HK1064053B - Process for phase transfer catalyzed glycosidation of an indolopyrrolocarbazole - Google Patents

Description

Phase transfer catalyzed glycosidation of indolopyrrolocarbazoles

Background

The present invention relates to a novel glycosidation process for the preparation of intermediates useful in the preparation of indolopyrrolocarbazole derivatives which inhibit the growth of tumor cells and are therefore useful in the treatment of cancer in mammals and the like.

In the field of cancer chemotherapy, a large number of compounds have been used as antitumor agents. However, there is still a need to develop more effective compounds against various tumors (see Japanese cancer society 47 th proceedings of the exemplary Association, pp. 12-15 (1988)). This need has led to the development of indolocarbazole derivatives (see U.S. Pat. Nos. 4,487,925; 4,552,842; 4,785,085; 5,591,842 and 5,922,860; Japanese patent No. 20277/91; Journal of antibiotics, Vol. 44,723 and 728 (1991); WO 91/18003; WO 98/07433; and EP 0545195A 1). These compounds all exhibit topoisomerase inhibitor action and are therefore useful in the treatment of Cancer (Cancer chemother. pharmacol.34 (suppl): S41-S45 (1994)).

Because of the success of these compounds in treating various cancers, there is a need to develop improved synthetic methods for them. (see Bioorg & Med. chem. letters 2000, 10, 419; Tetrahedron 1997, 53, 5937; Tetrahedron 1997, 53, 585; and Synthesis1976, 414). However, the prior art processes still suffer from various problems including the use of undesirable solvents, mercury or silver salts, low yields and the formation of unwanted by-products requiring lengthy and cumbersome purification steps.

It is therefore an object of the present invention to provide a new route for the preparation of intermediates useful in the preparation of indolopyrrolocarbazole-derived antitumor substances while overcoming the problems inherent in the prior art synthesis.

Brief description of the invention

The present invention is a novel glycosidation process for the preparation of intermediates useful in the preparation of indolopyrrolocarbazole derivatives which inhibit the growth of tumor cells and are therefore useful in the treatment of cancer in mammals and the like, such as those represented by formula I below:

detailed description of the invention

One embodiment of the present invention is illustrated by a process for preparing a compound of formula I:

in the formula:

q is O, N-R, S or CH₂；

X¹And X²Independently selected from;

1)H，

2) the halogen(s) are selected from the group consisting of,

3)OH，

4)CN，

5)NC，

6)CF₃，

7)(C＝O)NO₂，

8)(C＝O)C₁-C₆an alkyl group, a carboxyl group,

9)(C＝O)OC₁-C₆an alkyl group, a carboxyl group,

10)OCH₂OCH₂CH₂Si(CH₃)₃，

11)NO₂，

12) 9-fluorenylmethylcarbonyl

13)NR₅R₆，

14)OC₁-C₆An alkyl group, a carboxyl group,

15)C₁-C₆an alkyl group, a carboxyl group,

16)C₁-C₆alkylene aryl, and

17)OC₁-C₆an alkylene aryl group;

r and R¹Independently are:

1)H，

2)(C＝O)C₁-C₆an alkyl group, a carboxyl group,

3)(C＝O)CF₃，

4)(C＝O)OC₁-C₆an alkyl group, a carboxyl group,

5) 9-fluorenylmethylcarbonyl group which is substituted,

6) a furanosyl radical, or

7) A pyranosyl group,

provided that R and R¹One is furanosyl or pyranosyl;

R²and R³Independently is OH or H, or

R²And R³Together form an oxo group;

R⁴comprises the following steps:

1)H，

2)C₁-C₁₀an alkyl group, a carboxyl group,

3)CHO

4)(C＝O)C₁-C₁₀an alkyl group, a carboxyl group,

5)(C＝O)OC₁-C₁₀an alkyl group, a carboxyl group,

6)C₀-C₁₀alkylene aryl, or

7)C₀-C₁₀alkylene-NR⁵R⁶；

R⁵And R⁶Independently are:

1)H，

2)(C₁-C₈alkyl) - (R⁷)₂，

3)(C＝O)O(C₁-C₈An alkyl group),

4) 9-fluorenylmethylcarbonyl group which is substituted,

5)OCH₂OCH₂CH₂Si(CH₃)₃，

6)(C＝O)(C₁-C₈an alkyl group),

7)(C＝O)CF₃or is or

8)(C₂-C₈Alkenyl) - (R⁷)₂Or R is⁵And R⁶Together with the nitrogen to which it is attached form an N-phthalimido group;

R⁷comprises the following steps:

1)H，

2)OH，

3)OC₁-C₆alkyl, or

4) Aryl, optionally substituted by up to two groups selected from OH, O (C)₁-C₆Alkyl) and (C)₁-C₃Alkylene) -OH;

the method comprises the following steps:

(a) reacting a furanose or pyranose with an activator to produce an activated sugar; and

(b) coupling the activated saccharide with a compound of formula IV in a two-phase system in the presence of an aqueous solution of an alkali metal hydroxide and a phase transfer catalyst to form a compound of formula I,

wherein if Q is O, S, CH₂Or N-R and R is not H, then R^1aIs H, otherwise R^1aSelected from R1.

