CA1335199C - 14-chlorodaumonycin and process for the preparation of 14-chlorodaunomycin, and process for the preparation of (2"r)-4'-o-tetrahydropyranyladriamycin - Google Patents

Abstract

(2"R)-14-Chloro-4'-O-tetrahydropyranyladriamycin of formula:

(XI) Also methods of preparing (2"R)-4'-O-tetrahydropyranyla-driamycin of formula:

(A) from 14-chlorodaunomycin of formula:

from 14-chlorodaunomycin of formula:

Description

This is a divisional application of copen~;ng application serial No. 569,227, filed on June 10, 1988.

The above noted parent application claims a new compound, 14-chlorodaunomycin and acid addition salts thereof, which themselves have antitumor activity and are useful as antitumor agent and also useful as intermediate compounds for the production of semi-synthetic antibiotics of anthracycline type valuable as antitumor agent. This invention also relates to an efficient process for the preparation of 14-chlorodaunomycin. This application claims a new and efficient process for the preparation of (2"R)-4'-O-tetrahydropyranyladriamycin, which is one of the antitumor agents of the semi-synthetic anthracycline derivative-type.

14-Chlorodaunomycin according to this invention is the compound of formula (I) o OH o ~\/\/~y~ 2Cl H3CO o OH O (I) H3C~o ~J 1 4'~/
I NH2 2' HO

This new compound of formula (I) is useful as an important intermediate product for use in the synthesis of the (2nR)-4'-O-tetrahydropyranyladr~amycin of for~ula (A) O OH

( ~ ~2~

CO o OH O (A) ~ ~J 1' 6" " 2"
NH2 2' ,~/

3"

which is practically.effective in the therapeutic treatment of tumor-bearing patients.

That 4'-O-tetrahydro~y anyladriamycin has antitumor activity is disclosed in Japanese patent publication No.
47194/81 and the U.S. patent No. 4,303,7~5.
The known processes for the preparation of (2"R)-4'-O-tetrahydLoyy anyladriamycin of formula (A) shown.
above, which employ daunomycin of formula (II) o OH

~\ ~ ~\

(II) H3C ~ ~
f~V
HO

as the starting compound, include the process as disclosed in Japanese patent application first publication "Kokai"
No. 156,300/81, U.S. patent No. 4,360,664 and European patent application No. 39,060-Al, as well as the process as disclosed in Japanese patent application first publication "Kokai" No. 104,299/80, U.S. patent No.
4,303,785 and European patent application No. 14,853-Al.
_ According to the first-mentioned process of Japanese patent application first publication "Kokai" No. 156,300/81 or U.S. patent No. 4,360,664 (2"R)-4'-O-tetrahydropyranyl-adriamycin (hereinafter sometime abbreviated as (2"R)-4'-O-THPADM)of the formula (A) is produced by brominating daunomycin (hereinafter sometime abbreviated as DM) of ~ 4 ~ 1335199 the formula (II) in the presence of methyl orthoformate, then treating hydrolytically the resulting reaction product, and by-produced 14-bromo-13-dimethyl-ketaldaunomycin of formula (IV') ~C~
. CH2Br 1~ }~

CO O OH d C ~ ~ (IV') N~2 ~0 with acetone and water, to produce 14-bromodaunomycin of formula (V) ~ 5 ~ 1335199 CH2Br OR

CO o OH O

C ~ O ~ (V) N~2 HO

and subsequently 4'-O-tetrahydropyranylating the 14-bromodaunomycin of formula (V) by reaction with 3,4-dihydro-2H-pyran, then hydrolyzing the resulting 14-bromo-4'-O-tetrahydropyranyldaunomycin and the otherwise O-tetrahydropyranylated by-products to produce the 4'-O-tetrahydropyranyladriamycin and the other hydrolyzed by-products, and finally separating the desirea (2"Rj-4'-O-THPADM from the undesired by-products through a - 10 column chromatography to recover the (2"R)-4'-O-THPADM.
- While, according to the second-ment-ioned process of the Japanese patent application first publication "Kokai" No.
- 104,299/80 or U.S. patent No. 4,303,785, (2"R)-4'-o-THPADM of formula (A) is produced by converting 14-bromodaunomycin of formula (V) into 14-acetoxydaunomycin l335l99 of formula (B) O OH o ~ C~
~ `'ON CH2 0 3 ~3 ~ 7 J

and then 4'-0-tetrahydropyranylating 14-acetoxydaunomycin, subsequently hydrolyzing the resulting 4'-0-tetra-hydropyranyl-14-acetoxydaunomycin and the otherwise O-tetrahydropyranylated by-products to produce the 4'-O-tetrahydropyranyladriamycin and the other hydrolyzed by-products, and finally separating ~he desired ~2"R)-4'-0-THPADM from the undesired by-products through a column chromatography for recovery and purification of ~ the desired (2"R)-4~0-THPADM product, with the aforesaid 4'-0-tetrahydropyranylation, the subsequent hydrolysis and the chromatographic separation of the (2"R)-4'-0-THPADM being conducted in the same manner as in the first-mentioned process of the Japanese patent application first publication "Kokai" No. 156,300/81 or U.S. patent No. 4,360,664. Incidentally, the absolute chemical structure of (2"R)-4'-O-THPADM of formula (A) described in the present invention has been determined by an X-ray analysis of a certain derivatives of (2"R)-4'-O-THPADM
~see Hamao Umezawa et al., "Journal of Anti~iotics"
37, 1094-1097 (1984~]. As the method for the preparation of (2"R)-4'-O-THPADM starting from adriamycin, there has been known another method as disclosed in U.s. patent No.

4,303,785 or in Japanese Patent Publication No. 47,194/81 anc Japanese patent application first publication "Kokai" No.
116,591/87, U.S. patent application SN. 925,774 or European patent application publication No. 228, 546-A2.

