethyl benzyl)-2-imidazoline salt hydrochlorate, its chemical structure is as follows.Xylometazoline hydrochloride has direct exciting α 1 acceptor and causes vasoconstrictive effect, thus hyperemia due to reducing inflammation and oedema, clinically in order to alleviate the nasal obstruction symptom that diseases such as acute and chronic rhinitis, sinusitis paranasal sinusitis, allergic rhinitis, hypertrophic rhinitis cause.
In the prior art, US6124338 discloses a kind of method for preparing xylometazoline, by 2,6-dimethyl-4-the tertiary butyl-1-aniline (2) gets 2 with polyformaldehyde reaction after diazotization, 6-dimethyl-4-the tertiary butyl-1-phenyl aldehyde (3), get 2 with sodium borohydride reduction then, 6-dimethyl-4-the tertiary butyl-1-phenylcarbinol (4), hydroxyl becomes chlorine in the presence of sulfur oxychloride, 2, the 6-dimethyl-4-tertiary butyl-1-chloromethylbenzene (5) must compound (7) after react in ethanol with sodium cyanide, last and quadrol cyclization obtains target compound (1), and its reaction formula is as follows:
Diazotization reaction in this synthetic method, general yield is not high; And use sulfur oxychloride that environment is had very big pollution; The aftertreatment of cyanation need be carried out the high-vacuum fractionation distillation, is difficult to amplify produce.The product impurity of this patented method gained is many, and it is low particularly to prepare the product purity of (1) by compound (7).In a word, this synthetic method craft route is long, and aftertreatment is loaded down with trivial details, and product yield is low, production cost is high, and this makes this technology be difficult to realize industrialized production.
And ES323985 is disclosed by 1, and 3-dimethyl-5-tert.-butylbenzene (8) is prepared into the method for compound (5), and its chloromethylation is with ZnCl
2Make catalyzer, but this reaction conversion ratio being low, only is 59%.
CN1088574 discloses the method by compound (8) preparation (5), adopts Paraformaldehyde 96, is catalyzer with the vitriol oil and feeds hydrogen chloride gas, yield 80-90%.Its reaction formula is as follows:
The crude product impurity that this chloromethylation obtains is many, need carry out the high-vacuum fractionation distillation, and post-processing difficulty is big.In addition, this technology need feed a large amount of hydrogen chloride gas, causes the spent acid solution discharging to increase, and environment is had very big pollution.
Summary of the invention
Purpose of the present invention is exactly at the prior art defective, provides that a kind of technology is simple, raw material is easy to get, operational safety, yield height, is fit to the synthesis technique of the xylometazoline hydrochloride of suitability for industrialized production.
Technical scheme of the present invention is: with 1,3-dimethyl-5-tert.-butylbenzene (8) is a starting raw material, in the presence of catalyzer, gets 2 with the chloromethylation reagent react, the 6-dimethyl-4-tertiary butyl-1-chloromethylbenzene (5); Carry out cyanation with sodium cyanide and get 2, the 6-dimethyl-4-tertiary butyl-1-benzyl cyanide (6); Get tosic acid xylometazoline (10) with quadrol tosilate (9) cyclization then; Xylometazoline is got xylometazoline hydrochloride (1) with the free back of alkali with the hydrogenchloride salify, and the total recovery of four-step reaction is 44%.
Synthetic route of the present invention is as follows:
The concrete synthesis technique step of the present invention is as follows:
(a) chloromethylation: with 1,3-dimethyl-5-tert.-butylbenzene (8) is as starting raw material, with compound (8): chloromethylation reagent: catalyst molar ratio is 1: (1.0～1.2): (0.1～0.2) feeds intake, reacted 1～3 hour down at 40～60 ℃, aftertreatment gets 2, the 6-dimethyl-4-tertiary butyl-1-chloromethylbenzene (5);
(b) cyanation: with compound (5): sodium cyanide: the mol ratio of catalyzer is 1: (1.0～1.4): (0.02～0.08) feeds intake, reflux 14～22 hours, and aftertreatment and recrystallization get 2, the 6-dimethyl-4-tertiary butyl-1-benzyl cyanide (6);
(c) ring-closure reaction: with compound (6) and quadrol tosilate (9) with 1: (1.0～1.3) mol ratio feeds intake, and is heated to 210～240 ℃ of reactions 0.5～2 hour, tosic acid xylometazoline (10).
(d) salt-forming reaction: compound (10) with alkali free after, again in organic solvent with the hydrogenchloride salify, regulate pH=4～5, xylometazoline hydrochloride (1) crude product, refining finished product.
