JPH0424343B2 - - Google Patents

Description

[Detailed Description of the Invention] [Field of Industrial Application] The present invention provides a novel intermediate for dobutamine, a dopamine derivative that has an excellent effect on rapidly decreased cardiac contractility and shock, a method for producing the same, and a novel intermediate thereof. The present invention relates to the method for producing dobutamine hydrochloride used.

[Prior Art] Conventionally, dobutamine hydrochloride, that is, 3,4-dihydroxy-N-[3-(4-hydroxyphenyl)
-1-methyl-n-propyl]-β-phenethylamine (compound ()) hydrochloride () There are several known techniques for producing hydrochloride, including Japanese Patent Publication No. 58-25656 and Japanese Patent Publication No. 62
21343, to name a few, hydrogenation of 4-(4-methoxyphenyl)-3-buten-2-one and addition of homoveratrylamine to the resulting reduced mixture. , followed by hydrogenation to obtain 3,4-dimethoxy-N-[3-(4-methoxyphenyl)-1-methyl-n-propyl]-β-phenethylamine (compound ()), followed by hydrobromic acid This is a method for producing dobutamine (compound ()) hydrochloride by performing demethylation. Another method is to react anisole with crotonyl chloride to obtain p-methoxyphenylpropenyl ketone, and react this with homoveratrylamine to obtain 3-(3,4-dimethoxyphenylethylamino). -1-(4-methoxyphenyl)butan-1-one (compound ()) is obtained, and then hydrogenated to obtain compound (). This is then subjected to a demethylation reaction using hydrobromic acid to produce dobutamine hydrochloride. In all of these methods, the compound () is obtained and then demethylated with hydrobromic acid to obtain the hydrochloride of the compound () dobutamine.

[Problem that the invention seeks to solve]

In such conventional manufacturing methods, the compound ()
When producing compound () by demethylating with hydrobromic acid, a large amount of organic solvent is used, and therefore, after the reaction is completed, a large amount of organic solvent and hydrobromic acid must be distilled off, and the reactant is It is colored, and it cannot be said that purification of the target product is easy, and a better method has been desired.

[Means for solving problems]

As a result of intensive research to solve the problems in the conventional methods as described above, we found that 3-(3,4-dimethoxyphenylethylamino)-1-(4-methoxyphenyl) was produced in the presence of hypophosphite. enyl)butane-1
-one (compound ()) or its acid addition salt and hydrobromic acid, a new substance 3-(3,4-dihydroxyphenylethylamino)-1-(4-hydroxyphenyl) Enyl)butan-1-one (compound ()) or its acid addition salt is synthesized, and then the acid addition salt is hydrogenolyzed in the presence of a palladium catalyst to produce less by-products and less coloring. , 4-dihydroxy-N-[3-(4-hydroxyphenyl)-1-methyl-n-propyl]-β-phenethylamine (dobutamine, compound ()) hydrochloride was discovered and the present invention was achieved. completed.

The general synthetic route of the present invention is shown by a chemical formula as follows.

To explain the present invention in more detail, the feature of the present invention is to demethylate the compound () or its acid addition temperature with hydrobromic acid in the presence of hypophosphite to form a novel compound () or its acid addition temperature. When obtaining an addition salt, the reaction can be completed with only hydrobromic acid without using an organic solvent, and less by-products are produced, and the degree of coloration of the main product can be lowered. . The acid addition salt of Compound () is then reduced to obtain the target dobutamine (Compound ()) hydrochloride, which is also relatively easy to purify by crystallization.

Next, each step of the present invention will be explained in more detail.

