JPH07103146B2 - Process for producing (2 "R) -4'-0-tetrahydropyranyl adriamycin - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel method for producing (2 ″ R) -4′-0-tetrahydropyranyladriamycin, which is one of anthracycline antitumor agents. .

[Conventional technology]

It is described in JP-B-56-47194 that 4'-0-tetrahydropyranyladriamycin has antitumor activity.

Formula (A) Starting from daunomycin (hereinafter abbreviated as DM) represented by (2 ″ R) -indicated by the following formula (III)
As a method for producing 4'-0-tetrahydropyranyladriamycin [hereinafter abbreviated as (2 "R) -4'-0-THPADM], the method described in JP-A-56-156300 The method described in Japanese Patent Application Laid-Open No. 55-104299 is known.The former method involves brominating DM and then treating it under acidic conditions to give the following formula (B): To produce 14-bromodaunomycin, which is then 4'-0-tetrahydropyranylated and subsequently hydrolyzed, followed by column chromatography to separate it from the by-product. This is a method of obtaining (2 ″ R) -4′-0-THPADM of (III).
In the latter method, 14-bromodaunomycin of the formula (B) is replaced by the following formula (C) The following formula was obtained by derivatization to 14-acetoxydaunomycin, followed by 4'-0-tetrahydropyranylation as in the former method, followed by hydrolysis, and separation and purification from by-products. (III) (2 ″ R)-
This is a method of obtaining 4'-0-THPADM. The absolute structure of (2 ″ R) -4′-0-THPADM of the following formula (III) described in the present invention is determined by X-ray diffraction of its derivative [Hamao Umezawa et al., “Journal. Journal of Antibiotics, 37, 1094-1097
Page (1984)]. As a method for producing (2 ″ R) -4′-0-THPADM starting from adriamycin, the methods described in JP-B-56-47194 and JP-A-62-116591 are known.

[Problems to be solved by the invention]

In the method of producing (2 ″ R) -4′-0-THPADM using DM as a raw material, tetrahydropyrani is introduced at the 4′-position of DM in the step of 4′-0-tetrahydropyranylation. A group having a desired (2 ″ R) configuration of the
In addition, as a stereoisomer thereof, a compound having a 4'-0-tetrahydropyranyl group having a (2 "R) configuration was also by-produced, and was further tetrahydropyranylated to the 9-position in addition to the 4'-position. It is unavoidable that the 9,4'-di-0-tetrahydropyranyl compound is by-produced, so starting from DM the desired (2 "R) -4'-0-THPADM
The yield of the desired product is significantly reduced in the case of producing.

As a method for improving such a low yield, the above 2
Although there is a method of recovering the by-product of the species and returning it to an appropriate synthetic intermediate for reuse (recycling), the two known methods described in the previous section show that the intermediate 14-bromodaunomycin is unstable. By-product recovery due to certain causes,
The reuse method is not established.

The present inventors solve this problem by passing through a stable synthetic intermediate, and obtain (2 "R) -4'-0-THPADM from the main product obtained in the step of tetrahydropyranylation. At the same time, by recovering the by-product of the tetrahydropyranylation step, returning it to a stable synthetic intermediate with high yield, and developing a new process for reuse (recycling), it is possible to use DM as a raw material. (2 "R) -4'-0-THPA
Research is being carried out to achieve the production of DM in high yield as a whole.

As described above, the daunomycin (DM) of the formula (A) is used as a starting material, and the 14-bromodaunomycin of the formula (B) is used as an intermediate to obtain (2 ″ R) -4′-0 of the following formula (III).
-Method for manufacturing THPADM (Japanese Patent Application Laid-Open No. 55-104299 and Japanese Patent Application Laid-Open No.
56-156300), since a large amount of by-products are generated in the step of tetrahydropyranylation, these conventional methods only obtain the target compound in a low yield. 14-Bromodaunomycin, which is an intermediate, is solid, and even when it is stored at -10 ° C for about 1 week, only about 2/3 of the initial amount of 14-bromodaunomycin is caused by the dissociation of the amino sugar bound at the 7-position. It is so unstable that it does not survive.