Another embodiment is the above process, wherein when R or R¹When defined as furanosyl or pyranosyl, respectively, R and R¹Independently selected from a furanosyl group of formula IIA or a pyranosyl group of formula IIB:

R⁸independently selected from:

1)H

2)C₁-C₆an alkyl group, a carboxyl group,

3)OH，

4) the halogen(s) are selected from the group consisting of,

5)O(C₁-C₆an alkyl group),

6)O(C₁-C₆alkylene) -aryl groups, which are preferably substituted with one another,

7)OSO₂(C₁-C₆an alkyl group),

8)OSO₂an aryl group, a heteroaryl group,

9)OCH₂OCH₂CH₂Si(CH₃)₃，

10)O(C＝O)(C₁-C₆an alkyl group),

11)O(C＝O)CF₃，

12) azido, or

13)NR⁵R⁶Or two R on the same carbon⁸Together being an oxygen bridge group, ═ N-R⁵Or ═ N-R⁷(ii) a And

the furanose or pyranose in step (a) is a furanose of formula IIIA or a pyranose of formula IIIB, respectively:

in another embodiment, the active agent in step (a) is selected from an acid halide, sulfonate, phosphate, borate or acetate, and the biphasic system in step (b) comprises an organic solvent selected from a hydrocarbon, nitrile, ether, halohydrocarbon, ketone or non-polar aprotic solvent.

Yet another embodiment is the above process wherein the active agent is selected from SOCl₂Or oxalyl chloride.

Another embodiment is a process wherein the two phase system described in the above process comprises methyl tert-butyl ether, methylene chloride or trifluorotoluene.

In yet another embodiment, the phase transfer catalyst in step (b) is (R)^a)₄M⁺A^-；

R^aIndependently is H or C₁-C₁₈An aliphatic hydrocarbon;

m is N or P; and

a is OH, F, Br, Cl, I, HSO₄、CN、MeSO₃Or PhCH₂CO₂。

A preferred embodiment is a process wherein the phase transfer catalyst in the above process is trioctylmethylammonium chloride.

Another preferred embodiment is the above process wherein the concentration of said aqueous alkali metal hydroxide solution of step (b) is from about 5 to about 95% weight/weight and said alkali metal hydroxide is selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide and cesium hydroxide.

Also preferred are processes wherein the concentration of the aqueous alkali metal hydroxide solution is from about 45 to 50% weight/weight and the alkali metal hydroxide is potassium hydroxide or sodium hydroxide.

A more preferred embodiment is a process for the preparation of a compound of formula V,

in the formula:

R⁴comprises the following steps:

1)H，

2)C₁-C₁₀an alkyl group, a carboxyl group,

3)CHO

4)(C＝O)C₁-C₁₀an alkyl group, a carboxyl group,

5)(C＝O)OC₁-C₁₀an alkyl group, a carboxyl group,

6)C₀-C₁₀alkylene aryl, or

7)C₀-C₁₀alkylene-NR⁵R⁶；

R⁵And R⁶Independently are:

1)H，

2)(C₁-C₈alkyl) - (R⁷)₂，

3)(C＝O)O(C₁-C₈An alkyl group),

4) 9-fluorenylmethylcarbonyl group which is substituted,

5)OCH₂OCH₂CH₂Si(CH₃)₃，

6)(C＝O)(C₁-C₈an alkyl group),

7)(C＝O)CF₃or is or

8)(C₂-C₈Alkenyl) - (R⁷)₂Or is or

R⁵And R⁶Together with the nitrogen to which it is attached form an N-phthalimido group;

R⁷comprises the following steps:

1)H，

2)OH，

3)OC₁-C₆alkyl, or

4) Aryl, optionally substituted by up to two groups selected from OH, O (C)₁-C₆Alkyl) and (C)₁-C₃Alkylene) -OH;

R⁹comprises the following steps:

1)H

2)C₁-C₆an alkyl group, a carboxyl group,

3)(C₁-C₆alkylene) -aryl groups, which are preferably substituted with one another,

4)SO₂(C₁-C₆an alkyl group),

5)SO₂an aryl group, a heteroaryl group,

6)CH₂OCH₂CH₂Si(CH₃)₃，

7)(C＝O)(C₁-C₆alkyl) or

8)(C＝O)CF₃；

The method comprises the following steps:

(a) reacting a sugar derivative of formula VI with an acid chloride to produce an active sugar; and

(b) coupling the activated saccharide with a compound of formula VII in tert-butyl methyl ether in the presence of aqueous alkali metal hydroxide and trioctylmethylammonium chloride to produce a compound of formula V:

yet another preferred embodiment is a process for the preparation of a compound of formula VIII:

the method comprises the following steps:

(a) reacting the sugar derivative of formula IX with thionyl chloride to produce an active sugar;

(b) coupling the activated saccharide to a compound of formula X in tert-butyl methyl ether in the presence of aqueous potassium or sodium hydroxide and trioctylmethylammonium chloride:

forming a glycosidated compound of formula XI;

(c) deprotecting to form deprotected glycosidation product XII by reacting glycosidation product XI with catalytic palladium in the presence of hydrogen;

(d) reacting the deprotected glycosidation product XII with an aqueous solution of an alkali metal hydroxide to form an anhydride XIII; and

(e) reacting the anhydride XIII with 2-hydrazino-1, 3-propanediol to produce the compound of formula VIII.

Also preferred is the above process for preparing a compound of formula V wherein step (A) is carried out at a temperature of about-10 ℃ to about 30 ℃ in t-butyl methyl ether or tetrahydrofuran and step (B) is carried out at a temperature of about 0 ℃ to about 40 ℃.

