KR920001139B1 - Method for production of 3.4-anhgdro vindlastin - Google Patents

Abstract

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Description

Method of preparing 3 ′, 4′-anhydrovinblastine

The present invention relates to a novel process for the efficient production of 3 ', 4'-anhydrovinblastine.

The compound obtained by the present invention not only has useful physiological activities such as antitumor activity itself, but is also useful as a raw material for producing vinblastine and vincristine known as anticancer agents.

3 ′, 4′-anhydrovinblastine (Δ ^15.20 —Anhydro-vin blastion) is a branched compound having antitumor activity (US Pat. No. 4,029,663).

3 ′, 4′-anhydrovinblastine is obtained from or extracted from Catharant-husroseus (nickname Vinca rosea, L), which is a plant of the genus Casarantes. It can be obtained by chemically reacting Catharanthine and Vindoline obtained from.

However, in the extraction method, the content of the plant is very small, and many compounds of the same kind are present in the plant, making it difficult to separate and purify.

On the other hand, as a chemical synthesis method, a method of oxidizing cassaranti by peracid, acylating the produced N-oxide, reacting with bindolin and then reducing with NaBH ₄ or the like (US Pat. No. 4,144,237) ) And casarantin and bindoline are known to be reduced to NaBH ₄ or the like after capping time in the presence of Fe ₃₊ .

However, in the former method, the isolation yield of 3 ′, 4′-anhydrovinblastine is low at 40%, and 10% isomers are generated at the same time, making separation and stagnation difficult.

In addition, the latter method shows a high value of 68.6% in liquid chromatography yield, but this reaction is also difficult to separate and purify, since various compounds are simultaneously produced, including 12.3% of vinblastine.

An object of the present invention is to further improve the yield in a method for producing 3 ′, 4′-anhydrovinblastine by reacting casalanthin and ^{bindolin in} the presence of Fe ³⁺ .

The present invention is to achieve the above object, in the above-mentioned known method, in the industrial view, the method of reducing the catharantine (Catharantine) and Vindoline (vindoline) in the presence of Fe ³⁺ and then reducing I thought.

Also reviewed in various fields, the prior coupling reaction after otherwise than one in view of the Fe ³⁺ knew it can leave residue in the reaction system to harmless subjected to the reduction reaction after removal of the Fe ³⁺ the result predicted by the prior art common sense target substance The yield of not only increases drastically. The separation and recovery of the desired substance was found to have an unexpected effect, which is particularly suitable as an industrial method, since it can be directly crystallized and recovered without requiring complicated separation and purification means such as chromatography.

As a result of further research based on this new knowledge, the present invention has been completed. That is, according to the first aspect of the present invention, after reacting casalanthin and ^{bindolin in} the presence of Fe ³⁺ , Fe ³⁺ is removed or Fe ³⁺ is inactivated and subsequently reduced to 3 ′, 4 ′ −. It is a method for producing anhydrobinblastine.

Moreover, 2nd invention is the method of manufacturing 3 ', 4'- anhydrobin blastine by inactivating Fe3 ⁺ by participation of an iron ligand in the said method.

In carrying out the present invention, the reaction between casaranti and bindolin in the presence of Fe ³⁺ may be carried out as in the prior art.

After the completion of the coupling reaction, Fe ³⁺ is removed or inactivated, but Fe ³⁺ is removed after the completion of the coupling reaction by adding a basic compound to generate Fe ³⁺ , which is commonly used for filtration and centrifugation. It is carried out by removing it from the system by the solid-liquid separation method.

As a basic compound used at this time, as long as it is a basic compound which can generate | occur | produce ^{Fe3 +} precipitation, without disturbing a reaction, any can be used. Examples include the following: metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, sodium carbonate, carbonates such as potassium carbonate, ammonium carbonate, bicarbonates such as sodium bicarbonate, urea, methylamine, ethylamine, Inactivation of amines such as dimethylamine and trimethylamine, quaternary ammonium hydroxides such as tetraethylammonium hydroxide, ammonia water, and Fe ³⁺ is used to remove or reduce the adverse effects or interferences of Fe ³⁺ in subsequent steps. Means processing.

Therefore, the deactivation treatment of Fe ³⁺ also includes a treatment for suppressing the coordination of iron with a useful component in the subsequent step, or an action for inhibiting the oxidation of iron.

For example, by changing the Fe ³⁺ was added to the iron after the completion of coupling the ligand to remove the adverse effect of disturbance to Fe ³⁺ in how to activate the pre-fire, by reduction of Fe ³⁺ or Fe ³⁺ iron metal inactivation And a method of forming a complex of different species by acting on a ligand of different species, and then converting the complex into a double salt to form a coprecipitation or a non-toxic lysate.

