CN111807975A - A kind of preparation method of dobutamine hydrochloride intermediate compound - Google Patents

Abstract

The invention discloses a preparation method of a dobutamine hydrochloride intermediate compound. The present invention adopts 3,4-dimethoxyphenethylamine and 4-(4-methoxyphenyl)-2-butanone as starting materials, acetic acid as catalyst, cyclohexane as reflux water separator, reflux separator The condensation product is obtained from water, which is further reduced by hydrogenation using potassium borohydride, and salified with hydrochloric acid to obtain the crude intermediate of dobutamine hydrochloride. Isopropanol is used to dissolve under reflux, filter while hot to remove inorganic salts produced during the preparation of the intermediate, and purify to obtain the dobutamine hydrochloride intermediate. The method avoids the high-pressure catalytic hydrogenation operation in the prior art, greatly reduces potential safety hazards, avoids the use of expensive metal catalysts, reduces production costs, and avoids the use of some highly toxic reagents and genotoxic reagents.

Description

A kind of preparation method of dobutamine hydrochloride intermediate compound

technical field

The invention belongs to the technical field of medicinal chemistry, and in particular relates to a preparation method of a dobutamine hydrochloride intermediate compound.

Background technique

With the development of modern society, people's dietary life has been greatly improved, followed by some "happy troubles", and the incidence of cardiovascular diseases is increasing year by year. The accelerated pace of life and the pressure of daily life make the incidence of cardiovascular disease tend to be younger. Heart failure and myocardial infarction are both cardiovascular diseases with high morbidity, and the market demand for cardiogenic shock drugs caused by cardiovascular diseases is increasing year by year. Dobutamine hydrochloride is an important anti-shock drug. The main function of dobutamine hydrochloride is to stimulate β-adrenergic receptors, which can enhance cardiac contraction, increase heart rate, increase blood pressure and dilate blood vessels. Dobutamine produced less heart rate and peripheral vasodilator effects. As a short-term treatment drug, the market prospect is good.

Dobutamine hydrochloride, the compound patent is US3987200, which was applied by Lilly Company in 1972. The current synthesis of dobutamine hydrochloride is mainly based on 3,4-dimethoxyphenethylamine and 4-(4-methoxyphenyl)-2-butanone as starting materials. After the salt reaction, the intermediate N-(3,4-dimethoxyphenethyl)-4-(4-methoxyphenyl)butan-2-amine hydrochloride (compound V) is obtained, and compound V is demethylated After purification, dobutamine hydrochloride is obtained. Among them, compound V is one of the most important intermediates of dobutamine hydrochloride. After demethylation and hydrochloric acid salt formation, dobutamine hydrochloride can be obtained.

In patent US3987200, the method for preparing compound V was reported using 3,4-dimethoxyphenethylamine and 4-(4-methoxyphenyl)-2-butanone as raw materials. The method for high-pressure hydrogenation of palladium carbon, directly condensing 3,4-dimethoxyphenethylamine and 4-(4-methoxyphenyl)-2-butanone, and acidifying to obtain compound V; Embodiment 2 adopts p-toluenesulfonic acid is used as a catalyst, and toluene is used as a backflow water separator to condense both 3,4-dimethoxyphenethylamine and 4-(4-methoxyphenyl)-2-butanone to obtain compound III, The compound V is obtained by hydrogenation reduction with palladium-carbon to form a salt. Both of the above-mentioned methods involve high-pressure hydrogenation reaction, which requires the use of expensive palladium-carbon noble metal catalysts, and the material cost is relatively high, and the safety hazard in the high-pressure hydrogenation operation process is relatively serious.

Shanghai No. 2 Pharmaceutical Factory reported that 3,4-dimethoxyphenethylamine and 4-(4-methoxyphenyl)-2-butanone were used as raw materials, under the catalysis of p-toluenesulfonic acid, benzene refluxed to separate water, Dehydration and condensation to obtain compound III, which is reduced with potassium borohydride, extracted with ether, and salified with ether hydrochloric acid solution to obtain compound V. Although this method does not use expensive palladium-carbon catalysts, the used catalyst p-toluenesulfonic acid easily reacts with alcohols to generate genotoxic impurity p-toluenesulfonate, benzene is very toxic, p-toluenesulfonic acid, benzene In the production of APIs, very strict control limits for the two materials need to be formulated separately, which invisibly increases the difficulty of impurity removal in the process and increases the risk of product quality. In addition, the use of ether extraction to remove inorganic salts is difficult to completely extract organic substances, and ether has a low flash point and a large risk factor during use.

