KR20020013080A - A process for preparing Eiprubicin and Pharmaceutically acceptable salt thereof - Google Patents

Abstract

PURPOSE: Provided is a process for preparing epirubicin and pharmaceutically acceptable salt thereof, thereby producing epirubicin in high yield and purity. CONSTITUTION: The preparing method of epirubicin represented by the formula(1) comprises the steps of: protecting 3'-amino group in saccharide region of doxorubicin to obtain a compound of the formula(2); protecting OH groups at No. 9 and No.14 of the compound of the formula(2) to obtain a compound of the formula(3); converting 4'- in saccharide region of the formula(3) to activated leaving group to obtain a compound of the formula(4); releasing the activated leaving group at 4'- to obtain a compound of the formula(5); hydrating 4'- in saccharide of the compound of the formula(5) to obtain a compound of the formula(6); and deprotecting aglycone to obtain a compound of the formula(1).

Description

Epirubicin, an anthracycline-based anticancer agent, and a method for producing a pharmaceutically acceptable salt thereof {A process for preparing Eiprubicin and Pharmaceutically acceptable salt thereof}

The present invention relates to a method for preparing epirubicin and pharmaceutically acceptable salts thereof, the method comprising first protecting a 3'-amino group of a sugar moiety using doxorubicin as a starting material, and a hydroxyl group at positions 9 and 14 of the aglycone moiety. Protecting the step, introducing an activator at the 4'-position of the sugar moiety, inverting and removing the deactivator at the 4'-position of the sugar moiety, and hydroxylating the 4'-position of the inverted sugar moiety. And, it comprises a step of removing the hydroxyl protecting group of aglycone to obtain epirubicin, according to the production method of the present invention can be produced in high yield, high purity epirubicin represented by the formula (1).

Epirubicin is an active substance classified as an anthracycline-based anticancer agent. Compared with doxorubicin, epirubicin has the same antitumor effect and reduced side effects. This substance is represented by the formula (1), and unlike the widely used doxorubicin and daunorubicin hydrochloride, it is characterized by the fact that the hydroxyl group at the 4 'position of the sugar portion is three-dimensionally arranged oppositely.

<Formula 1>

As a method for producing such epirubicin, Korean Patent No. 90-7318, PCT WO 96/29335, US Patent No. 4,058,519 and European Patent No. 0,848,009 A1 are known, and their preparation methods are as follows. It is summarized in three.

1) According to Korean Patent No. 90-7318,

This method is characterized in that the hydroxyl group of the sugar moiety is converted to a carbonyl compound, and then reduced by a reducing agent. In this method, reaction of sodium borohydride (NaBH ₄ ) at low temperature (-10 ^o C) results in 4'-hydroxy group inversion reaction, thus successfully producing the target N-trifluoroacetyl-4'-epi-doxorubicin hydrochloride. As a by-product, however, it is accompanied by the production of N-trifluoroacetyl doxorubicin hydrochloride, and this by-product is followed by deprotection of the trifluoroacetyl group with sodium hydroxide followed by 14-hydroxyl reaction via bromination. Induces production of doxorubicin. Doxorubicin, a byproduct produced with epirubicin, has similar problems in obtaining pure epirubicin because of similar physical and chemical properties.

2) According to International Patent Publication PCT / WO96 / 29335,

This method is poor in yield and reproducibility due to the instability of the protecting group used to protect the hydroxyl group at position 14, and the yield is very low in the step of using sodium hydroxide to remove the trichloroacetyl group, which is the protecting group of the amino group. There is a problem.

3) According to European Patent Publication EP 0.848.009A,

This method is characterized in that the sugar part and the aglycone part are separated to complete the skeleton of epirubicin by an appropriate chemical reaction.

However, since the a / b selectivity of the glycosidation process is low and the reagent (tetrakis (triphenylphosphine) palladium (0)) used in the deprotection process is expensive, the above process has a disadvantage in that it is not competitive in terms of practicality.

Therefore, the present inventors have made efforts to solve the above problems, and as a starting material, doxorubicin is used as a starting material to protect the 3'-amino group of the sugar moiety, and to protect the hydroxyl groups at positions 9 and 14 of the doxorubicin in which the amino group is protected, and 4 of the sugar moiety. It is possible to synthesize epirubicin and its salts in high yield and high purity as a unique method of converting the '-position to an activating leaving group, inverting it, and then removing the protecting group to obtain epirubicin and converting it to epirubicin hydrochloride. The present invention was completed by finding out.

