CN1791609A - Method of preparing 4-R-substituted 4-demethoxydaunorubicin - Google Patents

Abstract

A method of synthesizing 4-R-substituted anthracyclines and their corresponding salts from 4-demethyldaunorubicin includes the steps of treating 4-demethyldaunorubicin with a sulfonylating agent to form 4-demethyl-4-sulfonyl-R3-daunorubicin. 4-Demethyl-4-R3-sulfonyl-daunorubicin is then subject to a reducing agent in the presence of a transition metal catalyst in a temperature range of about 30 DEG C. to about 100 DEG C. in a polar aprotic solvent in an inert atmosphere. Protected 4-demethoxy-4-R-daunomycin then undergoes hydrolysis in a basic solution to form the 4-R-substituted anthracyclines. The novel method lacks the step of forming a stereospecific glycoside bond between aglycone and aminoglycoside. The method also increases the yield of the final product up to 30 to 40%.

Description

The preparation method of 4-R-substituted 4-demethoxy daunorubicin

related application

This application claims priority to US Provisional Application No. 60/472192, filed May 21, 2003, and US Application No. 10/831448, filed April 23, 2004. Both applications mentioned above are incorporated herein by reference in their entirety.

field of invention

The field of the invention involves the use of chemical methods for the preparation of anthracyclines. More specifically, the field of the invention relates to the preparation from 4-desmethyldaunorubicin of 4-R-substituted 4-demethoxydaunorubicin having the general formula (I) described more fully herein. method. When R=H, the present invention relates to a chemical method and process for preparing idarubicin from 4-desmethyldaunorubicin.

Background of the invention

Anthracyclines form one of the largest classes of naturally occurring bioactive compounds. Several compounds in this class have been shown to be clinically effective antineoplastic agents. These include, for example, daunorubicin, doxorubicin, idarubicin, epirubicin, pirarubicin, zorubicin, aclarmycin and carmine. For example, these compounds are useful in bone marrow transplantation, hepatocyte transplantation, breast cancer, acute lymphocytic and non-lymphocytic leukemia, chronic lymphocytic leukemia, non-Hodgkin's lymphoma, and other solid cancer tumors.

The currently known method for the preparation of the 4-desmethoxy-4-R-daunorubicin anthracycline (when R=H, the anthracycline is called idarubicin) is based on coupling Aglycone (synthesized by any known method), and in silver triflate (AgOSO ₂ CF ₃ ), trimethylsilyl triflate ((CH ₃ ) ₃ SiOSO ₂ CF ₃ ) or protect and activate daunosamine in the presence of mercury oxide-mercury bromide system (HgO ^- HgBr ₂ ). For example, it is currently known to use anthracenetetrone or isobenzofuran as a raw material to synthesize aglycone. Unfortunately, these methods for synthesizing aglycones are complicated by the formation of optically active centers at carbons _C7 and _C9 .

Another method for the synthesis of 4-desmethoxydaunorubicin (idarubicin) uses the daunorubicin aglycone, which is prepared by acidic hydrolysis of the daunorubicin starting material. In this approach, dounosamine, which is also used to modify the glycosylation of the aglycone, is simultaneously synthesized by chemical modification. Previous methods involved the substitution of 4-MeO aglycone substituents for hydrogen, NH _, or other chemical groups involved in the demethylation of daunorubicinone, resulting in 4-demethoxydaunorubicinone Sulfonation of the quinone and substitution of the 4-ArCH ₂ NH by the 4-ArSO ₂ O group (with further reduction of the benzyl group to form a 4-NH ₂ ^- group). See, US Patent No. 4,085,548 (Caruso et al., entitled "4-DEMETHOXY-4-AMINO-ANTHRACYCLINES", published January 15, 1991), the entire contents of which are incorporated herein by reference. Further reductive deamination produces 4-demethoxydaunorubicin (idarubicin). See European Patent Application No. 0328399, published August 16, 1989, the contents of which are incorporated herein by reference in their entirety.