SUMMARY OF THE INVENTION

The present invention provides a preparation method of dobutamine hydrochloride intermediate compound in order to solve the existing problems. The method avoids the use of highly toxic or warning structural reagents, and avoids operations with high risk factors, and the solvents used are all conventional reagents. , the toxicity is small, the solvent recovery is convenient, and an effective method for removing non-polar salts is provided in the post-processing process.

The technical solution adopted by the present invention to solve the technical problem is as follows: a preparation method of a dobutamine hydrochloride intermediate compound is provided, as follows:

The specific steps are:

(1) condensation reaction: take compound I and compound II as starting materials, add compound I, compound II, water-separating agent, and catalyst into the reactor, stir and heat up to reflux, and dewater the reflux until no more water comes out, A condensation product (compound III) is obtained;

(2) reduction reaction: atmospheric distillation removes the water separating agent, adds a solvent, a reducing agent, and stirs and heats up the reaction to obtain compound IV;

(3) salt-forming reaction: in the compound IV reaction solution, drip hydrochloric acid into a salt, obtain the crude product of compound V after cooling and crystallization, filtration and drying;

(4) Desalting by hot filtration: after the compound V crude product is heated up and dissolved in a solvent, desalted by hot filtration, cooled and crystallized to obtain the crude compound V crude product after demineralization;

(5) Refining: the crude compound V obtained in step 4 after desalination is dissolved in a solvent, cooled for crystallization, and dried to obtain compound V with high purity and high content.

Further preferably, the catalyst used in the condensation reaction in step (1) is one of formic acid, acetic acid and propionic acid, preferably acetic acid. Using formic acid or acetic acid or propionic acid as a catalyst avoids the introduction of p-toluenesulfonic acid genotoxic impurities.

Further preferably, the molar ratio of compound I and compound II described in step (1) is 1.3:1-1:1.3, preferably 1:1.05, compound II is cheaper than compound I, and compound II is slightly excessive, which can ensure compound I The reaction is sufficient, and the material cost can be reduced. In addition, the excess of compound II will produce relatively more by-products.

Further preferably, the molar ratio of the catalyst described in the step (1) to the compound I is 0.01:1-0.3:1, preferably 0.01:1, which can not only ensure the catalytic effect, but also prevent the catalyst dosage from being too high, and form a salt with the compound I, affect yield.

Further preferably, the reflux water separation solvent in step (1) is cyclohexane, the temperature used for the cyclohexane reflux separation is 80-85 °C, and the reaction time is 2-12 h, preferably 6-8 h, which can ensure the separation of water. water completely. Using cyclohexane as the reflux water separation solvent to carry out the condensation reaction avoids the use of highly toxic compounds toluene and benzene, and at the same time, because the azeotrope of cyclohexane/water is low, energy consumption can be reduced to a certain extent.

Further preferably, the reducing agent used in the hydrogenation reduction reaction of step (2) is a kind of in lithium borohydride, sodium borohydride and potassium borohydride, preferably potassium borohydride, potassium borohydride and alcohol solvent reaction are relatively mild, Reduce safety hazards in the reaction process.

Further preferably, the mole ratio of the reducing agent and compound I in step (2) is 0.25:1-1:1, preferably 0.5:1, and under the condition that the amount of catalyst is less, it is ensured that the reduction reaction is fully carried out.

Further preferably, the solvent used in the hydrogenation reduction reaction in step (2) is one of anhydrous methanol, anhydrous ethanol and isopropanol, preferably anhydrous ethanol; the hydrogenation reduction reaction temperature is 20-80 ° C , the reaction time is 1-12h, the preferred reaction temperature is 60-70°C, and the reaction time is 2-3h. At this temperature, the reaction rate is moderate and the reaction time is relatively short.

Further preferably, the solvent used for the demineralization of the crude compound V described in step (4) and step (5) is one of methanol, absolute ethanol and isopropanol, preferably isopropanol. Select one of methanol, absolute ethanol or isopropanol to remove salts by hot filtration, which can easily and thoroughly remove inorganic salts and ensure the content of the product. Among the above-mentioned three kinds of alcohols, compound V has the least solubility in isopropanol, and isopropanol is preferably the solvent for desalting and refining, which can ensure higher yield.

Further preferably, the solvent in step (4) and step (5) and the mass ratio of compound V crude product are 8:1-20:1, preferably 12:1, while ensuring that dissolving and filtering are more convenient, it reduces the amount of solvent. Usage amount.