[Means for solving problems]

The inventors of the present invention have described (2 ″ R) -of the following formula (III).
In the course of research to improve the production method of 4'-0-THPADM, the intermediate 14-bromodaunomycin or 14-
We succeeded in creating a novel compound, 14-chlorodaunomycin, focusing on the chloro group, which is more stable than the bromo group and iodo group of iododaunomycin and is not low in reactivity such as the fluoro group. We have succeeded in developing an efficient manufacturing method. That is, the present inventors ketalize and brominate DM in the presence of an orthoformate alkyl ester to produce a 14-bromo-13-dialkylketal daunomycin represented by the following formula (E),
This is hydrolyzed with an aqueous solution of an acid under acidic conditions to continuously perform a series of reactions to obtain an aqueous solution of 14-bromodaunomycin of the formula (B). When a large amount of a metal chloride, preferably an alkali metal or alkaline earth metal chloride, is added to the aqueous solution, a halogen exchange reaction between the 14-bromo group of 14-bromodaunomycin of the formula (B) and the metal chloride occurs, In the formula (I) described later
The formation of 14-chlorodaunomycin and the salting out of this product occur efficiently, 14-chlorodaunomycin is isolated by a simple method, and this compound is extremely stable compared to 14-bromodaunomycin. 14-chlorodaunomycin is represented by the formula (III) (2 ″ R)-
It has been found that it can be used as an intermediate for the synthesis of 4'-0-THPADM and is stable and can be recovered and reused.

Further, the present inventors have found that the halogen exchange reaction of 14-bromodaunomycin and the isolation of the product by salting-out can be carried out extremely efficiently in this manner to produce 14-chlorodaunomycin from daunomycin in a high yield. did.

Therefore, the present inventors have completed the invention of 14-chlorodaunomycin, and have the following formula (A): In an organic solvent solution, daunomycin or an acid addition salt thereof represented by the following formula (D) CH (OR) ₃ (D) [wherein R is a lower alkyl group] and an orthoformate alkyl ester and a brominating agent are used. After reaction, the following formula (E) A 14-bromo-13-dialkylketal daunomycin or an acid addition salt thereof, represented by the formula: wherein R has the above-mentioned meaning, and then the compound of the formula (E) is added to the aqueous solution of an acid under acidic conditions. And the following formula (B) produced by this hydrolysis The 14-bromo group of the 14-bromo compound of the formula (B) is reacted by adding an excess amount of solid metal chloride to a reaction solution containing water and containing 14-bromodaunomycin acid addition salt. Halogen exchange reaction of the following formula (I) A 14-chlorodaunomycin acid addition salt represented by the formula: and at the same time the acid addition salt of the compound of formula (I) was precipitated from the hydrous reaction solution and collected, if desired, A 14-chlorodaunomycin acid addition salt is treated under mildly alkaline conditions to produce 14-chlorodaunomycin in the form of the free base, of formula (I)
A patent was filed after completing the invention for a method for producing 14-chlorodaunomycin or an acid addition salt thereof (Japanese Patent Application No. 62-145339 filed on June 12, 1987, filed by the applicant of the present invention (Japanese Patent Application Laid-Open No. 1-345339). No. -117893); title of invention "14-chlorodaunomycin and method for producing the same").

Furthermore, the present inventors have found that 14-chlorodaunomycin created by the present inventors, unlike 14-bromodaunomycin, is hardly decomposed even when stored in a solid state at -10 ° C for about 1 week. It was found to be easy to handle as a raw material for industrial scale synthesis. In addition, 14-chlorodaunomycin is fairly stable even in a solution of an organic solvent, and even when a solution of 14-chlorodaunomycin in an organic solvent contains some amount of water and an acidic compound. It was found that the degradation rate of 14-chlorodaunomycin was significantly lower than that of 14-bromodaunomycin under the same conditions. Therefore, during the reaction step of reacting 14-chlorodaunomycin as a solution in an organic solvent with 3,4-dihydro-2H-pyran in the presence of an acid catalyst to form tetrahydropyranylation, the reaction system is extremely anhydrous. The raw material during this reaction step
The risk of 14-chlorodaunomycin itself degrading is low. Therefore, it has been found that the reaction step of tetrahydropyranylation of 14-chlorodaunomycin does not require care and equipment to keep it extremely anhydrous when it is carried out on an industrial scale, and has an advantage that it can be easily operated. Was done.