A reductive cross-condensation reaction of 4-desmethyl-4-Tf-daunorubicinone on a phosphine-Pd° catalytic complex has also been demonstrated. See, US Patent No. 5,587,495. In these reactions, 4-R substituted daunorubicin ketones are prepared, where R=

Similarly, reductive carbonylation of 4-Tf-daunorubicin ketone under the same catalyst conditions as described above forms 4-COOR substituted daunorubicin ketone. See US Patent No. 5,218,130. When formate is used as the ligand, the 4-O ^- _Tf group replaces the hydrogen to form 4-desmethoxydaunorubicinone. See US Patent No. 5,103,029.

Summary of the invention

The present invention relates to the method for preparing 4-R-substituted anthracycline antibiotics and corresponding salts thereof shown in following general formula (I) by 4-demethyldaunorubicin:

In the formula, R is hydrogen, a linear or branched oxygen [alkyl, alkenyl or alkynyl] with 1-16 carbon atoms, or a complex ester group COOR ₁ ', wherein, R ₁ ' is a group with at most 10 Straight chain or branched chain alkyl, alkenyl or alkynyl of carbon atoms, which comprises the following steps:

(1) 4-desmethyldaunorubicin or derivatives of 4-desmethyldaunorubicin shown in general formula (II) are provided:

In the formula, R ₁ includes H, acyl or acid halide, R ₂ includes H, acyl or acid halide, carbonate or Schiff base;

(2) Treat 4-desmethyldaunorubicin or a derivative of 4-desmethyldaunorubicin represented by general formula (II) with a sulfonating agent having the chemical formula R ₃ -SO ₂ -X, the formula Among them, R ₃ is an alkyl group, an alkyl halide or an aryl group, and X is a halogen atom, or -O ^- SO ₂ -R ₃ ; forming 4-demethyl-4- Sulfonyl-daunorubicin:

In the formula, R ₃ includes an alkyl group optionally substituted by one or more halogen atoms having 1-4 carbon atoms, or an aryl group optionally substituted by halogen, alkyl, alkoxy or nitro; R ₁ Include hydrogen, acyl, or acid halide; _R Include hydrogen, acyl, acid halide, carbonate group or Schiff base;

(3) 4-demethyl-4-sulfonyl-daunorubicin and reducing agent shown in general formula (III) are reacted in the presence of the compound shown in catalytic amount of general formula (IV):

ML _p L' _q (IV)

In the formula, M represents a transition metal atom; among L and L', L and L' represent the same or different anions or neutral molecules, and p and q vary between 0-4; thus the general formula (IV) is obtained Protected 4-desmethoxydaunorubicin as shown:

(4) hydrolyzing the protected 4-demethoxydaunorubicin in an alkaline solution to obtain 4-R-substituted anthracycline antibiotics represented by general formula (I).

The present invention uses a novel synthetic method without the step of forming a stereospecific glycoside between the aglycone and the aminoglycoside. The inventors have found that the new synthetic method increases the yield of the final product produced by (II) by up to 30 to 40%. It is therefore an object of the present invention to provide a synthetic method which reduces the steps involved in the preparation of 4-R-substituted 4-desmethoxydaunorubicins. Another object of the present invention is to provide a synthetic method with improved process yield.

Detailed description of the invention

The present invention relates to the method for preparing 4-R-substituted anthracycline antibiotics and corresponding salts thereof shown in the following general formula (I):

The general formula (I) illustrates salts of 4-R-substituted anthracyclines. However, it should be understood that the method contemplates the synthesis of 4-R-substituted anthracycline antibiotics represented by general formula (I) in salt and non-salt forms. As for the salt form represented by general formula (I), An ^- is preferably an anion of a strong acid, eg hydrochloric acid or hydrobromic acid. In the general formula (I), R includes hydrogen (for example, when it is idarubicin), a linear or branched oxygen [alkyl, alkenyl or alkynyl] having 1 to 16 carbon atoms. When straight-chain or branched-chain oxy [alkyl, alkenyl or alkynyl], R preferably has 4 or less carbon atoms.

The straight-chain or branched oxygen [alkyl, alkenyl or alkynyl] may be partially substituted by (unsubstituted and substituted) aryl groups which are substituted by any inert group such as alkyl, alkoxy or nitro replace. In addition, the shown linear or branched oxy group may be partially substituted with an alkoxy group, a trialkylsilyl group, an ester group or an amido group.