In the above-mentioned reactions steps (a), described chloromethylation reagent is one or more mixing in chloromethyl ether, bischlormethyl ether, the chloromethyl ether, preferred chloromethyl ether.
In the above-mentioned reactions steps (a), described catalyzer is zinc chloride or aluminum trichloride (anhydrous).
In the above-mentioned reactions steps (a), when temperature of reaction is 48～52 ℃, compound (8) is 1: 0.15 o'clock with catalyst molar ratio, reacts 2 hours, and the yield of compound (5) is the highest.
In the above-mentioned reactions steps (b), described solvent is one or more mixing in acetone, butanone, methylene dichloride, trichloromethane, toluene, chlorobenzene or the diethyl carbonate, preferred acetone.
In the above-mentioned reactions steps (b), described catalyzer is one or more mixing in potassiumiodide, sodium iodide, potassiumiodide, sodium iodide, Tetrabutyl amonium bromide, tetrabutylammonium iodide, tetraethylammonium bromide, the tetraethyl ammonium iodide, preferred potassiumiodide.
In the above-mentioned reactions steps (c), preferred compound (6) is 1: 1.12 with the mol ratio of quadrol tosilate (9), and temperature of reaction is 220～230 ℃, and the reaction times is 1 hour.
In the above-mentioned reactions steps (d), used alkali is one or more mixing in yellow soda ash, sodium bicarbonate, sodium hydroxide, salt of wormwood, saleratus, potassium hydroxide, sodium-acetate, ammoniacal liquor, SODIUM PHOSPHATE, MONOBASIC, the Sodium phosphate dibasic.Preferred sodium hydroxide, potassium hydroxide or ammoniacal liquor.
In the above-mentioned reactions steps (d), employed organic solvent is N, one or more mixing, ethyl acetate and ethanol mixed solvent in dinethylformamide, sherwood oil, ethanol, methyl alcohol, acetone, tetrahydrofuran (THF), ethyl acetate, methyl acetate, propyl acetate, isopropyl acetate, normal hexane, hexanaphthene, the methylene dichloride.
Synthesis technique of the present invention has been simplified operational process of craft, has improved xylometazoline hydrochloride intermediate and final product quality, has reduced the discharging of spent acid solution, has improved production efficiency.
Synthesis technique particular embodiment of the present invention is in the following areas:
1) starting raw material 1, and 3-dimethyl-5-tert.-butylbenzene (8) is cheap and easy to get.
2) chloromethyl ether is active strong chloromethylation reagent, the transformation efficiency height, simultaneously, and reaction product purity height, impurity is few, the reaction conditions gentleness.
3) compound (5) that obtains of chloromethylation need not purifying, can be directly used in next step reaction, has shortened the technological operation step, has improved yield.
4) cyanation mild condition, side reaction is few, and is simple to operate, is easy to aftertreatment, reduced labour intensity, improved Working environment.
5) solved the problem that is difficult to industrial amplification production in the patent route in the past.
6) product purity height (greater than 99.5%), yield height (total recovery 44%), quality reaches the newest standards of Chinese Pharmacopoeia, American Pharmacopeia, British Pharmacopoeia, European Pharmacopoeia, Japanese Pharmacopoeia.
Embodiment
Following embodiment is used for further narrating the present invention, but does not impose any restrictions.
Embodiment 12, the preparation of the 6-dimethyl-4-tertiary butyl-1-chloromethylbenzene
With 1,3-dimethyl-5-tert.-butylbenzene 81 grams (0.5 mole) and aluminum trichloride (anhydrous) 13.4 grams (0.1 mole) mix, and slowly drip 41 gram chloromethyl ethers (0.5 mole), then 40-45 ℃ of reaction 3 hours.Drip 100 ml waters after reducing to room temperature, fully stir, behind the branch vibration layer, organic layer is washed till pH=7 with saturated nacl aqueous solution, and anhydrous sodium sulfate drying gets oily matter 2 after the filtering and concentrating, 6-dimethyl-4-the tertiary butyl-1-chloromethylbenzene 88.4 grams (0.42 mole), yield 84%.
Embodiment 22, the preparation of the 6-dimethyl-4-tertiary butyl-1-chloromethylbenzene
With 1,3-dimethyl-5-tert.-butylbenzene 81 grams (0.5 mole) and zinc chloride 13.6 grams (0.1 mole) mix, and slowly drip 41 gram chloromethyl ethers (0.5 mole), then 45-50 ℃ of reaction 2.5 hours.Drip 120 ml waters after reducing to room temperature, post-treating method gets product 93.6 grams (0.44 mole), yield 89% with embodiment 1.
