TW200826947A - Method of producing anthracycline derivatives - Google Patents

Abstract

The present invention relates to methods of synthesizing anthracycline derivatives. Among other advantages, these methods offer simple and efficient manipulation of substituents on the sugar ring of anthracyclines. For example, the C-3' amino of such sugars may be protected such that alkylation of hydroxy positions, such as a C-4' hydroxy, may be regioselectively performed. These methods allow access to a variety of anthracycline derivatives, which may show antibiotic and/or anticancer activity.

Description

200826947 IX. DESCRIPTION OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention generally relates to the field of organic synthetic chemistry and anticancer agents. DETAILED DESCRIPTION OF THE INVENTION The method of the present invention provides an easy means of obtaining an anthracycline derivative: a method. In addition to being an antibiotic, an anthracycline is known to exhibit high antitumor activity and can be used as a chemotherapeutic agent. The methods discussed herein provide regioselective control of the functionalization of various positions on the onion ring. Thus, using these methods, different ranges of anthracycline derivatives can be produced. [Prior Art] A large number of antibiotics and other compounds used in the chemical method are glycosides whose glycosyl groups are shown as complex structures. In the case of an anthracycline antibiotic, the aglycone is a four-fold system containing hydroxyl, alkoxy and sulfhydryl substituents. An anthracycline antibiotic synthesized by an actinomycete such as (10) (for example, Streptomyces), such as a deoxypyranosyl group containing an L. configuration. 3-Amino-2,3,6-trideoxy-L -pipetamose is most often linked to aglycone by a samarium-sugar bond (for example, damosamine, acssamine, ristosamine) In the Confucian i: antibiotic group, new compounds in clinical trials are most often prepared from the results of multi-stage synthesis to obtain tetracyclic systems and sugar units. The key step in this production method is the formation of glycosidic bonds. This method allows for the acquisition of new anthracycline antibiotic analogs and candidate new drugs. See, for example, Grynkiewicz et al., 2002, and references cited therein. Regarding the manipulation of the natural anthraquinone: the sugar moiety, there is a lack of For the effective, regioselective control of the amine group 124529.doc 200826947 and the trans-substitution, for example, the complex structure of the compounds, the sensitivity of the compounds to the action of the acid, and the sensitivity and molecularity of the test There are many kinds of meridians in the middle, which makes it difficult to control In 1981, Cassinelli et al. reported an attempt to alkylate the C-4 of two different anthracycline sugar moieties. In both reactions, a mixture of & Among them, the product is a single-base product and the other product is a double-yard product. In fact, in the method, the target r; C·4' is not base-based. Previous attempts to manipulate the substituents of cyclamate have been frustrating. [SUMMARY] The present invention generally provides methods for obtaining an anthracycline derivative. In general, such methods allow manipulation of selected functionalities. The group does not interfere with the molecular group. In a particular embodiment, the functionality of the anthracycline sugar moiety can be specifically manipulated. In certain embodiments, the methods described herein allow the region to select 丨S. The hydroxyl group of the aglycone, such as an alkylated sugar ring, the basic hydroxy G also contains a C-3, an amine group that protects the sugar ring, and can promote subsequent = alkylation. These methods are also provided by (for example Avoid improper uranium and hydroxy group alkylation of Ό The total synthesis is carried out to produce a prior synthesis of the anthracyclines. In addition, these methods are more economical than, for example, total synthesis. It is found that any of the methods produced by the methods described herein include any The intermediate anthracyclines can be used as antibiotics, sputum intercalating agents' and/or anticancer agents and methods for their association. Thus, in certain embodiments, the invention encompasses the synthetic product anthracycline compounds The method comprises: protecting the first 124529.doc 200826947 C 徽 之 C-3, an amine group via a guanamine or a urethane, wherein the first anthracycline comprises c_3, an amine group and a C-4' Base; in the presence of an alkylating agent and a chlorinated hydrocarbon solvent, the base is [_ • 4 base, and the product anthracycline is obtained. The first anthracycline may be any anthracycline known to those skilled in the art. In certain embodiments, the first enantiomer is daunorubicin. As described below, a variety of protecting groups can be used to protect C_3, amine groups and those well known to those skilled in the art to immobilize such groups. In certain embodiments, the C-3, amine group is protected by a tris(fluoroethenyl, triethethoxy, chloroethyl, benzyloxycarbonyl, allyloxycarbonyl or butoxycarbonyl group) The alkylating agent is well known to those skilled in the art. In certain embodiments, the alkylating agent is a benzyl halide such as benzyl chloride, benzyl iodide or benzyl bromide. In certain embodiments The alkylating agent is an alkyl sulfonate or an aryl sulfonate such as mesylate, triflate, benzoate, 4-methylbenzenesulfonate or 4-nitro Benzene sulfonate. In some embodiments, the 'alkylating agent is benzyl sulfonate or benzyl phosphate _. In some of the methods described herein, the alkylation step can be carried out in the presence of a base. For example, the test may be a metal hydride such as sodium hydride, potassium hydride or calcium hydride. The base may be a non-nucleophilic organic base, examples of which are well known to those skilled in the art. In a particular embodiment, a non-nucleophilic organic base dBIJ. A variety of solvents can be used in certain processes of the invention. In certain embodiments, a gasified hydrocarbon solvent is used in, for example, an alkylation step. For example, chlorinated hydrocarbons The agent can be dichlorodecane or hydrazine, 2-dichloroethane. Other solvents that can be used in the alkylation step include DMF, DMS hydrazine, hydrazine methyl pyrrolidine self, HMpA or acetonitrile. In the middle, 帛-蒽 ring mycin contains the c_9 position of onion ring cyclamate 124529.doc 200826947 on the -C(0)CH3 group. In some methods of Tai Ba α, you can further manipulate this C (0) CH3 Group By way of example, a _c(〇)CH3 group can be converted to a _C(0)CH20H group via, for example, bromination followed by hydrolysis. The method described herein comprises a protected C. -3, the amine group and the alkylated C-4f are further reacted by the ruthenium and ring of the C- 4f to produce the product of interest 蒽 徽 。. For example, + δ ′ In addition, it contains de-blocking C-3' guanamine or guanidinium 舻 # π ® 曰. Right, then other substituents can be introduced into the C - 3 ' position. It can form during the synthesis of 蒽 蒽 专 专 专 η 京a variety of intermediates. In some embodiments, the method of the present invention can be used in the form of an intermediate form of the compound of the formula (1) during the synthesis. :

R1 is alkyl, aryl, aralkyl, decyl, alkoxy or aryloxy; wherein: R2 and R3 are each independently _Η, 〇Η or alkoxy; R4 is -Η, -ΟΗ , alkoxy or _; Υ and Υ are each independently a child of a double bond. Hard, σ 虱 atom, sulfur atom or nitrogen atom; 124529.doc 200826947 Z is -Η, -OH or sulfhydryl; R5 and R6 are each independently -Η, alkyl, aryl, aralkyl, decyl, alkoxy, aryloxy or -NR19R2G, wherein: R19 is -H, alkyl, aryl or aralkyl And R2G is a guanamine or urethane protecting group, the restriction condition is that R5 or R6 is -NR19R2G; R7 and R8 are each independently -Η or -OR21, wherein R21 is -Η, alkyl, aryl Or an aralkyl group, wherein the restriction is that at least one of R7 or R8 is -OR21; R9 is -Η, alkyl or aryl; and R1G, R11 and R12 are each independently -Η, alkyl, halogenated And -OR23, _SR23, -NH2, -NHR23, _N(R23)2, wherein R23 is -H, alkyl or aralkyl. Specifically, non-limiting examples of compounds that can be formed in the form of intermediates during the synthesis of the present invention include:

Nh2 124529.doc -9 200826947

OH NHR

BnO

NHR wherein R forms a guanamine or a urethane with a C-3'-NH group.