Furthermore, the fact that the starting material, 14-chlorodaunomycin, is difficult to decompose during the reaction step of tetrahydropyranylation is due to (2 ″ R) -4′-0-THPADM of the final target compound of formula (III).
It has been found that it contributes to the improvement of the yield.

Therefore, according to the first invention, the following formula (I) 14-Chlorodaunomycin or its acid addition salt shown in 4 was reacted with 3,4-dihydro-2H-pyran in the presence of an acid catalyst to form tetrahydropyranyl, which was formed by the following formula (II) (2 ″ R) -14-chloro-4′-0-tetrahydropyranyldaunomycin represented by
Separated from -chloro-4'-0-tetrahydropyranyldaunomycin and 14-chloro-9,4'-di-0-tetrahydropyranyldaunomycin and then obtained from this formula (II)
By converting the 14-chloro group of the compound of (2 ″ R) -4′-0-tetrahydropyranyladriamycin represented by the formula (II
A method for producing (2 ″ R) -4′-0-tetrahydropyranyladriamycin of I) is provided.

According to the second invention, the following formula (I) 14-Chlorodaunomycin or its acid addition salt shown in 4 was reacted with 3,4-dihydro-2H-pyran in the presence of an acid catalyst to form tetrahydropyranyl, which was formed by the following formula (II) (2 ″ R) -14-chloro-4′-0-tetrahydropyranyldaunomycin represented by
Separated from -chloro-4'-0-tetrahydropyranyldaunomycin and 14-chloro-9,4'-di-0-tetrahydropyranyldaunomycin and then obtained from this formula (II)
By converting the 14-chloro group of the compound of Of (2 "R) -4'-0-tetrahydropyranyladriamycin shown by the formula (IV) And (2 ″ S) -14-chloro-4′-0-tetrahydropyranyldaunomycin represented by the following formula (V) The above-mentioned 14-chloro-9,4'-di-0-tetrahydropyranyldaunomycin represented by
The compound of V) and the compound of formula (V) are hydrolyzed under acidic conditions to regenerate 14-chlorodaunomycin, and the regenerated 14-chlorodaunomycin is again reacted in the presence of an acid catalyst.
Tetrahydropyranylation by reaction with 3,4-dihydro-2H-pyran yields the compound of formula (II) above, wherein the 14-chloro group of the compound of formula (II) produced herein is converted into a 14-hydroxy group. Converted to (2 ″ R) -4 ′ of the above formula (III)
-(2- "R) -4'-0-of formula (III), characterized in that it produces -0-tetrahydropyranyladriamycin
A method of making tetrahydropyranyl adriamycin is provided.

The method of the first aspect of the present invention will be described below.

In the first process of the present invention, as the first step, the above-mentioned formula (I) 14-chlorodaunomycin or a salt thereof is added to 3,4-dihydro-2H-pyran in the presence of an acid catalyst in an organic solvent. The reaction is carried out to form tetrahydropyranylation. As the solvent used in this reaction, dimethylformamide, dimethylsulfoxide, methylene chloride, chloroform, tetrahydrofuran, dioxane, or a mixed solvent thereof is used. The reaction temperature is preferably in the range of 0 to 50 ° C, and the reaction time is preferably 1 to 72 hours. The acid catalyst used in the step of this tetrahydropyranyl reaction is d-camphorsulfonic acid, p-
It is appropriately selected from organic sulfonic acids such as toluene sulfonic acid; Lewis acids such as boron trifluoride; and mineral acids such as hydrochloric acid and sulfuric acid.

The reaction solution obtained by the tetrahydropyranylation reaction contains the desired compound of formula (II), the by-produced compound of formula (IV) and the compound of formula (V). Is neutralized with a weak alkali metal salt such as sodium hydrogen carbonate and extracted with an immiscible organic solvent such as chloroform to give the compound of formula (II), the compound of formula (IV) and the compound of formula (V). Extracted into the organic solvent of the extractant. These tetrahydropyranylation products contained in the extraction solution are separated by column chromatography on silica gel to give the desired product (2 ″ R) -14-chloro-4 of the formula (II). '-0-tetrahydropyranyldaunomycin and (2 "S) -14-chloro-4'-0-tetrahydropyranyldaunomycin of formula (IV),
The 14-chloro-9,4'-di-0-tetrahydropyranyldaunomycin of formula (V) can be separated separately.

