CN105622434B - The preparation method of 1 (2,5 Dimethoxyphenyl) 2 ethylaminoethanols - Google Patents
The preparation method of 1 (2,5 Dimethoxyphenyl) 2 ethylaminoethanols Download PDFInfo
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- CN105622434B CN105622434B CN201511035285.3A CN201511035285A CN105622434B CN 105622434 B CN105622434 B CN 105622434B CN 201511035285 A CN201511035285 A CN 201511035285A CN 105622434 B CN105622434 B CN 105622434B
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
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Abstract
The invention provides a kind of preparation method of midodrine hydrochloride intermediate 1 (2,5 Dimethoxyphenyl) 2 ethylaminoethanols.With 2,5 dimethoxy benzaldehydes are raw material, and 1 (2,5 Dimethoxyphenyl) 2 nitroethyl alcohols are condensed to yield with nitromethane under alkali effect, the latter using boron reducing agent through being reduced to obtain 1 (2,5 Dimethoxyphenyl) 2 ethylaminoethanols.The preparation method of 1 (2,5 Dimethoxyphenyl) 2 ethylaminoethanols provided by the invention, there is the features such as reaction condition is gentle, and operating process is simple, high income, environmentally friendly, and production cost is low, be suitable for industrialized production.
Description
Technical field
The present invention relates to a kind of intermediate 1- (2,5- Dimethoxyphenyls) -2- for treating low blood pressure medicine midodrine hydrochloride
The preparation method of ethylaminoethanol.
Background technology
The chemical name of midodrine hydrochloride is 2- amino-N- [2- (2,5- Dimethoxyphenyl) -2- hydroxyethyls]-acetyl
Amine hydrochlorate, it is the activator that a kind of strong selectivity acts on peripheral nerve alpha-receptor, is mainly used in treating orthostatic hypotension.
Its structure is as follows：
1- (2,5- Dimethoxyphenyls) -2- ethylaminoethanols are the important intermediates of synthetic hydrochloric acid midodrine.Document at present
In existing a variety of preparation methods reports.
Scheme I
It is after raw material is condensed with KCN, to restore cyano group system that WO9638143, which discloses one kind with 2,5- dimethoxy benzaldehydes,
The method (Scheme I) of standby 1- (2,5- Dimethoxyphenyls) -2- ethylaminoethanols.The method has used the potassium cyanide of severe toxicity, boron
Alkane, first step reaction are separated using column chromatography, and total recovery only has 34%, is not suitable for industrialized production.
Scheme II
US6201153 discloses another method for preparing 1- (2,5- Dimethoxyphenyl) -2- ethylaminoethanols, uses
Terephthaldehyde's ether is acylated, Azide, finally reduction obtains target product as initiation material through Friedel-Crafts
(Scheme II).The method has used the lithium aluminium hydride reduction of costliness higher as reducing agent, cost.And drawn using sodium azide
Enter amino, sodium azide is impacted easy blast, and reaction finishes the also danger close of the wastewater treatment containing sodium azide.
Scheme III
Chinese Journal of Pharmaceuticals, 2006,37 (7), 445-446, US6201153 methods are improved, using two
Benzylamine is reacted instead of sodium azide, is then sloughed benzyl with potassium borohydride reduction carbonyl, then catalytic hydrogenation and is obtained 1- (2,5-
Dimethoxyphenyl) -2- ethylaminoethanols (Scheme III).The method route is longer, and complex operation, the three wastes are more, to environment
It is unfriendly.
Catalytic hydrogenation is employed in patent CN201110002894.4 to be reduced, and is with the dangerous technique of China, is used
Expensive palladium catalyst and yield is relatively low, not economical enough.
The content of the invention
To solve the above-mentioned drawback in existing 1- (2,5- Dimethoxyphenyl) -2- ethylaminoethanol preparation methods, this hair
Bright to provide a kind of novel preparation method, this method high income, cost are low, safe, environmentally friendly, are adapted to industrialized production.