A final embodiment is a process wherein potassium hydroxide or sodium hydroxide is added prior to the addition of the trioctylmethylammonium chloride in step (b) in the above process.

The Compounds of the present invention may have asymmetric centers, chiral axes and chiral planes (as described in e.l. eliel and s.h. wilen, Stereochemistry of Carban Compounds, John Wiley & Sons, New York, 1994, 1119-1190) and exist as racemates, racemic mixtures and as individual diastereomers, with all possible isomers including optical isomers and mixtures thereof being included in the present invention. In addition, the mixtures disclosed herein may exist in tautomeric forms, and although only one tautomeric structure is depicted, both tautomeric forms are intended to be included within the scope of the invention.

When any variable (e.g. X) in any component¹、X²、R⁸、R⁹Etc.) occur more than one time, each occurrence is defined independently of the other occurrences. Likewise, combinations of substituents and variables are only possible if such combinations result in stable compounds. The lines drawn from the substituents to the ring system indicate that the indicated bond can be attached to any substitutable ring carbon atom. If the ring system is a polycyclic ring system, the bond is considered to be attached only to any suitable carbon atom on the proximal ring.

It is understood that the substituents and substitution patterns on the compounds of the present invention can be selectively determined by one skilled in the art to provide compounds that are chemically stable and that can be readily synthesized from readily available starting materials by techniques well known in the art and by the methods described below.

The term "alkyl" as used herein is intended to include branched, straight-chain and cyclic saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example at "C₁-C₆C in alkyl₁-C₆Defined to include groups having 1, 2, 3, 4,5, or 6 carbon atoms arranged in a linear, branched, or cyclic arrangement. E.g. "C₁-C₆Alkyl "specifically includes methyl, ethyl, propyl, butyl, pentyl, hexyl and the like, and cycloalkylSuch as cyclopropyl, methylcyclopropyl, dimethylcyclobutyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. The alkyl substituent may be unsubstituted or substituted with one to three substituents selected from the group consisting of: halogen, C₁-C₆Alkyl, OH, OC₁-C₆Alkyl, O (C ═ O) C₁-C₆Alkyl, O (C ═ O) OC₁-C₆Alkyl, amino, amido, CO₂H、CN、NO₂、N₃、C₁-C₆Perfluoroalkyl group and OC₁-C₆A perfluoroalkyl group. "alkoxy" represents an alkyl group having the indicated number of carbon atoms attached through an oxygen bridge.

The term "alkenyl" refers to a straight, branched or cyclic non-aromatic hydrocarbon group containing 2 to 10 carbon atoms and at least one carbon-carbon double bond. Preferably, there is one carbon-carbon double bond, and up to 4 non-aromatic carbon-carbon double bonds may be present. Thus "C₂-C₆Alkenyl "means alkenyl having 2 to 6 carbon atoms. Alkenyl groups include ethenyl, propenyl, butenyl, 2-methylbutenyl and cyclohexenyl. The linear, branched, or cyclic portion of the alkenyl group may contain double bonds and may be substituted (if a substituted alkenyl group is shown).

In some instances, the substituents may be limited to a range including 0 carbons, such as (C)₀-C₆) alkylene-NR⁵R⁶. If R is⁵And R⁶When H is taken, this definition will include NH₂and-CH₂NH₂、-CH₂CH₂NH₂、CH(CH₃)CH₂CH(CH₃)NH₂、-CH₂CH(NH₂)CH₃And the like. In these cases it is meant that the substituents on the divalent group may be attached at any position and are not limited to terminal positions.

The term "aryl" as used herein is intended to refer to substituted and unsubstituted phenyl or naphthyl. If substituted, it may be substituted with one to three substituents selected from the group consisting of: halogen, C₁-C₆Alkyl, OH, OC₁-C₆Alkyl, O (C ═ O) C₁-C₆Alkyl, O (C ═ O) OC₁-C₆Alkyl, amino, amido, CO₂H、CN、NO₂、N₃、C₁-C₆Perfluoroalkyl group and OC₁-C₆A perfluoroalkyl group.

As known to those skilled in the art, the term "halo" or "halogen" as used herein is intended to include chloro, fluoro, bromo and iodo.

When used as "(C)₁-C₈Alkyl) - (R⁷)₂"when defined, means the variable R⁷Attached at any position along the alkyl moiety. Therefore, if R is⁷Defined herein as OH, which definition shall include CH₂OH、CH₂CH₂OH、CH(CH₃)CH(OH)CH₃、CH(CH₃)CH(OH)CH₂-CH(OH)CH₃And the like.

The terms "alkylene" and "alkenylene" simply refer to an alkyl or alkenyl group as defined above, each having the indicated divalent carbon number. E.g. "C₁-C₄Alkylene "includes-CH₂-、-CH₂CH₂-、-CH(CH₃)CH₂-and the like.

R and R¹Included within the definition of (1) are furanose and pyranose derivatives. Preferred sugar derivatives are O-protected pyranoses, such as D-glucopyranose, 6-deoxy-6, 6-difluoro-D-glucopyranose; 6-deoxy-6-azido-D-glucopyranose; 6-amino-6-deoxy-D-glucopyranose; 6-azido-d-glucopyranose; 6-amino-D-glucopyranose; 4-deoxy-4, 4-difluoro-6-deoxy-6-azido-D-glucopyranose; 2-fluoro-D-glucopyranose; d-galactopyranose; 4-deoxy-D-galactopyranose; 4-deoxy-D-glucopyranose; and 4-methoxy-D-glucopyranose. (see, for example, WO98/07433, incorporated herein by reference). Preferred furanoses include xylofuranose, arabinofuranose, ribofuranose, arabinofuranose and 2-deoxyribofuranose.