Incidentally, (2 ″ R) -14-bromo-4′-0-tetrahydropyranyldaunomycin and (2 ″ S) -14-bromo-4′-0-tetrahydropyranyldaunomycin produced by the above-mentioned conventional method are Silica gel similar to the above, when subjected to separation and purification operation by column chromatography,
Even in this process, a considerable proportion is decomposed (dissociation of the amino sugar moiety).

In the first method of the present invention, in the second step, the 14-chloro group of the compound of formula (II) is dissolved in a solution obtained by dissolving the isolated compound of formula (II) in an organic solvent such as dimethyl sulfoxide. Carry out a reaction to convert to a 14-hydroxy group. This formula (I
The reaction for converting the 14-chloro group of the compound of I) into a 14-hydroxy group can also be carried out by directly hydrolyzing the compound of formula (II) with an alkali metal hydroxide or an alkali metal carbonate. However, preferably 14-of the compound of formula (II)
The reaction for converting a chloro group to a 14-hydroxy group is performed by the reaction of the formula (I
The compound of I) is represented by the following formula (VI) [Wherein R is a hydrogen atom, an alkyl group or an aralkyl group, preferably a lower alkyl group, and M is an alkali metal or an alkaline earth metal], or an alkali metal salt or an alkaline earth metal of an organic carboxylic acid. A salt, preferably an alkali metal alkanoate or an alkaline earth metal salt, particularly preferably lithium formate,
I) [Wherein R is a hydrogen atom bonded to the carboxyl group of the carboxylic acid used, or an alkyl group or an aralkyl group, preferably a lower alkyl group] to produce an ester compound of the formula (VII) By hydrolyzing the ester compound represented by
It may comprise forming I) of (2 "R) -4'-0-tetrahydropyranyladriamycin.

Reaction of (2 ″ R) -14-chloro-4′-0-tetrahydropyranyldaunomycin of formula (II) with an alkali metal salt of an organic carboxylic acid of formula (VI), for example lithium formate, gives formula (VII) To produce (2 "R) -14-0-acyl-4'-0-tetrahydropyranyl adriamycin. As the solvent used in this reaction, ethers such as dimethyl sulfoxide, dimethylformamide, dioxane, tetrahydrofuran, dimethoxyethane, etc., and ketones such as alkyl acetate and acetone are used. The reaction temperature is preferably 0 to 50 ° C, and the reaction time is preferably 1 to 48 hours. The thus-obtained ester compound of formula (VII) is added to an inert solvent such as ethers such as tetrahydrofuran and dioxane, ketones such as acetone, dimethylformamide, dimethylsulfoxide, or a mixed solvent consisting of these in an aqueous solution of sodium bicarbonate to add 10 to 40 When hydrolyzed at ° C, the formula (II
The (2 ″ R) -4′-0-THPADM of I) can be produced.

In the method of the second aspect of the present invention, the reaction step of tetrahydropyranylation of the compound of formula (I) and the step of converting the compound of formula (II) to the compound of formula (III) are carried out according to the first aspect of the present invention. It can be carried out in the same manner as the corresponding reaction step in the above method.

The compounds of formula (IV) and compounds of formula (V), which were by-produced in the first reaction stage and chromatographically separated from the compounds of formula (II), were dissolved in an inert organic solvent, Hydrolyzed with a strong acid in an inert solvent,
It can be returned to 14-chlorodaunomycin hydrochloride and reused. Examples of the inert organic solvent used in this hydrolysis reaction include ethers such as tetrahydrofuran and dioxane, ketones such as acetone, and dimethyl sulfoxide and N, N′-dimethylformamide. As the strong acid, an organic acid, particularly sulfonic acid or mineral acid can be used.

According to the second method of the present invention, the formula (III) (2 ″ R)
-4'-0-Tetrahydropyranyl adriamycin is obtained from daunomycin hydrochloride in a yield of 20.8%. This is a significant improvement in yield compared to the conventional method (the method described in JP-A-55-104299 has a yield of 6.9% and the method described in JP-A-56-156300 has a yield of 8.7%). .

