DE2713652A1 - METHOD OF MANUFACTURING ADRENOCHROME - Google Patents

Description

Applicant: Nippon Gohsei Kagaku Kogyo Kabushiki Kaisha No. 4-0-4 ·, Kamiyama-cho, Kita-ku

Osaka-ahi / Japan Process for the production of adrenochrome

The invention relates to a method for producing adrenochrome; it relates in particular to the economical production of high quality adrenochrome by oxidation of adrenaline in a shorter period of time.

Adrenochrome is a commercial intermediate for adrenochrome-monoaminoguanidine and adrenochrome-monosemicarbazone, known hemostatic agents. Adrenochrome has hitherto been produced on an industrial scale by oxidizing adrenaline or its Salts with ereussish meal (potassium ferricyanide) in an aqueous solution Medium. However, this method is inconvenient because a large amount of cyanide in the waste water must be treated. In the literature indicates that persulfates can also be used as oxidizing agents. The use of persulfates has the advantage that there are no problems as with the Prussian meal and that they are cheaper than Prussian meal. However, the oxidation reaction with the persulfates is slow and a long reaction time is required.

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This is disadvantageous in terms of the operating efficiency of an apparatus. This also leads to a reduction the yields of adrenochrome, since the adrenochrome formed can be further oxidized during the reaction, whereby it decomposes into a black by-product. That is why the oxidation with persulfates is suitable for large-scale production of adrenochrome impractical.

The aim of the present invention is therefore to provide an improved process for the production of adrenochrome by the oxidation of Show adrenaline with a persulfate. Another aim of the invention is to provide a process for economical production of adrenochrome by oxidation within a shorter period of time in high yields. The aim of the invention is it also, a process for the production of high purity Indicate adrenochrome.

These and other objects, features and advantages of the invention will become apparent from the following description.

It has now been found that the above objects according to the invention can be achieved by adding adrenaline or a salt thereof in an aqueous medium at pH 4-8 in Presence of at least one water-soluble salt of a metal selected from the group consisting of copper, zinc, nickel and cobalt with a Oxidized persulfate.

According to the invention, the rate of oxidation is increased by the presence of specific water-soluble metal salts and the oxidation reaction is completed in a short period of time. This increases both the operating efficiency a device as well as the yield of adrenochrome is increased, and a high quality one is also obtained Adrenochrome.

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Only through the special water-soluble ones mentioned above Metal salts can achieve these remarkable effects. If salts of metals other than those specified above, e.g. iron salts are used, they act on the adrenochrome formed in such a way that it is further oxidized whereby the formation of black by-products is increased, although the rate of oxidation is increased will.

According to the invention, any water-soluble salts of the above-mentioned metals, i.e. of copper, zinc, nickel and Cobalt, and usually the sulfates, hydrochlorides, nitrates and acetates are used. Examples for water-soluble salts that can be used according to the invention are copper (II) sulfate, copper (I) sulfate, nickel (II) sulfate, Cobalt (III) sulfate, cobalt (II) sulfate, zinc sulfate, Copper (II) chloride, copper (I) chloride, zinc chloride, nickel (lII) chloride, Nickel (II) chloride, cobalt (III) chloride, cobalt (II) chloride, Copper (II) acetate, copper (I) acetate, nickel (III) acetate, Nickel (II) acetate and copper (II) nitrate. Among these are the Copper (II) salts with regard to increasing the rate of oxidation particularly suitable and they are therefore used with preference according to the invention.

Examples of persulfates used in the present invention are potassium persulfate, sodium persulfate and ammonium persulfate. Sodium persulfate is particularly suitable from the standpoint of good solubility in water.

According to the invention, the reaction system must have a buffer pH 4 to 8 can be adjusted. Examples of suitable buffers are sodium hydrogen carbonate, sodium dihydrogen phosphate, Disodium hydrogen phosphate and sodium acetate. From the point of view From the point of view of the reaction rate, sodium hydrogen carbonate is the most commonly used.

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- Mr-

The oxidation reaction of adrenaline with the persulfate is carried out in an aqueous medium at pH 4 to 8 in the presence of the special water-soluble metal salt carried out. Usually a uniform aqueous adrenaline solution is used first prepared by adding an acid such as hydrochloric acid and acetic acid, to an aqueous dispersion of adrenaline or by direct dissolution of an adrenaline salt in Water. The aqueous solution thus prepared is then added to a separately prepared aqueous medium, which contains the persulfate, the water soluble metal salt and the buffer to start the reaction. During the If necessary, further persulfate, further water-soluble metal salt and further buffer can be added to the reaction Reaction system can be added.