In the known processes for the preparation of (2"R)-4'-O-THPADM with employing DM as a starting compound, such intermediate compound where the tetrahydro-pyranyl group as introduced to the 4'-position of DM
shows the desired (2"R)-configuration can be formed in the 4'-O-tetrahydropyranylation step. With these known processes, however, it is then impossible to avoid the by-formation of such compound where the 4'-O-tetrahydro-pyranyl group has the (2"S)-configuration, as a stereoisomer, and also the by-formation of such 9,4'-di-O-tetrahydro-pyranylated compounds due to that the tetrahydropyranylation - 8 - ~33S~99 has taken place not only at the 4'-position but also at the 9-position of DM. The yield of the desired (2"R)-4'-0-THPADM must therefore be very low, as long as it is prepared with starting from DM.
As a measure for improving such low yield of the intended final product, it will be possible to resort on such a method in which the above-described two by-products, namely the (2"S)-4'-0-tetrahydropyranylated product and the 9,4'-di-0-tetrahydropyranylated products, . 10 are recovered and then converted into intermediate product suitable for their recycle and re-use in the synthesis of (2"R)-4 '-O-THPADM. With the known two processes mentioned above, the 14-bromodaunomycin which is produced as the intermediate compound involved is unstable in its nature, and primarily due to this, it is not yet possible to provide and establish such a method which is suitable for the recovery, recycle and re-use of the by-products for the synthesis of the desired (2"R)-4'-O-THPADM.
We, the present inentors, have made extensive -- researches with a view toward exploiting and providing such an improved new process of preparing (2"R)-4'-- O-THPADM, which can solve the problems of the low efficiency of the prior art processes mentioned above, by making the new process feasible to be conducted via an intermediate product of high stability, in which the desired (2"R)-4'-O-THPADM can be obtained from the main reaction product of the 4'-O-tetrapyranylation step of the process and concurrently the by-products as for~ed in the tetra-hydropyranylation step can be recovered and convertedback into the lntermediate product of high stability in a high yield, and in which the highly stable intermediate product so recovered can be recycled and re-used for the synthesis of the desired final product, whereby the production of the desired (2"R)-4'-O-THPADM can be achieved in a high overall yield even when daunomycin (DM) is employed as the starting compound.
In the above-mentioned known processes for the preparation of (2n~)-4'-O-THPADM of formula (A) in which daunomycin (DM) of formula (II) is used as the starting compound, and which are effected via the 14-bromodaunomycin of formula (V) as the intermediate product (namely the processes of the aforesaid Japanese patent application first publication "Kokai" Nos.
104,299/80 and 156,300/81~, there are formed great amounts of the undesired by-products in the tetrahydropyranylation step so that the intended final compound can be obtained only in a low yield with these prior art processes.
The intermediate compound, 14-bromodaunomycin is so unstable that even when it has been stored in its solid - lo 1335199 state at -10C for about 1 week, 14-bromodaunomycin can remain only in such an amount which is as little as about two-thirds of its initial amount before its storage, due to that the amino sugar moiety bonded to the 7-position can be cleaved to bring about the degradation of 14-bromodaunomycin.
On the other hand, the known 14-halogenated derivatives of daunomycin include 14-iododaunomycin, in addition to the aforesaid 14-bromodaunomycin of formula (II). 14-Bromodaunomycin and 14-iododaunomycin are used as intermediate products which are important to produce adriamycin of formula (C) CO O OH b H3C ~ O ~

HO

from daunomycin of formula (II) (see Japanese patent pu~lication No. 46,597/72 or U.S. patent No. 3,803,124 for instance). 14-Bromodaunomycin may also be prepared by direct bromination of daunomycin (see the above-mentioned Japanese patent pu~lication No. 46,597/72 or U.S. patent No. 3,803,124~. A 14-iododaunomycin derivative which has been known hithertobefore is specifically 14-iodo-N-trifluoroacetyldaunomycin of formula (D) ~)~ E2I

H3Co O OH ~ (D) H3C ~ O

I NHCCF
HO ~ 3 which is prepared by a method comprising reacting an N-trifluoroacetylated derivative of daunomycin with iodine in the presence of calcium oxlde (see Japanese : patent publication No. 46,597/72, for instance). The other 14-halogenated derivative of daunomycin is a 14-fluoro derivative of daunomycin which was synthesized 133~199 only for the purpose of estimating its antitumor activity and which was reported by Terajima et al (see the "Kohen-Yo-shi-shu" for the fifty-fourth annual spring symposium of the "Japan Chemical Society" Vol. 3, III L 40).
As far as we, the present inventors, are aware of, 14-chlorodaunomycin is neither disclosed nor reported yet in any literatures.
In the course of our extensive researches in an attempt to provide an improved new process for the preparation of (2"R)-4'-O-THPADM of formula (A) as described in the above, we, the present inventors, have paid our attention on the utilizability of a chloro substituent which is more stable than the iodo group or the bromo group present in the 14-iododaunomycin or 14-bromodaunomycin as previously used as the intermediate compounds and which is not so unreactive as much as the fluoro group present in the 14-fluorodaunomycin, so that we have had an a~temp~ to firstly produce i4-chioro-daunomycin as a new compound. As a result of our investigations, we have now succeeded in producing 14-chlorodaunomycin, and we have also succeeded in exploiting an efficient process for the preparation of 14-chlorodaunomycin. Thus, we have now found that when a series of reaction stepscomprising the ketalation and bromination of DM in the presence of an alkyl orthoformate to produce a 14-bromo-14-dialkylketaldaunomycin of formula (IV), and the subsequent hydrolysis of the latter compound with an aqueous acid solution under acidic conditions to give an aqueous solution of 14-bromodaunomycin of formula (V) is carried out successively,and when a large amount of a metal halide, preferably, an alkali metal or alkaline earth metal halide is then added to said aqueous solution of 14-bromodanomycin of formula (V), a halogen-interchange reaction takes place between the 14-bromo group of 14-bromodaunomycin of formula (V) and the metal halide and thus 14-chloro-daunomycin of formula (I) can be produced efficiently with its salting-out from the reaction solution taking place efficiently so that the production and isolation of 14-chlorodaunomycin are effected in a facile way, and also that 14-chlorodaunomycin is extremely more stable than 14-bromodaunomycin, and further that 14-chlorodaunomycin - is usefui as an intermediate for the syr,thesis Gf (2"R~-4'-O-THPADM of formula (A) and is stable enough to permit the recovery, recycle and re-use of 14-chlorodaunomycin.
We have also found that 14-chlorodaunomycin can be prepared from daunomycin in a high yield as the consequence of that the halogen-exchange reaction between 14-bromodaunomycin and a metal chloride to produce 14-chlorodaunomycin takes place efflciently and co~ ently the reaction product, namely 14-chlorodaunomycln can be isolated efflciently from the reaction solutlon through its ~alting-out, as described in the above.
According to a first aspect of the parent ~rr~ t inn there i8 provided 14-chloro~nnomycin represented by formula (I) ~2Cl OH