R9 can generally be any knownAn O-protecting group of (1). Examples of such protecting groups include, but are not limited to: benzyl, p-nitrobenzyl, tolyl, and the like. A more preferred protecting group is benzyl (Bn), i.e. CH₂Ph. Other suitable protecting Groups will be familiar to those skilled in the art, examples of which are found in Peter G.M.Wuts and Protective Groups in Organic Synthesis of Theodora W.Greene; john Wiley&Sons, third edition (1999).

The term "two-phase system" as used herein refers to a two-phase solvent system comprising an aqueous phase and an organic phase.

The activating agent used to activate the saccharide for coupling can be readily selected by one skilled in the art. Examples of such agents include acid halides (e.g., SOCl)₂、POCl₃、SOBr₂、POBr₃、PBr₃And oxalyl chloride), sulfonyl halides, and the like. Preferred reagents are thionyl chloride and oxalyl chloride. Most preferred is thionyl chloride. Other reagents that may be used in the activation include triphenylphosphine/I₂And triphenylphosphine/azidodicarboxylate.

Suitable solvents for the reaction to activate the saccharide can be determined by one of ordinary skill in the art of chemistry. Preferred solvents are hydrocarbons (such as toluene, xylene, heptane and hexane), nitriles (such as acetonitrile), ethers (such as tert-butyl methyl ether and tetrahydrofuran), halogenated hydrocarbons (such as dichloromethane, carbon tetrachloride, chloroform, trifluorotoluene and dichlorobenzene), ketones (such as methyl isobutyl ketone and acetone), and nonpolar aprotic solvents (such as N, N-dimethylformamide and 1-methyl-2-pyrrolidone). More preferred solvents are tert-butyl methyl ether and tetrahydrofuran. The most preferred solvent is t-butyl methyl ether.

The activation reaction may be carried out at a temperature of about-50 ℃ to about 200 ℃. Preferred temperatures are from about-10 ℃ to about 30 ℃.

Likewise, suitable solvents for the biphasic coupling reaction can be readily determined by one skilled in the art. Suitable solvents include hydrocarbons (such as toluene, xylene, heptane and hexane), nitriles (such as acetonitrile), ethers (such as tert-butyl methyl ether and tetrahydrofuran), halogenated hydrocarbons (such as dichloromethane, carbon tetrachloride, chloroform, trifluorotoluene and dichlorobenzene), ketones (such as methyl isobutyl ketone and acetone) and non-polar aprotic solvents (such as N, N-dimethylformamide and 1-methyl-2-pyrrolidone). Preferred solvents are tert-butyl methyl ether, dichloromethane and trifluorotoluene.

The activation reaction may be carried out at a temperature of about-50 ℃ to about 200 ℃. The preferred temperature is about O to 40 ℃.

Preferred bases for the coupling reaction are alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide, potassium hydroxide and cesium hydroxide. More preferred are potassium hydroxide and sodium hydroxide. The alkali concentration in the water may vary from about 5-95% w/w. More preferably at a concentration of about 45-50% w/w.

Preferred phase transfer reagents in the coupling reaction are of the formula (R)^a)₄M⁺A^-Wherein R is^aIndependently is H or C₁-C₁₈An aliphatic hydrocarbon; m is N or P; and A is OH, F, Br, Cl, I, HSO₄、CN、MeSO₃Or PhCH₂CO₂. One preferred phase transfer catalyst is trioctylmethylammonium chloride. Other suitable phase transfer catalysts include, but are not limited to, tris [2- (2-methoxyethoxy) ethyl ] ethyl]Amine (TDA-1); BnEt₃N⁺Cl^-(ii) a And (Bu)₃NH⁺HSO₄ ^-。

Description of the flow

Scheme A illustrates one general method that can be used to prepare glycosidated base A-6. Other methods are known in the art, some of which are described in U.S. patent No. 5,922,860 to Kojiri et al (granted 7/13/2000), which is incorporated herein by reference. Scheme B shows the phase transfer catalyzed glycosidation of A-6 to produce intermediates of type B-3. Schemes C and D show possible further modifications to form compounds known to be useful as topoisomerase inhibitors.

Procedure A

R¹Is H or Q is N-H

Procedure B

Procedure C

Procedure D

Examples

The examples provided herein are intended to aid in the further understanding of the invention. The particular materials, species and conditions employed are intended to be illustrative of the invention further and are not to be construed as limiting the reasonable scope of the invention.

Intermediate 5 for the glycosidation reaction of the present invention is obtainable by the method of U.S. patent No. 5,922,860 to Kojiri et al (issued on 7/13/2000), which is hereby incorporated by reference. This process is briefly described in examples 1 to 5 below.

