JPS60115588A - Production of isosorbide-5-nitrate - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as a remedy for coronary arteriosclerotic cardiopathy easily in high purity, by isolating isosorbide-5-nitrate sodium hydrate, and treating the isolated isosorbide-5-nitrate sodium hydrate with an acid in a specific solvent. CONSTITUTION:Isosorbide-5-nitrate sodium hydrate of formula I (n is 2-8) is treated with an acid, e.g. hydrochloric acid, in water, an organic solvnt, e.g. methyl ethyl ketone, or a mixed solvent thereof to afford the aimed compound of formula II. EFFECT:The aimed substance is obtained in simple steps at a low cost, and mass production can be carried out.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an improved method for producing isosorbide 5-nitrate, and more particularly, in the process of producing isosorbide 5-nitrate of the formula by direct nitration of isosorbide, - A very economically advantageous process for preparing isosorbide-5-nitrate by isolating sodium ditolate hydrate and treating it with an acid.

Isosorbide 5-nitrate is one of the biological metabolites of insorbide nitrate (insorbide 2,5-dinitrate), which is a peripheral vasodilator that has been known for a long time. ,
It has recently been found to be effective for coronary heart diseases such as angina pectoris and myocardial infarction, and is considered useful as a therapeutic agent for these diseases.

There are many methods conventionally used to produce isosorbide 5-nitrate, but these include (1) isosorbide (1
, 4: Method of reacting 3,6-dianhydrone rubitol) with concentrated nitric acid or acetyl nitrate [Canadian Journal Op Chemistry (Can, J, C!
h, em,) + Volume 45, Page 2191, West German Published Patent Specification No. 2, 221, 080, U.S. Patent Specification No. 3, 886, 186, Japanese Patent Publication No. 55-2
No. 9996], (2) A method by partial hydrolysis of insorbide 2,5-dinitrate obtained by complete nitration of insorbide [Organic Magnetic Resonance (Organic Magnetic Resonance)
sonance), Volume 3, Page 693, European Patent Specification No. 59,664, JP-A-57-15
6492], (3) A method using Inmanite as a starting material (West German Patent Specification No. 2,903,927, French Patent Specification No. 2,447,933, Japanese Patent Application Laid-Open No. 127393/1982) (4) A method in which the hydroxyl group at the 2-position of isosorbide is selectively protected with a protecting group, the 5-position hydroxyl group is nitrated, and then the protecting group is removed (West German Published Patent Application No. 3.028,873
No. 3,128,102, European Patent Specification No. 45,076, No. 57,847, No. 64.19
No. 4, Japanese Unexamined Patent Publication No. 57-144288, No. 57-i8
No. 5286, No. 58-1s3ss, No. 58-
18386)).

However, all of these manufacturing methods have drawbacks and cannot be said to be necessarily satisfactory methods. For example (1
), the product contains four types of compounds including unreacted raw materials, namely isosorbide 2.57 dinitrate, isosorbide 2-nitrate, insorbide 5-nitrate and isosorbide, It is extremely difficult to efficiently separate each from these mixtures, especially isosorbide 2.
．． Because 5-dinitrate is explosive, it cannot be heated or concentrated under reduced pressure, and the only way to separate it is by column chromatography, and the reaction must be carried out at low temperatures. Furthermore, when acetyl nitrate is used as a nitrating agent, it has drawbacks such as handling problems due to its explosion hazard and low yield (approximately 20%), making it extremely difficult to use in industrial production. It is disadvantageous.

In the method (2) of partial hydrolysis of insorbide 2,5-dinitrate, it takes a long time when diluted hydrochloric acid is used, and when a hydrazine derivative is used, a large amount of isosorbide 2-nitrate is produced as a by-product. This method is completely inappropriate as an industrial production method, as it requires the use of column chromatography to separate the target product.

