JPH1067795A - Production of erythromycin derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject compound useful as a preventive, a therapeutic agent, etc., for digestive diseases while suppressing the formation of by-products, by reacting N-demethyl erythromycin A (salt) with an ISO propylating agent and treating the reaction product under an acidic condition. SOLUTION: N-Demethylerythromycin A of formula I or its salt is reacted with an isopropylating agent (e. g. 2-iodopropane) in the presence of a base such as triethylamine in a solvent such as acetonitrile at 60-65 deg.C for 24 hours while stirring to give N-demethyl-N-isopropylerythromycin A or its salt, the solvent is distilled away under reduced pressure and the resultant solution is treated with glacial acetic acid and methylene chloride, etc., under an acidic condition at a room temperature for one hours while stirring to give the objective N-demethyl-N-isopropyl-8,9-anhydroerythromycin A-6,9-hemiacetal (salt) of formula II useful for preventing and treating digestive diseases such as postoperative intestinal atresia, diabetic gastroparalysis, dyspepsia, chronic gastritis, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to digestive system diseases in mammals, in particular, postoperative ileus in humans, diabetic gastric palsy, dyspepsia, reflux esophagitis, pseudo ileus, and digestion associated with postgastrectomy syndrome. Respiratory symptoms (upper abdominal distension, upper abdominal pressure, nausea, vomiting, heartburn, loss of appetite, epigastric pain, epigastric tenderness, etc.)
The present invention relates to a method for producing an erythromycin derivative or a salt thereof useful as a medicament for preventing or treating chronic gastritis, irritable bowel syndrome, morphine and constipation by administration of an anticancer drug.

[0002]

2. Description of the Related Art As a compound having a gastrointestinal contraction motility promoting activity, JP-A-63-99092 (EP-A-021535)
5) and JP-A-63-99016 (EP-A-021535).
5) The erythromycin derivative N-demethyl-
N-isopropyl-8,9-anhydroerythromycin A-6,9-hemiacetal and N-demethyl-N
-Ethyl-8,9-anhydroerythromycin A-6,
9-Hemiacetal has been described. These two publications disclose N-demethyl-8,9-anhydroerythromycin A-6 as a method for producing N-demethyl-N-isopropyl-8,9-anhydroerythromycin A-6,9-hemiacetal. , 9-Hemiacetal is N-isopropylated, and N-demethyl-
N-ethyl-8,9-anhydroerythromycin A-
As a method for producing 6,9-hemiacetal, a method is disclosed in which N-demethyl-N-ethyl-erythromycin A is treated with glacial acetic acid to form a 6,9-hemiacetal ring. Further, these two publications disclose a method of purifying the target compound by silica gel column chromatography.

[0003]

However, when N-demethylerythromycin A is subjected to an N-alkylation reaction,
It is easy to introduce an alkyl group having 1 to 2 carbon atoms (that is, methyl and ethyl), but an alkyl group having 3 or more carbon atoms (that is, propyl, isopropyl, butyl, isobutyl and the like), particularly a branched alkyl group ( That is, isopropyl,
It is difficult to introduce isobutyl and the like, and since a large amount of by-products is produced, the yield is low and there is a problem as a production method used for industrial mass production. Therefore, the above-mentioned JP-A-63-9
The methods described in JP-A-9092 and JP-A-63-99016 are not practically used as industrial processes for producing N-demethyl-N-isopropyl-8,9-anhydroerythromycin A-6,9-hemiacetal. Did not. Further, N-demethyl-N-ethyl-erythromycin A is treated under acidic conditions to give N-demethyl-N-ethyl-8,
The method described in the above-mentioned JP-A-63-99092 and JP-A-63-99016 for obtaining 9-anhydroerythromycin A-6,9-hemiacetal is based on the starting material N-demethyl-N -Ethyl-erythromycin A and the product, N-demethyl-N-ethyl-8,9-anhydroerythromycin A-6,9-hemiacetal, are both difficult to purify, and therefore have a problem as an industrial production method. . Further, the purification method of the target compound by silica gel column chromatography disclosed in these two publications requires (i) an extremely long time for the chromatographic treatment and concentration of the eluate after the chromatographic treatment on an industrial large scale. This method is problematic for industrial use, such as necessity and (ii) silica gel is expensive and difficult to recycle, resulting in a large amount of waste.

[0004]

Means for Solving the Problems The present inventors have conducted intensive studies on the production of erythromycin derivatives and found that N
By reacting demethylerythromycin A with an isopropylating agent in the presence of a base and then treating it under acidic conditions, the formation of by-products is unexpectedly suppressed, and N-demethyl-N-isopropyl-8 is , 9-Anhydroerythromycin A-6,9-hemiacetal was found to be obtained in good yield. Further, after treating N-demethylerythromycin A under acidic conditions, it is further reacted with an ethylating agent, whereby N-demethyl-N
-Ethyl-8,9-anhydroerythromycin A-6,
It has been found that 9-hemiacetal can be obtained in good yield. Furthermore, the present inventors, for example, N-demethyl-N-
Isopropyl-8,9-anhydroerythromycin A
8,6 represented by the formula (VI) represented by -6,9-hemiacetal and N-demethyl-N-ethyl-8,9-anhydroerythromycin A-6,9-hemiacetal
When the 9-anhydroerythromycin A-6,9-hemiacetal derivative is recrystallized from hydrated isopropanol, surprisingly, isopropanol solvated crystals are formed, impurities can be efficiently removed, and crystals with high purity can be obtained in good yield. I found that. By this isopropanol solvation crystallization method, for the first time, it has become possible to produce without using a silica gel column chromatography step, which has conventionally been difficult to mass-process and has many problems in industrialization. Based on these findings, the present inventors have conducted further intensive studies, and as a result, completed the present invention.