The water-soluble metal salt is used in an amount of from 0.0005 to 0.05, preferably from 0.001 to 0.01 mol per mol of adrenaline used. When the amount of the water-soluble metal salt is less than 0.0005 mol, the rate of oxidation becomes is not increased, and when the amount of the water-soluble metal salt is more than 0.05 mol, that is formed Adrenochrome continues to oxidize, decomposing into a black by-product. The persulfate and the buffer will be in an amount from 1.8 to 2.5, preferably from 1.9 to 2.4 mol per mole of adrenaline or in an amount from 4 to 7, preferably from 4.5 to 6 moles per mole of adrenaline used.

The reaction is carried out at a temperature of -5 to 20 _tons, preferably from 0 to 3 ° C. With the progress of reaction, the colors R _e action mix purple due to formation of adrenochrome and its color becomes deeper with increasing Adrenochrombildung. The reaction is continued until the extinction at a wavelength of 495 πια, which by sampling from the reaction mixture to a

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appropriate point in time during the reaction is measured, reached the maximum. In this way, further oxidation of the adrenochrome formed can be kept to a minimum and the adrenochrome can be obtained in a maximum yield · That required for the maximum yield Reaction time varies within the range of 30 to 60 minutes depending on the type of water-soluble used Metal salt. The most important feature of the present invention is that the adrenochrome within such can be obtained in high yields over a short period of time.

After the reaction has ended, the adrenochrome is obtained in the form of a solution. The adrenochrome itself is very unstable because of an ortho-quinoid structure and therefore in the Usually stabilizes the adrenochrome by converting it into conventional derivatives with hydrazines, such as aminoguanidine, Semicarbazide, phenylhydrazine, o-nitrophenylhydrazine, p-nitrophenylhydrazine and 2, ^ - Dinitrophenylhydrazine, transferred and isolated. In particular that with aminoguanidine or semicarbazide Stabilized adrenochrome, i.e. the adrenochrome monoaminoguanidine or adrenochrome monosemicarbazone, are used as a hemostat ika available in stores. These hydrazine derivatives serve both to stabilize the adrenochrome and to produce it of commercially available drugs. In addition, the adrenochrome monoaminoguanidine produced according to the invention and the adrenochrome monosicarbazone stained far less than those obtained by one procedure using a persulfate in combination with iron salts, and their transmission (light permeability) is very high, especially when used in the form of a solution such as an injection solution.

The stabilization of the adrenochrome by the hydrazine derivative and the isolation of the product obtained are in

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usually carried out as follows: first the hydrazine derivative, such as the aminoguanidine and semicarbazide, the reaction mixture containing the adrenochrome formed added. The hydrazine derivative is usually dissolved in water in the form of the hydrochloride or sulfate and all at once or added in portions to the reaction mixture. The amount the hydrazine derivative added is appropriately selected within the range of 0.9 to 1.2 Moles per mole of adrenochrome. The stabilization treatment is suitably carried out for 30 minutes to 2.5 hours at one temperature carried out from 0 to 15 ° C. The stabilization will preferably carried out at a pH of 2 to 5. After the stabilization has ended, the adrenochrome derivative is isolated from the reaction mixture by separating off the Precipitate in the usual way, for example by filtering and then washing. The adrenochrome derivative is obtained in the form of a powder. Before the separation, the treated reaction mixture with an alkali, such as sodium hydroxide, neutralized to precipitate the dissolved adrenochrome derivative. The isolated powder can be used on can be purified in a conventional manner, for example by treatment with activated charcoal, by treatment with a chelate and by Recrystallization.

The invention is illustrated in more detail by the following examples, without, however, being restricted thereto.

Example 1 and Comparative Examples 1 and 2

In a 1 liter beaker were 0.25 g (0.001 mol) of cupric sulfate pentahydrate and 50 * 0 g (0.21 mol) of sodium persulfate in 400 g of water were dissolved and 44.1 g (0.525 mol) of sodium hydrogen carbonate were added added to adjust the pH to 7.3. The solution was cooled to 0 to 3 ° C and an aqueous solution was added consisting of 22.0 g

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(0.10 moles) of adrenaline hydrochloride and 50 grams of water. The mixture immediately turned purple in color as a result of the Formation of adrenochrome and began to foam. The reaction was continued with stirring while keeping the temperature was held at 0 to 3 ° C. During the reaction, part of the reaction mixture (1 g) was removed from time to time, diluted to 1000 ml with water and the extinction of the diluted solution at a wavelength of 4-95 nm measured. The absorbance increased over time.