A kind of preparation method of 1- (2,5- Dimethoxyphenyl) -2- ethylaminoethanols, described 1- (2,5- dimethoxy benzenes
Base) -2- nitroethyl alcohols are made by following method：
(1) with 2,5- dimethoxy benzaldehydes as raw material, using saturated fat alcohol roh as solvent, in the presence of alkali
It is condensed with nitromethane, reaction terminates addition acid and neutralized, and filters, is dried to obtain 1- (2,5- Dimethoxyphenyl) -2- nitre
Base ethanol；
(2) with 1- (2,5- Dimethoxyphenyl) -2- nitroethyl alcohols as raw material, using saturated fat alcohol roh as solvent,
Reduced using boron reducing agent, obtain 1- (2,5- Dimethoxyphenyl) -2- ethylaminoethanols.
Further, the alkali in described step (1) is alkali metal hydroxide, alkaline earth metal hydroxide or other nothings
The one or more of machine alkali or organic base, the dosage of alkali is the 1 of the mole of 2,5- dimethoxy benzaldehydes in the step (1)
~10 times, nitromethane dosage is 1~8 times of 2,5- dimethoxy benzaldehyde moles in the step (1).
Further, in the step (1), the setting-up point is -10 DEG C~20 DEG C, and the reaction time is anti-for detection
Untill answering completely, the sour dosage is 1~5 times of 2,5- dimethoxy benzaldehyde moles.
Further, in the step (1), described acid is inorganic acid.
Further, in the step (1), the acid is hydrochloric acid, the one or more in sulfuric acid, nitric acid.
Further, the acid is organic acid.
Further, it is described sour for acetic acid, the mixture of the one or both of butyric acid.
Further, in the step (2), R is selected from the alkane of carbon number 1 to 5 in described saturated fat alcohol roh
One or more in base, water, ethyl acetate, tetrahydrofuran, ether, isopropyl ether, methyl tertiary butyl ether(MTBE), benzene, toluene.
Further, in the step (2), the temperature of the reduction reaction is -30~100 DEG C, is preferably -10~0 DEG C.
Further, the boron reducing agent described in the step (2) is one kind in sodium borohydride, potassium borohydride, borine
Or several mixture.
It is of the invention to be relative to the beneficial effect of prior art：
(1) it is safer without catalytic hydrogenation, reaction condition milder, production.
(2) mild condition, the product purity obtained is high, suitable for industrialized production.
The present invention is further illustrated below by embodiment, provides the implementation detail of the present invention, but is not intended to
Limit protection scope of the present invention.The equivalent substitution done of technical characteristic to the present invention is correspondingly improved, and still falls within this hair
Within bright protection domain.
Embodiment
Embodiment 1：
(1) preparation of 1- (2,5- Dimethoxyphenyl) -2- nitroethyl alcohols
294.0g nitromethanes (4.8mol), 200.0g are added in the 2L four-hole bottles equipped with electric mixer and thermometer
(1.2mol) 2,5- dimethoxy benzaldehydes and 480ml ethanol, the temperature of the reaction solution is down to 10~15 DEG C, is then added dropwise
126ml (1.32mol) 10.5M sodium hydrate aqueous solution, is added dropwise rear insulated and stirred 30 minutes.660ml is added afterwards
(1.62mol) 2.45M acetic acid aqueous solution is neutralized, and continues stirring reaction 30 minutes, is filtered, by filter cake with a small amount of petroleum ether
Elution twice, is dried to obtain 261.7g 1- (2,5- Dimethoxyphenyl) -2- nitroethyl alcohols, and HPLC purity is 98.9%, yield
For 96%.