In certain embodiments, the C-4' hydroxyl group of the product anthracycline produced by the method of the present invention is hydroxyl or alkylated (to form a -OR group). In certain embodiments, the C-3' amine group of the product anthracycline is -NHR24, wherein R24 is -H, alkyl, aryl or aralkyl. The product anthracycline can also be a compound of formula (II):

R6 Ri2 wherein 124529.doc -10- (II) 200826947 R1 is alkyl, -COCH2R13 or -C(OH)-CH2R13, wherein: R13 is -Η, -OH, alkoxy, alkyl, aryl, seven c(〇)(CH2)pCH3 (where p = an integer from 1 to 20)...〇c(〇)(CH2)j(CH=CH)m(CH2)nCH3(wherein " is an integer between } and 3, ^ is an integer between 1 and 6, and η is an integer between 1 and 9), -0C(0)(CH2)rCH2NH2 or -〇c(〇)(CH2)rC02H (where r is 1 and 9) R and R are each independently -H, -OH or alkoxy; R4 is -H, -OH, alkoxy or halide; Y1 and Y2 are each independently a double bonded oxygen atom a sulfur atom or a nitrogen atom; Z is -H, -OH or an acid group; R is a succinyl group or an aryl group; and R, R and Rl2 are each independently Η, 炫, halide, -OR19, _SR19, _NH2, _NHR19, _N(R19)2, wherein R19 is -Η, alkyl or aralkyl; and or: (i) one of R5 and R6 is _Η, and one of R5 and R6 is X a -alkyl-aryl ring dAAr) substituent wherein: X is -N, -S, -SO or -S02; A is a burnt group;

Ar is a substituted 5-membered ring, a heteroatom 5-membered ring, a hetero atomic 6-membered ring or a substituted benzene ring of the formula: 124529.doc -11 - 200826947

Wherein: R14 to R18 are each independently Η, -OH, -N02, -NH2, _, an alkoxy group having -20 carbon atoms, an alkyl group having 1 to 20 carbon atoms, having 1-20 An aryl group, an alkylamino group, an alkylthio group, a cyano group, a sulfur group or a aryl group; and A is -(CH2)t-, wherein t=0-l〇; wherein, if R5 is -XAAr substituents wherein R6 is not a -XAAr substituent, and if R6 is a -XAAr substituent, then R5 is not a -XAAr substituent;

And R 7 and R 8 are each independently _H, alkyl, _, -OR19, -SR19, _Nh2, _NHRi9, -N(R19)2 or a saccharide, wherein 19 is an alkyl group or an aryl group; Or R7 and R8 are each independently _H, alkyl, _, OR19, -SR19, -NH2, -NHR19 or _N(R19)2' wherein R19 is _H 'alkyl or aryl; and 124529 .doc -12· 200826947 (ii) R5 and R6 are each independently -Η, alkyl, _,

-OR19, -SR, -NH2, _NHR19, _N(R19)2 or a saccharide wherein R19 is -Η, alkyl or aralkyl; one of R7 and R8 is Η; and one of R7 and R8 Is an X-alkyl-aryl ring dAAr) substituent, wherein: X is -0, -N, -S, -SO or -S02; A is a burnt group; and Γ. Αι is a substituted 5-membered ring, a hetero atom 5-membered ring, a hetero atom 6-membered ring or a substituted benzene of the formula

Wherein: R14 to R18 are each independently -Η, 〇Η, -N02, -NH2, a halide, an alkoxy group having 1 to 2 carbon atoms, an alkyl group having 1 to 20 carbon atoms, having 1· An aryl group of 20 carbon atoms, an alkylamino group, an alkylthio group, a cyano group, a thiocyano group or a fluorenyl group; and the hydrazine is -(CH2)t-, wherein t=0-10; 124529.doc -13 - 200826947 wherein R8 is not a -XAAr substituent if R7 is a -XAAr substituent, and R7 is not a -XAAr substituent if R8 is a -XAAr substituent; or R7 and R8 are each independently -Η, alkyl i, -OR19, -SR19, -NH2, -NHR19 or -N(R19)2, wherein R19 is -Η, alkyl or aryl. Specifically, non-limiting examples of the product anthracycline which can be produced by the method of the present invention include:

In any of the methods of the invention, the product anthracycline may additionally be included in a pharmaceutically acceptable composition. These compositions are described in more detail below. The product anthracycline may be administered or delivered to the target cell or may be administered to the subject. The product anthracycline is effective in treating a subject, such as by administering a dose of cancer 124529.doc -14-200826947 or a subject infected with a bacterium to produce a therapeutic benefit. The subject may also be susceptible to bacterial infection: the administration of the product onion cyclamate may provide prophylactic therapeutic benefits to the subject. When applied to a cell, the terms "contact" and "exposure" are used herein to describe a method of administering or delivering a compound of the invention to a target cell or placing the compound of the invention directly juxtaposed to a target cell. Cast,, and, pass " can be used interchangeably with ''contact' and 'exposure'. (., ί As used herein, the term 'effective' (for example, "effective amount,") means to achieve the desired, desired or desired result as appropriate. For example, "effective s therapeutic compounds" The amount (for example, is effective for re-inhibition to reduce, decrease, inhibit or otherwise eliminate cancer cell growth: or effective for treating bacterial infections). $双^ Τ 对=二之,,治:" means to the subject Or application to the therapeutic benefit of a procedure or physical illness or health-related condition for another person. Example = for obtaining a subject for a cancer or bacterial infection (eg, :: and... can cause The treatment comprising administering a compound of the invention. 4, such as a human milk spray animal), as the term is used throughout the application, the treatment refers to promoting or enhancing the medical condition of the subject regarding the condition = or + treatment effective" Anything in the system. This includes, but is not limited to, reducing the onset, frequency, or severity of a good condition. For example, the compound of the present invention with a symptom or symptom of + = can reduce the therapeutically effective amount. Can cure effectively The invention of the second invention "makes the tumor recipient to improve the infection, or delicious = infected with the bacteria to prevent bacterial infection. 124529.doc 200826947 (Example t::::: compound contains an effective amount - or A variety of candidate substances can be accepted as V: the additive of T. The handle group is more than the internal one, which means that the 嗝 嗝 A short σσ酉 music or pharmacologically connectable, 曰 right §, when the animal is administered For example, humans do not produce harmful, allergic or other adverse reactions. _2 familiar with this ¥ #I@ Μ According to this disclosure, the technicians will know the preparation of the medical group containing active ingredients. Shell or jaw

Seien... thing, as by ph_aceuticai

^ PHnti^ ^Pany? 1990 (., ^ is incorporated herein by way of example). Any of the limitations of the present invention-embodiments discussed with == can be applied to embodiments of the present invention. Furthermore, any of the compositions of the present invention can be used in any of the methods of the present invention, and any of the methods of the present invention can be used to produce or utilize any of the compositions of the present invention. Although the disclosure proves to be merely a substitute and a definition of "and/or", unless the term is not only a substitute or a substitute, but the term "or" is used in the patent application. Used to mean " and / or ". The term "term," is used throughout the application to indicate the value of the error standard deviation of the device and/or method used to determine the value. Unless otherwise specifically indicated, as used in this specification, One or more may be used. When used in conjunction with a word, including ", the word "a" as used in the scope of the present application may mean one or more. As used herein, the term "at least" The other objects, features, and advantages of the present invention will be apparent from the embodiments of the appended claims. Special examples are given only by way of explanation, as