In the method (3) using inmanite as a starting material, in addition to the fact that the raw material inmanite is difficult to obtain compared to insorbide, the tosylated product of the hydroxyl group at the 2-position needs to be further converted to benzoate. The process is long and the processing operations are complicated, such as the use of highly dangerous acetyl nitrate for nitration of the hydroxyl group at the 5-position, and the need to debenzoate the 2-position. This is disadvantageous for commercial production.

In addition, in method (4), the hydroxyl group at the 2-position is once protected, the hydroxyl group at the 5-position is nitrated, and then the hydroxyl group at the 5-position is deprotected, making the process long and complicated. Acetyl nitrate is often used in the reaction, which is dangerous, and the product after removing the protecting group at the 2-position contains many by-products, making it necessary to use column chromatography to separate the target product. This method has several disadvantages, and it cannot be said to be a satisfactory method in terms of yield.

The present inventors have conducted extensive research on a method for overcoming the drawbacks of such conventional production methods and obtaining insorbido-5-nitrate in high yield and high purity through simple operations. In the nitration reaction, by reacting isosorbide with concentrated nitric acid in a specific solvent system,
Isolupido 5-nitrate is produced as the main component,
The formation of by-products such as inrubido 2,5-dinitrate is much smaller than in the conventional method. By treating the scales, crystals of sodium insorbido 5-nitrate hydrate can be isolated with extremely high purity, and the crystals of the hydrate can be easily converted to cyisosorbide 5-nitrate by acid treatment. They discovered scales and completed the present invention based on this knowledge.

That is, the present invention provides insorbido 5-motorate sodium hydrate represented by the general formula % (1) (n is 2 to 8) in water, an organic solvent, or a mixed solvent thereof. Ison Rubido 5 characterized by treatment with acid
- A method for producing nitrate, in which isosorbide is reacted with concentrated nitric acid in a solvent containing an aromatic hydrocarbon, the resulting nitrated mixture is then neutralized, and the by-produced isosorbide 2,5-dinitrate is separated. Thereafter, the residue was treated with an aqueous sodium hydroxide solution to form the general formula (n
Provided is a method for producing insorbido 5-nitrate, which comprises isolating sodium isosorbide 5-nitrate hydrate represented by (1) and further treating it with an acid in water, an organic solvent, or a mixed solvent thereof. It is something to do.

Examples of solvents containing aromatic hydrocarbons used in the method of the present invention include aromatic hydrocarbons such as benzene, toluene, xylene, cumene, and tetralin, lower alkanoic acids such as acetic acid, and corresponding anhydrides of lower alkanoic acids. Preferably, a mixed solvent with One kind or two or more kinds of aromatic hydrocarbons may be used, but it is particularly preferable to use benzene.

The ratio of ison rubide and concentrated nitric acid used in the nitration reaction in the method of the present invention is in the range of 1.0 to 1.5 molar equivalents, preferably about 1.2 molar equivalents in terms of 100% nitric acid, per 11 moles of ink rubide. It is desirable to use concentrated nitric acid in such proportions as to give molar equivalents.

As this concentrated nitric acid, fuming nitric acid is preferably used.

Further, the reaction temperature for nitration is usually in the range of 10 to 60°C, preferably in the range of 30 to 40°C.

The solvent used in the process of converting insorbido 5-nitrate sodium hydrate into insorbido 5-nitrate in the method of the present invention is water, an organic solvent, or a mixed solvent thereof.

Examples of organic solvents used here include chloroform, methylene chloride, methyl chloroform, ethyl acetate,
Examples include butyl acetate, methyl ethyl ketone, methyl isobutyl ketone, and among these, methyl ethyl ketone is preferred, and a mixed solvent of water and methyl ethyl ketone is particularly preferred. In addition, the acids used in this step include, for example, inorganic acids such as hydrochloric acid and sulfuric acid, acetic acid,
Examples include organic acids such as methanesulfonic acid.