H3C ~ ~

or an acid addition salt thereof.
The acid addition salt of 14-chlorodaunomycin includes a salt of 14-chlorodaunomycin with a pharmaceutically acceptable inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid and hydrobromic acid, or with a pharmaceutically acceptable organic acid such as acetic acid, propionic acid, maleic acid, citric acid, succinic acid and methanesulfonic acid.
According to the second aspect of the parent application there is provided a process for the preparation of 14-chlorodaunomycin of formula (I) O OH o ~\ / ~ < CH2Cl OH
~\~ / ( I ) H3C~ ~J
,C~V

HO

or an acid addition salt thereof, which comprises reacting daunomycin of formula (II) O OH Q

~ ~/1\/~ ~/~1 CH3 W\,~/ ( I I ) ~3C~O~

f~

HO

or an acid addition salt thereof with an alkyl ortho-formate of formula (III) CH(OR)3 (III) wherein R is a lower alkyl group, and a brominating agent in solution in an organic solvent to form a 14-bromo-13-dialkylketaldaunomycin of formula (IV) O 0~
RO GR
\C/
. CH2Br (IV) CO O OH O

~3C ~ ~

¦ NH2 ~0 wherein R is as defined above, or an acid addition salt thereof, hydrolyzing the compound of formula (IV) by treating with an aqueous solution of an acid under acidic conditions, then adding an excess amount of a solid metal chloride to the resulting aqueous reaction mixture containing the acid-addition salt of 14-bromodaunomycin so produced and represented by formula (V) o o~ o / ~ CH2Br ~ ~ t V ) ~3C ~ ~
,~

HO

to dissolve the solid metal chloride into said aqueous reaction mixture and to react the dissolved metal chloride with the 14-bromodaunomycin acid-addition salt so that the 14-bromo group of 14-bromodaunomycin of formula (V) undergoes the halogen-exchange reaction with the metal chloride to produce the acid-addition salt or 14-cniorodaunomycin of formula ~I) and concurrently allowing the acid-addition salt of the 14-chlorodaunomycin of formula (I) to be precipitated from the resulting aqueous reaction solution by the salting-out of the 14-chlorodaunomycin acid-addition salt, and recovering the acid-addition salt of 14-chlorodaunomycin from the aqueous reaction solution, and when desired, treating the recovered 14-chlorodaunomycin acid-addition salt with an aqueous alkaline compound under weakly akaline conditions to afford 14-chlorodaunomycin in its free base form.

More particularly the amount of the solid metal chloride being such that a part of the metal chloride as dissolved from the added solid metal chloride into the aqueous reaction mixture is sufficient to convert all the 14-bromodaunomycin present into the 14-chlorodaunomycin and the remaining parts of the dissolved metal chloride are sufficient to cause the resultant 14-chlorodaunomycin acid-addition salt to be precipitated from the reaction solution by the salting-out process.