It is an object of the present invention to provide a method for preparing epirubicin represented by the formula (1) and pharmaceutically acceptable salts thereof in high purity, high yield and economical.

In order to achieve the above object, the present invention provides a method for preparing epirubicin represented by the following formula (1) and a pharmaceutically acceptable salt thereof.

<Formula 1>

Hereinafter, the present invention will be described in detail.

The present invention provides a method for producing epirubicin represented by the formula (1).

Method for producing formula (1) according to the present invention,

1) protecting the 3'-amino group of the sugar moiety of doxorubicin hydrochloride to obtain formula (2) (first step);

2) protecting the hydroxyl groups at positions 9 and 14 of the compound of formula (2) to obtain formula (3) (second step);

3) converting 4′- of the sugar moiety of formula (3) into an leaving group to obtain formula (4) (third step);

4) obtaining a chemical formula (5) by inverting and removing the 4 ′ deactivation group of the sugar moiety (fourth step);

5) hydroxylating 4'- of the inverted sugar moiety to obtain formula (6) (stage 5); And

6) removing the protecting group of the aglycone to obtain epirubicin of the formula (1) (sixth step).

The reaction is represented by the following scheme.

Hereinafter, the preparation method of the present invention will be described in detail for each reaction step.

1.Protecting the 3'-amino group of the sugar moiety of doxorubicin hydrochloride (Step 1)

Doxorubicin hydrochloride and a general amino group protective reagent are stirred in an appropriate solvent under an appropriate base to replace the 3'-amino group with a protecting group to obtain a compound of formula (2).

R ₁ in the formula (2) is an acetyl, trifluoroacetyl, alkoxycarbonyl group. By suitable solvent is meant a lower alcohol and a highly polar organic solvent which can be arranged in straight or branched chains having 1 to 6 carbon atoms. In particular, methanol, ethanol, dimethylformamide, dimethyl sulfoxide are useful. The reaction temperature means from 0 ^o C to the reflux temperature of the solvent.

Also, common amino group protecting reagents are acyl halides having lower alkyl groups which can be arranged in straight or branched chains having 1 to 6 carbon atoms, and straight or branched chains having 1 to 6 carbon atoms substituted by halogen. Acyl halides having lower alkyl groups which may be present, acyl anhydrides having lower alkyl groups which may be arranged in straight or branched chains having 1 to 6 carbon atoms, straight or branched chains having 1 to 6 carbon atoms substituted by halogen Acyl anhydride having a lower alkyl group which may be arranged in a chain, a straight or branched chain having 1 to 6 carbon atoms, or a straight or branched chain having 1 to 6 carbon atoms substituted by a halogen or a lower alkyl group which may be arranged in a chain. And alkoxycarbonyl halides having a lower alkyl group which can be arranged as follows.

Suitable bases mean inorganic bases such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate and the like, triethylamine, pyridine and the like and organic bases.

The compound of formula (2) obtained by the above reaction can be purified in high yield using an appropriate temperature and an appropriate recrystallization solvent.

By suitable recrystallization solvent is meant a mixed solvent of lower ethers or ketones and hydrocarbons which can be arranged in straight or branched chains having 1 to 6 carbon atoms in any ratio, wherein hydrocarbons are hexane, petroleum Benzene, petroleum ether refers to any ratio means lower ether or ketones: hydrocarbons = 1: 0 to 10.

Appropriate temperature means from -5 ^o C to room temperature.

2. Protection of Amino Group Protected Doxorubicin with Hydroxyl Groups 9 and 14 (Step 2)

The doxorubicin derivative of the formula (3) is obtained by dissolving the compound represented by the formula (2) in an appropriate solvent and adding and stirring a hydroxyl protecting reagent at positions 9 and 14 under appropriate acid conditions.

In the above formula (3), R ₁ is as described above, R ₂ , R ₃ each represent an independent variable, hydrogen or a lower alkyl group that can be arranged in a straight or branched chain having 1 to 6 carbon atoms. .

Suitable solvents include lower hydrocarbons which can be arranged in straight or branched chains having 1 to 6 carbon atoms including halogen and lower ethers which can be arranged in straight or branched chains or rings having 1 to 6 carbon atoms. Means a mixed solvent mixed in any ratio, wherein the arbitrary ratio means lower alcohol or lower hydrocarbons: lower ether = 1: 0 to 10.