Example 1

Preparation of a compound represented by formula 1:

284g of 6-benzyloxyindole were dissolved in 3 l of THF, and 2.7 l of lithium hexamethyldisilazide (1M solution in THF) were added. After the mixture was stirred at-10 ℃ for 45 minutes under a nitrogen atmosphere, 3 liters of a THF solution containing 340g of 2, 3-dibromo-N-methylmaleimide was added thereto over 1 hour. After the addition was complete, the resulting mixture was stirred at 0 ℃ for 15 minutes. The reaction mixture was poured into 10 l of 2N hydrochloric acid solution and extracted with 30 l of ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and then saturated aqueous solution of sodium chloride, dried and concentrated. The residue obtained was recrystallized from methanol to 410.0266[ C ]₂₀H₁₅N₂O₃Br]IR(KBr，cm^-1)：3330，3318，1762，1701，1606，1511，1450，1165，1135，1041，794.¹H-NMR(300MHz，CDCl₃δ ppm): 8.60(1H, brs), 7.96(1H, d, J ═ 8.1Hz), 7.94(1H, d, J ═ 2.5Hz), 7.33 to 7.47(5H, m), 7.00(1H, dd, J ═ 2.5, 8.8Hz), 6.97(1H, d, J ═ 2.5Hz), 5.13(2H, s), 3.16(3H, s). HRMS (m/z): measured value 410.0292, calculated value

Example 2

Preparation of a compound represented by formula 2:

1.00g of the compound 1 obtained in example 1, 637mg of di-tert-butyl dicarbonate and 3mg of 4-N, N-dimethylaminopyridine were dissolved in 200mL of THF, and the resulting solution was stirred at room temperature for 1 hour. After the reaction mixture was concentrated, the obtained residue was recrystallized from ethyl acetate-hexane to obtain the desired compound (2).

IR(KBr，cm^-1): 1740, 1714, 1614, 1527, 1487, 1443, 1373, 1227, 1153.HRMS (m/z): measured value 510.0771, calculated value 510.0791[ C ]₂₅H₂₃N₂O₅Br]¹H-NMR(300MHz，CDCl₃，δ.ppm)：8.10(1H，s)，7.91(1H，d，J＝2.3Hz)，7.73(1H，d，J＝8.9Hz)，7.34-7.50(5H，m)，7.03(1H，dd，J＝2.3，8.5Hz)，5.16(2H，s)，3.18(3H，s)，1.68(9H，s).

Example 3

Preparation of a compound represented by formula 3:

218.4mg of 6-benzyloxyindole was dissolved in 20mL of THF, and 2.35mL of lithium hexamethyldisilazide (1M in THF) was added. After the mixture was stirred at 0 ℃ for 15 minutes under a nitrogen atmosphere, 10mL of a THF solution containing 500mg of the compound (2) obtained in example 2 was added dropwise thereto over a period of 10 minutes. After the addition was completed, the resulting mixture was stirred at room temperature for 0.5 hour. The reaction mixture was poured into 100mL of 2N hydrochloric acid solution and extracted with 400mL of ethyl acetate. The organic layer was washed with water, saturated aqueous sodium bicarbonate and then with saturated aqueous sodium chloride, dried and concentrated. The obtained residue is on

Recrystallization from benzene-hexane afforded the desired compound (3).

HRMS (m/z): measured value 653.2556, calculated value 653.2526[ C ]₄₀H₃₅N₃O₆]IR(KBr，cm^-1)：1740，1701，1646，1623，1543，1445，1155.¹H-NMR(300MHz，CDCl₃，δppm)：8.41(1H，brs)，7.97(1H，s)，7.84(1H，brs)，7.68(1H，brs)，7.16-7.43(10H，m)，6.98(1H，d，J＝9.2Hz)，6.85(1H，brs)，6.74(1H，d，J＝9.2Hz)，6.58(1H，d，J＝9.2Hz)，6.52(m，d，J＝9.2Hz)，5.05(2H，s)，5.02(2H，s)，3.19(3H，s)，1.67(9H，s).

Example 4

Preparation of Compound represented by formula 4

100mg of the compound (3) obtained in example 3 was dissolved in 10mL of methylamine (40% methanol solution), and the solution was stirred at room temperature for 30 minutes. After the reaction mixture was concentrated, the obtained residue was recrystallized from methylene chloride-acetone-hexane to obtain 68.6mg of the desired compound (4).

HRMS (m/z): measured value 553.1982, calculated value 553.2002[ C ]₃₅H₂₇N₃O₄]IR(KBr，cm^-1)：3419，3350，1759，1697，1620，1533，1454，1383，1292，1167.¹H-NMR(300MHz，DMSO-d₆，δppm)：11.48(2H，s)，7.62(2H，s)，7.28-7.45(10H，m)，6.95(2H，d，J＝1.2Hz)，6.70(2H，d，J＝8.7Hz)，6.39(2H，dd，J＝1.2，8.7Hz)，5.04(4H，s)，3.03(3H，s).

Example 5

Preparation of Compound represented by formula 5

1.01g of the compound (4) obtained in example 4 and 456.1mg of 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone were dissolved in 50mL of toluene, and the solution was stirred at 110 ℃ for 40 minutes. After the reaction mixture was returned to room temperature, insoluble matter was removed by filtration and washed with 30mL of methanol. The residue was recrystallized from dimethylsulfoxide-dichloromethane-methanol to obtain the desired compound (5).