In the process according to the second aspect of the parent application, the starting daunomycin of formula (II) may be used in its free base form or as an acid addition salt (preferably the hydrochloride) thereof, and the starting daunomycin is reacted with excessive amounts of an alkyl orthoformate of formula (III) and a brominating agent such as bromine, pyridinium hydrobromide perbromide, pyrrolidone hydrotribromide, and phenyl-trimethylammonium perbromide. As illustrative ~
examples of the alkyl orthoformate of formula (III) employed in the above process, may be mentioned lower (C1-C6) alkyl orthoformates such as methyl orthoformate and ethyl orthoformate. In this way, both the ketalation and bromination of DM take place to give the 14-bromo-13-dialkylketaldaunomycin of formula (IV). The desirable reaction temperature of these reactions may range from 0C to 30C, while the perferable reaction time may range from 30 minutes to 4 hours.- The 14-bromo-14-dialkylketaldaunomycin of the formula (IV) obtained by the above reactions is then hydrolytically treated with an aqueous solution of an acid (eg, hydrobromic acid) in an inert organic solvent. It is desirable to conduct this hydrolysis reaction at a reaction temperature of 0 - 50C for l - 48 hours. As illustrative examples of the inert organic solvent mentioned above, may be mentioned alcohols such as methanol and ethanol, ketones such as acetone, and ethers such as tetrahydroruran, dioxane and dimethoxyethane. Illustrative examples of the acid which are useful for the hydrolysis may include strong mineral acids such as hydrochlorlc acid, hydrcbromic acid, sulfuric acid and phosphoric acid, as well as strong organic acids such as organic sulfonic acids, e.g., - methanesulfonic acid and toluenesulfonic acid. From the resulting water-cont~- ni ng reaction mixture containing the acid-addition salt of 14-bromodaunomycin so produced is removed the organic solvent phase, and to the resultant aqueous solution of 14-bromodaunomycin is added a large amount of a metal chloride in a solid form. The large amount of the solid metal chloride is dissolved in ~he water-containing reaction mixture ana the dissolved metal chloride is reacted with 14-bromodaunomycin to produced 14-chlorodaunomycin, which is then salted-out from the reaction solution due to the presence of the large amount of the metal chloride as dissolved in the reaction solution,whereby 14-chlorodaunomycin hydrochloride precipitates. The precipitate is then collected and dried, thereby affording 14-chloro-- daunomycin hydrochloride as powder. As exemplary metal chlorides which are useful in the above halogen-exchange reaction, may be mentioned not only the chlorides of Alk~li metals such as lithium, sodium and potassium but also the chlorides of alkaline earth metals such as barium.
The excess amount of the solid metal chloride added to the aqueous reaction mixture con~A;n;ng the 14---bromodaunomycin acid addition salt produced may be such amount of the metal chloride that a part of the metal chloride as dissolved from the added solid metal chloride into said aqueous reaction mixture is sufficient to convert all the 14-bromodaunomycin present into the 14-chlorodaunomycin and the re~in;ng parts of the dissolved metal chloride are sufficient to cause the resultant 14-chlorodaunomycin acid-addition salt to be precipitated from the reaction solution by the salting-out process.
According to preferred embodiment of the process of ~ ~yy~ a ~t of the p~nt applicAti~n, the preparation of 14-chlorodaunomycin can be effected continuously and easily by employing the following procedures. Thus, daunomycin of the formula lII) or its acid addition salt is reacted with-an alkyl orthoformate of formula (III) and a brominating agent in an organic solvent solution to form a 14-bromo-13-dial~ylacetaldaunomycin of formula (IV) or its acid addition salt. Propylene oxide is then added to the resulting reaction mixture containing the compound of formula (IV) so that propylene oxide reacts with the by-produced hydrogen bromide present in the reaction mixture, whereby the hydrogen bromide is captured and eliminated. From the resulting reaction mixture, the organic solvent is distilled off to concentrate the reaction mixture. An other organic solvent (for example, isopropyl ether)incapable of dissolving the reaction product of formula (IV) is added to the concentrated reaction mixture, so that the compound of formula (IV) is caused to precipitate. The thus-precipitated compound of formula (IV) is recovered by filtration and is dissolved in a liquid mixture of the aforementioned inert organic solvent, preferably acetone, with an aqueous solution of an acid, whereby the acidic hydrolysis of the compound of the formula (IV) is performed with said acid in said liquid mixture to give 14-bromodaunomycin of formula (V). The resulting reaction solution containing 14-bromodaunomycin so produced is then washed with a water-immiscible organic solvent to remove therefrom the organic solvent which was employed in the hydrolysis reaction, and to remove the undesired reaction by-products. To the remaining aqueous solution thus-washed and containing 14-bromodaunomycin formula (V), is added in small portions an excess amount of an alkali metal chloride or ~ ne earth metal chloride, preferably, sodium chloride or potassium chloride in the solid form, so that the metal chloride reacts with the compound of formula (V), to effect the halogen-interchange reaction, whereby the 14-bromo group of the compound of formula (V) is replaced by with a 14-chloro group, and ~t the same time, the salting-out of the 14-chlorodaunomycin of formula (I) is involved. As a result, the hydrochloride of 14-chlorodaunomycin of formula (I) is thus formed and obtained as a precipitate.
According to the process of the second aspect of the p~nt appli~ticn, the r~ion steps for ~ing 14-chlorodaunomycin may be carried out in a continuous and facile way, and this process can readily afford the hydrochloride of 14-chlorodaunomycin of formula (I~ in a favorably high yield of 73~ or more as calculated from the starting hydrochloride of daunomycin of formula (I~). When 14-chlorodaunomycin is used in the synthetic production of (2nR)-4'-O-THPADM of formula (A), the recovery and re-use of the undesired by-products as formed can be performed readily and effficiently so as to enable the (2"R)-4'-O-THPADM of formula (A) to be obtained in a favorable overall yield of 20.8% or more, as detailed hereinafter. ~his yield of 20.8~ or more of (2"R)-4'-O-THPADM is a remarkable improvement as compared with such poor yield of (2"R)-4'-O-THPADM which is usually amounting to about 6 to 9% obtained when the prior art processes of the foresaid Japanese patent application first publication "Kokai" No. 104,299/80 or U.S. patent No. 4,303,785 and Japanese patent application first publication "Kokai" No. 156,300/81 or U.S. patent No. 4,360,664 are conducted. According to the first and second aspects of this invention, there are thus provided 14-chlorodaunomycin which is useful as an important intermediate compound for different derivatives of adriamycin, especially (2"R)-4'-O-THPADM, as well as a process of producing the 14-chlorodaunomycin.
Besides, we have further confirmed that 14-chlorodaunomycin according to this invention shows remarkable antitumor activity against various kinds of experimental tumors, as illustrated by the following tests, and that 14-chlorodaunomycin of this inventions may be used as an antitumor agent.
Antitumor activities of 14-chlorodaunomycin against various experimental tumors, including murine leukemia P-388 cells, murine leukemia P-388 cells (resistant to adriamyci~), murine melanoma Bl6 cells, human lung cancer PC14 cells and murine leukemia L-1210 cells, were tested and evaluated in vitro by the following procedure:-The tumor cells were cultivated in RPMI 1640medium supplemented with 10% fetal calf serum, lO~M
2-hydroxyethyldisulfide and kanamycin at 50 ~g/mQ
(the growth medium), under air containing 5% CO2 at 37C.
The tumor cells were incubated at initial densities of 1.5 x 104 cells/mQ with murine melanoma B16; 2 x 104 cells/mQ with murine leukemia P388, P388/
ADR and L-1210; and 2.5 x 104 cells/mQ with human lung cancer PC14 cells in the growth medium further containing graded concentrationsof each test compound, for 72 hours.
The IC50 value, namely the 50% growth inhibitory concentration of the tested compound was evaluated by MTT assay method (see Mosmann, T; "J. Immunol. Methods", 65, 55-63 (1983).

Table 1 Antitumor activities (IC50 values, ng/mQ) of 14-chlorodaunomycin against experimental tumors IC50 value (ng/mQ) Tumors resis-tant to Test Compounds P-388 adriamycin B16PC14 L-1210 chlorodaunomycin96.3 552 93.0960 268 Daunomycin (comparative) 16.3 668 44.9237 65.5 Adriamycin (comparative) 33.0 2060 101765 154 - Furthermore, we, the present inventors, have found that 14-chlorodaunomycin as prepared newly by us is easy to handle as a starting material for a synthetic method of producing various anthracycline derivatives on an industrial scale, because, unlike 14-bromodaunomycin, 14-chlorodanomycin in a solid form undergoes no substantial decomposition even when it has been stored at -10C for 1 week or so. It has also been uncovered that 14-chlorodaunomycin is somewhat stable even in its solution -in an organic solvent and that even when the solution of 14-chlorodaunomycin in the organic solvent contains some water and an acidic compound, the decomposition rate of 14-chlorodaunomycin is considerably smaller than that of 14-bromodaunomycin which would be placed under the same conditions. We have also found that when the reaction stage of reacting 14-chlorodaunomycin with 3,4-dihydro-2H-pyran in a solution in an organic solvent in the presence of an acid catalyst to tetrahydropyranylate the 14-chlorodaunomycin is effected for the synthesis of (2"R)-4'-O-THPADM of formula (A), there is little danger of decomposition of the starting 14-chlorodaunomycin itself, even if no special care is exercised to maintain the reaction system in an extremely anhydrous state.
The reaction stage for the tetrahydropyranylation of 14-chlorodaunomycin has hence now been found to have an advantage that it requires neither care nor faclities for maintaining the reaction system in an extremely anhydrous condition upon its commercial working and it can hence been worked out easily.
It has also been found that the resistance of the starting 14-chlorodaunomycin to decomposition in the reaction stage of its tetrahydropyranylation can contribute to give an improved yield of (2"R)-4'-O-THPADM
of formula (A), the intended final antitumor compound.