The present invention relates to erythromycin derivatives, especially N-demethyl-N-isopropyl-8,9-anhydroerythromycin A-6,9-hemiacetal and N
The present invention provides a high-yield, high-quality production method suitable for industrial mass production of -demethyl-N-ethyl-8,9-anhydroerythromycin A-6,9-hemiacetal. That is, the present invention provides (1) Formula (I)

Embedded image Reacting N-demethylerythromycin A or a salt thereof represented by the formula (II) with an isopropylating agent:

Embedded image A method for producing N-demethyl-N-isopropylerythromycin A or a salt thereof represented by the following formula (2):

Embedded image Wherein N-demethyl-N-isopropylerythromycin A or a salt thereof represented by the formula (III) is treated under acidic conditions:

Embedded image N-demethyl-N-isopropyl-8,9-
Process for producing anhydroerythromycin A-6,9-hemiacetal or a salt thereof, (3) Formula (I)

Embedded image Reacting N-demethylerythromycin A or a salt thereof represented by the formula (III) with an isopropylating agent, and then treating the mixture under acidic conditions.

Embedded image N-demethyl-N-isopropyl-8,9-
Process for producing anhydroerythromycin A-6,9-hemiacetal or a salt thereof, (4) Formula (I)

Embedded image Treating N-demethylerythromycin A or a salt thereof represented by the formula (IV) under acidic conditions:

Embedded image A method for producing N-demethyl-8,9-anhydroerythromycin A-6,9-hemiacetal or a salt thereof represented by the formula: (5) Formula (IV)

Embedded image (V) wherein N-demethyl-8,9-anhydroerythromycin A-6,9-hemiacetal) is reacted with an ethylating agent.

Embedded image A method for producing N-demethyl-N-ethyl-8,9-anhydroerythromycin A-6,9-hemiacetal or a salt thereof represented by the following formula: (6) Formula (I)

Embedded image Wherein N-demethylerythromycin A or a salt thereof represented by the formula (V) is treated under acidic conditions and then reacted with an ethylating agent.

Embedded image A method for producing N-demethyl-N-ethyl-8,9-anhydroerythromycin A-6,9-hemiacetal or a salt thereof represented by the following formula: (7) Formula (VI)

Embedded image Wherein R ¹ and R ² are the same or different and have 1 carbon atom
Represents an alkyl having 6 to 6 carbon atoms, an alkenyl having 2 to 6 carbon atoms or an alkynyl having 2 to 6 carbon atoms, R ³ represents hydrogen or a hydroxyl group, and R ⁴ and R ^{5 each} represent a hydrogen atom and the other represents a hydroxyl group. Or R ⁴ and R ⁵ are bonded to each other to represent O =, R ⁶ represents hydrogen or an optionally substituted hydroxyl group, and R ⁷ represents hydrogen or a hydroxyl group. Wherein the crude crystal of the 8,9-anhydroerythromycin A-6,9-hemiacetal derivative or a salt thereof is recrystallized from aqueous isopropanol as a solvate. -Anhydroerythromycin A-
The present invention relates to a method for producing a substantially pure crystal of a 6,9-hemiacetal derivative or a salt thereof.

A description of the above formulas, as well as definitions included within the scope of the present invention, and preferred examples thereof are set forth below. In the method of the present invention, N-demethyl-N-isopropyl-8,9-anhydroerythromycin A-6,9-
Hemiacetal is reacted, for example, with a halogen compound in the presence of a base using N-demethylerythromycin A (described in JP-A-47-9129) as a starting compound,
Subsequently, it can be produced by treating under acidic conditions. Also, N-demethyl-N-ethyl-8,9-
Anhydroerythromycin A-6,9-hemiacetal is, for example, N-demethylerythromycin A (described above).
As a starting compound, treated under acidic conditions, and then reacted with a halogenated compound in the presence of a base. Examples of the halogen compound include a halogenated C having an alkyl having 1 to 6 carbon atoms (eg, methyl, ethyl, propyl, hexyl, etc.) and a halogen.
_1-6 alkyl, alkenyl of 2 to 6 carbon atoms (e.g., vinyl, 1-propenyl, allyl, hexenyl, etc.) and halogenated C _2-6 alkenyl halogen is bonded or alkynyl (e.g. 2 to 6 carbon atoms, ethynyl, 1-propynyl, 2-propynyl, hexynyl and the like) such as a halogen is bound halogenated C _2-6 alkynyl and the like and. Preferred examples of the halogen compound include, for example, in the case of N-demethyl-N-isopropyl-8,9-anhydroerythromycin A-6,9-hemiacetal, isopropyl halide is mentioned, and N-demethyl-N-ethyl- In the case of 8,9-anhydroerythromycin A-6,9-hemiacetal, an ethyl halide is exemplified.
As the halogen in the halogen compound, chlorine, bromine, iodine, particularly iodine is preferable. Specific examples of the halogen compound include methyl iodide, ethyl iodide, propyl iodide, isopropyl iodide, propenyl iodide, ethynyl iodide, propynyl iodide, and the like. Propyl iodide and isopropyl iodide are preferred. The amount of the halogen compound to be used in the reaction is about 1 to 100 molar equivalents, preferably 2 to 25 molar equivalents, per 1 mol of the starting compound N-demethylerythromycin A (or its bis form).