Appropriate acid conditions generally mean conditions in which inorganic acids such as hydrochloric acid, bromic acid, iodic acid and the like or organic acids such as acetic acid, oxalic acid and 4-toluenesulfonic acid are added to the reaction solvent.

The hydroxyl protecting reagents at positions 9 and 14 are alkoxyalkenes represented by R ₂ CH═C (OMe) R ₃ .

The reaction temperature means from 0 ^o C to the reflux temperature of the solvent.

3. Preparation of Derivatives Substituted with Leaving Groups with 4 'Position of Sugar Part Activated

The compound represented by the formula (3) is dissolved in a suitable solvent, added with a degassing reagent and an opposite inorganic or organic base, stirred at an appropriate temperature, and then terminated. To 4'-position of the active exit Substituted compound of formula (4) is obtained.

X in the formula (4) means a general leaving group such as trichloromethanesulfonyloxy, methanesulfonyloxy, 4-toluenesulfonyloxy and the like, and R ₁ , R ₂ , and R ₃ are as described above.

R ₄ is hydrogen, a lower acyl group which may be arranged in a straight or branched chain having 1 to 6 carbon atoms, a trialkylsilyl group represented by -Si (R ₆ ) (R ₇ ) (R ₈ ), methoxy Mean alcohol common groups such as methyl, wherein R ₆ , R ₇ , R ₈ is an independent variable, respectively, means a lower alkyl group that can be arranged in a straight or branched chain having 1 to 6 carbon atoms.

By suitable solvent is meant a lower hydrocarbon which can be arranged in straight or branched chains having 1 to 6 carbon atoms including halogen.

The general inorganic base or organic base means sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, triethylamine, pyridine and the like.

Appropriate temperature means from 0 ^o C to the reflux temperature of the solvent.

Degassing reagent means 4-toluenesulfonyl chloride, methanesulfonyl chloride, trichloromethanesulphonic anhydride and the like.

Common alcohol protection reagents are lower acyl halides that can be arranged in straight or branched chains having 1 to 6 carbon atoms, trialkylsilyl halides represented by -Si (R ₆ ) (R ₇ ) (R ₈ ), Methoxymethyl halide and the like.

4. Preparation of isopropylidene-9,14-yl-4'-epidoxorubicin derivatives with protected amine groups (step 5)

The compound represented by the formula (4) is dissolved in a suitable solvent to add an organic base and an organic acid, respectively, or a mixed solution of organic base and organic acid dissolved in a suitable solvent is added and stirred at an appropriate temperature to obtain a compound of the formula (5), respectively. .

R ₅ in formula (5) includes a lower alkyl group which may be arranged in a straight or branched chain having 1 to 6 carbon atoms, an alkancarbonyl group including-(CH ₂ ) _p -OR ₉ or 1 to 5 hetero atoms. And an aromatic carbonyl group having 5 to 15 carbon atoms, where p means 1 to 6, and R ₉ is a lower alkyl group or halogen which may be arranged in a straight or branched chain having 1 to 6 carbon atoms. It means a lower alkyl group that can be arranged in a straight or branched chain having 1 to 6 carbon atoms substituted.

R ₁ , R ₂ , R ₃ , and R ₄ are as described above.

By suitable solvent is meant lower hydrocarbons which can be arranged in straight or branched chains having 1 to 6 carbon atoms including halogen, or ketones which can be arranged in straight or branched chains having 1 to 6 carbon atoms. . Especially dichloromethane, dichloroethane, acetone, 2-butanone, etc. are useful.

Appropriate temperature means from 0 ^o C to the reflux temperature of the solvent.

Organic acids include lower alkyl groups which may be arranged in straight or branched chains having 1 to 6 carbon atoms, alkancarbonyl acids including-(CH ₂ ) _p -OR ₉ or 1 to 5 hetero atoms, It means an aromatic carbonyl group having 5 to 15, wherein p means 1 to 6.

An organic base is represented by N (R ₁₀ ) (R ₁₁ ) (R ₁₂ ), where R ₁₀ , R ₁₁ , and R ₁₂ are independent variables, each being hydrogen, straight or branched having 1 to 6 carbon atoms. It means a lower alkyl group which can be arranged in a chain.

Or a process for preparing a compound of formula (4) and a process for preparing a compound of formula (5) in the same reactor ( in-situ ) to obtain a compound of formula (5), respectively.