Compared with the prior art, the present invention has the following beneficial effects:

1. the method provided by the invention has avoided the high pressure catalytic hydrogenation reaction conditions in the existing technology, avoided the use of highly toxic reagent p-toluenesulfonic acid, toluene or benzene, used conventional reagent acetic acid to be a catalyzer, and Hexane is used as the reflux water separator to carry out the condensation reaction, and potassium borohydride is hydrogenated and reduced to prepare the intermediate. Provided is a method for removing salt by thermal filtration using conventional alcohols, which improves the purity and yield of the product and reduces the hidden danger of operation safety in the production process.

2. The preparation method of the dobutamine hydrochloride intermediate prepared by the present invention is easy to operate, has low safety risk, obtains a high-purity and high-content intermediate compound, and is more suitable for industrial scale production.

Description of drawings

Figure 1: HPLC detection spectrum of the dobutamine hydrochloride intermediate obtained in Example 1.

Detailed ways

The present application will be further described in detail below in conjunction with the examples. It should be understood that the specific embodiments described herein are only used to explain the related invention, but not to limit the invention.

Example 1

A preparation method of dobutamine hydrochloride intermediate (compound V),

1. Add 203g of 3,4-dimethoxyphenethylamine, 210g of 4-(4-methoxyphenyl)-2-butanone, 0.7g of acetic acid, and 1.2L of cyclohexane into the 3L reactor, stir and heat up 80-85 ℃ to reflux, reflux water separation reaction, heat preservation and reflux reaction for 6h, at this time there is no more water out;

2. Under normal pressure, the cyclohexane was evaporated, recovered, evaporated cleanly, and then cooled to room temperature, added with 2.0 L of absolute ethanol, 30.2 g of potassium borohydride, stirred and heated to 60-70 ° C, and kept stirring for 2-3 h. Stop the heat preservation and lower the temperature to below 40°C;

3. Under stirring conditions, add 0.2L of concentrated hydrochloric acid dropwise, cool down to 20-30°C, stir and keep warm for 2-3h, filter, and dry the filter cake at 50-60°C in a blast oven to obtain 362g of filter cake;

4. Add the above-mentioned dried filter cake into a 10L reactor, add 5.4L isopropanol, stir and heat up to reflux, keep stirring for 0.5h, filter while hot into another clean 10L reactor, stir and cool down for crystallization, and cool down. to 20-30°C, keep stirring for 1 h, filter, and blow dry at 50-60°C to obtain 298g of solid;

5. Add the above-mentioned dried solids into a 5L reactor, add 4.5L isopropanol, stir to heat up to dissolve, cool down to 20-30°C, keep for 1 hour for crystallization, filter, and blow dry the filter cake at 50-60°C, 283 g of compound V were obtained with a purity of 99.94%, and the molar yield of dobutamine hydrochloride intermediate (compound V) was 66.5%.

Embodiment 2

A preparation method of dobutamine hydrochloride intermediate (compound V),

1. Add 223g of 3,4-dimethoxyphenethylamine, 200g of 4-(4-methoxyphenyl)-2-butanone, 6.7g of acetic acid, and 1.2L of cyclohexane into the 3L reactor, stir and heat up 80-85 ℃ to reflux, reflux water separation reaction, heat preservation and reflux reaction for 6h, at this time there is no more water out;

2. The cyclohexane was evaporated under normal pressure, evaporated cleanly, then cooled to room temperature, added with 2.0 L of anhydrous ethanol, 30.2 g of potassium borohydride, stirred and reacted at room temperature for 10 h, stopped the heat preservation, and cooled to room temperature;

3. Under stirring conditions, add 0.2L of concentrated hydrochloric acid dropwise, cool down to 20-30°C, keep stirring for 3 hours for crystallization, filter, and place the filter cake in a blast oven to dry at 50-60°C to obtain 353g of filter cake;

4. Add the above-mentioned dried filter cake into a 5L reactor, add 2.8L absolute ethanol, stir and heat up to reflux, keep stirring for 0.5h, filter while hot into another clean 5L reactor, stir and cool down for crystallization, and cool down. to 0-10°C, keep stirring for 1 hour, filter, and dry by blasting at 50-60°C to obtain 286g of solid;

5. Add the above-mentioned dried solids into a 5L reactor, add 2.3L of absolute ethanol, stir to heat up to dissolve, cool down to 0-10°C, keep stirring for 1 hour for crystallization, filter, and dry the filter cake by blasting at 50-60°C , to obtain 257 g of compound V with a purity of 99.99%, and the molar yield of dobutamine hydrochloride intermediate (compound V) was 60.4%.