The results of the maximum absorption and the time it took to reach the value are in the Table I below.

The same procedures as above were repeated, this time not using copper (II) sulfate (comparative example 1) or 0.278 g (0.001 mol) of iron (II) sulfate heptahydrate instead of copper (II) sulfate were used (comparative example 2).

As used herein, the term "maximum absorption" is a relative value based on the maximum absorbance of Comparative Example 1 (which was set at 100) j should be understood.

Table I.

Example no. Metal salt time maximum absorption (min.)

Example 1 Copper (II) sulfate 30 125

Comparative Example 1 - 150 100

Comparative Example 2 Iron (II) sulfate 4-5 90

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AO

As indicated in Table I above, it was found that in the process of the invention the adrenochrome was obtained at a reaction rate in good yield.

Then each reaction mixture was treated with aminoguanidine to stabilize the adrenochrome formed, and the product was isolated in order to identify it and evaluate its quality as follows: To the reaction mixture containing the adrenochrome formed, an aqueous solution of Aminoguanidine hydrochloride, prepared by dissolving 11.1 g of aminoguanidine hydrochloride in 50 g of water, was added. Hydrochloric acid was added dropwise to the mixture to adjust the pH to 2.9. The stabilization treatment was carried out at a temperature of 0 to 3 ° C for 40 minutes with stirring, and it was continued by increasing the temperature to 15 ° C over a period of 40 minutes. After the completion of the stabilization, the reaction vessel was neutralized with a 4% by weight aqueous sodium hydroxide solution, and the precipitates were filtered off and dried to obtain 21.6 g of a crude powder of adrenochrome monoaminoguanidine. Then, the crude powder was dissolved in a 5% by weight aqueous sulfuric acid solution, and after the treatment with activated carbon, 1.12 g of ethylenediaminetetraacetic acid was added to the solution. Then, a 4% by weight aqueous sodium hydroxide solution was added and the precipitates were separated to obtain purified adrenochrome monoaminoguanidine.

The infrared absorption spectra and the ultraviolet absorption spectra of the purified adrenochrome monoaminoguanidine obtained in Example 1 and Comparative Examples 1 and 2 were investigated. The infrared absorption spectra showed characteristic absorptions at 3330, 317O, 1640, 1590,

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Αλ

1500, 1395, 1365, 1330, 1295, 1150, ΙΟ7Ο, 860, 815 and 720 cm ~. The ultraviolet absorption spectra showed a maximum absorption at 34-8 nm and 445 mn.

The color of the raw adrenochrome monoaminoguanidine was also determined. Furthermore, the melting point (the decomposition temperature) and the transmittance of the purified adrenochrome monoaminoguanidine solution determined. The light transmittance (transmission) was determined by adding 1.5 g of the purified powder 5.9 ml of 1 η methanesulfonic acid, dilute with water to 20 ml and measuring a relative value, based on water, at a wavelength of 660 nm. The results thereby obtained are given in Table II below.

Metal salt

Color of the raw powder

Melting point (decomposition temperature) ( ⁰ C)

Light transmission (%)

Table II Comparison
example 1 Comparison
example 2 example
1 Iron (H) -
sulfate Copper (II) -
sulfate yellowish
orange dark reddish
Brown yellowish
orange 198-201 198-201 198-201 69 10 70

The infrared absorption spectrum, d * s ultraviolet absorption spectrum and the melting point agreed with those of the authentic adrenochrome monoaminoguanidine and the Formation of the desired product was thereby confirmed.

Examples 2 to 4

The procedures of Example 1 were repeated, this time using the water-soluble salts shown in Table III

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were used in an amount of 0.001 mol each in place of Xupfer (II) sulfate. The results obtained are given in the following section III.

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Table III

Example metal salt no.

O CD OO

3 4-

Adrenochrome

Adrenochrome monoaminoguanidine

Time until maximum absorption occurs (min.)

Absorption maximum

Color of raw adrenochrome monoamine guanidine

Zinc sulfate heptahydrate

Nickel (II) sulfate heptahydrate

Cobalt (III) sulfate heptahydrate

60

125

120

120

yellowish-orange

dark yellowish orange

CD

cn

The infrared absorption spectrum, the ultraviolet absorption spectrum and the melting point (decomposition temperature) of each purified adrenochrome monoaminoguanidine matched those of the authentic adrenochrome monoguanidine, and this resulted in the formation of the desired product confirmed.