Further, in the above two known methods, (2 ″ R) -4′-
Although no pure crystals of 0-tetrahydropyranyladriamycin have been obtained, in the method of the present invention, a step of recovering and purifying (2 ″ R) -4′-0-tetrahydropyranyladriamycin of formula (III) By performing an acidic water extraction method using a formic acid-sodium formate buffer at (2 "
R) -4'-0-Tetrahydropyranyladriamycin can be well purified and obtained as pure crystals. Therefore, the present invention provides high yield and high purity of (2 "R) -4'-0-
A method of making tetrahydropyranyl adriamycin is provided.

Of the formula (I) used as starting compound in the process according to the invention
Since 14-chlorodaunomycin is a novel compound, its synthetic method will be described here. In these synthetic methods, as described above, daunomycin of formula (A) or an acid addition salt thereof is reacted with an orthoformate alkyl ester of formula (D) and a brominating agent such as bromine. Examples of the orthoformate alkyl ester of the formula (D) used here include lower (C ₁ -C ₆ ) alkyl esters of orthoformate such as methyl orthoformate and ethyl orthoformate. In this way, DM ketalization and bromination reaction occur. The reaction temperature of this reaction is preferably 0 to 30 ° C., and the reaction time is preferably 30 minutes to 4 hours. 14-Bromo-1 of formula (E) obtained by this reaction
The 3-dialkyl ketal daunomycin is hydrolyzed with an aqueous solution of the acid in an inert solvent. This reaction is 0-50
It is preferable to carry out the reaction at a reaction temperature of ° C for 1 to 48 hours. Examples of the above-mentioned inert solvent include alcohols such as methanol and ethanol, ketones such as acetone, and ethers such as tetrahydrofuran, dioxane and dimethoxyethane. Examples of the acid used for hydrolysis include strong mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, as well as strong organic acids such as organic sulfonic acids such as methanesulfonic acid and toluenesulfonic acid. Thus obtained 14
-After removing only the organic solvent from the water-containing reaction solution containing the bromodaunomycin acid addition salt, when a large amount of metal chloride was added to the resulting aqueous solution in a solid state, salting out also occurred.
-Chlorodaunomycin hydrochloride precipitates and is collected and dried to obtain a powder. Examples of the metal chlorides used here include alkali metal chlorides such as lithium, sodium and potassium, as well as alkaline earth metal chlorides such as barium.

The production of 14-chlorodaunomycin can be carried out continuously and simply as follows. That is, a daunomycin of the formula (A) or an acid addition salt thereof is reacted with an orthoformate alkyl ester of the formula (D) and a brominating agent in a solution of an organic solvent to prepare a 14-bromo-13-dialkylacetal daunomycin of the formula (E). Or to form an acid addition salt thereof,
Propylene oxide was added to a reaction solution containing the compound of the formula (E) to react with by-product hydrogen bromide present in the reaction solution, and was captured and removed. From the obtained reaction solution, an organic solvent was removed. An organic solvent (for example, isopropyl ether) which does not dissolve the reaction product is added to the concentrated solution by distillation to concentrate the compound of the formula (E). The compound is taken, dissolved in the above-mentioned inert organic solvent, preferably a mixed solution of acetone and an aqueous solution of an acid, to hydrolyze the compound of the formula (E) to obtain a compound of the formula (B) 14 -Bromodaunomycin was obtained, and the reaction solution was washed with a water-immiscible organic solvent to remove the organic solvent used in the reaction and the reaction by-products, and the washed aqueous solution of the compound of formula (B) was treated with an alkali metal. Chloride or alkaline earth metal chloride, preferably salt A solid-state excess of sodium or potassium chloride is added little by little to carry out a reaction to carry out a halogen exchange reaction for exchanging the 14-bromo group of the compound of the formula (B) for a 14-chloro group and also causing salting out. When,
The resulting 14-chlorodaunomycin hydrochloride of formula (I) is obtained as a precipitate.

Hereinafter, the present invention will be described in more detail with reference to Reference Examples and Examples.