According to a first aspect of this application, -there is thus provided a process for ~he preparation of (2~R)-4'-0-tetrahydropyranyladriamycin of ormula (A) O OH O

C ~3 ~\ CH20H
H3CO O OH O (A) H3C ~ ~

/~0 which comprises reacting 14-chlorodaunomycin of formula (I~

O OH

~H2Cl ~ OH

H3C ~ O ~
,~
Hl NH2 or an acid addition salt thereof with 3,4-dihydro-2H-pyran in the presence of an acid catalyst to tetrahydropyranylate the 4'-hydroxy group of 14-chlorodaunomycin, separating the resultant (2"R)-14-chloro-4'-0-tetrahydropyranyldaunomycin of formula (VI~

O OH O

CH~C1 3 O OH o (VI) H3C ~ O ~
,~
/~o~l 2 ~\/ ' from the (2"S)-14-chloro-4'-0-tetrahydropyranyldaunomycin by-produced and also from the 14-chloro-9,4'-di-0-tetrahydropyranyldaunomycin by-produced, and then converting the 14-chloro group of the compound of formula (VI) into a 14-hydroxyl group to form the (2"R)-4'-0-tetrahydropyranyladriamycin of formula (A).

13~5199 In a seox~ aspect of this appl;c~ti~n, there is providea a process for the p~eparation of (2nR)-4'-O-tetrahydLo~lanyladriamycin of formula (A3.

o OH O

~ ~ C1120E;

H3C ~ O
,~
~ O ~ o 2 S or an acid addition salt thereof, which comprises reacting 14-chlorodaunomycin of formula (I) O OH o CH2Cl ~ OH

H3C ~ O ~
,~

HO

_ 30 _ 1~35199 or an acid addition salt thereof with 3,4-dihydro-2H-pyran in the presence of an acid catalyst to tetrahydropyranylate the 4'-hydroxy group of 14-chlorodaunomycin, separating the resultant (2"R)-14-chloro-4'-0-tetrahydropyranyl-daunomycin of formula (VI) O OH O
, , ~J (VI) H3C ~ ~
,G~
O ~ 1 2 ~rom the 52"S!-14-chloro-4'-0-tetrahydropyranyldaunomycin by-produced of formula (VII) - 31 - 13~5199 ~\ CH2Cl 3 O O OH O (VII) ~3C ~ ~
~0\ ~V

~

and also from the 14-chloro-~ di-0-tetrahydropyranyl-daunomycin by-produced of ~ormula (VIII) o OH o ll 11 1 11 H3CO O OH O (VIII) ~\o ~
H3~/

o \~o 2 . - 32 - 1335199 and then converting the 14-chloro group of the compound of formuIa (VI) into a 14-hydroxyl group to form (2"R)-4'-0-tetrahydropyranyladriamycin of formula (A) O OH O

~ \ CH2OH

H3C ~ O ~ (A) /\o~l 2 ~/

and recovering the by-produced (2"S)-14-chloro-4'-0-tetrahydropyranyldaunomycin of formula(VII) and 14-chloro-9,4'-di-0-tetrahydropyranyldaunomycin of formula (VIII~, hydrolyzing the thus-recovered compound of formula (VII) and compound of the formula (VIII) under acidic conditions to regenerate 14-chlorodaunomycin, again tetrahydropyranylating the 4'-hydroxy group of the regenerated 14-chlorodaunomycin by reaction with 3,4-dihydro-2H-pyran in the presence of an acid catalyst, thereby to ~o~e a ~ro~A crop of the compouna of formula (VI~, and then con~erting the 14-chloro group of the ~eCQ~ crop compound of formula (VI) into a 14-hydL~yl group so as to glve a ~c~ 1 crop of the (2~R)-4'-O-tetrahydro~y~anyladriamycin of ~ A (A).
The process according to the first aspect of thiC apQl ;C~tinn will hereinafter be descrlbed.
In the first step of the process according to the first aspect of this ~rrl;c~tion~ 14-chlorodaunomycin of formula (I) or a salt thereof is reacted with 3,4-aihydro-2H-pyran in the presence of an acid catalyst in an organic ~olvent so as to tetrahyd o~y a~ylate the 4'-hydroxy group of 14-chlorodaunomycin. As exemplary solvents which are useful for this tetrahydlG~y~anylation reaction, may be mentioned dimethylformamide, dimethylsulfoxide, methylene chloride, chloroform, tetrahydrofuran, dioxane, or a mixed solvent thereof.
The reaction temperature may desirably range from 0C
to SO~C, and the desirable reaction time may range from 1 hour to 72 hours. The acid catalyst employed ln the stage of this tetrahydropyranylation reaction may be chosen suitably from organic sulfonic acids such as d-camphorsulfonic acid and p-toluenesulfonic acid, Lewis acids such as boron trifluoride, and mineral acids such as hydrochloric acid and sulfuric acid.

_ 34 - 1335199 The reaction mixture obtained from the tetrahydro-pyranylation reaction contains the compound of formula (VI) formed as intended, along with the compounds of formulae (VII) and (VIII) as by-produced. This reaction mixture is then neutralized with a mild alkali metal salt such as sodium hydrogencarbonate and then extracted with an immiscible organic solvent such as chloroform, whereby the compound of formula (VI), the compound of formula (VII) and the compound of formula (VIII) are - lO extracted into the organic solvent employed as an extractant.
The resulting extract solution containing these tetrahydropyranylated products (VI), (VII) and (VIII) is subjected to column chromatography on silica gel for the separation of these products, so that the principal product, namely, the intended (2"R)-14-chloro-4'-0-tetrahydropyranyldaunomycin of formula (VI), the by-produced (2"S)-14-chloro-4'-0-tetrahydropyranyldaunomycin of fcrmula (VTI) a..d 1 A -chlvrc-~,4'-di-O~te'rah-y-drv pyranyldaunomycin of formula (VIII) can be separated from one another.
Incidentally, when the unstable (2"R)-14-bromo-4'-0-tetrahydropyranyldaunomycin and (2"S)-14-bromo-4'-O-tetrahydropyranyldaunomycin which are formed in the prior art processes described hereinbefore are subjected to the step for the separation and purification of them _ 35 _ ~ 1 3351 99 by the column chromatography on silica gel in the same manner as described above, substanti-al portions of them can be decomposed (i.e., the cleavage of the amino sugar moiety from the aglycon) already in this step.
In the second step of the process according to the first aspect of this ~rrlic~ti~n, the reaction is carried out to convert the 14-chloro group of ~he isolated compound of formula (VI) into a 14-hydroxyl group, and this reaction may be effected in a solution of the compound of formula (VI) dissolved in an organic solvent such as dimethylsulfoxide. The reaction for the conversion of 14-chloro group of the compound of formuia IVI) into the 14-hydroxyl group may be carried out directly by hydrolyzing the compound (VI) with an alkali metal hydroxide or alkali metal carbonate.
However, the reaction for converting the 14-chloro-group of the compound (VI~ into the 14-hydroxyl group may preferably be effected by a method which comprises reacting the compound of formula (VI) with an alkali metal salt or alkaline earth metal salt of an organic - carboxylic acid represented by formula (IX):
O
Il (IX) R'-C-OM
wherein ~ means a hydrogen atom or an alkyl or aralkyl group, preferably, a lower alkyl group and M denotes an alkali metal or alkaline earth metal, for example, preferably, an alkali metal or alkaline earth metal alkanoate, more preferably, lithium formate to give an ester compound of formula (X):