HRMS (mr/z): measured value 551.1829, calculated value 551.1845[ C ]₃₅H₂₅N₃O₄]IR(KBr，cm.^-1)：3257，1740，1675，1620，1571，1402，1246，1178.¹H-NMR(300MHz，DMSO-d₆，δppm)：11.46(2H，s)，8.79(2H，d，J＝8.5Hz)，7.53(4H，d，8.5Hz)，7.35-7.44(8H，m)，7.02(2H，dd，8.5，0.8Hz)，5.25(4H，s)，3.13(3H，s).

Example 6

Step 1:

100g (185mmol) of 2, 3, 4, 6-tetrabenzyl-D-glucopyranose (6-1) are mixed with 360ml of FM at 23 ℃ and then cooled to 9 ℃. Thionyl chloride (16.2 mL; 222mol) was added slowly over 15 minutes, during which time the temperature rose to 20 ℃. The solution was warmed to about 30 ℃ for 1 hour. The solution was then cooled to-10 ℃ and 10% w/w KOH (about 150mL) was added, while the temperature did not exceed 0 ℃. The solution was warmed to 22 ℃. The aqueous layer was extracted with tert-butyl methyl ether (MTBE) (1X 300 mL). The combined organic layers were then washed with brine (1X 150mL) and water (1X 200 mL). The solution was concentrated under reduced pressure to a level of 350mL and used in the next step without purification.

Step 2:

72g (131mmol) of compound 5 of example 5 above were dissolved in 600mL of MTBE and stirred at 23 ℃ for 10 minutes. The 6-2 solution prepared in step 1 above was then added, and after 10 minutes, 45% w/w aqueous KOH (300mL) was added. After another 10 minutes, 40% w/w Aliquat * 336(72g solution in 110g MTBE) was added slowly over 22 minutes. Aliquat * 336 is a trade name for trioctylmethylammonium chloride sold by aldrich chemical co. The solution was stored at 23 ℃ for 6 hours, then 350mL of water was added and allowed to mix for 5 minutes. The layers were separated and the aqueous layer was washed with MTBE (1X 300 mL). The combined organic layers were then washed with 10% w/w citric acid (1X 300mL) and water (1X 300 mL). The organic layer was stirred at 22 ℃ overnight, during which time the product (6-3) began to crystallize. The solution was then concentrated to a level of 625mL at atmospheric pressure (boiling point 55 ℃). At this point, the solution was cooled to 23 ℃ and methanol (225mL) was added slowly over 1 hour. The slurry was then cooled to-5 ℃ and held for 45 minutes. The solid was separated and washed with cooled 1: 1 methanol/MTBE (2X 400 mL). Vacuum drying at 25-40 deg.C, and purifying by liquid chromatography to obtain product 6-3 with purity over 99%.

The following examples (U.S. Pat. No. 5,922,869 to Kojiri et al, and incorporated herein by reference) illustrate the use of the glycosidation products in the synthesis of known topoisomerase inhibitors (9).

Example 7

Preparation of a compound represented by formula 7:

100mg of Compound 6-3 was dissolved in 6mL of chloroform-methanol (2: 1), and a catalytic amount of palladium black was added thereto. The mixture was stirred under a hydrogen atmosphere for 2 hours. After removing the catalyst by filtration, the filtrate was concentrated. The obtained residue was recrystallized from methanol-acetone-ethyl acetate-hexane, developed with Sephadex LH-20, eluted with chloroform-methanol-ethanol-tetrahydrofuran (5: 2: 1), and recrystallized from acetone-methanol-hexane to give the desired compound (7). Measured value 533.1429, calculated value 533.1434[ C ]₂₇H₂₃N₃O₉]IR(KBr，cm^-1)：3328，1733，1683，1678，1540，1417，1126，1081，611.¹H-NMR(300MHz，DMSO-d₆，δppm)：11.20(1H，s)，9.76(1H，s)，9.74(1H，s)，8.88(1H，d，J＝8.6Hz)，8.80(1H，d，J＝8.6Hz)，7.18(1H，d，J＝2.1Hz)，6.99(1H，d，J＝2.1Hz)，6.82(1H，dd，J＝2.1，8.6Hz)，6.80(1H，dd，J＝2.1，8.6Hz)，5.97(1H，J＝8.9Hz)，5.86(1H，t，J＝4.0Hz)，5.33(1H，d，J＝4.9Hz)，5.12(1H，d，J＝4.3Hz)，4.94(1H，d，J＝5.2Hz)，4.02(1H，dd，J＝3.0，10.7Hz)，3.94(1H，m)，3.78(1H，m)，3.52(2H，m)，3.16(3H，s).

Example 8

Preparation of a compound represented by formula 8:

1.2g of compound (7) was dissolved in 40mL of a 10% aqueous potassium hydroxide solution, and the solution was stirred at room temperature for 1 hour. The reaction mixture was neutralized by adding 40mL of 2N hydrochloric acid, followed by extraction with 1L of methyl ethyl ketone. The organic layer was washed with saturated aqueous sodium chloride, dried and concentrated. The obtained residue was recrystallized from acetone-heptane to obtain the desired compound (8).

HRMS (m/z): measured value 520.1147, calculated value 520.1118[ C ]₂₆H₂₀N₂O₁₀]IR(KBr，cm^-1)：3311，1810，1739，1652，1626，1558，1405，1091，611.¹H-NMR(300MHz，DMSO-d₆，δppm)：11.4(1H，s)，9.95(1H，s)，9.92(1H，s)，8.69(1H，d，J＝7.7Hz)，8.63(1H，d，J＝7.7Hz)，7.25(1H，d，J＝1.5Hz)，7.03(1H，d，J＝1.5Hz)，6.90(1H，dd，J＝1.5，7.7Hz)，6.87(1H，d，J＝1.5，7.7Hz)，6.06(1H，d，J＝8.0Hz)，5.95(1H，t，J＝4.6Hz)，5.38(1H，d，J＝5.1Hz)，5.16(1H，d，J＝5.2Hz)，4.99(1H，d，J＝5.2Hz)，3.30-4.10(6H，m).