Next, one example of a preferred embodiment of the present invention will be described. First, isonolpito is added to the above-mentioned aromatic hydrocarbon-containing solvent and heated to completely dissolve it, and then the internal temperature is preferably adjusted to 30 to 30. 2) O-conversion reaction is carried out by directly dropping a predetermined amount of fuming nitric acid while maintaining the temperature in the range of 40°C. After the dropwise addition is completed, the reaction solution is stirred at room temperature for about 2 hours, and then poured into ice water. Then, as a neutralizing agent, solid alkali hydroxide, alkali carbonate, or a concentrated aqueous solution thereof is preferably used. After neutralization to pH 6.8 to 7.0, the mixture is separated into an organic layer containing by-produced isonorpitole-2,5-dinitore-1. and an aqueous layer. The aqueous layer is then extracted using an inert solvent that is substantially immiscible with water, and the solvent is distilled off under reduced pressure to obtain an oily residue containing isosorbide 5-nitrate as a main component.

Examples of the inert solvent include chloroform, methylene chloride, methyl chloroform, ethyl acetate, butyl acetate, methyl ethyl ketone, methyl isobutyl ketone, and among these, methyl ethyl ketone has excellent extraction efficiency of the target product.

After dissolving the oily residue containing insorbido 5-2L-rate as a main component in water or isopropyl alcohol, for example, a concentrated aqueous sodium hydroxide solution with a concentration of 30% by weight is added. , white crystals of highly pure sodium isonorpitote 5-nitrate hydrate containing almost no by-products are immediately precipitated.

Since this crystal is sparingly soluble in isopropyl alcohol and acetone but soluble in ethyl alcohol, it can be purified if necessary, for example, by dissolving the crystal in ethyl alcohol and adding chloroform.

As a result of various physical and chemical measurements, the thus obtained isonorpitoh 5-nitrate sodium hydrate is expressed by the general formula (11) % formula % () (n in the formula is 2 to 8). The purified product is white flaky crystals with a melting point of 101-102°C.

When left at room temperature, this material gradually loses moisture, loses its luster, and absorbs carbon dioxide from the air. In addition, the solubility in water is 20-25% at room temperature,
The pH of the aqueous solution is 12.0.

Furthermore, it is stable in concentrated sodium hydroxide solution, but
Easily decomposes in methanol and aqueous solutions. The moisture content of this product is about 8 molecules at the coarse crystal stage, and n is 2 to 2.
The water content state of No. 4 is relatively stable.

Note that even when an aqueous potassium hydroxide solution, aqueous ammonia, or an aqueous alkali carbonate solution is applied to the oily residue containing insorbido-5-nitrate as a main component, the corresponding hydrates do not precipitate as crystals.

Next, the isonorpitose 5-nitrate sodium hydrate thus obtained is preferably placed in a mixed solvent of water and an organic solvent such as methyl ethyl ketone, and the above acid is added thereto to adjust the pH to about 7. After setting it to 0,
The organic solvent layer is separated and the organic solvent in the organic solvent layer is distilled off under reduced pressure to obtain crude crystals of insorbido 5-nitrate.

By recrystallizing this crude crystal product using a single solvent such as chloroform or methylene chloride, or a mixed solvent of methanol or ethanol and n-hexane as necessary, a pure product can be obtained with a high yield. can. The infrared absorption spectrum, thin layer chromatography, and measurement of optical rotation and melting point showed that this product was completely consistent with isonorpitou 5-nitrate obtained by another method. The attached figure shows the infrared absorption spectrum of the recrystallized product.

In the method of the present invention, by using a solvent containing an aromatic hydrocarbon in the nitration reaction, the production rate of the target isonorpitole 5-nitrate is higher than that of the conventional method. 2) Work safety is high because acetyl nitrate is not used for zero conversion, and high purity isonorpitot 5-nitrate.
Since sodium hydrate is isolated and converted to isonorpitou-5-nitrate with an acid, it has the characteristics that highly pure influpitote-5-nitrate can be easily obtained, and the method of the present invention is used. As a result, the influpitot-5-nitrate can be obtained through a simple process and at low cost, and can be mass-produced.

Next, the present invention will be explained in more detail with reference to Examples.