First, in the first step, compound () is obtained from compound () by using hydrobromic acid, but since an excessive amount of hydrogen bromide is used, the hydrobromide salt of compound () is usually obtained. When this salt is reduced in the next step, the salt is usually converted to a salt of an acid other than hydrobromic acid, such as hydrochloric acid, sulfuric acid, acetic acid, methanesulfonic acid, ethanesulfonic acid, and the like, and then reduced. There are two methods for converting the hydrobromide of compound () to other acid addition salts. One is to convert the hydrobromide of compound () into an acid addition salt other than hydrogen bromide, such as hydrochloric acid or sulfuric acid. The other method is to add an acid and remove and replace the hydrobromic acid.The other method is to neutralize the hydrobromide of the compound () by adding an alkali to obtain the free base of the compound (). Add an acid other than hydrobromic acid,
This is a method of forming a salt of compound ().
Furthermore, if this first step is carried out in the presence of a hypophosphite, such as sodium hypophosphite or potassium hypophosphite, the generation of by-products and the degree of coloration of the reaction solution can be further suppressed. The amount of hypophosphite used is usually 1% of the compound () or its acid addition salt.
It can be used in an amount of 0.01 to 1.0 parts by weight, preferably 0.1 to 0.5 parts by weight. Hydrobromic acid used in this step generally has a concentration of around 47% by weight, and the amount used is 10 to 40% by weight per 1 part by weight of the compound () or its acid addition salt.
It is used in a range of parts by weight, preferably 20 to 30 parts by weight. The reaction temperature ranges from 60℃ to reflux temperature (approximately
126℃), and the lower the temperature, the slower the reaction progresses.
Generally, the temperature is preferably 90°C or higher. The reaction time varies depending on the amount of hydrobromic acid used and the reaction temperature, but is approximately 2 to 30 minutes.
It is 8 hours. When compound () or its acid addition salt is demethylated with hydrobromic acid and then cooled, compound () usually precipitates as a hydrobromide salt. This is collected by filtration, washed with water, and dried to form a compound ()
The hydrobromide salt is obtained. The resulting hydrobromide salt is dissolved in water and neutralized with an alkali to obtain the free base compound (). If this free base () or its hydrobromide salt is boiled with an aqueous solution of an acid other than hydrobromic acid, such as hydrochloric acid or sulfuric acid, an acid addition salt of the compound () is obtained,
Further, by further recrystallizing with methanol or the like, a highly pure acid addition salt of the compound () can be obtained.

Next, in the second step, that is, the step of synthesizing hydrochloric acid of compound () dobutamine from compound () or its acid addition salt, a general reduction method is used when carbonyl is reduced to methylene (hydrolysis). is taken. For example, the hydrochloride of the compound () dobutamine can be easily synthesized from the addition salt of an acid other than hydrobromic acid of the compound () by hydrogenolysis using a catalyst such as palladium-carbon, platinum black, or platinum oxide. can do. In this step, when hydrogenolysis is performed using palladium-carbon or the like as a catalyst, the acid addition salt of the target compound () is obtained by carrying out the reaction under normal pressure or pressurized hydrogen in the presence of a polar solvent and an acid. is obtained. Examples of the polar solvent in this case include water, methanol, ethanol, etc., and the amount used is approximately 5 to 50 times the weight of the compound () or its acid addition salt, preferably approximately 10 to 30 times the weight of the compound () or its acid addition salt. It's double the amount. Examples of acids include acids such as hydrochloric acid, sulfuric acid, acetic acid, methanesulfonic acid, and ethanesulfonic acid, as well as mixed acids thereof, and the amount used is approximately 0.01% by weight based on the compound () or its acid addition salt.
~3.0 times the amount, preferably 0.1 to 1.0 times the amount. When palladium (5%)-carbon is used as a catalyst, the amount used is approximately 0.05 to 0.5 times, preferably 0.1 to 0.3 times, the weight of the compound () or its acid addition salt. be. The hydrogen pressure at this time is approximately 2 to 10 kg/cm ² . The reaction temperature is approximately
The temperature is about 10 to 80°C, preferably about 20 to 70°C. The reduction reaction is terminated when a stoichiometric amount of hydrogen reacts with the compound () or its acid addition salt.
Thereafter, the catalyst is filtered and after concentration the acid addition salt of compound () is obtained as a pale yellow crystalline residue. Next, when the acid addition salt is an acid addition salt other than hydrochloride, it is converted to the hydrochloride. If necessary, then
Recrystallization from an aqueous hydrochloric acid solution yields the hydrochloride of compound () (dobutamine) as white crystals.