Example 9

Preparation of topoisomerase inhibitor of formula 9:

500g of Compound 8 are dissolved in 50mL of DMF, and 152mg of 2-hydrazino-1, 3-propanediol are added. The mixture was stirred at 80 ℃ for 1 hour. After concentrating the reaction mixture, the obtained residue was purified with Sephadex LH-20 (chloroform-methanol-ethanol-water ═ 5: 2: 1) to obtain compound 9.

HRMS (m/z): measured value 609.1816, calculated value 609.1833[ C ]₂₉H₂₈N₄O₁₁]IR(KBr，cm.sup.-1)：3415，3353，1749，1652，1575，1540，1375，1197，609.¹H-NMR(300MHz，DMSO-d₆，δppm)：11.20(1H，s)，9.78(1H，s)，9.75(1H，s)，8.87(1H，d，J＝8.6Hz)，8.79(1H，d，J＝8.6Hz)，7.18(1H，d，J＝2.0Hz)，6.98(1H，d，J＝2.0Hz)，6.82(1H，dd，J＝2.0，8.6Hz)，6.80(1H，dd，J＝2.0，8.6Hz)，5.97(1H，J＝8.3Hz)，5.86(1H，d，J＝3.8Hz)，5.55(1H，d，J＝2.6Hz)，5.32(1H，d，J＝4.6Hz)，5.11(1H，d，J＝5.3Hz)，4.91(1H，d，J＝5.1Hz)，4.53(2H，t，J＝5.4Hz)，4.02(1H，m)，3.85-3.95(2H，m)，3.78(1H，m)，3.40-3.60(6H，m)，3.20-3.30(1H，m).

Claims (11)

1. A process for preparing a compound of formula I:

in the formula:

q is O, N-R, S or CH₂；

X¹And X²Independently selected from;

1)H，

2) the halogen(s) are selected from the group consisting of,

3)OH，

4)CN，

5)NC，

6)CF₃，

7)(C＝O)NO₂，

8)(C＝O)C₁-C₆an alkyl group, a carboxyl group,

9)(C＝O)OC₁-C₆an alkyl group, a carboxyl group,

10)OCH₂OCH₂CH₂Si(CH₃)₃，

11)NO₂，

12) 9-fluorenylmethylcarbonyl

13)NR₅R₆，

14)OC₁-C₆An alkyl group, a carboxyl group,

15)C₁-C₆an alkyl group, a carboxyl group,

16)C₁-C₆alkylene aryl, and

17)OC₁-C₆an alkylene aryl group;

r and R¹Independently are:

1)H，

2)(C＝O)C₁-C₆an alkyl group, a carboxyl group,

3)(C＝O)CF₃，

4)(C＝O)OC₁-C₆an alkyl group, a carboxyl group,

5) 9-fluorenylmethylcarbonyl group which is substituted,

6) a furanosyl radical, or

7) A pyranosyl group,

provided that R and R¹One is furanosyl or pyranosyl;

R²and R³Independently is OH or H, or

R²And R³Together form an oxo group;

R⁴comprises the following steps:

1)H，

2)C₁-C₁₀an alkyl group, a carboxyl group,

3)CHO

4)(C＝O)C₁-C₁₀an alkyl group, a carboxyl group,

5)(C＝O)OC₁-C₁₀an alkyl group, a carboxyl group,

6)C₀-C₁₀alkylene aryl, or

7)C₀-C₁₀alkylene-NR⁵R⁶；

R⁵And R⁶Independently are:

1)H，

2)(C₁-C₈alkyl) - (R⁷)₂，

3)(C＝O)O(C₁-C₈An alkyl group),

4) 9-fluorenylmethylcarbonyl group which is substituted,

5)OCH₂OCH₂CH₂Si(CH₃)₃，

6)(C＝O)(C₁-C₈an alkyl group),

7)(C＝O)CF₃or is or

8)(C₂-C₈Alkenyl) - (R⁷)₂Or is or

R⁵And R⁶Together with the nitrogen to which it is attached form an N-phthalimido group;

R⁷comprises the following steps:

1)H，

2)OH，

3)OC₁-C₆alkyl, or

4) Aryl, optionally substituted by up to two groups selected from OH, O (C)₁-C₆Alkyl) and (C)₁-C₃Alkylene) -OH;

the method comprises the following steps:

(a) reacting a furanose or pyranose with an activator to produce an activated sugar; and

(b) coupling the activated saccharide with a compound of formula IV in a two-phase system in the presence of an aqueous solution of an alkali metal hydroxide and a phase transfer catalyst to form a compound of formula I,

wherein if Q is O, S, CH₂Or N-R and R is not H, then R^1aIs H, otherwise R^1aIs selected from R¹，

WhereinThe phase transfer catalyst is selected from trioctylmethylammonium chloride, tris [2- (2-methoxyethoxy) ethyl ] ethyl]Amine (TDA-1), BnEt₃N⁺Cl^-And (Bu)₃NH⁺HSO₄ ^-。