Example 1 450 me of benzene, 150 me of acetic acid and 1 of acetic anhydride
Add Influpito 1507 to 50ml of mixed solvent,
Dissolve by heating to 0-55℃, then heat this mixture to 30℃
Fuming nitric acid (dl, 50, purity 94%) after cooling to
82.5 f was added dropwise over a period of 2 hours while keeping the internal temperature at 30 to 35°C, and after the addition, the excess was stirred at room temperature for 2 hours.

Next, the obtained reaction solution is poured into ice water lt, and while stirring, a 30% by weight aqueous sodium hydroxide solution is carefully added to adjust the pH to 7.0. Of the two liquid layers obtained here, the aqueous layer is separated, and the organic layer is extracted three times with 150 ml of water. Then, combine all the aqueous layers and add 500 ml of methyl ethyl ketone.
Extracted four times with rnl and distilled the extract under reduced pressure to obtain an oily residue 1150f.

This oily substance 1501 and isopropyl alcohol 500-
was added and dissolved, and after cooling to 0°C, 1100 ml of a 30% by weight aqueous sodium hydroxide solution was added at once, and white crystals were immediately precipitated. After continued stirring at 0°C for 2 hours, the crystals were collected by filtration, washed with a small amount of isopropyl alcohol, and after air-dried at room temperature overnight, crude crystals of sodium influpitot 5-nitrate hydrate 1481 were obtained. .

Yield: 47.6% (based on 4 moles of water content).

This crude crystal 841 is suspended in a mixture of 148 tnl of ice water and 296 mg of methyl ethyl keto, and cooled 6N hydrochloric acid is added thereto to adjust the pH to 7.0. Then, the aqueous layer was separated into an aqueous layer and an organic layer, and the aqueous layer was added with 148 ml of methyl ethyl ketone.
Extract 3 times. All of the obtained organic layers were combined and dehydrated over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 45 crude crystals of insorbido 5-nitrate. Next, chloroform 180- was added to the crude crystals for recrystallization to obtain 40 pure white crystals of influpitot 5-21.
I got a 7.

This product has a melting point of 90.6℃, [α]20+175.6
゜(C1,O,, ethanol), thin layer chromatography single subbot (cnct3: MeOH=10:
IV/V), the absorption of the nitroester group in the infrared absorption spectrum is 1650.1635 cm' (N
O2), 1281c+n'(NO2), 846 L:r
n-' (ON).

Example 2 4.5 t of benzene, 1.5 t of acetic acid and 1.54 t of acetic anhydride
Add 1.5 kg of influpito to the mixed solvent of
After heating to 5℃ and stirring for 20 minutes to completely dissolve the mixture, cool the mixture to 35℃ and add fuming nitric acid (dl, 50
, purity 94%) 9 was added dropwise to 0.825 over 2 hours while maintaining the internal temperature at 30 to 35°C.

Then, after stirring the reaction solution for 2 hours at room temperature,
Pour 10 ml of ice water into it and add 3.35 Ky of anhydrous sodium carbonate.
was added to adjust the pH to 6.87-7 (l). The aqueous layer and organic layer obtained here were separated, and the organic layer was extracted three times with 1.5 t of water.

Extract 4 times at 6t. The entire extract obtained was immediately distilled under reduced pressure to obtain an oily residue. ．． I got 527Kg. Next, 2 tons of water was added to this oily residue to dissolve it, and the mixture was cooled to 0°C for 30 minutes.
When 2 tons of 0% by weight aqueous sodium hydroxide solution is gradually added while stirring, white crystals are immediately precipitated.

Next, the crystals are collected by filtration and washed with a small amount of aqueous sodium hydroxide solution. The influpitote 5-nitrate crystals obtained here were suspended in a mixed solvent of 2 tons of ice water and 3 tons of methyl ethyl ketone, and chilled 6N hydrochloric acid was added thereto to adjust the pH to 6.
．． Adjust to 8-7.0. The 2o. The layers are separated and the aqueous layer is extracted three times with methyl ethyl ketone 21. Next, all the organic layers were combined and dehydrated with anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a solid residue 1.
, 112 Kq was obtained. Chloroform 4. Add OL and perform recrystallization to obtain Influpitot 5.
-0.890 kg of pure crystals of nitrate were obtained.

