CN102381991A - Method for synthesizing DL-Octopamine hydrochloride - Google Patents

Abstract

The present invention relates to a method for synthesizing DL-Octopamine hydrochloride. A technical problem to be settled is providing a chemical synthesis method of the DL-Octopamine hydrochloride. The method has the following advantages: high efficiency, low cost, high suitability for large-scale industrial production, and stable quality of the obtained product. According to the method of the invention, phenol is used as an initial raw material. The phenol reacts with aminoacetonitrile hydrochloride in nonpolar solvent at the presence of Lewis acid catalyst. Ketoimine is obtained and an intermediate is obtained through hydrolysis. The intermediate is dissolved in mixed solvent of water and methanol and is inputted into a high-pressure autoclave. The DL-Octopamine hydrochloride is obtained through catalytic hydrogenation by 5% Pd/C.

Description

A kind of compound method of chapter amine hydrochlorate

Technical field

The invention belongs to the synthetic field of organic chemistry, specifically is a kind of chemical synthesis process of chapter amine hydrochlorate.

Background technology

The chapter amine hydrochlorate, chemical name 1-(4-hydroxy phenyl)-2-monoethanolamine hydrochloride, another name octopamine, positive synephrine, norsympatol.The chemical structural formula of chapter amine hydrochlorate is following:

Molecular formula is C ₈H ₁₁NO ₂ ^.HCl, molecular weight are 189.64.Its purposes and synephrine hydrochloride are similar.It derives from the dry young fruit of rutaceae bitter orange (Citrus aurantium L.), is suprarenin alpha-receptor stimulant, the effect that have vasoconstriction, produces the rising blood pressure.The chapter amine hydrochlorate has recorded three state's pharmacopeia and the Ph.Ges in Northern Europe; It is natural stimulant; Without any side effects and positive reaction; Clinical ypotension, collapse and shock, postural hypotension etc. when being used to treat bronchial asthma and operation and anesthesia, and be widely used in healthcare such as medicine, food, beverage.Foreign study finds that synephrine boosts except that having, the Antishock function, also have following effect: improve metabolism, increase heat exhaustion, improve energy level, oxidation of fat, fat-reducing.Therefore, the chapter amine hydrochlorate is commonly used to be the effective constituent in the slimming medicine, and has advantages such as purity height, stable in properties, easy preservation, makes it have using value widely.

Because plant origin is limited, its output can not adapt to growing demand always.Do not find related methods of synthesis in the existing document yet.

Summary of the invention

The technical issues that need to address of the present invention are, overcome the chemical synthesis process that a kind of chapter amine hydrochlorate is provided, and this method is efficient, low-cost and suitable large-scale industrial production, and the constant product quality that obtains, content is greater than 98%.

The present invention is achieved through following technical scheme, it is characterized in that comprising the steps:

1, a kind of compound method of chapter amine hydrochlorate, as follows:

A) acylation reaction:

With phenol is main raw material, in the presence of the Lewis acid catalyst, reacts in non-polar solvent with the aminoacetonitriles hydrochloride, obtains ketoimine through reaction, obtains the amino acetophenone hydrochloride of midbody 1-(4-hydroxy phenyl)-2-through hydrolysis again; The concrete reaction as follows:

B) reduction reaction:

The amino acetophenone hydrochloride of midbody 1-(4-hydroxy phenyl)-2-is dissolved in the mixed solvent of water and methyl alcohol, drops into autoclave, the Pd/C catalytic hydrogenation with 5% obtains the chapter amine hydrochlorate; The concrete reaction as follows:

Described phenol: Lewis acid: aminoacetonitriles hydrochloride mol ratio is 1:1:1 ~ 2; Lewis acid is selected from aluminum chloride, iron(ic)chloride, zinc chloride, boron trifluoride or titanium tetrachloride; Temperature of reaction is 0 ~ 25 ℃, and the reaction times is 18 ~ 24h, 35 ~ 60 ℃ of hydrolysis temperatures; Used non-polar solvent is selected from one or more mixture of methylene dichloride, ethylene dichloride, tetracol phenixin or toluene;

Described reduction reaction pressure-controlling 1.5 ± 0.1Mpa, temperature of reaction is 20 ~ 45 ℃, the reaction times is 7 ~ 24h; The volume ratio of water and methyl alcohol is 1:0.5 ~ 1:5.