5. Preparation of Isopropylidene-9,14-yl-4'-epidoxorubicin derivative (Step 5)

The compound represented by the formula (5) is dissolved in a suitable solvent, an appropriate base is added, stirred at an appropriate temperature, and the 4- 'position of the sugar moiety is hydroxideed to obtain a compound of the formula (6).

R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are as described above.

Suitable solvents include lower alcohols which can be arranged in straight or branched chains having 1 to 6 carbon atoms, ether or cyclic ethers and water which can be arranged in straight or branched chains having 1 to 6 carbon atoms. 1-solvent, 2-solvent or 3-solvent mixed solvent mixed in any ratio, wherein the arbitrary ratio is alcohol: ether: water = 0 ~ 10: 0 ~ 10: 0 ~ 10 Means. A mixture of water in which a common water-soluble inorganic salt or a phase transfer catalyst (e.g. ammonium hydrogen sulfate) is dissolved and hydrocarbons which can be arranged in a straight or branched chain having 1 to 6 carbon atoms including halogen in an arbitrary ratio Say a solvent. The arbitrary ratio here refers to water: hydrocarbons = 1: 1 to 10.

Suitable base is represented by M _z (OR ₁₃ ) and its hydrate, M _z H _q (CO ₃ ), where M means alkali metal and alkaline earth metal, q, is 0 to 1 and z is 1 To 2; And R ₁₃ is hydrogen, a lower alkyl group which can be arranged in a straight or branched chain having 1 to 6 carbon atoms. At this time, lithium hydroxide, sodium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate and the like are particularly useful.

Appropriate temperature means 0 ^o C to 100 ^o C.

6. Preparation of Epirubicin (Step 6)

The compound represented by the formula (6) was dissolved in a suitable solvent, an appropriate acid was added thereto, stirred at a suitable temperature, and then an appropriate inorganic base or a suitable anionic exchange resin was added to obtain a compound of the formula (1).

Suitable solvents include lower alcohols that can be arranged in straight or branched chains having 1 to 6 carbon atoms, ether or cyclic ethers and water which can be arranged in straight or branched chains having 1 to 6 carbon atoms. It means a 1-solvent, 2-solvent or 3-solvent mixed solvent mixed in the ratio of. At this time, the arbitrary ratio means alcohol: ether: water = 0 ~ 10: 0 ~ 10: 0 ~ 10 respectively.

By suitable acids is meant monocarboxylic or dicarboxylic acids, hydrochloric acid, sulfuric acid, nitric acid, oxalic acid, citric acid and the like which can be arranged in straight or branched chains having 1 to 10 carbon atoms.

Suitable inorganic bases refer to lithium hydroxide, sodium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate and the like.

Should be spleen suitable anionic exchange IRA-45 (OH ^-) means the like.

Appropriate temperature means 0 ^o C to 100 ^o C.

The present invention also provides a method for preparing the epirubicin salt represented by the general formula (7).

The method for preparing the epirubicin salt is prepared by adding a pharmaceutically acceptable free acid by a method known to epirubicin of the formula (1), and an organic acid and an inorganic acid may be used as the free acid. Hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid and the like can be used, and organic acids include citric acid, acetic acid, lactic acid, tartaric acid, maleic acid, fumaric acid, gluconic acid, methanesulfonic acid, glycolic acid, succinic acid, 4-toluenesulfonic acid, and gallic acid. Luteuronic acid, embonic acid, glutamic acid, aspartic acid and the like can be used.

The most preferred salt in the present invention is the hydrochloride, which is converted into epirubicin hydrochloride by dissolving epirubicin in a suitable solvent and then reacting with the hydrochloride salt of the pyridine derivative.

By suitable solvent is meant a mixture of chloroform and methanol. By pyridine derivatives is meant pyrimidinium chloride, 2,6-lutidine hydrochloride or 4-picoline hydrochloride.

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

However, the following examples are illustrative of the present invention, and the content of the present invention is not limited by the examples.

On the other hand, the molecular structure of the compound of the present invention was confirmed by infrared spectroscopy, ultraviolet-visible light spectroscopy, mass spectroscopy, nuclear magnetic resonance spectrum.