O OH O
~ X J J ~ H

H3C ~ ~ (X) ,G~

/~ ~

wherein R' means a hydrogen atom or an dikyl or araikyi group, preferably, a lower alkyl group which was bonded to the carboxyl group of the carboxylic acid (IX) used, and then hydrolyzing the ester compound of formula (X) under alkaline conditions to afford the (2"R)-4'-0-tetrahydropyranyladriamycin of formula (A).
When (2"R)-14-chloro-4'-0-tetrahydropyranyl-daunomycin of formula (VI) is esterified by reaction with an alkali metal salt of an organic carboxylic acid `- 1335199 of formula (IX), for example, lithium formate, (2"R)-14-0-acyl-4'-0-tetrahyd~o~y~anyladrlamycin of formula (X) is formed. As exemplary solvents which arë useful for this ester$fication reaction, may be men~on~
aimethylsulfoxlde, dimethylformamide, ethers such as ~ n?, tetrahydrofuran and dimethoxyethane, alkyl acetates, ketones such as acetone, and the like.
me reaction temperature may decirably be 0 - 50C, and the desirable reaction time may range from 1 hour to 48 hours. Then hydrolysis of the ester ço~round of formula (X) is effected at 10 - iooc in an inert sol~ent, for example, an ether such as tetrahydrofuran or dioxane, ketone such as acetone, dimethylformamlde, dimethyl-sulfoxlde or a mixed solvent thereof ln the pres~oe of an aqueous solution of sodium bicarbonate addea, whereby - (2~R3-4'-0-~HPADM of formula (A) can be prepared.
In the process accordlng to the second aspect of this appl ic~ti~n, the reaction step for the tetrahydro-- pyranylation of the compound of formula (I) and the reaction step for the conversion of the compound of formula (VI) lnto the desired compouna of formula (A) may be practised in the same manner as in ~he corresponding reaction steps of the process according to the third aspect of thls lnvention.
The co.u~o~,ds of forr~ e (VII) and (VIII) 13351g3 which have been by-produced in the first reaction step of the present process and separated chromatographically from the compound of formula (VI) can be converted into 14-chlorodaunomycin hydrochloride by dissolving them in S an inert organic solvent and hydrolyzing them with a strong acid in the inorganic solvent, and the 14-chlorodaunomycin so regenerated can be recyclea and re-used in the subsequent run of the synthesis of (2nR)-4'-O-THPADM. Illustrative examples of the inert organic solvent employed in the above hydrolytic reaction may include ethers such as tetrahydrofuran and dioxane, ketones such as acetone, dimethylsulfoxide, and N,N'-dimethylformamide. As the strong acid, an organic acid, especially, sulfonic acid or a mineral acid may be used.
According to the process of the second aspect of this A~rlic~ti~n, (2"R)-4'-O-tetrahydropiranyladriamycin of formula (A) can be obtained in-a yield of 20.8~ from daunomycin hydrochloride. The yield of (2"R)-4'-O-THPADM has thus been improved remarkedly, as compared with those available by the prior art processes (the yield amounted only to 6.9% by the process described in the Japanese Patent Application first publication "Rokai"
No. 104,299/80; and 8.7~ by the process described in the Japanese Patent Application first publication "Ko~ai"
No. 156,300/81).

133519g The (2"R)-4'-0-tetrahydropyranyladriamycin of formula (A) has not been obtained in any pure and crystalline product form according to the above-mentioned two known prior art processes, but the processes of the first and second aspects of this application can make it possible that good purification of the (2"R)-4-0-tetrahydropyranyladriamycin to give it as a pure crystalline product is achieved when the acidic water-extraction method with making use of a formic acid-sodium formate buffer solution is effected upon recovery and purification of the (2"R)-4-0-tetrahydropyranyladriamycin of formula (A). The present invention has therefore provided an improved process for preparing (2"R)-4'-0-tetrahydropyranyladriamycin of a high purity and in a high yield.

In a third aspect this application provides (2"R)-14-chloro-4'-0-tetrahydropyranyldaunomycin of formula (XI) O OH o -,H 2 ~3CO O OH ~ I (XI ) H3C~

/~
~V

This invention is now illustrated with reference to the following Examples, to which this invention is not limited.