Embodiment 32, the preparation of the 6-dimethyl-4-tertiary butyl-1-chloromethylbenzene
With 1,3-dimethyl-5-tert.-butylbenzene 50 grams (0.31 mole) and zinc chloride 6.3 grams (0.046 mole) mix, and slowly drip chloromethyl ether 27 grams (0.34 mole), then 48-52 ℃ of reaction 2 hours.Drip 60 ml waters after reducing to room temperature, post-treating method gets product 59.6 grams (0.28 mole), yield 92% with embodiment 1.
Embodiment 42, the preparation of the 6-dimethyl-4-tertiary butyl-1-chloromethylbenzene
With 1,3-dimethyl-5-tert.-butylbenzene 81 grams (0.5 mole) and aluminum trichloride (anhydrous) 3.6 grams (0.05 mole) mix, and slowly drip 48 gram chloromethyl ethers (0.6 mole), then 50-55 ℃ of reaction 2 hours.Drip 900 ml waters after reducing to room temperature, post-treating method gets product 92.6 grams (0.44 mole), yield 88% with embodiment 1.
Embodiment 52, the preparation of the 6-dimethyl-4-tertiary butyl-1-chloromethylbenzene
With 1,3-dimethyl-5-tert.-butylbenzene 162 grams (1.0 moles) and zinc chloride 18 grams (0.13 mole) mix, and slowly drip 89 gram chloromethyl ethers (1.1 moles), then 50-55 ℃ of reaction 2 hours.Drip 220 ml waters after reducing to room temperature, post-treating method gets product 190.0 grams (0.90 mole), yield 90% with embodiment 1.
Embodiment 62, the preparation of the 6-dimethyl-4-tertiary butyl-1-chloromethylbenzene
With 1,3-dimethyl-5-tert.-butylbenzene 162 grams (1.0 moles) and zinc chloride 14 grams (0.1 mole) mix, and slowly drip 97 gram chloromethyl ethers (1.2 moles), then 55-60 ℃ of reaction 1 hour.Drip 250 ml waters after reducing to room temperature, post-treating method gets product 183.6 grams (0.87 mole), yield 87% with embodiment 1.
Embodiment 72, the preparation of the 6-dimethyl-4-tertiary butyl-1-benzyl cyanide
Sodium cyanide 30.5 grams (0.62 mole), sodium iodide 3.6 grams (0.024 mole) and 75 milliliters of acetone are added in the there-necked flask, stir down and drip 2, the 6-dimethyl-4-tertiary butyl-1-chloromethylbenzene 100 grams (0.48 mole), reflux is 18 hours then.Suction filtration is removed solid salt after reducing to room temperature, uses the small amount of acetone washing salt.Filtrate merges, concentrating under reduced pressure, and gained oily matter is cooled to 5 ℃ of crystallizations with 40 milliliters of dissolve with ethanol, gets 2 after the solid filtering drying, the 6-dimethyl-4-tertiary butyl-1-benzyl cyanide 75.6 grams (0.38 mole), yield 79%.
Embodiment 82, the preparation of the 6-dimethyl-4-tertiary butyl-1-benzyl cyanide
24 gram sodium cyanides (0.49 mole), 4 gram potassiumiodides (0.024 mole) and 400 milliliters of methylene dichloride are added in the there-necked flask, stir down and drip 2, the 6-dimethyl-4-tertiary butyl-1-chloromethylbenzene 100 grams (0.48 mole), reflux is 20 hours then.Post-treating method gets product 65.3 grams (0.32 mole), yield 68% with embodiment 7.
Embodiment 92, the preparation of the 6-dimethyl-4-tertiary butyl-1-benzyl cyanide
Sodium cyanide 28 grams (0.57 mole), potassiumiodide 4 grams (0.024 mole) and 250 milliliters of acetone are added in the there-necked flask, stir down and drip 2, the 6-dimethyl-4-tertiary butyl-1-chloromethylbenzene 100 grams (0.48 mole), reflux is 20 hours then.Post-treating method gets product 76.4 grams (0.38 mole), yield 80% with embodiment 7.
Embodiment 10 2, the preparation of the 6-dimethyl-4-tertiary butyl-1-benzyl cyanide
Sodium cyanide 23.5 grams (0.48 mole), potassiumiodide 1.6 grams (0.01 mole) and 250 milliliters of acetone are added in the there-necked flask, stir down and drip 2, the 6-dimethyl-4-tertiary butyl-1-chloromethylbenzene 100 grams (0.48 mole), reflux is 22 hours then.Post-treating method gets product 71.8 grams (0.36 mole), yield 75% with embodiment 7.