〔Example〕

The present invention will be illustrated below with examples, but the manufacturing method is not limited thereto.

Example 1 Preparation of 3-(3,4-dihydroxyphenylethylamino)-1-(4-hydroxyphenyl)butan-1-one.

In a 300ml four-bore flask, add 10g of 3-(3,4-dimethoxyphenylethylamino)-1-(4-methoxyphenyl)butan-1-one hydrochloride, 262g of 47wt% hydrobromic acid, and sodium hypophosphite. - 2.5 g of hydrate was added and reacted under reflux for 2 hours. The reaction mixture was then cooled, and the precipitated crystals were filtered and dried to obtain 7.5 g of pale pink crystals. Next, this crude product was dissolved in 150 ml of warm water, and after decolorizing with activated carbon, the filtrate was diluted with 1N aqueous sodium hydroxide solution until the pH was adjusted.
7.0, filter the precipitated white crystals,
After drying, 5.0 g of 3-(3,4-dihydroxyphenylethylamino)-1-(4-hydroxyphenyl)butan-1-one was obtained.

Melting point: 138-141℃ Infrared absorption spectrum (νmax cm ^-1 , KBr tablet) 3450; 3120; 1650; 1590 1510; 1420; 1380; 1290 1240; 1180; 850 Elemental analysis value (as C ₁₈ H ₂₁ NO ₄ ) Theory Value (%) Actual value (%) C 68.55 68.24 H 6.71 6.57 N 4.44 4.58 Example 2 3-(3,4-dihydroxyphenylethylamino)-1-(4-hydroxyphenyl)butan-1-oic acid Production of addition salts.

In a 300ml four-bore flask, add 10g of 3-(3,4-dimethoxyphenylethylamino)-1-(4-methoxyphenyl)butan-1-one hydrochloride, 218g of 47wt% hydrobromic acid, and sodium hypophosphite. - 2.5 g of hydrate was added and reacted under reflux for 3 hours.
The reaction mixture was then cooled, and the precipitated crystals were filtered and dried to obtain 8.0 g of pale pink crystals. Next, this crude product was dissolved in 80 ml of warm water, decolorized with activated carbon, cooled, crystallized, filtered, and dried to obtain white crystalline 3-(3,4-dihydroxyphenylethylamino)-1-(4 -Hydroxyphenyl)butane-
6.4 g of 1-one hydrobromide was obtained.

Melting point 188-190℃ Infrared absorption spectrum (νmax cm ^-1 , KBr tablet): 3400; 3320; 3260; 3000 2800; 1660; 1600; 1520 1280; 1210; 1170 Elemental analysis value (as C ₁₈ H ₂₂ BrNO ₄ ) Theory Value (%) Actual value (%) C 54.56 54.47 H 5.60 5.75 N 3.53 3.53 Br 20.41 20.25 Next, this hydrobromide salt was recrystallized from 4N hydrochloric acid to give white crystalline 3-(3,4-dihydroxyphenylethyl Amino)-1-(4-hydroxyphenyl)butan-1-one hydrochloride was obtained.

Melting point: 179-181℃ Infrared absorption spectrum (νmax cm ^-1 , KBr tablet): 3375; 3275; 3200; 2800; 1658; 1600; 1518; 1282; 1210; 1170 Elemental analysis value (as C ₁₈ H ₂₂ ClNO ₄ ) Theoretical value (%) Actual value (%) C 61.45 61.23 H 6.30 6.25 N 3.98 4.09 Cl 10.08 10.26 Example 3 3,4-dihydroxy-N-[3-(4-hydroxyphenyl)-1-methyl-n -propyl]-
Production of β-phenethylamine hydrochloride.