- 39a - 1335199 Example 1 PreParation of 14-chlorodaunomycin and its hydrochloride from daunomycin Daunomycin hydrochloride (4.94g) was dissolved in 50ml of methanol and 50ml of dioxane, and mixed with 4.4ml of methyl orthoformate and 0.60ml of bromine. The reaction solution was stirred at 10 - 15C for 1 hour and then treated with 1.55ml of propylene oxide. After 30 minutes at 4C, the reaction mixture was concentrated to its one-fourth volume. The concentrate was poured into 530 mQ of isopropyl ether and the red precipitate formed was collected by centrifugation, followed by washing with 70 mQ of isopropyl ether.
185 mQ of acetone and 180 mQ of 0.25M-hydrobromic acid were added to the precipitate, and the mixture was stirred for 2 days at room temperature. The reaction mixture was washed with 210 mQ-portions of isopropyl ether three times under shaking, and the aqueous layer was separated. To the aqueous solution containing 14-bromodaunomycin hydrobromide was added solid sodium chloride (65g) in small portions, and the precipitate formed was collected by centrifugation. The precipitate was twice washed with 20% aqueous solution of sodium chloride, collected by filtration and dried to give 5.0g of red powder of crude 14-chlorodaunomycin hydrochloride.
The crude product of 14-chlorodaunomycin hydrochloride was dissolved in 235 mQ of a 7% aqueous solution of sodium hydrogen carbonate, and the resultant 14-chlorodaunomycin (in the free base form) was extracted with 450 mQ of methylene chloride, with 200 mQ-portions of methylene chloride for three times, and further with , 210 mQ-portions of a mixed solvent of methylene chloride and methanol (6:1). The extracts were combined, dried -over anhydrous sodium sulfate, and concentrated to 35 mQ
under reduced pressure. The concentrate was added dropwise to 180 mQ of isopropyl ether, and the deposited 14-chlorodaunomycin (free base) was collected by filtration. Yield: 3.65 g.
Melt;ng point: 174 - 176C (decomposed).
Mass spectrum (FD): m/e 562(M+l) .
In 50 mQ of a mixed solvent of methylene chloride and methanol (3:1) was dissolved 3.6 g of 14-chloro-daunomycin (free base) obtained above. Under ice-cooling the resultant solution, 6.4 mQ of a solution of lM-hydrogen chloride in methylene chloride was added gradually. The solution was added dropwise to isopropyl ether (280 mQ) and the precipitate formed was collected and washed with isopropyl ether, thereby obtA;n;ng 3.83 g of 14-chlorodaunomycin hydrochloride. Yield: 73~.
Melting point: 166 - 167C.
NMR (D2o,ppm) ~: 1.35 (5'-methyl), 2.60-2.96 (10-methylene), 3.7g (3'-methine), 3.90 (4-o-methyl), 4.28 (5'-methine), 5.49 (l'-methine), 7.33 (2- and 3-methine), 7.60 (l-methine).
Example 2 (a) Tetrahydropyranylation reaction of 14-chlorodaunomycin:

14-Chlorodaunomycin hydrochloride (3.83 g) was dissolved in dry DMF (90 mQ) and mixed with 18 mQ of 3,4-dihydro-2H-pyran and pyridinium d-camphor-sulfonate (2.1 g) as catalyst. The mixture was stirred at 10C.
Each 4 mQ-portions of 3,4-dihydro-2H-pyran and pyridinium d-camphorsulfonate (0.4 g) were added-to the mixture at twenty hours and 29 hours later, respectively. After 44 hours, the reaction mixture was diluted with 180 mQ
of chloroform and washed with each 180 mQ of 1% solution of sodium hydrogen carbonate twice.
The chloroform solution was further washed twice with 180 mQ-portions of a 1% aqueous solution of sodium hydrogen carbonate, twice with 180 mQ-portions of a 0.1% aqueous solution of sodium hydrogen carbonate and with water (100 mQ), and was thendried over anhydrous - sodium sulfate. The dried chloroform solution was chromatographed on a column of silica gel (250 g), using a mix~d solvent of chloroform and methanol ~70:1) as eluent. The eluate containing (2nR)-14-chloro-4'-O-tetrahydropyranyldaunomycin was concentrated to yield 958 mg of (2"R)-14-chloro-4'-O-tetrahydro-pyranyldaunomycin as red powder.
In addition, such fractions of the eluate containing (2"S)-14-chloro-4'-O-tetrahydropyranyldaunomycin and 14-chloro-9,4'-di-O-tetrahydropyranyldaunomycin were ~ 43 ~ 1335199 combined and concentrated to dryness, so that 3.23 g of a mixture of these by-products was recovered.
(b) Production of (2"R)-4'-O-tetrahydropyranyl-adriamycin The (2"R)-14-chloro-4'-O-tetrahydropyranyl-adriamycin (200 mg-) obtained in the procedure (a) of Example 2 was dissolved in dimethyl sulfoxide (6 mQ) and mixed with lithium formate monohydrate (204 mg). The reaction mixture was stirred at room temperature for 5 hours. The mixture was diluted with ethyl acetate (35 mQ) and washed with 35 mQ of water. The organic layer was separated, washed four times with 30 mQ-portions of water, and concentrated to an oil under reduced pressure.
The oil contAinlng (2nR)-14-formyl-4'-O-tetra-hydropyranyladriamycin was dissolved in tetrahydro-furan (6 mQ), and treated with 2.4 mQ of 0.1 M solution Oc sodi~.~ hydroger. carbGr.ate. The r..- xtur2 'waS stlr 2d at room temperature for 3.5 hours to conduct the hydrolytic reaction. Methylene chloride (50 mQ) was added to the reaction mixture, and the solution was washed three times with 40 mQ-portions of water.
The methylene chloride solution was extracted with formate buffer (pH 3.3, 30 mQ) in four portions.
An aqueous sodium hydroxide solution was added - 44~
133~199 to adjust the pH of the combined buffer extracts to 7.5 and the product was extracted with methylene chloride (25 mQ) in four portions. The methylene chloride extract, was dried over anhydrous sodium sulfate and concentrated to dryness to give 122 mg of (2"R)-4'-O=t~trAhydropyranyladriamycin as a crude product. The crude product was crystallized from methylene chloride, followed by recrystallization from methylene chloride to afford 93 mg of (2"R)-4'-O-TNPADM as a pure product.
Melting point: 184 - 186C (decomposed).
[~]D0: +210 ( c 0.2, chloroform).

IR(in KBr):vmax (cm 3460 (o-methyl and hydroxyl), 1720 (carbonyl), 1620 and 1580 (quinone) - lH-NMR (CDCl3) ~:
1.34 (5'-methyl), 1.45-1.87 (tetrahydropyranyl), 2.10-2.40 (8-methylene), 3.00 (3i-methine)~
3.00-3.31 (10-methylene), 3.67 (4'-methine), 3.98-4.05 (5'-methine), 4.09 (4-o-methyl), 4.71 (2"-methine, anomeric of tetrahydro-pyranyl), 4.75 (14-methylene), 5.32 (7-methine), -- 5.52 (l'-methine), anomeric of daunosamine), 7.40 (3-methine), 7.79 (2-methine), 8.04 (1-methine).