Embodiment 11 2, the preparation of the 6-dimethyl-4-tertiary butyl-1-benzyl cyanide
Sodium cyanide 33 grams (0.67 mole), 5.7 gram sodium iodides (0.038 mole) and 350 milliliters of acetone are added in the there-necked flask, stir down and drip 2, the 6-dimethyl-4-tertiary butyl-1-chloromethylbenzene 100 grams (0.48 mole), reflux is 14 hours then.Post-treating method gets product 71.6 grams (0.36 mole), yield 75% with embodiment 7.
The preparation of embodiment 12 tosic acid xylometazolines
With 2, the 6-dimethyl-4-tertiary butyl-1-benzyl cyanide 50 grams (0.25 mole) and quadrol tosilate 75 grams (0.325 mole) mix, and are warming up to 210～220 ℃ of reactions 1.5 hours.Pour out while hot, the cooling after fixing gets tosic acid xylometazoline 99.6 grams (0.240 mole), yield 96%.
The preparation of embodiment 13 tosic acid xylometazolines
With 2, the 6-dimethyl-4-tertiary butyl-1-benzyl cyanide 50 grams (0.25 mole) and quadrol tosilate 70 grams (0.30 mole) mix, and are warming up to 225～235 ℃ of reactions 1 hour.Post-treating method gets tosic acid xylometazoline 100.5 grams (0.242 mole), yield 97% with embodiment 12.
The preparation of embodiment 14 tosic acid xylometazolines
With 2, the 6-dimethyl-4-tertiary butyl-1-benzyl cyanide 50 grams (0.25 mole) and quadrol tosilate 65 grams (0.28 mole) mix, and are warming up to 220～230 ℃ of reactions 1 hour.Post-treating method gets tosic acid xylometazoline 101.2 grams (0.243 mole), yield 98% with embodiment 12.
The preparation of embodiment 15 tosic acid xylometazolines
With 2, the 6-dimethyl-4-tertiary butyl-1-benzyl cyanide (0.25 mole) and quadrol tosilate 58 grams (0.25 mole) mix, and are warming up to 230～240 ℃ of reactions 30 minutes.Post-treating method gets tosic acid xylometazoline 98.5 grams (0.237 mole), yield 95% with embodiment 12.
The preparation of embodiment 16 xylometazoline hydrochlorides
30 gram tosic acid xylometazolines (0.072 mole), be dissolved in 900 ml waters, be warming up to 90 ℃, add 150 milliliter of 10% aqueous sodium hydroxide solution, stirred 30 minutes, reduce to the room temperature after-filtration, filter cake is washed with water to washing lotion pH=7, the solid xylometazoline that must dissociate after drying after the xylometazoline that will dissociate is dissolved in 150 milliliters of ethyl acetate, drips ethanol solution of hydrogen chloride to pH5.Use 50 milliliters of dehydrated alcohol heating for dissolving after the gained solid filtering drying again, the activated carbon decolorizing after-filtration, filtrate adds 135 milliliters of ethyl acetate, be cooled to 5 ℃, stir 1 hour after-filtration, filter cake washs with ethyl acetate, gets xylometazoline hydrochloride 12.4 grams (0.044 mole) after the drying, yield 61%, purity 99.76% (high performance liquid phase).
The preparation of embodiment 17 xylometazoline hydrochlorides
30 gram tosic acid xylometazolines (0.072 mole), be dissolved in 1000 ml waters, be warming up to 90 ℃, add ammoniacal liquor, stirred 20 minutes, reduce to the room temperature after-filtration, filter cake is washed with water to washing lotion pH=7, the solid xylometazoline that must dissociate after drying after the xylometazoline that will dissociate is dissolved in 150 milliliters of ethyl acetate, drips ethanol solution of hydrogen chloride to pH4.Use 50 milliliters of dehydrated alcohol heating for dissolving after the gained solid filtering drying again, the activated carbon decolorizing after-filtration, filtrate adds 150 milliliters of ethyl acetate, be cooled to 10 ℃, stir 1 hour after-filtration, filter cake washs with ethyl acetate, gets xylometazoline hydrochloride 11.8 grams (0.042 mole) after the drying, yield 58%, purity 99.80% (high performance liquid phase).