Embodiment 3

A preparation method of dobutamine hydrochloride intermediate (compound V),

1. Add 203g of 3,4-dimethoxyphenethylamine, 260g of 4-(4-methoxyphenyl)-2-butanone, 0.7g of acetic acid, and 1.5L of cyclohexane into the 3L reactor, stir and heat up 80-85 ℃ to reflux, reflux water separation reaction, heat preservation and reflux reaction for 6h, at this time there is no more water out;

2. The cyclohexane was evaporated under normal pressure, evaporated cleanly and then cooled to room temperature, added 3.0L of isopropanol, added 21.2g of sodium borohydride in portions, stirred and heated to 60-70°C, kept the reaction for 2h, and stopped the insulation , cooled to room temperature;

3. Under stirring conditions, add 0.2L of concentrated hydrochloric acid dropwise, cool down to 20-30°C, stir and keep warm for 3 hours, filter, and place the filter cake in a blast oven to dry at 50-60°C to obtain 349g of filter cake;

4. Add the above-mentioned dried filter cake into a 10L reactor, add 5.2L isopropanol, stir and heat up to reflux, keep stirring for 0.5h, filter while hot into another clean 10L reactor, stir and cool down for crystallization, and cool down. to 20-30°C, keep stirring for 1 hour, filter, and blow dry at 50-60°C to obtain 290g of solid;

5. Add the above-mentioned dried solids into a 5L reactor, add 4.4L isopropanol, stir and heat up to dissolve, cool down to 20-30°C, keep for 2 hours for crystallization, filter, and blow dry the filter cake at 50-60°C, 278 g of compound V were obtained, the purity was 99.8%, and the molar yield of dobutamine hydrochloride intermediate (compound V) was 65.3%.

Except for the technical features described in the specification, the other technical features are known technologies by those skilled in the art, and in order to highlight the innovative features of the present invention, the remaining technical features are not repeated here. To sum up, the above are only preferred embodiments of the present invention, and should not limit the scope of the present invention. It should still fall within the scope of the patent of the present invention.

Claims (10)

1. a preparation method of dobutamine hydrochloride intermediate (compound V),

The specific steps are: (1) condensation reaction: take compound I and compound II as starting materials, add a catalyst, and a water separating agent, and under reflux conditions, condensation reaction occurs to obtain compound III; (2) reduction reaction: compound III is in a solvent and undergoes reduction reaction with a reducing agent to obtain compound IV; (3) salt-forming reaction: in the compound IV reaction solution, drip hydrochloric acid into salt, cooling and crystallization, and the crude product of compound V is obtained after drying; (4) Desalting by hot filtration: after the compound V crude product is heated up and dissolved in a solvent, desalted by hot filtration, cooled and crystallized to obtain the crude compound V after the demineralization; (5) Refining: the crude compound V obtained in step 4 after desalting is heated up and dissolved in a solvent, cooled for crystallization, and dried to obtain compound V with high purity and high content. 2. preparation method according to claim 1 is characterized in that: the catalyst used in the condensation reaction described in step (1) is a kind of in formic acid, acetic acid, propionic acid. 3. preparation method according to claim 2 is characterized in that: described catalyst and compound I mol ratio are 0.01:1-0.3:1. 4 . The preparation method according to claim 1 , wherein the molar ratio of compound I to compound II in step (1) is 1.3:1-1:1.3. 5 . 5. preparation method according to claim 1 is characterized in that: the described reflux water separation solvent of step (1) is cyclohexane, the temperature used for described cyclohexane reflux separation is 80-85 ℃, and the reaction time is 2-12h. 6 . The preparation method according to claim 1 , wherein the reducing agent used in the hydrogenation reduction reaction of step (2) is one of lithium borohydride, sodium borohydride and potassium borohydride. 7 . 7. preparation method according to claim 6 is characterized in that: the mol ratio of described reducing agent and compound I is 0.25:1-1:1. 8 . The preparation method according to claim 1 , wherein the hydrogenation reduction reaction temperature in step (2) is 20-80° C., and the reaction time is 1-12 h; the solvent used in the hydrogenation reduction reaction is no solvent. 9 . One of water methanol, absolute ethanol and isopropanol. 9. preparation method according to claim 1, is characterized in that: described step (4) hot filtration salt removal and step (5) the used solvent of refining is a kind of in methanol, absolute ethanol and isopropanol. 10. preparation method according to claim 9 is characterized in that: described step (4) and step (5) described solvent and compound VI crude product mass ratio is 8:1-20:1.

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