Reference Example 1 Production of 14-chlorodaunomycin and its hydrochloride from daunomycin Daunomycin hydrochloride (4.94 g) was added to methanol (50 ml).
Dissolve in a mixture of dioxane and dioxane (50 ml), add methyl orthoformate (4.4 ml) and bromine (0.60 ml) to this solution, and add 10
Stir at ~ 15 ° C for 1 hour. Propylene oxide was added to the reaction solution and stirred at 4 ° C. for 30 minutes, and then the reaction solution was concentrated to 1/4 amount. This concentrated solution was poured into isopropyl ether (530 ml), and the resulting red precipitate of 14-bromo-13-diacetal daunomycin hydrobromide was collected by centrifugation and further washed with isopropyl ether (70 ml).

Acetone (185 ml) and 0.25N hydrobromic acid (185 m
l) was added and dissolved, and the mixture was stirred for 2 days at room temperature for hydrolysis. Isopropyl ether (210 ml) was added to the reaction solution of this hydrolysis, and the mixture was stirred with shaking and allowed to stand, and the upper layer was separated and removed. This operation was repeated two more times to obtain
While the aqueous solution containing 14-bromodaunomycin hydrobromide was cooled with ice, solid sodium chloride (65 g) was added little by little to carry out the reaction and salting out. The resulting 14-chlorodaunomycin hydrochloride red precipitate was collected by centrifugation and 20%
It was washed with an aqueous sodium chloride solution. The precipitate was collected by filtration, washed with 20% aqueous sodium chloride solution, and dried to obtain 5.0 g of crude 14-chlorodaunomycin hydrochloride.

235 ml of this crude product was added to a 7% sodium hydrogen carbonate aqueous solution.
The resulting 14-chlorodaunomycin (free base) was extracted once with 450 ml of methylene chloride, three times with 200 ml, and twice with 210 ml of a mixture of methylene chloride and methanol (6: 1). The extracts were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to about 35 ml. This concentrated solution was added dropwise to 180 ml of isopropyl ether, and the resulting 14-chlorodaunomycin (free base) was collected by filtration. Yield 3.65
g, melting point: 174-176 ° C (decomposition point) Mass spectrum (FD): m / e562 (M + 1) ⁺ 3.6 g of this 14-chlorodaunomycin (free base) was mixed with methylene chloride and methanol (3: 1). ) Was dissolved in 50 ml, and 6.4 ml of 1N-hydrogen chloride-methylene chloride solution was gradually added under ice cooling. This solution was added to isopropyl ether (280m
l), and the resulting precipitate was collected by filtration and washed with isopropyl ether to give 14-chlorodaunomycin hydrochloride 3.83 g (yield 73%).

Mp: 166~167 ℃ NMR: δppm (D 2 0); 1.35 (5 ' position - methyl), from 2.60 to 2.9
6 (10-methylene), 3.79 (3'-methine), 3.90
(4-position-0-methyl), 4.28 (5'-methine), 5.49
(1'-methine), 7.33 (2- and 3-methine),
7.60 (1st place-methine).

Example 1 (a) Tetrahydropyranylation reaction of 14-chlorodaunomycin 14-chlorodaunomycin hydrochloride (purified product; 3.83 g) was dissolved in dry DMF (90 ml), and 3,4-dihydro-2H was added to the solution. -Pyran (18 ml) and d-camphorsulfonic acid pyridine salt (2.1 g) as a catalyst were added, and the mixture was stirred at 10 ° C.
After 20 and 29 hours, 3,4-dihydro-2H-
Pyran (4 ml) was added, and d-camphorsulfonic acid pyridine salt (0.4 g) was added. The mixture was stirred for a total of 44 hours. 180 ml of chloroform and 1% sodium bicarbonate water (180 m
l) was added, and the mixture was shaken and stirred for extraction.

The produced (2 "R) -14-chloro-4'-0-tetrahydropyranyldaunomycin and (2" S) -14-chloro-
Chloroform extract containing 4'-0-tetrahydropyranyldaunomycin and 14-chloro-9,4'-di-0-tetrahydropyranyldaunomycin was added to 1% sodium bicarbonate water (180 ml).
Twice with 0.1% sodium bicarbonate water (180 ml), then water (100 m
After washing with l), it was dehydrated over anhydrous sodium sulfate.
This chloroform solution was subjected to column chromatography packed with 250 g of silica gel and developed with chloroform-methanol (70: 1). (2 "R) -14-chloro-4 '
-Development liquid containing 0-tetrahydropyranyldaunomycin was collected and concentrated to dryness to give a red powder (2 "R)-
958 mg of 14-chloro-4'-0-tetrahydropyranyldaunomycin were obtained.