Claims (10)
1. the synthetic method of an xylometazoline hydrochloride compound, this technology comprises the steps:
(a) chloromethylation: with 1,3-dimethyl-5-tert.-butylbenzene is a starting raw material, in the presence of catalyzer, gets 2 with the chloromethylation reagent react, the 6-dimethyl-4-tertiary butyl-1-chloromethylbenzene;
(b) cyanation: 2, the 6-dimethyl-4-tertiary butyl-1-chloromethylbenzene and sodium cyanide in the presence of catalyzer, react 2, the 6-dimethyl-4-tertiary butyl-1-benzyl cyanide;
(c) ring-closure reaction: with 2, the 6-dimethyl-4-tertiary butyl-1-benzyl cyanide mixes with the quadrol tosilate, and cyclization is carried out in heating, gets the tosic acid xylometazoline;
(d) salt-forming reaction: tosic acid xylometazoline alkalization is for behind the free alkali, again in solvent with the hydrochloric acid salify, xylometazoline hydrochloride.
2. method according to claim 1 is characterized in that: the reagent of chloromethylation described in the reactions steps a is one or more mixing in chloromethyl ether, bischlormethyl ether, the chloromethyl ether.
3. method according to claim 1 is characterized in that: catalyzer described in the reactions steps a is zinc chloride or aluminum trichloride (anhydrous).
4. method according to claim 1 is characterized in that: the described catalyzer of reactions steps b is one or more mixing in potassiumiodide, sodium iodide, potassiumiodide, sodium iodide, Tetrabutyl amonium bromide, tetrabutylammonium iodide, tetraethylammonium bromide, the tetraethyl ammonium iodide.
5. method according to claim 1, it is characterized in that: the described organic solvent of reactions steps d is N, one or more mixing in dinethylformamide, sherwood oil, ethanol, methyl alcohol, acetone, tetrahydrofuran (THF), ethyl acetate, methyl acetate, propyl acetate, isopropyl acetate, normal hexane, hexanaphthene, the methylene dichloride.
6. according to claim 1,2 or 3 described synthetic methods, it is characterized in that: among the reactions steps a 1,3-dimethyl-5-tert.-butylbenzene: chloromethylation reagent: catalyst molar ratio is 1: 1.0～1.2: 0.1～0.2.
7. synthetic method according to claim 6 is characterized in that: temperature of reaction is at 40～60 ℃ among the reactions steps a.
8. according to claim 1 or 4 described synthetic methods, it is characterized in that: among the reactions steps b 2, the 6-dimethyl-4-tertiary butyl-1-chloromethylbenzene: sodium cyanide: the mol ratio of catalyzer is 1: 1.0～1.4: 0.02～0.08.
9. synthetic method according to claim 1 is characterized in that: among the reactions steps c 2, the 6-dimethyl-4-tertiary butyl-1-benzyl cyanide: quadrol tosilate mol ratio is 1: 1.0～1.3.
10. synthetic method according to claim 9 is characterized in that: temperature of reaction is at 210～240 ℃ among the reactions steps c.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103224468A (en) * | 2013-05-10 | 2013-07-31 | 范强 | Tetrahydrozoline synthesis method |
| CN103351343A (en) * | 2013-07-12 | 2013-10-16 | 天津华津制药有限公司 | Synthetic method for xylometazoline hydrochloride |
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| US5969137A (en) * | 1996-09-19 | 1999-10-19 | Virginia Commonwealth University | Benzylamidine derivatives with serotonin receptor binding activity |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5969137A (en) * | 1996-09-19 | 1999-10-19 | Virginia Commonwealth University | Benzylamidine derivatives with serotonin receptor binding activity |
Non-Patent Citations (2)
| Title |
|---|
| 《化学研究与应用》 19991231 申东升 芳香烃氯甲基化反应的综述 第229-234页 2-3,6-7 第11卷, 第3期 2 * |
| 《现代药物与临床》 20100330 黄淑云等 盐酸赛洛唑啉的合成工艺 第145-147页 1-10 第25卷, 第2期 2 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103224468A (en) * | 2013-05-10 | 2013-07-31 | 范强 | Tetrahydrozoline synthesis method |
| CN103351343A (en) * | 2013-07-12 | 2013-10-16 | 天津华津制药有限公司 | Synthetic method for xylometazoline hydrochloride |
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Application publication date: 20101229 Assignee: HUBEI YUANDA TIANTIANMING PHARMACEUTICAL CO., LTD. Assignor: Wuhan Wuyao Technology Co., Ltd. Contract record no.: 2014420000053 Denomination of invention: Method for synthesizing xylometazoline hydrochloride compound Granted publication date: 20120509 License type: Exclusive License Record date: 20140428 |
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