Various changes and modifications of the spirit and scope of the present invention will become apparent to those skilled in the art. [Embodiment] The present invention provides a disadvantage of the prior art by providing a method capable of easily obtaining an anthracycline derivative. For example, the present inventors have discovered how to selectively modify p by converting (e.g., an amine or a carbamic acid § derivative) such that other positions of certain anthracyclines (especially unprotected by (iv) groups The position) is retained undisturbed and thus can be further modified. In certain embodiments, the substituted acid retardant (eg, trisodium acetate, ethyl difluoroacetate or benzyloxy carbonate) The action of the ester can be such that the corresponding acid amine can be obtained. The amino carboxylic acid can also be produced. In addition, the C-4' hydroxyl position such as the onion ring sugar can be used in the hydroxyl group of the anthracycline. The method discovered by the above is functionalized in a manner that is not complicated by selectivity (for example, alkylation). For example, benzyl bromide in the presence of a chlorinated hydrocarbon solvent such as methylene chloride can make selectivity C-4 in the alkylated sugar ring, hydroxyl group. The alkylation of the hexyl group makes it possible to further manipulate the other positions of the anthracycline and make it possible to rapidly prepare the medically applicable anthracycline. Suen cyclin has four sugars linked via glycosidic bonds Prime-ring structure. Such cytotoxic agents usually have a role in the role of electron-withdrawing agents and electron-preserving agents. Doxorubicin and daunorubicin are examples of such compounds. Compounds act by DNA insertion. Non-limiting examples of onioncycline include daunorubicin, doxorubicin, epirubicin 124529.doc • 17- 200826947 Pirubicin, idarubicin, Oralazine (py romycin), carbomycin (I)酉曰 酉曰 (for example, agglutinin 14_ acetate, doxorubicin guanidine-propionate, doxorubicin

Xin fee i曰 apron 14-benzoate and doxorubicin 丨 4 phenyl acetate), 4-episomycin, 4'_epimycin, 4'-iododano Neomycin, 4, iodine agglutinin, 4-deoxynomycin, 4, _ deoxynomycin, 3, hydroxydodone, s, 3, hydroxy doxorubicin, 4_ Demethoxy daunorubicin, 4-desmethoxy doxorubicin, 4'-e-deoxyoxynomycin and 4,-epi-4-demethoxy doxorubicin. Other anthracyclines are known in the art, such as those described in U.S. Patent No. 6,673,9 () No. 7, which is incorporated herein by reference in its entirety. The methods of the invention can be used in synthetic protocols to obtain certain of these and other known anthracyclines as well as novel anthracyclines. Furthermore, anthracyclines comprising (in female) C 4 hydroxy and c-31 amine groups are useful as synthetic starting materials in certain methods of the invention. Such starting materials are known by known synthetic methods or are commercially available from chemical trading companies such as Sigma-Aidrich (Milwaukee, WI). Β·Chemical definitions The term ''amino group π' means ΝΗ2; term, nitro, meaning Ν〇2 '5 术 吾 卤 或 或 或 或 或 或 或 或 或 或 表示 表示 表示 表示 表示 化学 化学 化学 化学 ' ' ' ' ' ' ' ' ' ' ' ' ' Or seven terms thiol '' or 'thiol' means _SH; the term "cyano" means _CN; the term, azido '' means _N3; the term, 矽alkyl, means -SiH; and the term, hydroxy, meaning -OH 〇 浯 alkyl" includes linear alkyl, branched alkyl, cycloalkyl (alicyclic), 124529.doc -18- 200826947 An alkyl group substituted without a hetero atom, an alkyl group substituted with a hetero atom, an alkyl group substituted without a hetero atom, and an iCn alkyl group substituted with a hetero atom. • In certain embodiments, a lower alkyl group is contemplated. The term "lower alkyl" refers to an alkyl group of 1 -6 • fluorene atoms (ie 1, 2, 3, 4, 5 or 6 carbon atoms). The term "Cn alkyl group which is not substituted with a hetero atom" means a group having a linear or branched, cyclic or non-% structure, and additionally has no carbon-carbon double bond or a bond, and additionally has a total of η One carbon atom (all non-aromatic), three or more hydrogen atoms and no hetero atom. For example, a C-C1G alkyl group which has not been substituted with a hetero atom has 1 to 10 carbon atoms. (Me), -CH2CH3(Et), _CH2CH2CH3 ... Ρ γ), _CH(CH3)2(/, pr), _ch (CH2 from cyclopropyl), -CH2CH2CH2CH3 (Bu), -CH(CH3)CH2CH3 (p. Dibutyl), -CH2CH(CH3)2 (isobutyl), -C(CH3)3 (tert-butyl), -CH2C(CH3)3 (neopentyl), cyclobutyl, cyclopentyl and The cyclohexyl group is a non-limiting example of an alkyl group which is not substituted with a hetero atom. Other such non-limiting examples of alkyl groups which are not substituted with a hetero atom include an old-CHr cyclopropyl-CHy ring. The term "Cn alkyl substituted by a heterologous I" refers to a group having a single saturated carbon atom as a point of attachment, a carbon-free carbon double bond or a bond, which additionally has a straight chain or a branch. Chain, ring or acyclic structure, in addition Has a total of 11 carbon atoms (all are non-aromatic), 0, 1 or more hydrogen atoms, at least one hetero atom 'where each hetero atom is independently selected from N, 〇, ρ, a group consisting of ci, Br, I, si, p, and s. For example, an alkyl group substituted with a hetero atom has 1 to 10 carbon atoms. The following groups are all non-limiting alkyl groups substituted with a hetero atom. Examples: trifluoromethyl, _CH2f, _CH2 汾, -ch2oh > .ch2〇ch3 ^ -CH2OCH2CF3 ^ -CH2〇C(〇)CH3 > 124529.doc 19 200826947 -ch2nh2 . -CH2NHCH3 ^ -CH2N(CH3 ) 2 ^ -CH2CH2C1 ^ -CH2CH2OH > -CH2CH2OC(0)CH3 ' -CH2CH2NHC02C(CH3)3 > -CH2Si(CH3)3 and -C(〇H)-CH2〇H. The term "aryl" includes A hetero atom-substituted aryl group, a hetero atom-substituted aryl group, a heteroatom-substituted Cn aryl group, a hetero atom-substituted Cn aryl group, a heteroaryl group, a heterocyclic aryl group, a carbocyclic aryl group, a aryl group An aryl group and a monovalent group derived from a polycyclic fused hydrocarbon (PAH). The term "Cn aryl group substituted without a hetero atom means a group having a single carbon atom as a point of attachment, wherein the carbon The sub-soil system contains only a portion of the aromatic ring structure of a carbon atom, which additionally has a total of _ carbon atoms, 5 or more hydrogen atoms, and no heteroatoms. For example, a C6_C1() aryl group substituted with no I heteroatom has 6 to 1 carbon atoms. Non-limiting examples of aryl groups which are not substituted with a hetero atom include phenyl (ph), methylphenyl, (dimethyl)phenyl, _c6H4CH2CH3, -C6H4CH2CH2CH3, _C6H4CH(CH3)2 > -C6H4CH (CH2 2 ^ -C6H3(CH3)CH2CH3 ^ -c6h4ch=ch2 . . . C6H4CH=CHCH3 > .C6H4C^CH ^ .C6H4C^ 3 π group and bionic self-biphenyl group. The term "C: aryl" substituted by a hetero atom means a group having a mono-aromatic carbon atom or a single hetero atom as a point of attachment, which additionally has a total of 11 carbon atoms and at least 1 hydrogen atom. And at least one hetero atom, wherein each hetero atom is independently selected from