1. Preparation of Epirubicin

Example 1 Preparation of Epirubicin (Formula 1)

(Step 1) Preparation of Compound of Formula (2)

Preparation of 3'-N-trifluoroacetyldoxorubicin

To a 100 ml suspension of 10.0 g of doxorubicin hydrochloride, 2.9 g of sodium bicarbonate and 8.3 ml of trifluoroacetic acid ethyl ester were added at 0 ^° C., followed by stirring at room temperature. After completion of the reaction, the reaction solution was diluted with 300 ml of ethyl acetate and washed with water. The organic layer is washed with 2N aqueous hydrochloric acid solution and saturated brine. Dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and crystallized with hexane to obtain 10.6 g (yield 96%) of the target 3'-N-trifluoroacetyl doxorubicin.

NMR (acetone-d ₆ , 200 MHz): 14.00 (s, 1H), 13.28 (s, 1H), 8.11 (d, 1H), 7.93 (dd, 1H), 7.88 (t, 1H), 7.62 (dd, 1H ), 5.48 (d, 1H), 5.23 (dd, 1H), 4.84 (s, 1H), 4.72 (s, 2H), 4.37 to 4.10 (m, 2H), 4.05 (s, 3H), 3.71 (s, 1H), 3.06 (ABq, 2H), 2.48 (dt, 1H), 2.29-2.15 (m, 3H), 1.79 (dd, 1H), 1.27 (d, 3H)

(Step 2) Preparation of a Compound of Formula (3)

Preparation of N-trifluoroacetyl-isopropylidene-9,14-yl-doxorubicin

To 1.53 g of 3'-N-trifluoroacetyl doxorubicin (Formula 2), 100 ml of detrahydrofuran was added, followed by addition of para-toluenesulfonic acid monohydrate (0.17 g) and 2-methoxypropene (2.59 g). Stir at room temperature for 4 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, extracted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. After drying over anhydrous sodium sulfate, filtration and concentration under reduced pressure, the residue was purified by column chromatography (toluene: acetone = 6: 1) to obtain 1.39 g of N-trifluoroacetyl-isopropylidene-9,14-yl-doxorubicin (yield 85). %)

NMR (acetone-d ₆ , 200 MHz): 14.07 (s, 1H), 13.33 (s, 1H), 8.10 (d, 1H), 7.84 (dd, 1H), 7.91 (t, 1H), 7.59 (dd, 1H) ), 5.33 (d, 1H), 5.06 (t, 1H), 4.45 (ABq, 2H), 4.46-4.30 (m, 2H), 4.13 (d, 1H), 4.03 (s, 3H), 3.64 (br s , 1H), 3.22 (ABq, 2H), 2.36 (m, 2H), 2.15 (dd, 1H), 1.73 (dd, 1H), 1.49 (s, 3H), 1.46 (s, 3H), 1.21 (d, 3H)

(Step 3) Preparation of a compound of formula (5)

Preparation of N-trifluoroacetyl-4'-O-acetyl-isopropylidene-9,14-yl-4'-epidoxorubicin

1.39 g of N-trifluoroacetyl-isopropylidene-9,14-yl-doxorubicin (Formula 3) was dissolved in methylene chloride (100 ml), cooled to 0 C and then pyridine (3.8 ml), trifluoro Methanesulphonic anhydride (2.3 g) is added. After stirring for 2 hours, N, O-bis (trimethylsilyl) acetamide (2.54 ml) was added and stirred for 2 hours. Triethylamine (13.1 ml) and acetic acid (3.75 ml) were added to the above solution and stirred overnight. After the reaction was completed, the reaction solution was washed with water, diluted hydrochloric acid aqueous solution and saturated brine. Dehydrated with anhydrous sodium sulfate, filtered and concentrated under reduced pressure, purified by column chromatography (toluene: acetone = 10: 1), and purified by N-trifluoroacetyl-4'-O-acetyl-isopropylidene-9,14-yl 1.2 g of -4'- epidoxorubicin (yield 82%) is obtained.

NMR (acetone-d ₆ , 200 MHz): 14.06 (s, 1H), 13.26 (s, 1H), 8.25 (d, 1H), 7.95 (dd, 1H), 7.91 (t, 1H), 7.61 (dd, 1H) ), 5.35 (t, 1H), 5.09 (t, 1H), 4.64 (t, 1H), 4.47 (ABq, 2H), 4.42 (m, 2H), 4.04 (s, 3H), 3.25 (ABq, 2H) , 2.36 (d, 2H), 2.10 (m, 2H), 1.95 (s, 3H), 1.57 (s, 3H), 1.48 (s, 3H), 1.13 (d, 3H)

(Step 4) Preparation of a Compound of Formula (6)