Solvents used in the reaction include halogenated hydrocarbons (eg, chloroform, dichloromethane, etc.), ethers (eg, ethyl ether, tetrahydrofuran, etc.), ketones (eg, acetone, methyl ethyl ketone, etc.), esters (eg, Eg, ethyl acetate, etc.), alcohols (eg, methanol, ethanol, etc.), nitriles (eg,
Acetonitrile, etc.), amides (eg, N, N-dimethylformamide, N, N-dimethylamide, etc.), preferably nitriles, ketones, especially acetonitrile. Examples of the base used in the reaction include tertiary amines (eg, triethylamine, tri-n-propylamine, etc.), metal carbonates (eg, potassium carbonate, sodium carbonate, lithium carbonate, etc.), and metal hydrogen carbonates (eg, sodium hydrogen carbonate). , Potassium hydrogen carbonate and the like), and preferably sodium carbonate and triethylamine. The reaction is performed under ice cooling (about 0 ° C.)
To the boiling point of the solvent (about 100 ° C.), preferably from room temperature (about 15 to 25 ° C.) to about 80 ° C. As the acid in the treatment under acidic conditions, for example, organic acids (formic acid,
Acetic acid, propionic acid, oxalic acid, fumaric acid, maleic acid, etc.) or mineral acids (sulfuric acid, phosphoric acid, etc.),
Acetic acid is particularly preferred. These acids can be appropriately diluted and used with halogenated hydrocarbons, ethers, ketones and the like. The amount of the acid used is about 1 to 200 molar equivalents relative to 1 mol of N-demethylerythromycin A,
Preferably it is 30 to 100 molar equivalents. The reaction is carried out under ice cooling (about 0 ° C.) to the boiling point of the solvent (about 100 ° C.), preferably at room temperature (about 15 to 25 ° C.) to about 80 ° C. The obtained target compound N-demethyl-N-alkyl, N-demethyl-N-alkenyl or N-demethyl-N-alkynyl-8,9-anhydroerythromycin A-6,9-hemiacetal is known per se. means,
For example, it can be purified by concentration, liquid conversion, phase transfer, solvent extraction, crystallization, crystallization and isolation, followed by recrystallization, chromatography and the like. In the present invention,
The target compound N-demethyl-N-alkyl-, N-demethyl-N-alkenyl- or N-demethyl-N-alkynyl-8,9-anhydroerythromycin A-6,9-hemi obtained according to the above method. The crude crystal of the compound represented by the above formula (VI) containing an acetal is recrystallized as a solvate of isopropanol from hydrated isopropanol, that is, a mixed solvent of isopropanol / water. After this, acetonitrile /
By recrystallization from a mixed solvent such as water, the target compound represented by the formula (VI) can be obtained as substantially pure crystals in high yield. Equation (VI) above
Wherein R ¹ and R ² are the same or different and have 1 to 6 carbon atoms.
(Eg, methyl, ethyl, propyl, isopropyl, hexyl, etc.), alkenyl having 2 to 6 carbons (eg, vinyl, 1-propenyl, allyl, hexenyl, etc.) or alkynyl having 2 to 6 carbons (eg, ethynyl) ,
1-propynyl, 2-propynyl, hexynyl, etc.),
It preferably represents alkyl having 1 to 4 carbon atoms, more preferably ethyl or isopropyl. R ³ represents hydrogen or a hydroxyl group. R ⁴ and R ⁵ are one in which hydrogen is the other and the other is a hydroxyl group, or R ⁴ and R ⁵ are bonded to each other to form O
=, Preferably one is hydrogen and the other is a hydroxyl group. R ⁶ represents hydrogen or a hydroxyl group which may be substituted. In this case, the optionally substituted hydroxyl group means a hydroxyl group, an alkyl having 1 to 6 carbons (eg, methyl, ethyl, propyl, isopropyl, hexyl, etc.), an alkenyl having 2 to 6 carbons (eg, vinyl , 1-propenyl, allyl, hexenyl, etc.) or 2 carbon atoms
6 to alkynyl (eg, ethynyl, 1-propynyl, 2
-Propynyl, hexynyl, etc.), and preferably represents a hydroxyl group or a hydroxyl group or a group having 1 to 4 carbon atoms.
A hydroxyl group substituted with an alkyl, more preferably a hydroxyl group. R ⁷ represents hydrogen or a hydroxyl group, preferably a hydroxyl group. In the present invention, specific examples of the compound represented by the above formula (VI) include, for example, N-demethyl-N-isopropyl-8,9-anhydroerythromycin A-
6,9-hemiacetal, N-demethyl-N-ethyl-
8,9-Anhydroerythromycin A-6,9-hemiacetal, 12-dehydroxy-4 "-dehydroxy-
N-demethyl-N-isopropyl-8,9-anhydroerythromycin A-6,9-hemiacetal, N-demethyl-N-isopropyl-12-methoxy-8,9-
Anhydroerythromycin A-6,9-hemiacetal and N-demethyl-N-isopropyl-12-
Methoxy-11-oxo-8,9-anhydroerythromycin A-6,9-hemiacetal, more preferably N-demethyl-N-isopropyl-8,9-
Anhydroerythromycin A-6,9-hemiacetal is mentioned. The isopropanol used for recrystallization is used in an amount of about 1 to 20 times, preferably 2 to 5 times, the volume of the substrate.
Double volumes, preferably 2 to 10 volumes are used.
The ratio of isopropanol to water is approximately 1: 0.5 to 1: 3, preferably 1: 1 to 1: 2. Further, the obtained target compound may form a salt by treating with an acid. Examples of the acid include organic acids (eg, glycopeptonic acid, stearic acid, propionic acid, lactopionic acid, oxalic acid, maleic acid, fumaric acid, succinic acid, lactic acid, trifluoroacetic acid, acetic acid, methanesulfonic acid, paratoluene Sulfonic acid, benzenesulfonic acid, etc.), and mineral acids (eg, sulfuric acid, hydrochloric acid, hydroiodic acid, phosphoric acid, nitric acid, etc.). As the salt of the target compound of the present invention, a pharmaceutically acceptable salt is preferable, for example,
Examples thereof include salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like. Preferred examples of the salt with an inorganic acid include, for example, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Suitable examples of salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p -Salts with toluenesulfonic acid and the like.
Preferred examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, ornithine, and preferred examples of the salt with an acidic amino acid include, for example, salts with aspartic acid, glutamic acid, and the like. Can be