Moreover, the method of leaving in the system without removing the above-mentioned precipitation with Fe3 ⁺ basic compound at all, or removing a part of this precipitation and remaining the remainder is an example of a preferable inactivation method.

In the Fe ³⁺ inert treatment, the method of inactivating by adding an iron ligand is a method of adding a compound coordinated to an iron ligand, that is, Fe ³⁺ .

Although the following compounds are illustrated as an iron ligand used by this invention, complexing agents other than these can also be used widely.

Lower fatty acids: formic acid, acetic acid, propionic acid, butyric acid, gillacetic acid, trimethylacetic acid, capronic acid, enanthic acid, caprylic acid and the like. Dicarboxylic acid: aliphatic dicarboxylic acid (aquatic acid, malonic acid, succinic acid, glutanoic acid, adipic acid, maleic acid, fmaric acid, pimeric acid, etc.): aromatic dicarboxylic acid; Phthalic acid, isophthalic acid, terephthalic acid, etc. Ketocarboxylic acid: pyruvic acid hydroxycarboxylic acid: Aliphatic hydroxycarboxylic acid (glycolic acid, lactic acid, hydroacrylic acid, glycelic acid, malic acid, tartaric acid, succinic acid, citric acid).

Aromatic oxycarbonic acid (sarylic acid, oxyanic acid, molar asset, etc.), diol: ethylene glycol, catechol, ascorbic acid, polyaminocarboxylic acid: EDTA, sugar derivatives such as: glucose, fructose, sucrose, albine salts; Cyanide: Potassium cyanide, sodium cyanide, tributylammonium cyanide, etc. Thiocyanide: Fluoride, such as potassium thiocyanate, sodium thiocyanate, tributylammonium thiocyanate: Pyridine derivatives, such as sodium fluoride and potassium fluoride: Phenanthrene derivative ratio Pyridyl derivatives

Phosphoric acid and condensed phosphoric acid: polyphosphoric acid, metaphosphoric acid, pyrophosphoric acid, phosphoric acid and salts thereof

These iron ligands are preferably 0.5 to 200 times mole, preferably 1 to 10 times mole relative to Fe ³⁺ .

After deactivating Fe ³⁺ in this manner, a reducing agent is added to the reaction system to produce a target compound.

In the case where precipitation of Fe ³⁺ occurs by inactivation treatment, the treatment may be performed on a reaction liquid such as a filtrate after the precipitation is removed.

On the other hand, the precipitates removed are washed with a wet solvent, and then the filtrate is combined with the reaction liquid such as the filtrate to the supernatant, concentrated under reduced pressure to remove the wet solvent, and then added with water, and then reduced with a reducing agent such as NBH _4, or concentrated under reduced pressure. after the pH <6, without, may even fractions and reducing by adding a reducing agent such as NBH ₄ in the water column.

In addition, the precipitation produced by the inactivation treatment does not remove this, and in the case where the inactivation treatment is performed in the liquid phase, the organic layer obtained by extracting the aqueous layer with an organic solvent is concentrated as it is under reduced pressure, and reduced after adding water. There is this.

As a reducing agent, the following are illustrated without limitation.

Hydrogen compound: Sodium borohydride, potassium borohydride, titanium borohydride, sodium cyanoborohydride; Metal: zinc, iron, stone, aluminum, magnesium; I can listen to the guitar.

When the reducing agent is strong, the amount of the reducing agent may be reduced, or the reducing agent itself may be modified or masted.

Although the coupling reaction may be carried out in an air atmosphere, better results can be obtained if the coupling reaction is carried out under a nitrid atmosphere or under nitrogen ventilation.

The 3 ', 4'- anhydrovinblastine produced by these methods can be obtained by extracting with an organic solvent.

According to the present invention, since the purity of the target compound is very high, it can be freely crystallized and can be sufficiently recovered by recrystallization without having to perform separation and stabilization such as column treatment, which was necessary in the case of the conventional method of low yield.

In this way, the separation is easy, so the method is very suitable as an industrial method.

By the method of the present invention, the yield of 3 ′, 4′-anhydrovinblastine is improved from 68.6% to 89% in liquid chromatography yield, and 3 ′, 4 ′ is used as high purity crystal without the need for separation and purification Anhydrobinblastine can be obtained.

EXAMPLE

The present invention will be described in more detail with reference to the following Examples, which do not limit the present invention.

Example 1

180 ml of water is added to a 500 ml reaction vessel and iced with N ₂ gas. Thereto, 20 ml of 184 mg (480 µmol) of half sulfate of casalanthin and 220 mg (480 µmol) of bindolin were dissolved in 20 ml of water and 0.4 ml of 2N-HCl, to which FeCL ₃ · 6H _{2 was added.} The reaction was started by adding 8.1 g of O in 50 ml of water.