R may also include a complex ester group, COOR ₁ ', where R ₁ ' is a straight or branched chain alkyl, alkenyl or alkynyl group having up to 10 carbon atoms.

The synthetic method of the 4-R-substituted anthracycline antibiotic shown in general formula (I) is to provide raw material compound, preferably 4-demethyldaunorubicin or 4-demethyldaunorubicin of general formula The derivative starts with:

In the formula, R ₁ includes H, an acyl group or an acid halide, and R ₂ includes H, an acyl group or an acid halide, a carbonate or a Schiff base (preferably COCF ₃ ).

Next, the compound represented by the general formula (II) is treated with a sulfonating agent having the chemical formula R ₃ -SO ₂ -X, wherein, R ₃ is an alkyl group, a haloalkyl group or an aryl group, and X is a halogen atom, or -O ^- SO ₂ -R ₃ . The reaction is preferably carried out in pyridine in the presence of a hindered tertiary amine such as N,N-diisopropylethylamine and a catalytic amount of N,N-dimethylaminopyridine. Most of the reactions involve _C4 -OH. Furthermore, the hydroxyl groups at C ₆ , C ₁₁ and C ₉ mainly react in conditions that allow the use of unprotected 4-desmethyl-4-sulfonyl-daunorubicin at these carbon positions. Derivatives. Above steps make 4-demethyl-4-sulfonyl-daunorubicin shown in general formula (III):

In the formula, _R3 includes an alkyl group having 1-4 carbon atoms optionally substituted by one or more halogen atoms, or an aryl group optionally substituted by halogen, alkyl, alkoxy or nitro. Preferred groups for _R3 include trifluoromethyl, 4-fluorophenyl and 4-tolyl. R ₁ preferably includes hydrogen, acyl, or acyl halide. _R2 preferably includes hydrogen, an acyl group, an acid halide, a carbonate group or a Schiff base (ie, a compound formed by a condensation reaction between an aromatic amine and an aldehyde or ketone).

Then, the 4-desmethyl-4-sulfonyl-daunorubicin represented by general formula (III) is used in a catalytic amount (10000:1 to 1:1, preferably 20:1 to 100:1, in moles In the presence of the compound represented by the general formula (IV) of the ratio), react with a reducing agent to obtain the protected 4-demethoxy daunorubicin represented by the general formula (V).

ML _p ' _q (IV)

In the formula, M represents a transition metal atom, preferably palladium or nickel. L and L' can be the same or different molecules, representing the same or different anions or neutral molecules. L and L' anions include anions such as HCOO ⁻ , CH ₃ COO ⁻ and Cl ⁻ . Examples of neutral molecules include neutral solvent molecules, mono- or diphosphines, phosphates or diamines, preferably chelated diphosphines such as 1,3-diphenylphosphinopropane, 1,1'-bis(di phenylphosphino)ferrocene and 1,2-bis(N-1-phenylethyl)N-(diphenylphosphino)amino)ethane. In general formula (IV), p and q vary between 0-4.

Preferably, the reducing agent is a formate anion (eg, formic acid or a salt of formic acid) or an unsaturated compound under reducing conditions, such as CO or substituted alkenyl and alkynyl groups.

Preferably, the reaction is carried out in an aprotic polar solvent (preferably alkyl amides) in an inert atmosphere at a temperature in the range of about 30-100°C. The protected 4-demethoxy daunorubicin shown in general formula (V) is as follows:

Then, the protected 4-demethoxy daunorubicin (R ₁ or R ₂ is not H) is hydrolyzed in an alkaline solution to remove the protecting group, and the 4- R-substituted anthracycline antibiotics. The alkaline solution is preferably formed in water or alcohol, preferably water or methanol.

The examples described below illustrate the preparation of 4-R-substituted anthracyclines (idarubicin) of general formula (I) from 4-desmethyldaunorubicin.

Example 1

First, 2 g of 3'-trifluoroacetamido-4-desmethyldaunorubicin (R ₁ =H, R ₂ =trifluoroacetyl) was dissolved in 0.2 L of pyridine.

Next, 4ml of diisopropylethylamine and 0.5g of 4-dimethylaminopyridine were added to the solution of step (a) in Example 1.

Next, the solution in step (b) of Example 1 was quenched to 0° C., and 2.5 ml of freshly distilled trifluoromethanesulfonic anhydride was added.