The compound of the present invention is compounded with a pharmaceutically acceptable carrier and is orally or parenterally administered as a solid preparation such as tablets, capsules, granules and powders; or as a liquid preparation such as syrups and injections. Can be administered in a controlled manner. Pharmaceutically acceptable carriers include various organic or inorganic carrier materials commonly used as pharmaceutical materials, such as excipients, lubricants, binders, and disintegrants in solid preparations; solvents and dissolution aids in liquid preparations. , Suspending agents, tonicity agents, buffers,
It is formulated as a soothing agent. If necessary, formulation additives such as preservatives, antioxidants, coloring agents and sweeteners can also be used. Preferred examples of the excipient include lactose, sucrose, D-mannitol, starch, crystalline cellulose, light anhydrous silicic acid, and the like. Preferred examples of the lubricant include, for example, magnesium stearate, calcium stearate, talc, colloidal silica and the like. Preferable examples of the binder include, for example, bound cellulose, sucrose, D-mannitol, trihalose, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, and the like. Preferable examples of the disintegrant include starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, sodium carboxymethyl starch and the like. Preferred examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, tricaprylin and the like.

Preferred examples of the solubilizer include polyethylene glycol, propylene glycol, D-mannitol, trihalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. No. Preferred examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate; for example, polyvinyl alcohol, Examples include hydrophilic polymers such as polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose. Suitable examples of the tonicity agent include, for example, sodium chloride, glycerin, D-mannitol and the like. Preferred examples of the buffer include buffers such as phosphate, acetate, carbonate, and citrate. Preferred examples of the soothing agent include benzyl alcohol and the like. Preferred examples of preservatives include:
For example, paraoxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like can be mentioned. Preferable examples of the antioxidant include, for example, sulfite, ascorbic acid and the like. Erythromycin derivatives obtained according to the present invention, for example N-demethyl-N-isopropyl-8,
9-anhydroerythromycin A-6,9-hemiacetal, N-demethyl-N-ethyl-8,9-anhydroerythromycin A-6,9-hemiacetal, 12
-Dehydroxy-4 "-dehydroxy-N-demethyl-
N-isopropyl-8,9-anhydroerythromycin A-6,9-hemiacetal, N-demethyl-N-isopropyl-12-methoxy-8,9-anhydroerythromycin A-6,9-hemiacetal, or N
-Demethyl-N-isopropyl-12-methoxy-11
-Oxo-8,9-anhydroerythromycin A-6,
Specific examples of the preparation of 9-hemiacetal or a salt thereof include those exemplified in the following Reference Examples.

[0010] The erythromycin derivatives targeted by the present invention, specifically, for example, N-demethyl-N-isopropyl-8,9-anhydroerythromycin A-6,9-hemiacetal and N-demethyl-N-ethyl-8 , 9-
Anhydroerythromycin A-6,9-hemiacetal is less toxic and can be used in mammals (eg, humans, horses, cows,
Gastrointestinal disorders in pigs, dogs, cats, mice, rats, etc.), especially human postoperative ileus, diabetic gastroparesis, dyspepsia, reflux esophagitis, pseudo ileus, gastrointestinal symptoms associated with postgastrectomy syndrome (Abdominal bloating, epigastric overpressure, nausea, vomiting, heartburn, anorexia, epigastric pain, epigastric tenderness, etc.),
It can be used as a medicament for preventing or treating chronic gastritis, irritable bowel syndrome, morphine and constipation due to administration of anticancer drugs.