From Ν, 〇, F, Cl, Br, I

A group consisting of Si, P, and S. For example, 1 to 10 carbon atoms. Examples of substituents include, but are not limited to, a Ci-Cig heteroaryl group which is not substituted with a hetero atom, such as, the aryl group may be substituted by two, three, four or five. ;) a sulfhydryl group, a nitro group, an amine group , a dentate, an alkoxy group, an aryl group, a thiol group, a thio group, a thio group, and a thiol group. Non-limiting examples of the aryl group substituted by the pyrogen 124529.doc -20·200826947 include the following groups: -C6H4F, -C6H4C1, -C6H4Br, _C6H4I, -C6H4OH, -C6H4OCH3, -C6H4OCH2CH3, -C6H40C(0) CH3, -C6H4NH2, -C6H4NHCH3, -C6H4N(CH3)2, -C6H4CH2OH, -C6H4CH20C(0)CH3, -C6H4CH2NH2, -C6H4CF3, -C6H4CN, -C6H4CHO, -C6H4CHO, -C6H4C(0)CH3, -C6H4C( 0) C6H5, -C6H4C02H, -c6h4co2ch3, -C6H4CONH2, -c6h4conhch3, -C6H4CON(CH3)2, furan

A thiol group, a thienyl group, a pyridyl group, a pyrrolyl group, a pyrimidinyl group, a pyrazinyl group, a quinolyl group, a fluorenyl group and an imidyl group. The term "aralkyl" includes aralkyl groups which are not substituted with a hetero atom, aralkyl groups which are substituted with a hetero atom, Cn aralkyl groups which have not been substituted with a hetero atom, Cn aralkyl groups which have been substituted with a hetero atom, and heteroaryl Alkyl and heterocyclic aralkyl. In certain embodiments, a lower arylalkyl group is encompassed. The term "lower arylalkyl group" is intended to have 7 to 12 carbon atoms (i.e., 7, 8, 9, 10, " or 12 carbon atoms) of aralkyl. The term "Cn aralkyl group which is not substituted with a hetero atom" means a group having a single saturated carbon atom as a point of attachment, and additionally has a total of n carbon atoms, wherein at least 6 rabbit atoms are derived from a aryl group containing only carbon atoms. Ring structure with 7 or more hydrogenogens: and no heteroatoms. For example, a 7 10 aryl group substituted without a hetero atom has 7 to 1 G carbon atoms. Aromatic alkyl groups which are not substituted with a hetero atom are non-limiting examples: phenylmethyl group, Βη) and phenylethyl group. $ 经 经 杂 杂 杂 杂 杂 杂 杂 杂 杂 杂 杂 cn cn cn cn cn cn cn cn cn cn cn cn cn cn cn cn cn cn cn cn cn cn cn cn cn cn cn cn cn cn cn cn cn cn cn cn cn Or more than one hydroquinone + β prematurely incorporated into ... and at least one hetero atom 'where at least one carbon atom is incorporated into the square bad structure, and the other ice atoms are independently selected from the group consisting of Ν, 124529.doc 200826947 a group consisting of 〇, F, C1, Br, Si, ?, and 8. For example, a heteroatom-substituted C2-C1G heteroarylalkyl group has 2 to 10 carbon atoms. • The term ''acid group, Including linear fluorenyl, branched fluorenyl, cyclodecyl, cyclic fluorenyl, fluorenyl group substituted with a hetero atom, fluorenyl group substituted with a hetero atom, cn fluorenyl group substituted without a hetero atom, Atom substituted Cn decyl, alkylcarbonyl, alkoxycarbonyl and aminocarbonyl. In certain embodiments, a lower fluorenyl group is encompassed. The term "low carbon fluorenyl" refers to a thiol group of U carbon atoms (also That is, 1, 2, (, 3, 4, 5 or 6 carbon atoms). The term "Cn thiol group substituted without a hetero atom" means having a carbonyl as a point of attachment a single carbon atom group, which additionally has a linear or branched, cyclic or acyclic structure, additionally has a total of 11 carbon atoms, 1 or more hydrogen atoms, a total of one oxygen atom, and no additional For example, a C1_C1G fluorenyl group substituted without a hetero atom has 1 to 10 gorges. -CHO, -c(o)ch3, -C(0)CH2CH3, -C(0)CH2CH2CH3, -C (0)CH(CH3)2 > -C(0)CH(CH2)2 . .C(〇)C6H5 ^ -C(0)C6H4CH3 ^ -C(0)C6H4CH2CH3 and -COC0H3(CH3)2 groups a non-limiting example of a fluorenyl group substituted without a hetero atom. The term cn thiol group substituted by a hetero atom means a group having a single carbon atom as a point of attachment (a carbon atom is a part of a carbonyl group), In addition, it has a linear or branched, cyclic or acyclic structure, and additionally has a total of n carbon atoms, one, one or more than one hydrogen atom, at least one additional in addition to the oxygen atom of several groups. a hetero atom in which each additional hetero atom is selected from the group consisting of N, 0, F, a, Br, Si, p^. For example, a heteroatom-substituted C1_C1G fluorenyl group has from 10 to 10 carbon atoms. ._c(o )ch2cf3, -C〇2h, _c〇2CH3, _c〇2CH2CH3, -C02CH2CH2CH3 > -C02CH(CH3)2,.C02CH(CH2)2 > -C(0)NH2 124529.doc -22- 200826947 (amine Mercapto), -C(0)NHCH3, -C(0)NHCH2CH3, -CONHCH(CH3)2, -CONHCH(CH2)2, -CON(CH3)2 and _C〇NHCH2CF3 groups are heteroatoms A non-limiting example of a substituted thiol group. The term ''alkoxy'' includes straight chain alkoxy, branched alkoxy, cycloalkoxy, cyclic alkoxy, alkoxy substituted without a heteroatom, alkoxy substituted with a hetero atom. a cn alkoxy group substituted with a hetero atom and a cn alkoxy group substituted with a hetero atom. In certain embodiments, lower alkoxy groups are contemplated. The term π lower alkoxy π means an alkoxy group of 1 to 6 carbon atoms (i.e., 1, 2, 3, 4, 5 or 6 carbon atoms). The term Cn alkoxy group as defined by π without a hetero atom refers to a group having the structure -〇R' wherein R is a Cn alkyl group which is unsubstituted by a hetero atom as defined above. Alkoxy groups which are not substituted by a hetero atom include: -och3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2 and -OCH(CH2)2. The term "heteroatom-substituted cn alkoxy" refers to a group having the structure -Ο R where R is a heteroatom-substituted cn alkyl group as defined above. For example, -OCH2CF3 is a heteroatom-substituted alkoxy group. The term π aryloxy '' includes aryloxy groups which are not substituted by a hetero atom, aryloxy groups which are substituted by a hetero atom, cn aryloxy groups which are not substituted with a hetero atom, cn aryloxy groups which are substituted by a hetero atom, and heteroaryl Oxyl and heterocyclic aryloxy. The term "Cn aryloxy group substituted with a hetero atom" means a group having the structure -OAr, wherein Ar is a Cn aryl group which is not substituted with a hetero atom as defined above. A non-limiting example of an aryloxy group substituted with a hetero atom is -〇C6H5. The term "Cn aryloxy substituted by a hetero atom" means a group having the structure -OAr, wherein Ar is a Cn aryl group substituted by a hetero atom as defined above. 124529.doc -23 - 200826947 The term "π-alkylamino" includes straight-chain alkylamino, branched alkylamino, cycloalkylamino, cyclic alkylamino, alkyl without a hetero atom Amino, - a heteroatom-substituted alkylamino group, a non-heteroatom-substituted cn alkylamino group - and a heteroatom-substituted Cn alkylamine group. In certain embodiments, a low stone reductane is contemplated. Amino group. The term "lower alkylamino" refers to an alkylamino group of 丨6 carbon atoms (ie, 1, 1, 2, 4, 5 or 0 carbon atoms). A heteroatom-substituted Cn alkylamine group means a group having a single nitrogen atom as a point of attachment (*, which additionally has one or two saturated carbon atoms bonded to a nitrogen atom, and additionally has a linear chain Or a branched, cyclic or acyclic structure containing a total of n carbon atoms (all non-aromatic), 4 or more hydrogen atoms, for a total of 1 nitrogen atom, and no additional heteroatoms. The alkylamino group substituted without a hetero atom has from ???one carbon atom. The term cn alkylamino group substituted without a hetero atom, includes A group of the structure NHR, wherein R is a G alkyl group which is unsubstituted with a hetero atom as defined above. The alkyl group which is not substituted with a hetero atom will include, _Nhch2CH3, c; -NHCH2CH2CH3^-NHCH (CH3 2 > -NHCH(CH2)2 > ^NHCH2CH2CH2CH3 ^ -NHCH(CH3)CH2CH3 ^ -NHCH2CH(CH3)2 ^ -NHC(CH3)3, _N(CH3)2, -N(CH3)CH2CH3, - N(CH2CH3)2, pyrrolidinyl and Ipiperidinyl. The term "heteroatom-substituted Cnalkylamino" means a group having a single nitrogen atom as a point of attachment, and additionally has 1 or 2 a saturated carbon atom attached to a nitrogen atom, having no carbon-carbon double bond or multiple bonds, additionally having a linear or branched, cyclic or acyclic structure, and having a total of 11 carbon atoms (all are non-aromatic , 0, 1 or 1 with a hydrogen atom and up to v 1 additional heteroatom (more precisely, except for the gas atom of the junction 124529.doc -24-200826947) where each additional heteroatom is independently A group consisting of N, q, F, CM, Br, I, Si, P, and S. For example, a pyridyl group substituted with a hetero atom has 1 to 10 carbon atoms. A heteroatom-substituted Cn alkylamino group '' includes a group having the structure _nhr, wherein R is a cyano group substituted by a hetero atom as defined above. ''includes linear amidine, branched guanamine, cyclodecylamino, cyclic guanylamino, guanamine group without heteroatom, amide group substituted with heteroatom, without heteroatom substitution G amide, heteroatom-substituted cn amide, alkylcarbonylamino, arylcarbonylamino, alkoxycarbonylamino, aryloxycarbonylamino, decylamino, alkylamine Alkylamino group, arylaminocarbonylamino group and urea group. The term "Cn amidino group substituted with a hetero atom" means a group having a mono-nitrogen atom as a point of attachment, and additionally having a bond to a nitrogen atom via a carbon atom, and having a straight chain or a branched chain, Cyclic or non-%, , σ, additionally having a total of 11 carbon atoms, one or more hydrogen atoms, a total of 1 oxygen atom, a total of (10) nitrogen atoms, and no additional heteroatoms. For example, 5, a C1_C1G fluorenylamino group substituted without a hetero atom has a 醯 醯 amino group substituted to 10 carbon atoms without a hetero atom, including a group having a structure R, wherein the term is as defined above. C" group substituted without a hetero atom. • The Cong (q) CH3 group is a 14-membered mantle made of non-heteroatom-substituted aramid (9). The side of the molecule, which is substituted by a hetero atom, refers to a group having a mono-nitrogen atom as a point of attachment, and has a (a) group attached via a carbon atom = a mouse atom, and has a straight chain or a branch. Chains, rings, or #3 have a total of § ten n aromatic or non-aromatic carbon atoms, one, one, or one, with at least one additional hetero atom (except for a few extra atoms) a group of additional heteroatoms independently selected from the group consisting of N, 〇, ρ, i Sl? and s. For example, after substitution with a hetero atom, The guanamine group has a carbon atom. The term "Cn oxime group substituted by a hetero atom" includes a group having a structure-dirty, and the term "Non-atom atom-like" is used as defined above. (3) The base group is a non-limiting example of a heteroatom-substituted amidino group. The protecting group as described herein may also comprise a guanamine such as (4) to protect the amine group.