Examples 5 to 9

The production of adrenochrome, its stabilization and Isolation were carried out under the conditions given in Table IV below using the procedures of Example 1 carried out. The results obtained are given in Table IV below.

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Table IV

Example 5 Example 6 Example 7 Example 8 Example 9

Agents used persulfate

Metal salt

buffer

Sodium persulfate

Copper (II) chloride

Sodium persulfate

Copper (II) acetate

Ammonium persulfate

Copper (II) sulfate

Sodium persulfate

Cobalt (III) chloride

Sodium persulfate

Copper (II) chloride

Sodium Hydro- Sodium Hydro- Disodium Hy- Sodium Hydro- Sodium Acegen Carbonate gen carbonate drug phosphate gen carbonate tat

Melting point of the purified powder (decomposition temperature) ( ⁰ C)

Color of the raw powder

198-201

yellowish orange

198-201

yellowish orange

197-200

198-201

dark yellowish yellowish orange orange

197-200

dark yellowish orange

-Your-

The infrared absorption spectrum, the ultraviolet absorption spectrum and the melting point of the purified powder agreed with those of the authentic adrenochrome monoaminoguanidine, respectively matched and the reaction product was identified as adrenochrome monoaminoguanidine.

Example 10 and Comparative Examples 3 and 4

Adrenochrome was prepared in the same manner as indicated in Example 1, but this time instead of Sodium hydrogen carbonate sodium acetate was used and the reaction was carried out for 1 hour. Then became the reaction mixture obtained stabilized in the same manner as indicated in Example 1, but this time instead of aminoguanidine hydrochloride, semicarbazide hydrochloride for the production of adrenochrome monosicarbazone was used.

In addition, the same procedures as above were repeated, this time, however, copper (II) sulfate was omitted (comparative example 3) or iron (II) sulfate instead of copper (II) sulfate was used (Comparative Example 4). The results obtained are given in Table V below.

Table V

Metal salt

Color of the raw
Powder

Example 10

Copper (II) acetate

reddish orange

Melting point of the cleaned powder (decomposition temperature) (° C) 220-222

Compare - example 3

Compare example 4

Ferrous sulfate

dark red-reddish-orange-brown

214-222

218-222

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Λ}

Each infrared absorption spectrum of Examples 10 and The purified powder obtained in Comparative Examples 3 and 4- showed the characteristic absorptions at 3350 » 3190, 1700, 1660, 1560, 1410, 1295, 1 ^ 95, 1095, 1O6O, 810 and 560 cm x each ultraviolet absorption spectrum of the purified powder had an absorption maximum at 353 to 354 nm. The melting point, the infrared absorption spectrum and the ultraviolet absorption spectrum agreed with those of the authentic adrenochrome monosicarbazone and the reaction product was identified as adrenochrome monosemicarbazone.

Examples 11-13

The procedures of Example 10 were repeated, this time using zinc sulfate heptahydrate instead of copper (II) sulfate (Example 11), nickel (II) oil sulfate heptahydrate (Example 12) or cobalt (Hl) sulfate heptahydrate (Example 13) is used became. Similar results as in Example 10 were obtained «

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Claims (7)

Applicant: Nippon Gohsei Kagaku Kogyo Kabishiki Kaisha No. 40-4. Kamiyama-cho, Kita-ku ^ * 3 f fl to Bli l l · / Japan Claims Process for the production of adrenochrome by oxidizing adrenaline or a salt thereof with a Persulfate in an aqueous medium at pH 4 to 8, characterized in that the oxidation in the presence of at least a water-soluble salt of a metal from the group consisting of copper, zinc, nickel and cobalt. 2. The method according to claim 1, characterized in that the water-soluble salt in an amount of 0.0005 to 0.05 Mole per mole of adrenaline is used. 3 · The method according to claim 1 or 2, characterized in that the adrenochrome obtained by reaction with a Hydrazine derivative is stabilized. 4. The method according to claim 3 »characterized in that aminoguanidine is used as the hydrazine derivative. 5. The method according to claim 3, characterized in that semicarbazide is used as the hydrazine derivative. 6. The method according to claim 3i, characterized in that that phenylhydrazine is used as the hydrazine derivative. 709842AO727 ORIGINAL INSPECTED 7. The method according to claims 3 to 6, characterized in that that the obtained adrenochrome derivative is separated from the aqueous medium. 709842/0727