10 g of 3-(3,4-dihydroxyphenylethylamino)-1-(4-hydroxyphenyl)butan-1-one hydrochloride in a glass autoclave;
Add 150 ml of methanol, 2.7 g of methanesulfonic acid and 2.5 g of 5% palladium-carbon,
Hydrogenolysis was carried out at a temperature of about 60° C. under a hydrogen pressure of Kg/cm ² . A stoichiometric amount of hydrogen was observed to be absorbed after 8 hours. Thereafter, the catalyst was filtered off, and the solvent was distilled off from the filtrate to obtain 12.5 g of a pale yellow crystalline residue. This residue was dissolved in 100 ml of warm water, decolorized with activated carbon,
100 ml of water and 100 ml of concentrated hydrochloric acid were added to the filtrate, and the mixture was stirred under reflux for 1 hour. Thereafter, the mixture was cooled and the precipitated white precipitate was filtered. This was recrystallized again from 4N hydrochloric acid to obtain the target product, 3,4-dihydroxy-N-[3-(4
4.8 g of -hydroxyphenyl)-1-methyl-n-propyl]-β-phenethylamine hydrochloride was obtained. Melting point 184-187℃.

Example 4 3,4-dihydroxy-N-[3-(4-hydroxyphenyl)-1-methyl-n-propyl]-
Production of β-phenethylamine hydrochloride.

10 g of 3-(3,4-dihydroxyphenylethylamino)-1-(4-hydroxyphenyl)butan-1-one hydrochloride in a glass autoclave;
150 ml of methanol, 5 ml of concentrated hydrochloric acid and 2.5 g of 5% palladium-carbon were added and hydrogenolyzed at a temperature of about 60° C. under a hydrogen pressure of 4 kg/cm ² . A stoichiometric amount of hydrogen was observed to be absorbed after 7 hours. Thereafter, the catalyst was filtered off, and the solvent was distilled off from the filtrate to obtain 14.5 g of a pale yellow residue. This residue was dissolved in 100 ml of warm water and decolorized with activated carbon. 3 ml of concentrated hydrochloric acid was added to this solution, the precipitated yellow oil was removed by decantation, 100 ml of water and 100 ml of concentrated hydrochloric acid were added, and the mixture was stirred under reflux for 1 hour. Thereafter, the mixture was cooled and the precipitated white precipitate was filtered. This was recrystallized again from 4N hydrochloric acid to obtain the desired product, 3,4-dihydroxy-N-
[3-(4-hydroxyphenyl)-1-methyl-
n-propyl]-β-phenethylamine hydrochloride 3.8
I got g. Melting point 184-187℃.

〔Effect of the invention〕

According to the method of the present invention, since the first step is carried out by adding hypophosphite without using an organic solvent, the degree of coloring of the obtained intermediate and the generation of by-products are kept to a lower level. As a result, in the second step, the degree of coloring of the finally obtained dobutamine hydrochloride is small, and its purification is relatively easy.

Claims (1)

[Claims] 1 formula 3-(3,4-dihydroxyphenylethylamino)-1-(4-hydroxyphenyl) represented by
Butan-1-one and its acid addition salts. 2 In the presence of hypophosphite, 3-(3,
4-dimethoxyphenylethylamino)-1-(4
3-(3,4-dihydroxyphenylethylamino)-1-(4-hydroxyphenyl) by reacting -methoxyphenyl)butan-1-one or its acid addition salt with hydrobromic acid. A method for producing butan-1-one or an acid addition salt thereof. 3, consisting of hydrogenolysis of 3-(3,4-dihydroxyphenylethylamino)-1-(4-hydroxyphenyl)butan-1-one acid addition salt in the presence of a palladium catalyst. 4-dihydroxy-N-[3-(4-hydroxyphenyl)-
A method for producing 1-methyl-n-propyl]-β-phenethylamine hydrochloride.