The term "alkylthio" includes straight-chain thiol, tetrakisylthio, cyclodextylthio, cyclo (tetra)thio, non-heteroatom-substituted alkylthio, hetero atomic A sulfur group, a non-atom-substituted thio group, and a hetero atom are substituted. Alkylthio group. In certain embodiments, a low carbon alkylthio group is contemplated. The term "low carbon alkylthio" refers to an alkylthio group of (1) carbon atoms (i.e., 1, 2, 3, 4, 5 or 6 carbon atoms). The term "non-heteroatom-substituted decylthio" refers to a group having the structure _SR wherein r is as defined above and the Cn alkyl-scH3 group is unsubstituted with a hetero atom. An example of an alkylthio group substituted with a hetero atom. The term "Cn alkylthio group substituted by a hetero atom" means a group having the structure _SR, wherein r is a heteroatom-substituted G alkyl group as defined above. The compound of the invention may contain one or more Asymmetric centers and thus may exist as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomeric forms. In some embodiments, there is a single Diastereomers. All possible stereoisomers of the compounds of the invention are encompassed within the scope of the invention. However, in certain aspects, specific diastereomers are encompassed. The center of the palm may have 124529.doc •26-200826947 as defined by IUPAC 1974 Recommendati〇ns. In some aspects, certain compounds of the invention may contain a specific carbon core. Modifications or derivatives of the compounds, agents and active ingredients disclosed throughout this specification are encompassed by methods and compositions suitable for use in the present invention, as known to those skilled in the art. Method Injury derivatives and needles; their desirable properties to characterize the derivative. In some instances, "derivative" refers to a chemical modification that retains the desired effect of the compound prior to chemical modification. The compound, therefore, the anthracycline derivative can be referred to as a chemically modified compound that retains the desired effect of the parental onion cyclamycin prior to chemical modification of the anthracycline. These effects may be enhanced (eg 'slightly more effective, twice as effective, etc.) or weakened (eg, slightly less effective, less effective 2 times, etc.), but may still be considered as ringworms (4) organisms. An anthracycline derivative having the same activity or action as the onion cyclamycin: Of course 'the derivatives may exhibit opposite effects. For example, the derivative may be added, removed or substituted - or on multiple parent molecules Chemical moieties. Non-limiting examples of modifications that can be made to the types and structures disclosed herein include the addition or removal of low carbon unsubstituted alkyl groups such as methyl, ethyl, or propyl or such as hydroxymethyl. Or aminomethyl substituted Carbon group; slow base and ruthenium; warp group; stone base, amine group, decylamine and azo group; sulfuric acid base, 4 acid m base, sulfhydryl group, sulfhydryl group, stone wind base, squamous acid purpose & , phosphonic acid groups, fluorenyl groups, and amide substituents. Additional modifications may include the addition or removal of one or more atomic framework atoms, for example, propyl substituted ethyl; from larger or smaller aromatic groups Substituted phenyl. Or, 124529.doc -27- 200826947 In a bad or bicyclic structure, a hetero atom such as N, s or hydrazine can be substituted into the structure instead of a carbon atom. Methods for purifying the compounds of the invention will be well known. It will be apparent to those skilled in the art that the compounds of the invention can generally be purified in any step, including purification of the intermediates and purification of the final product. In some of the examples, purification is carried out by means of Shixi gum column chromatography, HPLC or crystallization. The anthracycline prepared by the method of the present invention may be a prodrug and/or a solvate. As used herein, the term "prodrug" is understood to mean a compound that is chemically converted by metabolic or chemical means to produce any of the formulae, or a salt thereof and/or a solvent, when administered in a mammalian or dual manner. Compound (5) '1991; Bundgaard, Cong) compound. The invention