The compounds of interest according to the invention, N-demethyl-N-isopropyl-8,9-anhydroerythromycin A-6,9-hemiacetal and N-demethyl-
N-ethyl-8,9-anhydroerythromycin A-
The dose of 6,9-hemiacetal can be variously selected depending on the administration route and the condition of the patient to be treated.
For oral administration per day per person, for example, about 0.1
In the case of parenteral administration (e.g., intravenous injection, etc.), for example, about 0.5 mg / kg, preferably 1.0 to 100 mg / kg.
It can be selected from the range of 01 to 100 mg / kg, preferably 0.1 to 10 mg / kg.

[0012]

DESCRIPTION OF THE PREFERRED EMBODIMENTS Hereinafter, the present invention will be described more specifically with reference to Reference Examples and Examples, but the present invention is not limited to these. Reference Example 1 Production of N-demethylerythromycin A A solution of 23.0 kg of erythromycin A (Upjohn, USA) dissolved in 196 L of methanol and 21.6 kg of sodium acetate trihydrate in 46 L of water And heated to 50 ° C, stirring and 8.1kg iodine
Was added. 1N Na after 10 minutes to maintain pH 8-9
35 L of OH, 19 L of 1N NaOH after 30 minutes, 4.1 kg of iodine after 60 minutes and 7.4 L of 1N NaOH, 9.9 L of 1N NaOH after 75 minutes and 2.1 k of iodine after 105 minutes
g and 1N NaOH 7.4 L, 1N NaO after 135 minutes
H12L was added. The reaction was further stirred at 50 ° C. for 1 hour. The reaction was cooled and sodium thiosulfate 5.8k
g, a solution containing 17.5 L of concentrated aqueous ammonia and 175 L of water were added, and the mixture was extracted twice with 115 L of methylene chloride. After the methylene chloride solution was washed with 44 L of dilute aqueous ammonia containing 9 L of concentrated aqueous ammonia, the solvent was distilled off under reduced pressure. After 35 L of acetone was added to the obtained residue to dissolve it, 35 L of isopropyl ether and 5 L of concentrated aqueous ammonia were added to crystallize, and white crystals of N-demethylerythromycin A were obtained.
6.9 kg (74.9% yield) were obtained.

Reference Example 2 Preparation of N-demethylerythromycin A Erythromycin A [same as above] 150.0 g was dissolved in 1680 ml of methanol, and a solution obtained by dissolving 142.0 g of sodium acetate trihydrate in 600 ml of water was added. Was. 1
62.0 g of iodine was added to methanol 1 while maintaining the pH of the reaction solution at 8.5 and the temperature at 50 ° C. by appropriately adding NNaOH.
A solution dissolved in 500 ml was added over 2 hours. After further reacting with stirring at 50 ° C. for 1 hour, the same treatment as in Reference Example 1 was performed to obtain white crystals of N-demethylerythromycin A 1
32.0 g (90% yield) were obtained.

Reference Example 3 Production of N-demethylerythromycin A N-demethylerythromycin A obtained in Reference Example 2
10.0 g was dissolved in 15 ml of methanol at room temperature.
l and crystallized to give N-demethylerythromycin A9.
02 g (yield 90%) was obtained.

Example 1 Preparation of N-demethyl-N-isopropyl-8,9-anhydroerythromycin A-6,9-hemiacetal N-demethylerythromycin A obtained in Reference Example 1
To 16.9 kg, 20.0 kg of 2-iodopropane, 5.9 kg of triethylamine and 42 L of acetonitrile were added.
The mixture was stirred and reacted at 0 to 65 ° C for 24 hours. The solvent was distilled off under reduced pressure from the reaction product after stirring to obtain N-demethyl-N-isopropylerythromycin A. To this N-demethyl-N-isopropylerythromycin A, add 71 L of glacial acetic acid.
And 141 L of methylene chloride were added thereto, and the mixture was stirred at room temperature for 1 hour to react. The reaction product was poured into 327 L of cold water containing 141 L of aqueous ammonia, and extracted twice with 71 L of dichloromethane. The dichloromethane solution was washed with 142 L of water, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off from the filtrate obtained under reduced pressure. The obtained residue was dissolved in 14 L of acetonitrile, and 14 L of water was added for crystallization.
White crystals of demethyl-N-isopropyl-8,9-anhydroerythromycin A-6,9-hemiacetal 1
4.0 kg (80% yield) were obtained.

Example 2 Preparation of N-demethyl-N-isopropyl-8,9-anhydroerythromycin A-6,9-hemiacetal N-demethylerythromycin A obtained in Reference Example 3
35.4 g of 2-iodopropane, 30.0 g of anhydrous sodium carbonate and 150 ml of acetonitrile were added to 30.0 g, and the mixture was stirred at 73 to 78 ° C. for 8 hours to react. After evaporating the solvent under reduced pressure from the reaction product after stirring, 300 ml of dichloromethane and 300 ml of water were added to the residue and dissolved by stirring. The dichloromethane layer is separated and the aqueous layer is further diluted with 100 ml of dichloromethane.
And extracted and added to the separated dichloromethane layer. The obtained dichloromethane solution was washed with 200 ml of water, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure from the obtained filtrate to obtain N-demethyl-N-isopropylerythromycin A. This N-demethyl-N
-150 ml of glacial acetic acid in isopropyl erythromycin A,
Dichloromethane (75 ml) was added, and the mixture was stirred and reacted at room temperature for 1 hour. The reaction was carried out using cold water 72 ml containing 240 ml of aqueous ammonia.
It was poured into 0 ml and extracted twice with 240 ml of dichloromethane.
After washing with 240 ml of water and drying treatment with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure from the filtrate obtained by filtration. The obtained residue was dissolved in 130 ml of acetonitrile, 130 ml of water was added for crystallization, and N-demethyl-N-isopropyl-8,9-anhydroerythromycin A-
6,9-hemiacetal 25.0 g (80.6% yield)
I got