In addition, (2 "S) -14-chloro-4'-0-tetrahydropyranyldaunomycin and 14-chloro-9,4'-di-0-
The developing solutions containing tetrahydropyranyldaunomycin were combined and concentrated to dryness to yield 3.23% of the mixture of these by-products.
got g.

(B) Production of (2 ″ R) -4′-0-tetrahydropyranyladriamycin (2 ″ R) -14-chloro-4′-0 obtained in Example 1 (a)
-Tetrahydropyranyldaunomycin 200 mg was dissolved in dimethylsulfoxide (6 ml), lithium formate hydrate (204 mg) was added to this solution, and the mixture was stirred at room temperature for 5 hours.
The reaction solution was diluted with ethyl acetate (35 ml), water (35 ml) was added, the mixture was shaken and stirred, and then the organic layer was separated. The organic layer was further washed with water (30 ml each) four times and then concentrated under reduced pressure. An oil containing this (2 "R) -14-formyl-4'-0-tetrahydropyranyladriamycin was obtained.

This oil was dissolved in tetrahydrofuran (6 ml),
0.1 M aqueous sodium hydrogen carbonate (2.4 ml) was added thereto, and the mixture was stirred at room temperature for 3.5 hours to carry out a hydrolysis reaction. Methylene chloride (50 ml) was added to the reaction solution to dilute it, and the mixed solution was washed by shaking with water (40 ml each) three times. To this methylene chloride solution, formic acid-sodium formate buffer solution (30 ml) of pH 3.3,
The mixture was divided into four portions and shaken well to extract.

The aqueous layers of the extracts were collected, sodium hydroxide solution was added to adjust the pH of the aqueous solution to 7.5, and then the solution was added to methylene chloride (25 ml).
This solution was divided into portions and added to this aqueous solution, and extracted by shaking. The methylene chloride extracts were combined, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain 122 mg of a crude product of (2 "R) -4'-0-tetrahydropyranyladriamycin. Was crystallized from methylene chloride and recrystallized from methylene chloride to obtain 93 mg of a pure product.

Melting point 184-186 ℃ (with decomposition) [α] ▲ ²⁰ _D ▼ + 210 ℃ (c0.2, chloroform) IR (KBr); 3460 (0-methyl and hydroxyl), 1720 (carbonyl), 1620 and 1580 cm ^-1 (Quinon). ¹ H-NMR (CDCl ₃ ) δ1.34 (5′-methyl), 1.45-1.87
(Tetrahydropyranyl), 2.10-2.40 (methylene at 8th position), 3.00 (methine at 3'position), 3.00-3.31 (methylene at 10th position), 3.67 (methine at 4'position), 3.98-4.05 (methine at 5'position), 4.09 (4-position 0-methyl), 4.71 (2'-position methine, tetrahydropyranyl anomeric), 4.75 (14-methylene), 5.32 (7-position methine), 5.52 (1'-methine, daunosamine anomeric), 7.40 (3rd place methine), 7.
79 (2nd methine), 8.04 (1st methine).

It should be noted that when calculated by subtracting the amount of 14-chlorodaunomycin hydrochloride recovered in Example 2 described later, the consumed 14
-Based on chlorodaunomycin hydrochloride (2 "R)-
The yield of 4'-0-THPADM was 28%. The yield from daunomycin hydrochloride was 20.8%.

Example 2 Recovery of 14-Chlorodaunomycin Hydrochloride 3.23 g of the by-product mixture obtained in Example 1 (a) was dissolved in 80 ml of a mixture of acetone-0.25N hydrobromic acid (1: 1), and the mixture was stirred at room temperature. The mixture was stirred for 30 hours and hydrolyzed under acidic conditions. Isopropyl ether (45 ml) was added to the reaction solution and shaken to remove the supernatant. After repeating this operation two more times,
Sodium chloride (14 g) was added to the obtained aqueous solution to salt out and the resulting 14-chlorodaunomycin red precipitate was washed with a 20% aqueous sodium chloride solution to obtain a crude product of 14-chlorodaunomycin hydrochloride. This was purified by the method described in Reference Example 1 to obtain 14-chlorodaunomycin hydrochloride powder.
Obtained 2.34 g.