The solvate of the compound is preferably a hydrate. X An anthracycline prepared by the method of the present invention may contain - or a plurality of commercially acceptable salts. The term "pharmaceutically acceptable = salt," as used herein, refers to a therapeutically acceptable salt of a compound of the invention that is substantially non-toxic to living organisms, including those dependent on the presence of the present invention. The substituents in the compounds are prepared by reacting the compound of the present invention with an inorganic or organic acid, or by a reaction. The examples which can be used for the preparation of a pharmaceutically acceptable salt include: hydrochloric acid, phosphoric acid, a...6 (4) Manufactured shellfish and bean noodles, sulphuric acid, hydroiodic acid, phosphorous acid and similar yttrium. It can be used to prepare organic examples including: aliphatic monocarboxylic acid 1 σ salt Acid ^ ^ ^ Carboxy i, such as oxalic acid, carbonic acid, citric acid, succinic acid, _ lean from ^ 4 butadiene, earth-heteroatom substituted alkanoic acid, aliphatic and aromatic sulfur 124529.doc -28- 200826947 Acids and similar acids. Thus pharmaceutically acceptable salts prepared from inorganic or organic acids include hydrogenates, hydrobromides, nitrates, sulfates, pyrosulfates, hydrogen sulfates, sulfites, Hydrogen sulfate, phosphate, mono-hydrogen phosphate, dihydrogen phosphate, partial phosphorus Acid salt, pyrophosphate, hydroiodide, hydrofluoride, acetate, propionate, formate, oxalate, citrate, lactate, p-toluenesulfonate, methanesulfonate And maleic acid salts and the like. The pharmaceutically acceptable salts include the carboxylate or sulfonate groups visible in the compounds of the invention and inorganic cations such as sodium, potassium, ammonium or calcium or the like a salt formed between an organic cation of isopropylammonium, trimethylammonium, tetramethylammonium and imidazole rust. It is recognized that the formation of a particular anion or cation of a portion of any of the salts of the present invention is generally not critical, as long as the salt as a whole It is pharmaceutically acceptable. The additional examples of pharmaceutically acceptable salts and methods for their preparation and application are described herein by reference. (4) (10) Moxibustion <

Pharmace^tical Salts: Properties ^ Selection and Use{V. H. Stahl & C. G. Wermuth, Verlag Helvetica (5) (6) Acta, 2002) 〇 The term "saccharides" includes oxidized, reduced or substituted saccharides. The saccharides of the present invention include, but are not limited to, ribose, arabinose, xylose, lyxose, allose, ahrose, glucose , mannose, fructose, glucose, idose, galactose, talose, ribulose, sorbose, tagat〇se, gluconic acid, glucose Aldehydic acid, gluconic acid, iduronic acid (idur〇nic 124529.doc •29-200826947 acid), rhamnose, trehalose, N-ethyl glucosamine Amino sugars, N-ethyl thioglycolic acid, sialic acid, &, such as acetals, amines and phosphorylated sugars, oligosaccharides, and various open-chain sucrose derivatives of sucrose and Its analogues. The term "nucleophile" or "nucleophilic" as used herein generally refers to an atom with a lone pair of electrons. These terms are well known in the art and include seven h, a thiol, a carbon anion, and a hydroxyl group. .

As used herein, the term "leaving group" generally refers to a group that can be readily replaced by a nucleophile such as an amine, alcohol or thiol nucleophile. Such leaving groups are well known and include carboxylic acid esters. , N-hydroxysuccinimide, N-hydroxybenzodiazepine, difluoromethanesulfonate, tosylate, mesylate, alkoxy, thioalkoxy and the like. When the chemical reaction is carried out selectively on one of the reactive sites or the official b-group of the polyfunctional compound, the other reactive sites must be temporarily blocked. As used herein, the t H-based system is used for the purpose. A group for the purpose of temporarily blocking. During the synthesis of certain compounds of the present invention, various functional groups must generally be protected with a protecting group (or a protecting agent) in each step of the synthesis. The base should remain unprotected. The term "functional soil& is the art of how to classify chemically reactive groups. Examples of functional groups include trans-amines, amines, thio-chlorides, amines, and rebellions. Base, base, etc. for each of these types of functional groups Preservation of protection: In a method of the present invention, 'special coverage of anthracycline, which may contain - or more than one sulfhydryl group. 124529.doc -30- 200826947 There is a large amount of familiarity with this technique for the placement of protecting groups. Methods well known to those skilled in the art for their reactivity, placement and use, see, for example, Greene and Wuts, incorporated herein by reference in their entirety.

The 1 999 ° protecting group acts to protect one or more functional groups (eg, -NH2, -SH, -COOH) during subsequent unsuccessful reactions due to the freedom (in other words, 'unprotected') functional groups. It will react and functionalize in a manner that is inconsistent with its need for subsequent reactions, or free functional groups will interfere with the reaction. The same protecting group can be used to protect one or more of the same or different functional groups. Different protecting groups can also be used to protect the same type of functional groups of a single compound in multiple steps. When the protecting group is no longer needed, it is emptied by methods well known to those skilled in the art. For deprotectors and their uses, see for example,

Greene and Wuts, 1999. The agent used to remove the protecting group is sometimes referred to as a deprotecting agent or a deblocking agent. The protecting group must be readily removable by the use of deprotecting agents known to those skilled in the art (as known to those skilled in the art). It is well known that certain deprotecting agents remove certain protecting groups and are not other groups, while other deprotecting agents remove multiple protecting groups from various types of functional groups. Thus, the first deprotecting agent can be used to remove one type of protecting group, followed by a second deprotecting agent to protect the group, and the like. The makeup protection base of Li (4) is familiar with π α. See for example,

Greene and Wuts, 1999, Chapter 7. In some examples of the sinus sinensis, the amine protecting groups which can be used in the process include, for example, a third butoxy group, a fluorenyloxy group, a decyl group, a trityl group, a group, and a triethylene acetyl group. 124529.doc -31· 200826947 base, two gas ethyl, gas ethane, trifluoroethenyl, difluoroacetinyl, fluoroethane, chloroformate, 4-phenyloxycarbonyl, 2_Methyloxycarbonyl: 1·^oxyoxyl group, 4-fluorooxyl group, 4·chlorooxyl group,