Example 3 Preparation of N-demethyl-N-isopropyl-nor-8,9-anhydroerythromycin A-6,9-hemiacetal N-demethyl-N-isopropyl- obtained in Example 2
To 5.00 g of 8,9-anhydroerythromycin A-6,9-hemiacetal was added 12.5 ml of isopropanol, dissolved while heating, and 15 ml of water was added in three portions to crystallize, and N-demethyl was added. -N-isopropyl-8,9
4.90 g of anhydroerythromycin A-6,9-hemiacetal isopropanol 1 solvate (yield 9
0%). 4.90 g of the solvate was crystallized in a mixed solvent of acetonitrile / water and purified N-demethyl-N-
4.11 g of isopropyl-nor-8,9-anhydroerythromycin A-6,9-hemiacetal (yield 82
%).

Example 4 N-Demethyl-8,9-anhydroerythromycin A
Production of -6,9-hemiacetal N-demethylerythromycin A obtained in Reference Example 1
20 ml of glacial acetic acid was added to 5.00 g, and the mixture was stirred and reacted at room temperature for 1 hour. Cold water 120 containing 40 ml of ammonia water
The mixture was poured into 1 ml and extracted twice with 40 ml of dichloromethane. The dichloromethane solution was washed with 40 ml of water, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure from the filtrate obtained. The obtained residue was dissolved in 25 ml of ethyl acetate under heating, cooled and crystallized to give N-demethyl-
4.14 g (85% yield) of white crystals of 8,9-anhydroerythromycin A-6,9-hemiacetal was obtained.

Example 5 Preparation of N-demethyl-N-ethyl-8,9-anhydroerythromycin A-6,9-hemiacetal The N-demethyl-8,9-anhydroerythromycin A obtained in Example 4 -6,9-hemiacetal 5.50
kg, iodoethane 16.7kg, triethylamine 3.6
0 kg and 25 L of methanol were added, and the mixture was stirred and reacted at 50 to 55 ° C. for 2.5 hours. The solvent was distilled off from the reaction product under reduced pressure, and 50 L of dichloromethane and water 1 were added to the obtained residue.
00L was added and dissolved. The dichloromethane layer was separated, and the aqueous layer was further extracted with 50 L of dichloromethane and added to the separated dichloromethane layer. The obtained dichloromethane solution was washed with 50 L of a saturated sodium hydrogen carbonate solution,
After drying with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure from the filtrate obtained by filtration. The obtained residue was dissolved in 20 L of acetone, and crystallized by adding 25 L of water.
3.81 kg of white crystals of demethyl-N-ethyl-8,9-anhydroerythromycin A-6,9-hemiacetal
(74% yield).

Reference Example 4 Production of N-demethyl-N-isopropyl-8,9-anhydroerythromycin A-6,9-hemiacetal The N-demethyl-8,9-anhydroerythromycin A obtained in Example 4 5.00 g of -6,9-hemiacetal
Then, 12.1 g of 2-iodopropane, 7.2 g of triethylamine and 35 ml of N, N-dimethylformamide were added, and the mixture was stirred and reacted at 50 to 55 ° C. for 34 hours. The reaction was added to 100 ml of water and extracted twice with 50 ml of dichloromethane. The dichloromethane solution was washed with 50 ml of water, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure from the filtrate obtained. The obtained residue is purified by silica gel chromatography [developing solvent, dichloromethane / methanol (10: 1)], and then crystallized in a mixed solvent of acetonitrile / water to give N-demethyl-N-isopropyl-8,9-anhydro. 1.78 g (33% yield) of white crystals of erythromycin A-6,9-hemiacetal were obtained.

Reference Example 5 Production of N-demethyl-N-isopropyl-8,9-anhydroerythromycin A-6,9-hemiacetal N-demethyl-N-isopropyl- obtained in Example 1
9.37 kg of 8,9-anhydroerythromycin A-6,9-hemiacetal was converted to 3.7 L of isopropyl ether /
Crystallization was carried out in a mixed solvent consisting of 19 L of n-hexane. The obtained crystals were purified by silica gel chromatography (developing solvent, dichloromethane: methanol = 10: 1), the effective fractions were collected, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in 42 L of acetonitrile, and 42 L of water was dissolved.
In addition, the mixture was crystallized to obtain 6.78 kg of purified N-demethyl-N-isopropyl-8,9-anhydroerythromycin A-6,9-hemiacetal. (Yield 72%)