(2) preparation of 1- (2,5- Dimethoxyphenyl) -2- ethylaminoethanols
500ml ethanol is added in 2L reaction bulbs, stirs lower addition 100.0g 1- (2,5- Dimethoxyphenyl) -2- nitros
Ethanol is cooled to -10 DEG C, and 54 grams of sodium borohydrides are added portionwise, add insulation reaction 2 hours.HPLC detection reactions finish, and add
500ml water, remove solvent under reduced pressure, filter, dry 122 grams of crude products.It is recrystallized to give 72g white solids, HPLC purity
98.4%, yield 83%.
Embodiment 2：
(1) preparation of 1- (2,5- Dimethoxyphenyl) -2- nitroethyl alcohols
7.32g (0.12mol) nitromethane, 10.0g are added in the 1L four-hole bottles equipped with electric mixer and thermometer
(0.06mol) 2,5- dimethoxy benzaldehydes and 25ml methanol, the temperature of the reaction solution is down to 5~10 DEG C, is then added dropwise
21ml (0.066mol) 12.5% potassium hydroxide aqueous solution, is added dropwise rear insulated and stirred 30 minutes.33ml is added afterwards
(0.081mol) 15% acetic acid aqueous solution is neutralized, and continues stirring reaction about one hour, is filtered, by filter cake water wash two
It is secondary, filter, be dried to obtain 10.88g 1- (2,5- Dimethoxyphenyl) -2- nitroethyl alcohols.HPLC purity is 99.7%, yield
For 80%
(2) preparation of 1- (2,5- Dimethoxyphenyl) -2- ethylaminoethanols
500ml methanol is added in 2L reaction bulbs, stirs lower addition 100.0g 1- (2,5- Dimethoxyphenyl) -2- nitros
Ethanol is cooled to -10 DEG C, and 54 grams of potassium borohydrides are added portionwise, add insulation reaction 3 hours.HPLC detection reactions finish, and add
500ml water, remove solvent under reduced pressure, filter, dry 112 grams of crude products.It is recrystallized to give 64g white solids, HPLC purity
98.2%, yield 73%.
Embodiment 3：
(1) preparation of 1- (2,5- Dimethoxyphenyl) -2- nitroethyl alcohols
146.4g (2.4mol) nitromethane, 200.0g are added in the 2L four-hole bottles equipped with electric mixer and thermometer
(1.2mol) 2,5- dimethoxy benzaldehydes and 600ml ethanol, the temperature of the reaction solution is down to 0~5 DEG C, is then added dropwise
400ml (2.64mol) 6.6M sodium hydrate aqueous solution, is added dropwise rear insulated and stirred 30 minutes.660ml is added afterwards
(1.62mol) 2.45M aqueous hydrochloric acid solution is neutralized, and continues stirring reaction about one hour, is filtered, by filter cake water wash two
It is secondary, filter, obtain faint yellow solid shape 1- (2,5- Dimethoxyphenyl) -2- nitroethyl alcohols, directly carried out without drying next
Step reaction, HPLC purity are 99.0%.
(2) preparation of 1- (2,5- Dimethoxyphenyl) -2- ethylaminoethanols
300ml methanol and 200ml water are added in 2L reaction bulbs, stirs lower addition 100.0g 1- (2,5- dimethoxy benzenes
Base) -2- nitroethyl alcohols are cooled to -10 DEG C, and 54 grams of potassium borohydrides are added portionwise, add insulation reaction 3 hours.HPLC detection reactions
Finish, add 500ml water, remove solvent under reduced pressure, filter, dry 118 grams of crude products.It is recrystallized to give 70g white solids, HPLC
Purity 98.2%, yield 80%.