1117';? 7 Ac A O/ dJh J: Q
4 Lil" + "+20 + +M+ 80 (C1
, 0, ethanol), thin layer chromatography single spot (C!HCl3:MeOH=10:1
v/V) Example 3 Insorbide 15f was added to a mixed solvent of benzene 60- and acetic anhydride 15-, dissolved by heating, and then the mixed solution was
After cooling to 5°C, add fuming nitric acid (dl, 50, purity 94%).
) 7.5 V was added dropwise over a period of 1 hour, keeping the internal temperature at 35°C. After stirring the reaction solution for 2 hours at room temperature, it is poured into 150ml of ice water, and anhydrous carbonic acid is added to adjust the pH to 6.8-7.0. Next, separate into an organic layer and an aqueous layer, add 20% of water to the organic layer, and repeat 3 times.
Extract times. The resulting aqueous layers were combined and extracted 4 times with 50% of methyl ethyl ketone. This extract was distilled under reduced pressure to remove the solvent, leaving an oily residue 13. I got Of.

After 18 me of water was added to this oily residue to dissolve it, 20 of a 30% by weight aqueous sodium hydroxide solution was added while cooling with ice, and white crystals were immediately precipitated. After stirring at θ°C for 2 hours, the crystals are collected by filtration and washed with a small amount of 30% by weight aqueous sodium hydroxide solution.

Next, pour this crystal into 15m7 of ice water! and methyl ethyl ketone 2
The mixture is suspended in a mixed solvent with 0-, and while stirring, 6N hydrochloric acid is added to adjust the pH to 6.8 to 7.0.

The aqueous layer produced here was diluted with 20 rnl of methyl ethyl ketone.
After extraction, the entire extract was dehydrated with anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a solid residue of 8.01 g. The residue was dissolved in chloroform and crystallized by adding n-hexane to obtain 5.81 g of white crystals of insorbido 5-nitrate.

Yield 29.6% Examples 4 to 11 White crystals of isosorbide 5-nitrate were obtained by carrying out the same operation as in Example 3, changing the molar ratio of isosorbide to nitric acid and the solvent in the nitration as shown in the table below. Obtained.

The yield and yield are shown in the table.

[Brief explanation of the drawing]

The figure shows an infrared absorption spectrum of purified inrubido-5-nitrate obtained by the method of the present invention. Patent applicant: Toshin Chemical Co., Ltd. Agent Akira Agata

Claims (1)

[Claims] Isosorbide 5-nitrate sodium hydrate represented by the general formula % formula %] (in the formula, n is 2 to 8) in water, an organic solvent, or a mixed solvent thereof. Ison Rubido 5 characterized by treatment with acid
- H4 method for nitrate. 2. The method according to claim 1, wherein the organic solvent is methyl ethyl ketone. 3. Ison rubide is reacted with concentrated nitric acid in a solvent containing an aromatic hydrocarbon, the resulting nitrated mixture is neutralized, and the by-produced insorbide 2,5-dinitrate is separated, and then an aqueous sodium hydroxide solution is added. Isolubido 5-nitrate sodium hydrate represented by the general formula % (in the formula % is 2 to 8) is isolated, and this product is further mixed with water, an organic solvent, or a mixed solvent thereof. A method for producing insorbido 5-nitrate, which comprises treating with an acid in the process. 4. The method according to claim 3, wherein the aromatic hydrocarbon is benzene. 5. The method according to claim 3 or 4, wherein the temperature in the 5' nitration reaction is 30 to 40°C. 6. The method according to claim 3, 4 or 5, wherein the concentrated nitric acid is fuming nitric acid. 7. The method according to claim 3, 4, 5 or 6, wherein the organic solvent is methyl ethyl ketone.