Preparation of Isopropylidene-9,14-yl-4'-epidoxorubicin

1.2 g of N-trifluoroacetyl-4'-O-acetyl-isopropylidene-9,14-yl-4'-epidoxorubicin (Formula 5) was added to tetrahydrofuran (12 ml), methyl alcohol (12 ml), water (6 ml) was added to the solution, then sodium hydroxide (0.58 g) was added and stirred for 6 hours. After the reaction was neutralized with concentrated hydrochloric acid, chloroform (80 ml) was added thereto. The organic layer is washed with water and brine, dried over anhydrous sodium sulfate and filtered. Concentration of the above solution under reduced pressure yields 0.87 g (89% yield) of red isopropylidene-9,14-yl-4'-epidoxorubicin.

NMR (chloroform-d, 200 MHz): 7.95 (d, 1H), 7.70 (t, 1H), 7.27 (d, 1H), 5.27 (d, 1H), 5.02 (t, 1H), 4.80 (br s, 1H ), 4.34 (ABq, 2H), 4.02 (s, 4H), 3.22 (ABq, 2H), 2.97 (br, 2H), 2.30 (d, 2H), 2.01 (m, 2H), 1.24 (d, 3H) , 1.23 (s, 6H)

(Step 5) Preparation of Epirubicin (Formula 1)

0.85 g of isopropylidene-9,14-yl-4'-epidoxorubicin (Formula 6) was added to the diluted hydrochloric acid solution, followed by stirring for 5 hours. The aqueous layer was adjusted to pH> 6 with aqueous sodium hydroxide solution, extracted with chloroform, the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and filtered. Concentration of the above solution under reduced pressure yields 0.71 g of red epirubicin (90% yield).

NMR (chloroform-d, 200 MHz): 16.15 (s, 1H), 14.01 (s, 1H), 8.02 (dd, 1H), 7.78 (t, 1H), 7.38 (dd, 1H), 5.45 (m, 1H) , 4.76 (s, 2H), 4.07 (s, 3H), 3.75 (m, 1H), 3.13 (ABq, 2H), 3.02 to 2.73 (m, 2H), 2.30 (dd, 2H), 1.33 (d, 3H) )

2. Preparation of Epirubicin

Example 2 Preparation of Epirubicin Hydrochloride (Formula 7)

After dissolving 1.1 g of epirubicin (Formula 1) in methanol (10 ml), methanolic hydrochloric acid (40 ml) was added dropwise. After stirring for 1 hour, excess ethyl ether was added to the reaction solution, and the resulting solid was filtered and dried to yield 1.03 g of red epirubicin hydrochloride (yield 88%).

NMR (dimethylsulfoxide-d ₆ , 200MHz): 14.02 (s, 1H), 13.23 (s, 1H), 8.00 ~ 8.20 (br, 3H), 7.90 (m, 2H), 7.65 (m, 1H), 5.76 (d, 1H), 5.49 (s, 1H), 5.26 (s, 1H), 4.93 (m, 2H), 4.64 (d, 2H), 3.98 (br. s, 4H), 3.11 (m, 2H), 2.94 (m, 2H), 2.02-2.17 (m, 3H), 1.75 (m, 1H), 1.19 (d, 3H)

Example 3 Preparation of Epirubicin Hydrochloride (Formula 7)

After adding 1.1 g of epirubicin to 40 ml of chloroform and 4 ml of methanol, 238 mg of pyridinium chloride was added at room temperature and stirred at room temperature for 1 hour. The resulting solid was filtered and dried to give 1.1 g of red epirubicin hydrochloride (yield 94%). Get

Example 4 Preparation of Epirubicin Hydrochloride (Formula 7)

In Example 3, 2,6-lutidine hydrochloride instead of pyridinium chloride is used to obtain epirubicin hydrochloride at 93%.

Example 5 Preparation of Epirubicin Hydrochloride (Formula 7)

In Example 3 4'-epirubicin hydrochloride is obtained as 91% using 4-picoline hydrochloride instead of pyridinium chloride.

As described above, according to the preparation method of the present invention, the reaction process is short, gentle, and high yield can be obtained economically with high purity epirubicin and pharmaceutically acceptable epirubicin salt.