Claims (6)
- A kind of 1. preparation method of 1- (2,5- Dimethoxyphenyl) -2- ethylaminoethanols, it is characterised in that：Described 1- (2,5- Dimethoxyphenyl) -2- nitroethyl alcohols are made by following method：(1) with 2,5- dimethoxy benzaldehydes as raw material, using saturated fat alcohol roh as solvent, in the presence of alkali with nitre Methylmethane is condensed, and reaction terminates addition acid and neutralized, and filters, is dried to obtain 1- (2,5- Dimethoxyphenyl) -2- nitro second Alcohol；(2), using saturated fat alcohol roh as solvent, used as raw material with 1- (2,5- Dimethoxyphenyl) -2- nitroethyl alcohols Boron reducing agent is reduced, and obtains 1- (2,5- Dimethoxyphenyl) -2- ethylaminoethanols；Wherein, the alkali in described step (1) is alkali metal hydroxide, alkaline earth metal hydroxide or other inorganic bases or had The one or more of machine alkali, the dosage of alkali is 1~10 times of the mole of 2,5- dimethoxy benzaldehydes in the step (1), Nitromethane dosage is 1~8 times of 2,5- dimethoxy benzaldehyde moles in the step (1)；In the step (1), the setting-up point is -10 DEG C~20 DEG C, untill the reaction time is detection reaction completely, institute The dosage for stating acid is 1~5 times of 2,5- dimethoxy benzaldehyde moles；In the step (2), the temperature of the reduction reaction is -10~0 DEG C；The boron reducing agent is sodium borohydride or hydroboration Potassium.
- 2. the preparation method of 1- (2,5- Dimethoxyphenyl) -2- nitroethyl alcohols as claimed in claim 1, it is characterised in that： In the step (1), described acid is inorganic acid.
- 3. the preparation method of 1- (2,5- Dimethoxyphenyl) -2- nitroethyl alcohols as claimed in claim 1, it is characterised in that： In the step (1), the acid is hydrochloric acid, the one or more in sulfuric acid, nitric acid.
- 4. the preparation method of 1- (2,5- Dimethoxyphenyl) -2- nitroethyl alcohols as claimed in claim 1, it is characterised in that： In the step (1), the acid is organic acid.
- 5. the preparation method of 1- (2,5- Dimethoxyphenyl) -2- nitroethyl alcohols as claimed in claim 1, it is characterised in that： In the step (1), the acid is acetic acid, the mixture of the one or both of butyric acid.
- 6. the preparation method of 1- (2,5- Dimethoxyphenyl) -2- nitroethyl alcohols as claimed in claim 1, it is characterised in that： In the step (2), the one or more in described saturated fat alcohol roh in alkyl of the R selected from carbon number 1 to 5.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996038143A1 (en) * | 1995-06-02 | 1996-12-05 | Synaptic Pharmaceutical Corporation | The use of alpha-1c-selective adrenoceptor agonists for the treatment of urinary incontinence |
| CN101407474A (en) * | 2008-11-18 | 2009-04-15 | 东华大学 | Preparation of 2-bromo-4,5-dimethoxy benzenepropanenitrile |
| CN102060719A (en) * | 2011-01-07 | 2011-05-18 | 天津市炜杰科技有限公司 | Method for preparing midodrine hydrochloride intermediate 1-(2,5-dimethoxy benzaldehyde)-2-aminoethanol |
-
2015
- 2015-12-31 CN CN201511035285.3A patent/CN105622434B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996038143A1 (en) * | 1995-06-02 | 1996-12-05 | Synaptic Pharmaceutical Corporation | The use of alpha-1c-selective adrenoceptor agonists for the treatment of urinary incontinence |
| CN101407474A (en) * | 2008-11-18 | 2009-04-15 | 东华大学 | Preparation of 2-bromo-4,5-dimethoxy benzenepropanenitrile |
| CN102060719A (en) * | 2011-01-07 | 2011-05-18 | 天津市炜杰科技有限公司 | Method for preparing midodrine hydrochloride intermediate 1-(2,5-dimethoxy benzaldehyde)-2-aminoethanol |
Non-Patent Citations (2)
| Title |
|---|
| 基于硼氢化钾-三氟化硼乙醚还原体系的3,4-二甲氧基苯乙胺合成新方法;李定中等;《广东化工》;20100228(第02期);第19-20页 * |
| 盐酸米多君的合成;孟庆玉等;《中国医药工业杂志》;20020520(第05期);第213-215页 * |
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