Reference Example 6 Production of N-demethyl-N-ethyl-8,9-anhydroerythromycin A-6,9-hemiacetal N-demethylerythromycin A obtained in Reference Example 1
5.00 g, 16.25 g of iodoethane, 3.15 g of triethylamine and 25 ml of methanol were added thereto.
The mixture was stirred and reacted at 2.5 ° C. for 2.5 hours. The solvent was distilled off from the reaction product under reduced pressure to obtain N-demethyl-N-ethyl-erythromycin A. 20 ml of glacial acetic acid was added to this N-demethyl-N-ethyl-erythromycin A, and the mixture was stirred and reacted at room temperature for 1 hour. The reaction was poured into 120 ml of cold water containing 40 ml of aqueous ammonia and extracted twice with 40 ml of dichloromethane. The dichloromethane solution was washed with 40 ml of water, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure from the filtrate obtained. The residue obtained is washed with acetone 20
and N-demethyl-N-ethyl-8,9-anhydroerythromycin A was crystallized by adding 40 ml of water.
3.95 g of white crystals of -6,9-hemiacetal (yield 7
8%).

Reference Example 7 Production of N-demethyl-N-isopropyl-8,9-anhydroerythromycin A-6,9-hemiacetal N-demethylerythromycin A obtained in Reference Example 1
After treating 1.00 g of glacial acetic acid in the same manner as in Reference Example 3, 1-g
1.18 g of iodopropane, 0.35 of triethylamine
g and 2.5 ml of acetonitrile, and in the same manner as in Reference Example 1, N-demethyl-N-isopropyl-8,9-
1.01 g (73% yield) of white crystals of anhydroerythromycin A-6,9-hemiacetal was obtained.

Reference Example 8 Production of Capsules As shown in Table 1, 1) 25 g, 2) 539 g, 3)
After mixing 360 g, 4) 120 g, 5) 60 g and 6) 60 g in a vertical granulator (Powrex, Japan),
556 g of an aqueous solution in which 7) 60 g and 8) 12 g were dissolved was added and kneaded. The kneaded product was extruded with a screen size of 0.8 mmφ using Dome Gran (Fuji Paudal Co., Japan), and the granulated product was converted into spherical granules with a marmelizer (Fuji Paudal Co.), followed by fluid granulation. The product was dried with a drier (manufactured by Powrex), and N-demethyl-N-isopropyl-
8,9-Anhydroerythromycin A-6,9-hemiacetal (abbreviated as compound A) main drug granules were obtained. N-Demethyl-N-isopropyl-8,9-anhydroerythromycin A-6,9-hemiacetal (Compound A) 840 g of the main drug particle is placed in a fluidized granulating dryer (manufactured by Powrex), and 96.9 g of 46.9 g is added. Coating was performed with 938 g of an aqueous solution containing the solution to give underhanging granules. Further, the same machine was used to put 760.2 g of underhang granules. 10) 586.2 g (175.8 g as solid content), 11) 52.8 g, 12) 17.4 g and 13) 7.8 g of suspension 1 containing , 894.2 g, to give enteric coated granules. 845 g of this enteric granule and 1
4) 2.5 g and 15) 2.5 g are mixed using a tumbler mixer (manufactured by Showa Kagaku Kikai Kosakusho, Japan). 765 g of the mixed particles were used as a No. 3 capsule by a capsule filling machine (manufactured by Xanasea). A 5.0 mg capsule was produced in the same manner.

[Table 1] It should be noted that the resulting capsules had good formulation characteristics such as acid resistance in the first liquid and dissolution in the second liquid.

Reference Example 9 Production of capsules Capsules A having the composition shown in Table 2 per capsule were produced as follows. First, 1) 87.5
g, 3) 542.5 g, 4) 490 g, and 5) 350 g were mixed well to give a spraying agent. 2) In a centrifugal flow type coating granulator (manufactured by Freund Corporation, CF-360φ)
2,730 g, and 6) 28 g of an aqueous solution 1,1
The above spray was coated while spraying 20 g. 3) 143.5 g, 4) 161 g,
5) Mix 157.5g well to make a spreader,
Subsequent to the above-mentioned spray, coating was performed to obtain spherical granules. The spherical granules were vacuum-dried at 40 ° C. for 16 hours and sieved with a round sieve to obtain a main drug particle of 710 to 1000 μm. 4,020 g of the main drug particles were placed in a fluidized-granulation dryer (manufactured by Powrex), and 7) coated with 4,020 g of an aqueous solution containing 201 g to give underhang granules. 8) 820.4 g (2,734.7 g as a 30% methacrylic acid copolymer-emulsion liquid) into 3,940 g of the undersized particles by the same machine.
8,838.7 g of a suspension containing 46.4 g, 10) 81.2 g and 11) 36.4 g were coated to give enteric granules. 4,501.8 g of the enteric granules and 12) 12.3
g and 13) 12.3 g of the mixed granules were prepared using a tumbler mixer (manufactured by Showa Chemical Machinery Co., Ltd.).
379.2 g was filled in a gelatin capsule No. 3 with a capsule filling machine (manufactured by Xanasea) to obtain a capsule A.

REFERENCE EXAMPLE 10 Capsules B and C having the composition shown in [Table 2] per capsule were produced in the same manner as in Reference Example 9. Reference Example 11 A capsule D containing 20 mg of the compound A per capsule was obtained using the mixed granules obtained in the production of the capsule C in Reference Example 10 and gelatin capsule No. 1.