Claims (18)

Protecting the 3'-amino group of the sugar moiety of doxorubicin hydrochloride to obtain formula (2) (first step); Protecting the hydroxyl groups at positions 9 and 14 of the compound of formula (2) to obtain formula (3) (second step); Converting 4′- of the sugar moiety of formula (3) into an leaving group to obtain formula (4) (third step); Removing the 4 ′ deactivation group of the sugar moiety and inverting to obtain formula (5) (step 4); Hydroxylating 4'- of the inverted sugar moiety to obtain formula (6) (stage 5); And A method for producing epirubicin of formula (1), comprising the step (sixth step) of obtaining epirubicin of formula (1) by removing the protecting group of aglycone. A method for producing a compound of formula (3), wherein the compound represented by formula (2) is dissolved in a suitable solvent to protect the hydroxyl groups at positions 9 and 14 using a protective reagent under appropriate acid conditions. The solvent according to claim 2, wherein the solvent is a mixed solvent of lower alcohol or lower hydrocarbons and lower ether in a ratio of 1:10 to 10, the acid is hydrochloric acid, bromic acid, acetic acid, oxalic acid or paratoluenesulfonic acid, and the hydroxyl group protecting reagent is R Alkoxyalkene represented by ₂ CH = C (OMe) R ₃ , wherein the reaction temperature is from 0 ^o C to the reflux temperature of the solvent. The compound represented by the formula (3) is dissolved in a suitable solvent, followed by adding a degassing reagent and a general inorganic or organic base, stirring at an appropriate temperature, and then terminating the reaction, or reacting a general alcohol protective reagent with the reaction solution. Method for producing a compound of formula (4). The solvent of claim 4 wherein the solvent is a lower hydrocarbon comprising halogen, the base is sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, triethylamine or pyridine and the temperature is from 0 ^o C to the reflux temperature of the solvent , Degassing reagent is 4-toluenesulfonyl chloride, methanesulfonyl chloride or trichloromethanesulphonic anhydride, alcohol protecting reagent is lower acyl halide, -Si (R ₆ ) (R ₇ ) (R ₈ ) It is a trialkylsilyl halide or methoxymethyl halide represented by the manufacturing method characterized by the above-mentioned. A method for producing formula (5), comprising dissolving the compound represented by formula (4) in an appropriate solvent to add an organic base and an organic acid, or adding a mixed solution of organic base and organic acid dissolved in a suitable solvent. The solvent of claim 6 wherein the solvent is acetone, 2-butanone, dichloromethane or dichloroethane and the temperature is from 0 ^° C. to the reflux temperature of the solvent, the organic acid is an alkancarbonyl acid containing a lower alkyl group, and the organic base is A amine having a lower alkyl group. A process for producing a compound of formula (6), wherein the compound represented by formula (5) is dissolved in a suitable solvent and reacted at a suitable temperature by adding an appropriate base. The solvent of claim 8 wherein the solvent is alcohol: ethers: water = 0-10: 0-10: 0-10 or water: hydrocarbons = 1: 1-10, and a suitable base is M _z (OR ₁₃ ) or Hydrate, M _z H _q (CO ₃ ), the temperature is from 0 ^o C to 100 ^o C manufacturing method characterized in that. Preparation of epirubicin (Formula 1) characterized by dissolving the compound represented by the formula (6) in an appropriate solvent, adding an appropriate acid, stirring at an appropriate temperature, and then adding an appropriate inorganic base or an anionic exchange resin. Way. The solvent according to claim 11, wherein the solvent is alcohol: ethers: water = 0 to 10: 0 to 10: 0 to 10, the acid is monocarboxylic acid, dicarboxylic acid, hydrochloric acid, sulfuric acid, nitric acid, oxalic acid or citric acid, and a base. is lithium hydroxide, sodium hydroxide, and sodium carbonate, sodium bicarbonate, potassium carbonate or potassium bicarbonate, an anionic exchange resin IRA-45 (OH ^-), characterized in that the in, and the temperature of 0 ^o C to 100 ^o C Manufacturing method. A method of dissolving epirubicin of formula (1) in an appropriate solvent and reacting at an appropriate temperature by adding pyridine derivative hydrochloride to convert to epirubicin hydrochloride (Formula 7). 13. A process according to claim 12 wherein the solvent is alcohol: alkyl halide = 0-10: 0-10, and the temperature is from 0C to 100C. 13. The process according to claim 12, wherein the pyridine derivative hydrochloride is pyrimidinium chloride, 2,6-lutimin hydrochloride or 4-picoline hydrochloride. Compound of formula (3). Compound of formula (4). Compound of formula (5). Compound of formula (6).