C:::porous carbonyl, benzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl, 4-bromoindole, 3-aminooxy, 4-nitrooxyl, 4- Cyanoyloxy, 2-(4-biphenyl)isopropoxy, i-diphenylethyl, "oxycarbonyl", 1,1-diphenylpropyloxycarbonyl, 2_ Phenylpropan-2-yloxycarbonyl, 2-(p-f-benzoyl)propan-2-yloxy, cyclopentyloxy benzyl, methylcyclopentyloxy , cyclohexyloxymethyl, L-methylcyclooxymethyl, 2.methylcyclohexyloxy, 2. (tolylmethyl fluorenyl) ethoxylated, 2-(methyl Further thiol) ethoxy group, 2_(triphenyl sulfene) oxycarbonyl methoxycarbonyl, 2-(trimethyldecyl) ethoxycarbonyl, allylicylcarbyl, i (trimethyl Basestone, methyl propyl oxycarbyl, 5-phenylindoleisocarbenyl, methoxycarbonyl, 4 ethoxylated oxycarbonyl, 2,2,2-trichloroethoxy Base, 2_B-radyl-2•propoxyl group, cyclopropylmethaneoxyl group, 4_(fluorenyloxy)oxyl group, isobornyloxym group, ^nooxyl group and base 9_D-methyl carbonate In certain embodiments of the invention, the amine protecting group is a third Toxy group. - 2· Solvents Solvent selection for the method of the invention may be, for example, which will facilitate dissolution of the reagent or (9) as) It is highly advantageous to promote the desired reaction (especially when θ is known). For example, the solvent may include: polar = solvent and non-polar solvent. Solvent selection includes, but is not limited to, tetrahydrofuran, monomethyl &amine, methanesulfoxide, dioxane, methanol, ethanol, hexane, 124529.doc -32 - 200826947 - methane, dichloromethane and acetonitrile. For any particular reaction or purification procedure, 'optional one' The above solvents may also be mixed into any solvent selection. Additionally, water such as distilled water may be used in place of the solvent to form the reaction medium. In certain embodiments, the chlorinated hydrocarbon solvent is used in certain steps of the methods discussed herein. Medium, such as C-4, -0H alkylation step. Non-limiting examples of chlorinated hydrocarbon solvents include dichloromethane, dichloroethane, and methylene chloride. In certain embodiments ,add The addition of a chlorinated hydrocarbon solvent promotes an alkylation step that improves yield and/or minimizes by-product yield. In light of the above definition, other chemical terms used throughout the application can be readily understood by those skilled in the art. Used alone or in any combination thereof. C. Examples include the following examples to illustrate certain preferred embodiments of the invention. Those skilled in the art will appreciate that the technical representations disclosed in the examples below are discovered by the inventors. Techniques that have a clear function in practice, and thus may be considered to be a preferred mode of practice. However, it will be apparent to those skilled in the art from this disclosure that many variations can be made in the particular embodiments disclosed and still The same or similar results can be obtained without departing from the spirit and scope of the invention. Example 1 Synthesis of 3_N-trifluoroethylidene _4·〇-benzyl daunrolin: (8S)-10-(2R,4R,5SM_trifluoroacetamidoaminotetrahydro-5- benzyloxy _6_Methyl-: 2H-pyran-2-yloxy)-8-ethenyl_7,8,9,1〇_tetrahydro-6,8 η·= 124529.doc -33- 200826947 Hydroxyl _1_methoxy 幷tetraphenyl _5,12_dione

Production of 3_N_trifluoroethylidene daunorubicin Daunromycin (1 g) was dissolved in methanol (4 mL) in a 25 mL flask. Triethylamine (0.6 mL) and ethyl trifluoroacetate (〇_6 mL) were introduced into the flask. ζ) The contents of the flask were agitated and the progress of the reaction was monitored (TLC analysis, gas/methanol/ammonia = 85/1 5/1). After completion of the reaction (about 1 h), the mixture was subjected to a rotary vacuum and the residue was dissolved in chloroform (20 mL), washed with 1 N aqueous hydrochloric acid and then neutralized with water. The gas imitation solution was dried over sodium sulfate, the desiccant was removed and the filtrate was evaporated under reduced pressure. The residue was dissolved in sputum 〇 mL) and the product was immersed in a house (20 mL). The product obtained (3_N-monofluoro-branched daunorubicin) was chromatographed and used in an additional step, such as in the synthesis discussed below. (Production of 3 - Ν - 二气乙牛- 4'·0· 基 达诺诺mycin dissolves 3,-Ν·trifluoroethyl hydrazinomycin (4.7 g; 7.5 mm 〇1) In dimethylformamide (47 mL), after cooling to temperature, add sodium nitride (4.5 g) and transfer the contents for several minutes. Add the base (1)·4 red) and the second gas. A hospital (1) 0 mL). Continuously for 2 h, maintaining temperature for generations. The reaction mixture is treated with aqueous acetic acid to reach a neutral pH, washed with water (m.), diluted with two gas (H) () mL), dried with sodium sulfate, and the solvent is removed after removal of the desiccant. Evaporation in a rotary vacuum evaporator. The residue was dissolved in 124529.doc -34 - 200826947: di-methane (2 mL) and the product was precipitated with hexane. The obtained product was purified by chromatography using a mixture of hexanes of acetic acid which was gradually increased in the amount of ethyl acetate. 1.5 g of the title compound were obtained (yield: 28%). The resulting compound may be an intermediate product for the production of doxorubicin derivatives, such as the following synthetic 4_〇-benzyl doxorubicin:

Cool down the solution of 3,_N-trifluoroethylidene daunorubicin (5〇g, 8〇2 surface in DMF (2G() mL) and add sodium hydride (60% in mineral oil) Dispersion) (1.2 m. Bu 48 g). After a very short transfer time, add the benzyl bromide (143 mL) to the methylene chloride (嶋mL) with the stirring of an overhead mechanical stirrer. The solution in the middle. With the continuous mechanical mixing, the cold bath was removed and the reaction mixture was allowed to warm to the foot temperature. The progress of the reaction was monitored by a rubberized sheet (5:1 toluene: acetone as a dissolving agent). After hr, the reaction mixture was cooled to _ 18. 〇 and then neutralized with a separately prepared dilute acetic acid (68 mL) solution. The obtained phase was separated and the organic phase was washed with water until neutral and dried over sodium sulfate. The desiccant was removed from the hydrazine and the solvent and the filtrate were concentrated in vacuo to give a residue. The residue was dissolved in dichloromethane (10 mL) and the crude product was precipitated from hexane. Subsequently, using column chromatography (4) Glue 6G) (with dichlorocarbyl, followed by 124529.doc -35-200826947 A-burn): C § Tongzhi, 曰人的粗solid:: (98: 2 and 95: 5) as a dissolving agent) the product was cut away from the slab. 17.2 g of pure product were obtained (yield 3 〇. 2%).氺氺氺氺*本氺氺*本氺氺氺氺氺氺氺氺氺氺氺氺氺氺 According to the contents of this disclosure, 实验 实验 实验 g g g g a a a a a a a a a a 主张 主张 主张 主张 主张 主张 主张 主张 主张 主张The present invention has been described with respect to the present invention, and the methods and apparatus disclosed herein are described in the context of the preferred embodiments. Step or step sequence;

= will become obvious '^ from the concept, spirit and percentage of the invention. More specifically, 'when the same or similar results are achieved, certain agents that are chemically and physiologically related may be substituted for the agents described herein will be changed'." All such similar substitutes and modifications are to be understood as being within the spirit, scope and concept of the appended claims. The following references are hereby incorporated by reference in their entirety An exemplary procedural or other detailed supplement is expressly incorporated herein by reference. U.S. Patent No. 6,673,907 to Polish Patent Application No. P 380,561

Bundgaard, H. ’ Design of Prodrugs, pp. 7-9, pp. 21-24, Elsevier, Amsterdam 1985.

Bundgaard ^ Drugs of the Future ^ 16:443-458 , 1991 〇 Cassinelli, G. et al., European Patent Application DE-EP 2251A (August 13, 1981) 〇 124529.doc -36- 200826947

El Khadem, ed. ''Recent Developments in the Chemistry of Doxorubicin-related anthracyline glycosides'', Academic Press, 1982 o Greene and Wuts, Protecting Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, Inc., 1999.