Beneficial effect: the inventive method is starting raw material with phenol, obtains the chapter amine hydrochlorate through acidylate, reduction two-step reaction synthetic, has that raw material is inexpensive, route is short, yield is high, constant product quality, and content is fit to advantages such as large-scale production greater than 98%.

Description of drawings

Fig. 1 is the infrared spectrogram of embodiment 1 product.

Embodiment

Through embodiment, further bright specifically below to technical scheme work of the present invention, but the present invention is not limited to this embodiment.

Embodiment 1

A) acylation reaction.In reaction kettle, add 120kg methylene dichloride, 38.5kg phenol and 35kg aminoacetonitriles hydrochloride successively.Be cooled to 5 ± 5 ℃, slowly add the 106kg aluminum trichloride (anhydrous) in batches, 10 ± 10 ℃ of controlled temperature, reinforced finishing, logical hydrogen chloride gas is not till absorbing.20 ± 5 ℃ of insulation reaction 18 hours add the tap water of 220kg in another reaction kettle, logical icy salt solution temperature is reduced to 5 ± 5 ℃; In good this still of material suction of insulation reaction, slowly suction, controlled temperature is at 40 ± 10 ℃; Reinforced finishing is warming up to 55 ± 5 ℃ and is incubated half a hour.Question response finishes, and logical cooling water temperature to 30 ± 5 ℃ is centrifugal, dries, and gets the amino acetophenone hydrochloride bullion of midbody 1-(4-hydroxy phenyl)-2-, uses an amount of recrystallizing methanol.Yield 80%.

B) reduction reaction.With the dissolving of 100kg tap water, in the suction hydrogenation still, the palladium charcoal is with in the methyl alcohol dilution suction still with the above-mentioned midbody for preparing, and suction remains methyl alcohol (amounting to 100kg) again.With nitrogen replacement 3 times, use hydrogen exchange again 2 times, open stirring, under the room temperature, hydrogenation to 1.5 ± 0.1Mpa leads directly to H-H reaction 24h.Reaction finishes, and puts into open-top pail, in first suction filtration to the press filtration still, adds the 1kg gac again, and press filtration in the suction water-bath concentration kettle, is distilled to dried to open-top pail.0.5 times of weight ethanol of suction again, water-bath distillation band water is to doing the ethanol of 0.8 times of weight of back suction; Normal pressure has been warming up to ethanol and has distillated, and is static, 0.8 times of ETHYLE ACETATE of suction; Stirring is cooled to 25 ± 5 ℃; Centrifugal, the acetone that drops into centrifugal material again 1.5 times of reaction kettle suction is warming up to 30 minutes centrifugal while hot chapter amine hydrochlorates that get of 40 ± 5 ℃ of stirrings, advances the drying room oven dry.Yield is 95%.The ir spectra (see figure 1) of products therefrom is consistent with document.(measured value: IR ν: 3460,1613,1515,1446,1128,1039,997,829, cm ^-1)

Embodiment 2

A) acylation reaction.In reaction kettle, add 120kg ethylene dichloride, 38.5kg phenol and 35kg aminoacetonitriles hydrochloride successively.Be cooled to 5 ± 5 ℃, slowly add aluminum trichloride (anhydrous) in batches, 10 ± 10 ℃ of controlled temperature, reinforced finishing, logical hydrogen chloride gas is not till absorbing.20 ± 5 ℃ of insulation reaction 18 hours add the tap water of 220kg in another reaction kettle, logical icy salt solution temperature is reduced to 5 ± 5 ℃; In good this still of material suction of insulation reaction, slowly suction, controlled temperature is at 40 ± 10 ℃; Reinforced finishing is warming up to 55 ± 5 ℃ and is incubated half a hour.Question response finishes, and logical cooling water temperature to 30 ± 5 ℃ is centrifugal, dries, and gets the amino acetophenone hydrochloride bullion of midbody 1-(4-hydroxy phenyl)-2-, uses an amount of recrystallizing methanol.Yield 85%.

B) reduction reaction.With the dissolving of 100kg tap water, in the suction hydrogenation still, the palladium charcoal is with in the methyl alcohol dilution suction still with the above-mentioned midbody for preparing, and suction remains methyl alcohol (amounting to 200kg) again.With nitrogen replacement 3 times, use hydrogen exchange again 2 times, open stirring, hydrogenation to 1.5 ± 0.1Mpa slowly is warming up to 50 ℃, logical H-H reaction 8h.Reaction finishes, and puts into open-top pail, in first suction filtration to the press filtration still, adds the 1kg gac again, and press filtration in the suction water-bath concentration kettle, is distilled to dried to open-top pail.0.5 times of weight ethanol of suction again, water-bath distillation band water is to doing the ethanol of 0.8 times of weight of back suction; Normal pressure has been warming up to ethanol and has distillated, and is static, 0.8 times of ETHYLE ACETATE of suction; Stirring is cooled to 25 ± 5 ℃; Centrifugal, the acetone that drops into 1.5 times of reaction kettle suction to centrifugal material again is warming up to 40 ± 5 ℃ and stirs and centrifugally while hot must expect in 30 minutes, advances the drying room oven dry.Yield is 90%.Ir spectra is with embodiment 1.