2. The method of claim 1, wherein when R or R¹When defined as furanosyl or pyranosyl, respectively, R and R¹Independently selected from a furanosyl group of formula IIA or a pyranosyl group of formula IIB:

R⁸independently selected from:

1)H

2)C₁-C₆an alkyl group, a carboxyl group,

3)OH，

4) the halogen(s) are selected from the group consisting of,

5)O(C₁-C₆an alkyl group),

6)O(C₁-C₆alkylene) -aryl groups, which are preferably substituted with one another,

7)OSO₂(C₁-C₆an alkyl group),

8)OSO₂an aryl group, a heteroaryl group,

9)OCH₂OCH₂CH₂Si(CH₃)₃，

10)O(C＝O)(C₁-C₆an alkyl group),

11)O(C＝O)CF₃，

12) azido, or

13)NR⁵R⁶Or two R on the same carbon⁸Together being an oxygen bridge group, ═ N-R⁵Or ═ N-R⁷(ii) a And

the furanose or pyranose in step (a) is a furanose of formula IIIA or a pyranose of formula IIIB, respectively:

3. the process of claim 2, wherein the active agent in step (a) is selected from the group consisting of acyl halides and the two-phase system in step (b) comprises an organic solvent selected from the group consisting of hydrocarbons, nitriles, ethers, halogenated hydrocarbons, ketones, or non-polar aprotic solvents.

4. The method of claim 3, wherein the active agent is selected from SOCl₂Or oxalyl chloride.

5. The process of claim 3, wherein the biphasic system comprises methyl tert-butyl ether, dichloromethane or trifluorotoluene.

6. The process of claim 3 wherein the concentration of the aqueous alkali metal hydroxide solution of step (b) is from about 5 to 95% weight/weight and the alkali metal hydroxide is selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide and cesium hydroxide.

7. The method of claim 6, wherein the concentration of the aqueous alkali metal hydroxide solution is about 45-50% weight/weight and the alkali metal hydroxide is potassium hydroxide or sodium hydroxide.

8. The method of claim 1, wherein the compound of formula I is a compound of formula V,

in the formula:

R⁴comprises the following steps:

1)H，

2)C₁-C₁₀an alkyl group, a carboxyl group,

3)CHO

4)(C＝O)C₁-C₁₀an alkyl group, a carboxyl group,

5)(C＝O)OC₁-C₁₀an alkyl group, a carboxyl group,

6)C₀-C₁₀alkylene aryl, or

7)C₀-C₁₀alkylene-NR⁵R⁶；

R⁵And R⁶Independently are:

1)H，

2)(C₁-C₈alkyl) - (R⁷)₂，

3)(C＝O)O(C₁-C₈An alkyl group),

4) 9-fluorenylmethylcarbonyl group which is substituted,

5)OCH₂OCH₂CH₂Si(CH₃)₃，

6)(C＝O)(C₁-C₈an alkyl group),

7)(C＝O)CF₃or is or

8)(C₂-C₈Alkenyl) - (R⁷)₂Or is or

R⁵And R⁶Together with the nitrogen to which it is attached form an N-phthalimido group;

R⁷comprises the following steps:

1)H，

2)OH，

3)OC₁-C₆alkyl, or

4) Aryl, optionally substituted by up to two groups selected from OH, O (C)₁-C₆Alkyl) and (C)₁-C₃Alkylene) -OH;

R⁹comprises the following steps:

1)H

2)C₁-C₆an alkyl group, a carboxyl group,

3)(C₁-C₆alkylene) -aryl groups, which are preferably substituted with one another,

4)SO₂(C₁-C₆an alkyl group),

5)SO₂an aryl group, a heteroaryl group,

6)CH₂OCH₂CH₂Si(CH₃)₃，

7)(C＝O)(C₁-C₆alkyl) or

8)(C＝O)CF₃；

The method comprises the following steps:

(a) reacting a sugar derivative of formula VI with an acid chloride to produce an active sugar; and

(b) coupling the activated saccharide with a compound of formula VII in t-butyl methyl ether in the presence of aqueous alkali metal hydroxide and trioctylmethylammonium chloride to form a compound of formula V:

9. the method of claim 1, wherein the compound of formula I is a compound of formula VIII:

the method comprises the following steps:

(a) reacting the sugar derivative of formula IX with thionyl chloride to produce an active sugar;

(b) coupling the activated saccharide to a compound of formula X in tert-butyl methyl ether in the presence of aqueous potassium or sodium hydroxide and trioctylmethylammonium chloride:

forming a glycoside compound of formula XI;

(c) deprotecting the glycosidation product XI by reaction with catalytic palladium in the presence of hydrogen to form a deprotected glycosidation product XII;

(d) reacting the deprotected glycosidation product XII with an aqueous solution of an alkali metal hydroxide to form an anhydride XIII; and

(e) reacting the anhydride XIII with 2-hydrazino-1, 3-propanediol to produce the compound of formula VIII.

10. The process of claim 8, wherein step (A) is carried out at a temperature of about-10 ℃ to about 30 ℃ in t-butyl methyl ether or tetrahydrofuran, and step (B) is carried out at a temperature of about 0 ℃ to about 40 ℃.

11. The process of claim 10 wherein in step (b) potassium hydroxide or sodium hydroxide is added prior to the addition of the trioctylmethylammonium chloride.