Next, the solution in step (c) of Example 1 was incubated at room temperature for 1 hour.

After the incubation, 0.15 L of concentrated hydrochloric acid, 0.2 kg of ice, and 0.2 L of dichloromethane were added to the incubated solution.

Next, the organic layer was washed in 0.2 L of distilled water, and the dichloromethane was removed by evaporation under partial vacuum.

After evaporation, 1.5 g of 4-trifluoromethanesulfonyl-3'-trifluoroacetamido-4-desmethyldaunorubicin were obtained with a purity of 85% (confirmed by HPLC).

The 4-trifluoromethanesulfonyl-3'-trifluoroacetylamino-4-desmethyldaunorubicin prepared in step (g) of Example 1 is used for the next synthetic step in Example 2, either No additional purification was required.

Example 2

1.5 g of 4-trifluoromethanesulfonyl-3'-trifluoroacetylamino-4-desmethyldaunorubicin (R ₁ =H, R ₂ =trifluoroacetyl, R ₃ = trifluoromethyl) was dissolved in 0.1 L of dimethylformamide.

During stirring, 2 g of triethylamine formate and 50 mg of palladium acetate were added to the mixture in step (a) of Example 2, and argon flow was passed through the mixture.

Then, the mixture of step (b) in Example 2 was heated to 50° C., and 200 mg of 1,1’-bis(diphenylphosphino)ferrocene was added.

Then, the mixture of step (c) in Example 2 was heated at 50° C. for 8 hours.

Then, the mixture of step (d) in Example 2 was poured into water under vigorous stirring to form a precipitate (4-desmethoxy-3'-trifluoroacetamidodaunorubicin).

The precipitate (4-desmethoxy-3'-trifluoroacetamidodaunorubicin) was filtered and purified by preparative chromatography.

The yield of this procedure was 0.8-0.85 g of 4-desmethoxy-3'-trifluoroacetamidodaunorubicin with a purity of 98% (confirmed by HPLC).

Example 3

0.85 g of 4-desmethoxy-3'-trifluoroacetamido daunorubicin was added to a stirred aqueous solution of 0.1 N NaOH (0.06 L) and incubated at 30 °C for 30 minutes. The color of the solution turned dark blue-purple.

The reaction mixture was then poured into 0.5 L of a 10-12% solution of chloroform in butanol (heated to 40° C.) with vigorous stirring.

Then, under vigorous stirring, hydrochloric acid (1:3) was added to the mixture, and titrated to pH 8.8-9.0.

Then, the obtained organic layer was washed in distilled water.

Then, 0.1 L of distilled water was added to the organic layer washed in step (d) of Example 3, and 0.8 N hydrochloric acid was added, and titrated to pH 3.5. The solution of step (e) in Example 3 was vigorously stirred, and the aqueous layer containing 4-desmethoxydaunorubicin hydrochloride (idarubicin) was separated. The solution of idarubicin hydrochloride was evaporated to 50% of its original volume and purified by chromatography. The eluate is evaporated and crystallized from a hydrophilic solvent, preferably a low molecular weight fatty alcohol.

The yield of this procedure was 0.6 g of 4-desmethoxydaunorubicin hydrochloride (idarubicin hydrochloride) with a purity of 99% (confirmed by HPLC).

While the embodiment of the present invention has been described, various modifications can be made without departing from the scope of the present invention. Accordingly, this invention should be limited only by the following claims and their equivalents.

Claims (13)

1. A method for preparing 4-R-substituted anthracycline antibiotics shown in general formula (I):

In the formula, R is hydrogen, a linear or branched oxygen [alkyl, alkenyl or alkynyl] with 1-16 carbon atoms, or a complex ester group COOR ₁ ', wherein, R ₁ ' is a group with at most 10 Straight chain or branched chain alkyl, alkenyl or alkynyl of carbon atoms, which comprises the following steps: (1) 4-desmethyldaunorubicin or derivatives of 4-desmethyldaunorubicin shown in general formula (II) are provided:

In the formula, R ₁ includes H, acyl or acid halide, R ₂ includes H, acyl or acid halide, carbonate or Schiff base; (2) Treat 4-desmethyldaunorubicin or a derivative of 4-desmethyldaunorubicin represented by general formula (II) with a sulfonating agent having the chemical formula R ₃ -SO ₂ -X, the formula Among them, R ₃ is an acyl group, an acid halide group or an aryl group, X is a halogen atom, or -O ^- SO ₂ -R ₃ ; forming 4-demethyl-4-sulfonyl-soft Erythromycin: In the formula, R ₃ includes haloalkyl or aryl; R ₁ includes hydrogen, acyl, or acid halide; R ₂ includes hydrogen, acyl, acid halide, carbonate group or Schiff base; (3) 4-demethyl-4-sulfonyl-daunorubicin and reducing agent shown in general formula (III) are reacted in the presence of the compound shown in catalytic amount of general formula (IV): ML _p L' _q (IV) In the formula, M represents a transition metal atom; among L and L', L and L' represent the same or different anions or neutral molecules, and p and q vary between 0-4; thus the general formula (IV) is obtained Protected 4-desmethoxydaunorubicin as shown: (4) hydrolyzing the protected 4-demethoxydaunorubicin in an alkaline solution to obtain 4-R-substituted anthracycline antibiotics represented by general formula (I). 2. The method of claim 1, wherein the transition metal M comprises palladium. 3. The method of claim 1, wherein the transition metal M comprises nickel. 4. The method of claim 1, wherein L comprises anions selected from HCOO ⁻ , CH ₃ COO ⁻ and Cl ⁻ , neutral solvent molecules, monophosphine, diphosphine, phosphate and diamine. 5. The method of claim 4, wherein L comprises 1,3-diphenylphosphinopropane, 1,1'-bis(diphenylphosphino)ferrocene and 1,2 - Chelating diphosphines of bis(N-1-phenylethyl)N-(diphenylphosphino)amino)ethane. 6. The method of claim 1, wherein L' comprises anions selected from HCOO ⁻ , CH ₃ COO ⁻ and Cl ⁻ , neutral solvent molecules, monophosphine, diphosphine, phosphate and diamine. 7. The method of claim 6, wherein L' comprises 1,3-diphenylphosphinopropane, 1,1'-bis(diphenylphosphino)ferrocene and 1, Chelating diphosphine of 2-bis(N-1-phenylethyl)N-(diphenylphosphino)amino)ethane. 8. The method of claim 1, wherein the reducing agent comprises formic acid or a formate salt. 9. The method according to claim 1, characterized in that, in general formula (I), R is a linear or branched oxygen [alkyl, alkenyl or alkynyl] with 1-16 carbon atoms 10. The method according to claim 9, wherein R comprises a linear or branched chain of 1-16 carbon atoms partially substituted by an alkoxy group, a trialkylsilyl group, an ester group or an amido group. Oxygen [alkyl, alkenyl or alkynyl]. 11. The method of claim 1, wherein R comprises a complex ester group COOR ₁ ', wherein R ₁ ' is a linear or branched alkyl, alkenyl or alkynyl group with up to 10 carbon atoms . 12. A method for preparing idarubicin shown in general formula (I): In the formula, R is hydrogen, and An ^- includes the anion of acid, and the method comprises the steps: (1) 4-desmethyldaunorubicin or derivatives of 4-desmethyldaunorubicin shown in general formula (II) are provided: In the formula, R ₁ includes H, and R ₂ includes trifluoroacetyl; (2) process 4-demethyldaunorubicin or 4-desmethyldaunorubicin derivatives represented by general formula (II) with a sulfonating agent comprising trifluoromethanesulfonic anhydride to form 4-tri Fluoromethylsulfonyl-3'-trifluoroacetylamino-4-desmethyldaunorubicin; (3) 4-trifluoromethanesulfonyl-3'-trifluoroacetylamino-4-demethyldaunorubicin reacts with a reducing agent in the presence of palladium acetate of a catalytic amount to obtain 4-demethoxy -3'-trifluoroacetylaminodaunorubicin; (4) hydrolyzing the 4-demethoxy-3'-trifluoroacetylamino daunorubicin in an alkaline solution to obtain idarubicin shown in general formula (I). 13. The method according to claim 12, characterized in that, idarubicin shown in general formula (I) comprises idarubicin hydrochloride.