-133~199 With subtracting the yield of 14-chlorodaunomycin hydrochloride which was recovered in Example 3 given below, the yield of (2~R)-4'-O-THPADM was calculated as amounting to 28% as based on the 14-chlorodaunomycin hydrochloride consumed.
Example 3 Recovery of 14-chlorodaunomycin hydrochloride 3.23 g of the mixture of the by-products which was obtained i~ the procedure (a) of Example 2 was dissolved in 80 mQ of a (1:1) mixed solvent of acetone and 0.25 M hydrobromic acid. The resultant solution was stirred at room temperature for 30 hours to regenerate 14-chlorodaunomycin. The reaction mixture was washed with 45 mQ-portions of isopropyl ether for three times, and the aqueous layer was separated.
Sodium chloride (14 g) was added to the aqueous solution of 14-chlorodaunomycin and the red precipitate formed was washed with a 20% solution of sodium chloride to give a crude product, which was purified in accordance with the method described in the Example 1 above, to afford 2.34 g of 14-chlorodaunomycin hydrochloride as a powder.
Melting point: 165 - 166C.
Mass spectrum (FD)(as free base): m/e 562 (M~1) .
lH-NMR spectrum of the regenerated 14-chlorodaumycin hydrochloride was identical to that of the 14-chlorodaunomycin hydrochloride which was obtained in the Example 1 above. Therefore, 2.34 g-portion of the starting 14-chlorodaunomycin hydrochloride (3.83 g) used in the procedure (a) of Example 2 was recovered from the--by-products--of the tetrahydropyranylation.
step (the recovered yield: 61~).

Claims (6)

1. THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
   PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
   
   l. A process for the preparation of (2"R)-4'-O-tetrahydropyranyladriamycin of formula (A) (A) which comprises reacting 14-chlorodaunomycin of formula (I) (I) or an acid addition salt of 14-chlorodaunomycin, with 3,4-dihydro-2H-pyran in the presence of an acid catalyst to tetrahydropyranylate the 4'-hydroxy group of 14-chlorodaunomycin, separating chromatographically on a column of silical gel the resultant (2"R)-14-chloro-4'-O-tetrahydropyranyldaunomycin of formula (VI) (VI) from the (2"S)-14-chloro-4'-O-tetrahydropyranyldaunomycin by-produced and also from the 14-chloro-9,4'-di-O-tetrahydropyranyldaunomycin by-produced, and then converting the 14-chloro group of the compound of formula (VI) into a 14-hydroxyl group to form the (2"R)-4'-O-tetrahydropyranyladriamycin of formula (A).
2. 2. A process for the preparation of (2"R)-4'-O-tetrahydropyranyladriamycin of formula (A) (A) or an acid additional salt thereof, which comprises reacting 14-chlorodaunomycin of formula (I) (I) or an acid addition salt of 14-chlorodaunomycin, with 3,4-dihydro-2H-pyran in the presence of an acid catalyst to tetrahydropyranylate the 4'-hydroxy group of 14-chlorodaunomycin, separating chromatographically on a column of silica gel the resultant (2"R)-14-chloro-4'-O-tetrahydropyranyldaunomycin of formula (VI) (VI) from the (2"S)-14-chloro-4'-O-tetrahydropyranyldaunomycin by-produced of formula (VII) (VII) and also from the 14-chloro-9,4'-di-O-tetrahydropyranyl-daunomycin by-produced of formula (VIII) (VIII) and then converting the 14-chloro group of the compound of formula (VI) into a 14-hydroxyl group to form (2"R)-4'-O-tetrahydropyranyladriamycin of formula (A) (A) and recovering the by-produced (2"S)-14-chloro-4'-O-tetrahydropyranyldaunomycin of formula (VII) and 14-chloro-9,4-di-O-tetrahydropyranyldaunomycin of formula (VIII), hydrolyzing the thus-recovered compound of formula (VII) and compound of the formula (VIII) under acidic conditions to regenerate 14-chlorodaunomycin, again tetrahydropyranylating the 4'-hydroxy group of the regenerated 14-chlorodaunomycin by reaction with 3,4-dihydro-2H-pyran in the present of an acid catalyst, thereby to produce a second crop of the compound of formula (VI), and then converting the 14-chloro group of the second crop compound of formula (VI) into a 14-hydroxyl group so as to give a second crop of the (2"R)-4'-O- tetrahydropyranyladriamycin of formula (A).
3. 3. The process as claimed in Claim 1 or 2, wherein the reaction for converting the 14-chloro group of the compound of formula (VI) into the 14-hydroxy group comprises hydrolyzing the compound of formula (VI) directly with an alkali metal hydroxide or carbonate.
4. 4. The process as claimed in Claim 1 or 2, wherein the reaction for converting the 14-chloro group of the compound of formula (VI) into the 14-hydroxyl group comprises reacting the compound of formula (VI) with an alkali metal or alkaline earth metal salt of an organic carboxylic acid of formula (IX) (IX) wherein R' means a hydrogen atom or an alkyl or aralkyl group and M denotes an alkali metal or alkaline earth metal to give an ester compound of formula (X) (X) wherein R' is as defined above, and then hydrolyzing the ester compound of formula (X) under alkaline conditions to afford (2"R)-4'-O-tetrahydropyranyladriamycin of formula (A).
5. 5. The process as claimed in Claim 1 or 2, wherein the reaction for converting the 14-chloro group of the compound of formula (VI) into the 14-hydroxyl group comprises reacting the compound of formula (VI) with an alkali metal or alkaline earth metal salt of an organic carboxylic acid of formula (IX) (IX) wherein R' means lower alkyl and M denotes alkali metal or alkaline earth metal alkanoate to give an ester compound of formula (X) (X) wherein R' is as defined above, and then hydrolyzing the ester compound of formula (X) under alkaline conditions to afford (2"R)-4'-O-tetrahydropyranyladriamycin of formula (A).
6. 6. The process as claimed in Claim 1 or 2, wherein the reaction for converting the 14-chloro group of the compound of formula (VI) into the 14-hydroxyl group comprises reacting the compound of formula (VI) with an alkali metal or alkaline earth metal salt of an organic carboxylic acid of formula (IX) (IX) wherein R' means lower alkyl and M denotes lithium formate to give an ester compound of formula (X) (X) wherein R' is as defined above, and then hydrolyzing the ester compound of formula (X) under alkaline conditions to afford (2"R)-4'-O-tetrahydropyranyladriamycin of formula (A).