Embodiment 3

A) acylation reaction.In reaction kettle, add 120kg ethylene dichloride, 38.5kg phenol and 35kgN-methylamino acetonitrilehydrochlorate successively.Be cooled to 5 ± 5 ℃, slowly add Zinc Chloride Anhydrous in batches, 10 ± 10 ℃ of controlled temperature, reinforced finishing, logical hydrogen chloride gas is not till absorbing.20 ± 5 ℃ of insulation reaction 24 hours add the tap water of 220kg in another reaction kettle, logical icy salt solution temperature is reduced to 5 ± 5 ℃; In good this still of material suction of insulation reaction, slowly suction, controlled temperature is at 40 ± 10 ℃; Reinforced finishing is warming up to 55 ± 5 ℃ and is incubated half a hour.Question response progression, logical cooling water temperature to 30 ± 5 ℃, centrifugal, dry, get the amino acetophenone hydrochloride bullion of midbody 1-(4-hydroxy phenyl)-2-, use an amount of recrystallizing methanol.Yield 75%.

B) reduction reaction.With the dissolving of 50kg tap water, in the suction hydrogenation still, the palladium charcoal is with in the methyl alcohol dilution suction still with the above-mentioned midbody for preparing, and suction remains methyl alcohol (amounting to 200kg) again.With nitrogen replacement 3 times, use hydrogen exchange again 2 times, open stirring, under the room temperature, hydrogenation to 1.5 ± 0.1Mpa leads directly to H-H reaction 18h.Reaction finishes, and puts into open-top pail, in first suction filtration to the press filtration still, adds the 1kg gac again, and press filtration in the suction water-bath concentration kettle, is distilled to dried to open-top pail.0.5 times of weight ethanol of suction again, water-bath distillation band water is to doing the ethanol of 0.8 times of weight of back suction; Normal pressure has been warming up to ethanol and has distillated, and is static, 0.8 times of ETHYLE ACETATE of suction; Stirring is cooled to 25 ± 5 ℃; Centrifugal, the acetone that drops into 1.5 times of reaction kettle suction to centrifugal material again is warming up to 40 ± 5 ℃ and stirs and centrifugally while hot must expect in 30 minutes, advances the drying room oven dry.Yield is 80%.Ir spectra is with embodiment 1.

Claims (1)

1. the compound method of a chapter amine hydrochlorate is characterized in that as follows:

A) acylation reaction:

With phenol is main raw material, in the presence of the Lewis acid catalyst, reacts in non-polar solvent with the aminoacetonitriles hydrochloride, obtains ketoimine through reaction, obtains the amino acetophenone hydrochloride of midbody 1-(4-hydroxy phenyl)-2-through hydrolysis again; The concrete reaction as follows:

；

B) reduction reaction:

The amino acetophenone hydrochloride of midbody 1-(4-hydroxy phenyl)-2-is dissolved in the mixed solvent of water and methyl alcohol, drops into autoclave, the Pd/C catalytic hydrogenation with 5% obtains the chapter amine hydrochlorate; The concrete reaction as follows:

；

Described phenol: Lewis acid: aminoacetonitriles hydrochloride mol ratio is 1:1:1 ~ 2; Lewis acid is selected from aluminum chloride, iron(ic)chloride, zinc chloride, boron trifluoride or titanium tetrachloride; Temperature of reaction is 0 ~ 25 ℃, and the reaction times is 18 ~ 24h, 35 ~ 60 ℃ of hydrolysis temperatures; Used non-polar solvent is selected from one or more mixture of methylene dichloride, ethylene dichloride, tetracol phenixin or toluene;

Described reduction reaction pressure-controlling 1.5 ± 0.1Mpa, temperature of reaction is 20 ~ 45 ℃, the reaction times is 7 ~ 24h; The volume ratio of water and methyl alcohol is 1:0.5 ~ 1:5.

Images