After blowing N ₂ for 3 hours under ice cooling, 12.2 g of NaOA _C was dissolved in 50 ml of water. There, 277 mg of NaBH _{4 is} added as a solid and stirred for 30 minutes.

The reaction mixture was extracted four times with 100 ml of ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was dissolved in 30 ml of chloroform and washed with 50 ml of saturated aqueous NaHCO ₃ solution.

The organic layer is dried over anhydrous sodium sulfate and then concentrated. 2 ml of metinol is added to the residue to form crystals. The produced crystals were filtered out to obtain 3 ', 4'-anhydrovinblastine at mp 200 to 204 (decomposition) as colorless crystals of 304 ml. The yield of the product was 80%.

This compound was identified as a natural 3 ′, 4′-anhydrovinblastine because it was 3.89 (3H · S) and 5.54 (3H · S) in ¹ H-nmr (CDCL ₃ ).

Example 2

Water (10 ml) was placed in a 50 ml reaction vessel and bubbled with nitrogen for 30 minutes while cooling with ice, followed by 20 µl (2.39 µmol) of 11.9 mM casalanthin 1/2 sulfate solution and 200 µl (2.41 µmol) hydrochloric acid solution of 12.0 mM vidoline. ) And 1.0 ml (1.20 mmol) of 1.2 M ferric chloride aqueous solution are added in this order, and the mixture is stirred for 3 hours while bubbling nitrogen under ice-cooling.

1 ml of 25% ammonia water is added to make alkaline, and extracted three times with 10 ml of ethyl acetate. The extracts were collected, dried under reduced pressure, and dissolved in 24 µl of water (10 ml) 2N-HCL. Then, 1 ml (227 µmol) of 228 mM aqueous solution of sodium borohydride was added and stirred for 30 minutes.

After that, 2 ml of 25% ammonia water was added, followed by extraction three times with 10 ml of ethyl acetate. The extracts were combined, dried under reduced pressure at 40 ° C. or lower, and analyzed under the following conditions by high performance liquid chromatography. As a result, 3 ', 4'- anhydrovinblastine was obtained with a yield of 89%.

Column: YNC-Packed columnAM-312 (S-5 120AODS)

Dissolution: CH ₃ CN: 0.01M aqueous ammonium carbonate solution = 3: 2

Flow rate: 1ml / min

Column Temperature: 45 ℃

Detection wavelength: 245nm

Retention time: 3 ′, 4′-anhydrovinblastine (40.8 minutes)

Example 3

In Example 2, instead of 1 ml of 25% ammonia water, 634 mg (3.6 mmol) of L-ascorbic acid was added, followed by adding 1 ml (227 µmol) of 227 mM aqueous solution of sodium hydride and stirring for 30 minutes, as in Example 2. The treatment afforded 3 ′, 4′-anhydrovinblastine with a yield of 88%.

Example 4

In Example 3, except that triammonium citrate was added instead of L-ascorbic acid, it treated like Example 3 and obtained 3 ', 4'- anhydrobinblastine in the yield of 87%.

Example 5

In Example 3, the same procedure as in Example 3 was carried out except that sodium pyruvate was added instead of L-ascorbic acid to obtain 3 ′, 4′-anhydrovinblastine in a yield of 85%.

Example 6

In Example 3, it treated like Example 3 except having added hydroxyl instead of L-ascolic acid, and obtained 3 ', 4'- anhydrobin blastine in the yield of 87%.

Example 7

In Example 3, the same process as in Example 3 was carried out except that malic acid was added instead of L-ascolic acid to obtain 3 ′, 4′-anhydrovinblastine in a yield of 88%.

Example 8

In Example 3, except that maleic acid was added instead of L-ascorbic acid, it processed like Example 3 and obtained 3 ', 4'- anhydrobin blastine in the yield of 84%.

Example 9

In Example 3, the same procedure as in Example 3 was conducted except that sodium fluoride was added instead of L-ascorbic acid to obtain 3 ′, 4′-anhydrovinblastine in a yield of 85%.

Example 10

In Example 3, except that arbutin was added instead of L-ascorbic acid, it treated like Example 3 and obtained 3 ', 4'- anhydrobinblastine in the yield of 82%.

Claims (2)

3 ', 4'-anhydrovinblastin characterized by reacting casarantin and ^{bindoline in} the presence of Fe ^3+, then removing Fe ³⁺ or inactivating Fe ³⁺ and then reducing Manufacturing method. The method for producing 3 ′, 4′-anhydrovinblastine according to claim 1, wherein Fe ³⁺ is inactivated by adding an iron ligand.