Grynkiewicz et al., Wiadomosci Chemiczne [Journal of Polish Chemical Society], 56: 536-560, 2002 o Remington's Pharmaceutical Sciences, 18th ed., Mack Printing Company, 1990 〇

Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Verlag Helvetica Chimica Acta, 2002 o 124529.doc -37-

Claims (1)

200826947 X. Patent application scope: 1 - A method for synthesizing a product of an encyclomycin compound, comprising: a) protecting C-3, an amine group of the first anthracycline via a guanamine or a urethane Wherein the first anthracycline comprises C-3, an amine group and a C-4, a hydroxyl group; b) alkylating the C-4, a hydroxyl group in the presence of an alkylating agent and a chlorinated hydrocarbon solvent; and c) The product anthracycline was obtained. 2. The method of claim 1, wherein the first anthracycline is daunorubicin. (3) The method of claim 1, wherein the C-3, the amine group is Protected by a fluoroacetyl protecting group, a trichloroethenyl protecting group, a chloroethylhydrazine protecting group, a benzyloxycarbonyl protecting group, an allyloxycarbonyl protecting group or a butoxycarbonyl protecting group. The method of claim 4, wherein the alkylating agent is a benzyl halide. 5. The method of claim 4, wherein the benzyl iota is benzyl, benzyl & moth or benzyl bromide. The method of item 1, wherein the alkylating agent is an alkyl sulfonate or an aryl group I. 7. The method of claim 6, wherein the sulfonate is mesylate or trifluoromethane Acid S, benzenesulfonate, 4-methylbenzenesulfonate or 4-nitrobenzenesulfonic acid m ° 8 · The method of claim 1, wherein the alkylating agent is benzyl sulfate or phosphoric acid The method of claim 1, wherein the alkylation is carried out in the presence of a base 124529.doc 200826947. The method of claim 9, wherein the base is a metal hydrogenation The method of the method of claim 10 wherein the metal hydride is sodium hydride, hydrogenation, hydrogenation or hydrogenation. 12. If the method of claim 9 is used, the test is a non-nucleophilic organic base. The method of claim 12, wherein the non-nucleophilic organic base is DBU. The method of claim 1, wherein the chlorinated hydrocarbon solvent is di-methane or hydrazine, 2-dichloroethane. The formula of the formula i, wherein the alkylation occurs further in the presence of F, DMS, N-methylpyrrolidinium, HMpA or acetonitrile. The first anthracycline comprises a group at the C-9 position of the anthracycline. 17. The method of claim 16, which additionally comprises converting the _c(〇)CH3 group to -C(〇 a CH2OH group. 18. The method of claim, which additionally comprises deblocking the c_3, the amine or the urethane. 1 9. The method of claim 1 further defines/疋 I am during the synthesis Method for forming a compound of formula (I) as an intermediate: 124529.doc 200826947 Y1 R2 Ζ Κ^Τ R6 r!2 where: R1 is alkyl, aryl, aralkyl, alkoxy or aryloxy R2 and R3 are each independently _H, -〇H or alkoxy; and soil R4 is -Η, ΟΗ, alkoxy Or a halide; Υ1 and Υ2 are each independently a double bond oxygen atom, a sulfur atom or a nitrogen atom Ζ is -Η, -ΟΗ or fluorenyl; each independently is _H, m group, aryl (tetra), aryl, alkoxy a aryloxy group or an NR19R2 fluorene wherein: R19 is -H, alkyl, aryl or aralkyl; and R is a capracin or carbamate protecting group, the limitation of which is R5 or R6 is - NR19R20; R7 and R8 are each independently _H or -OR2丨, wherein R2丨 is _H, alkyl, aryl or aralkyl, with the proviso that at least one of R7 or R8 is -OR21; R9 Is -Η, alkyl or aryl; and R 1 〇, " 12 , R and R are each independently _H, alkyl, halide, _〇r23, •SR23, -NH2, -NHR23, -NCR2 , wherein R23 is 124529.doc 200826947 - hydrazine, alkyl or aralkyl. 20. The method of claim 1, further defined as a method of forming any one or more of the following compounds as intermediates during the synthesis: NHCOCF3 NHCOCF3 Wherein R forms a decylamine or an amino decanoate having a C-3'-NH group. 21. The method of claim 1, wherein the C-4f hydroxyl group of the product anthracycline is hydroxyl or alkylated. 22. The method of claim 1, wherein the C-3' amine group of the product anthracycline is -NHR24, wherein R24 is -H, alkyl, aryl or aryl. The method of claim 1, wherein the product anthracycline is a compound of formula (II): Y1 r2 z Wherein: R1 is alkyl, -COCH2R13 or -C(OH)-CH2R13, wherein: R13 is -OH, alkoxy, alkyl, aryl, _〇c(〇)(CH2)pCH3 (wherein an integer from P = 1 to 20), -〇c(Q) (CH2)j (CH= CH)m(CH2)nCH3 (where j is an integer between 1 and 3, m is an integer between 1 and 6 and η is an integer between 1 and 9), _0C(0)(CH2)rCH2NH2 or - 〇c(〇) (CH2)rC〇2H (where r is an integer between 1 and 9); R2 and R3 are each independently -H, -OH or alkoxy; R4 is -H, -OH, alkane Oxygen or halide; Y1 and Y2 are each independently a double bond oxygen atom, a sulfur atom or a nitrogen atom; ', Z is -H, -OH or a stilbene group; R9 is -H, an alkyl group or an aryl group; R11 and R12 are each independently _H, alkyl, halide, 124529.doc c 200826947 -OR19, _SR19, _NHR19, _N(R19)2, wherein R19 is -H, alkyl or aralkyl; (i) One of R5 and R6 is -Η, and one of R5 and R6 is an X-alkyl-aryl ring dAAr) substituent, wherein X is -N, -S, -SO or - S02 ; A is a burnt base, and Ar is a substituted 5-membered ring, a heteroatom 5-membered ring, a hetero atomic 6-membered ring or a substituted benzene ring of the following formula. among them: R14 to R18 are each independently _H, _〇H, -N〇2, ΝΗ2, _, an alkoxy group having 1 to 20 carbon atoms, an alkyl group having 1 to 20 carbon atoms, having 1 An aryl group of -20 carbon atoms, an alkylamino group, an alkylthio group, a cyano group, a thiocyano group or a fluorenyl group; and hydrazine is -(CH2)t- (where t=0-10); R5 is a -XAAr substituent, then R6 is not a -XAAr substituent, and if R6 is a _XAAr substituent, then R5 is not a -XAAr substituent; and 124529.doc 200826947 R7 and R8 are each independently Η, alkyl, _, - R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R , halide, -OR19, -SR19, -NH2, -NHR19, _N(R19)2 or a saccharide 'wherein Rl 9 is -Η, alkyl or aralkyl; one of R7 and R8 is Η; One of R7 and R8 is an alkyl-aryl ring dAAr) substituent wherein: X is -Ο, -N, -SO or -S02; A is a burnt group; and Ar is a substituted 5 of the formula Member ring, heteroatom 5 member ring, hetero atom 6 member ring or substituted benzene ring: Wherein: R14 to R18 are each independently -Η, ·〇η, -N02, _NH2, ii, an alkoxy group having 1-20 carbon atoms, and a calcining group having 1-20 124529.doc 200826947 carbon atoms An aryl group having 1 to 20 carbon atoms, an alkyl group, a sulfur-burning group, a cyano group, a thiocyano group or a fluorenyl group; and hydrazine is -(CH2)t_ (where t=0-10); If R7 is a -XAAr substituent then R8 is not a -XAAr substituent, and if R8 is a -XAAr substituent then R7 is not a -XAAR substituent. 24. The method of claim 1, wherein the product anthracycline is selected from the group consisting of: 25. The method of claim 1, wherein the product anthracycline is additionally included in a pharmaceutically acceptable composition. 124529.doc 200826947 VII. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbolic symbol of the representative figure is simple: 8. If there is a chemical formula in this case, please reveal the best indication of the characteristics of the invention. Chemical formula: Y1 R2 Z R6 r12 (II) 124529.doc -4-