[0027]

[Table 2] It should be noted that the resulting capsules had good formulation characteristics such as acid resistance in the first liquid and dissolution in the second liquid.

Reference Example 12 Production of Capsules A capsule E having the composition shown in Table 3 per capsule was produced as follows. First, 1) 87.5g,
3) 542.5 g, 4) 490 g, and 5) 350 g were mixed well to prepare a spraying agent. In a centrifugal flow type coating granulator (manufactured by Freund Corporation, CF-360φ), 2) 2,
730 g, and 6) an aqueous solution 1,12 in which 28 g was dissolved
While spraying 0 g, the above-mentioned spraying agent was coated. Further, 3) 143.5 g, 4) 161 g, 5)
157.5 g was mixed well to give a hold down powder, which was subsequently coated to give spherical granules. The spherical granules were vacuum-dried at 40 ° C. for 16 hours and sieved with a round sieve to obtain a main drug particle of 710 to 1000 μm. The main drug particle 4,
020 g was placed in a fluidized-granulation dryer (manufactured by Powrex),
7) 879.0 g (2,930.0 g as a 30% methacrylic acid copolymer emulsion, 8) 264.0 g, 9) 8
9470. Suspension containing 7.0 g and 10) 39.0 g.
0 g was coated to obtain enteric coated granules. 4,936.4 g of this enteric granule, 14.0 g of 11) and 5.6 g of 12)
Was mixed with a tumbler mixer (manufactured by Showa Kagaku Kikai Kosakusho), and 4,956.0 g of the mixed particles were filled into gelatin capsule No. 3 using a capsule filling machine (manufactured by Xanasea) to obtain capsule E. .

REFERENCE EXAMPLE 13 In the same manner as in Reference Example 12, capsules F and G having the composition shown in [Table 3] per capsule were produced. REFERENCE EXAMPLE 14 Capsule H containing 20 mg of compound A per capsule was obtained by using the mixed granules obtained when producing capsule G in Reference Example 13 and gelatin capsule No. 1.

[0030]

[Table 3] It should be noted that the resulting capsules had good formulation characteristics such as acid resistance in the first liquid and dissolution in the second liquid.

[0031]

According to the production method of the present invention, the production of by-products is suppressed, and erythromycin derivatives, particularly 8,9-anhydroerythromycin A-, can be obtained in high yield and high purity.
6,9-Hemiacetal derivatives (for example, N-demethyl-N-isopropyl-8,9-anhydroerythromycin A-6,9-hemiacetal and N-demethyl-
N-ethyl-8,9-anhydroerythromycin A-
6,9-hemiacetal) can be provided, so that a very advantageous method can be provided as a production method used for industrial mass production of the derivative.

Claims (7)

[Claims] (1) Formula (I) Reacting N-demethylerythromycin A or a salt thereof represented by the formula (II) with an isopropylating agent: A method for producing N-demethyl-N-isopropylerythromycin A or a salt thereof represented by the formula: 2. A compound of the formula (II) Wherein N-demethyl-N-isopropylerythromycin A or a salt thereof represented by the formula (III) is treated under acidic conditions. N-demethyl-N-isopropyl-8,9-
A method for producing anhydroerythromycin A-6,9-hemiacetal or a salt thereof. 3. A compound of the formula (I) Reacting N-demethylerythromycin A or a salt thereof represented by the formula (III) with an isopropylating agent and then treating the mixture under acidic conditions. N-demethyl-N-isopropyl-8,9-
A method for producing anhydroerythromycin A-6,9-hemiacetal or a salt thereof. 4. A compound of the formula (I) Wherein N-demethylerythromycin A or a salt thereof represented by the formula is treated under acidic conditions: A method for producing N-demethyl-8,9-anhydroerythromycin A-6,9-hemiacetal or a salt thereof represented by the formula: 5. A compound of the formula (IV) Wherein N-demethyl-8,9-anhydroerythromycin A-6,9-hemiacetal represented by the formula is reacted with an ethylating agent. A method for producing N-demethyl-N-ethyl-8,9-anhydroerythromycin A-6,9-hemiacetal or a salt thereof represented by the formula: 6. A compound of the formula (I) Wherein N-demethylerythromycin A or a salt thereof represented by the formula is treated under acidic conditions and then reacted with an ethylating agent. A method for producing N-demethyl-N-ethyl-8,9-anhydroerythromycin A-6,9-hemiacetal or a salt thereof represented by the formula: 7. A compound of the formula (VI) Wherein R ¹ and R ² are the same or different and have 1 carbon atom
Represents an alkyl having 6 to 6 carbon atoms, an alkenyl having 2 to 6 carbon atoms or an alkynyl having 2 to 6 carbon atoms, R ³ represents hydrogen or a hydroxyl group, and R ⁴ and R ^{5 each} represent a hydrogen atom and the other represents a hydroxyl group. Or R ⁴ and R ⁵ are bonded to each other to represent O =, R ⁶ represents hydrogen or an optionally substituted hydroxyl group, and R ⁷ represents hydrogen or a hydroxyl group. Wherein the crude crystal of the 8,9-anhydroerythromycin A-6,9-hemiacetal derivative or a salt thereof is recrystallized from aqueous isopropanol as a solvate. -Anhydroerythromycin A-
A method for producing a substantially pure crystal of a 6,9-hemiacetal derivative or a salt thereof.