Mass spectrum as mp 165-166 ° C. The free base (FD): m / e562 ( M + 1) + 1 H-NMR spectra were consistent with 14-chloro Dow actinomycin obtained in Reference Example 1. Therefore, 2 out of 14-chlorodaunomycin hydrochloride (3.83 g) used in Example 1 (a).
34 g (61% recovery) was recovered from the by-product of the tetrahydropyranylation.

Claims (4)

[Claims] 1. The following formula (I) 14-Chlorodaunomycin or its acid addition salt shown in 4 was reacted with 3,4-dihydro-2H-pyran in the presence of an acid catalyst to form tetrahydropyranyl, which was formed by the following formula (II) (2 "R) -14-chloro-4'-O-tetrahydropyranyldaunomycin shown in (2" S) -14
Separated from -chloro-4'-O-tetrahydropyranyldaunomycin and 14-chloro-9,4'-di-O-tetrahydropyranyldaunomycin and then obtained from the formula (II)
By converting the 14-chloro group of the compound of (2 ″ R) -4′-O-tetrahydropyranyladriamycin represented by the formula (II
A method for producing (2 ″ R) -4′-O-tetrahydropyranyladriamycin of I). 2. The following formula (I) 14-Chlorodaunomycin or its acid addition salt shown in 4 was reacted with 3,4-dihydro-2H-pyran in the presence of an acid catalyst to form tetrahydropyranyl, which was formed by the following formula (II) (2 "R) -14-chloro-4'-O-tetrahydropyranyldaunomycin shown in (2" S) -14
Separated from -chloro-4'-O-tetrahydropyranyldaunomycin and 14-chloro-9,4'-di-O-tetrahydropyranyldaunomycin and then obtained from the formula (II)
By converting the 14-chloro group of the compound of Of (2 "R) -4'-O-tetrahydropyranyladriamycin shown by the formula (IV) And the above-mentioned (2 ″ S) -14-chloro-4′-O-tetrahydropyranyldaunomycin represented by the following formula (V) The above-mentioned 14-chloro-9,4'-di-O-tetrahydropyranyldaunomycin represented by
The compound of V) and the compound of formula (V) are hydrolyzed under acidic conditions to regenerate 14-chlorodaunomycin, and the regenerated 14-chlorodaunomycin is again reacted in the presence of an acid catalyst.
Tetrahydropyranylation by reaction with 3,4-dihydro-2H-pyran yields the compound of formula (II) above, wherein the 14-chloro group of the compound of formula (II) produced herein is converted into a 14-hydroxy group. Converted to (2 ″ R) -4 ′ of the above formula (III)
(2 ″ R) -4′-O— of formula (III) characterized by producing —O-tetrahydropyranyladriamycin
Method for producing tetrahydropyranyl adriamycin. 3. The reaction for converting the 14-chloro group of the compound of formula (II) into a 14-hydroxy group is carried out by directly hydrolyzing the compound of formula (II) with an alkali metal hydroxide or an alkali metal carbonate. A method according to claim 1 or claim 2 which comprises the following: 4. A reaction for converting a 14-chloro group of a compound of formula (II) into a 14-hydroxy group is carried out by converting a compound of formula (II) into the following formula (VI): [Wherein, R is a hydrogen atom or an organic group, preferably a lower alkyl group, and M is an alkali metal or an alkaline earth metal], an alkali metal salt or an alkaline earth metal salt of an organic carboxylic acid represented by the formula: Is an alkanoic acid alkali metal salt or alkaline earth metal salt, particularly preferably lithium formate to react with the following formula (VII) [Wherein R is a hydrogen atom bonded to the carboxyl group of the carboxylic acid used, or an organic group, preferably a lower alkyl group] to produce an ester compound represented by the formula (VII) The ester compound is hydrolyzed under alkaline conditions to give (2 ″ R) -4′-O— of formula (III).
A method according to claim 1 or 2 for producing tetrahydropyranyl adriamycin.