CH643272A5 - Process for the preparation of 5-fluorouracil derivatives - Google Patents

Abstract

Compounds of the formula <IMAGE> in which one of R<1> and R<2> is hydrogen and the other is certain glycoside residues as defined in Claim 1 are prepared. The process comprises reacting a compound of the formula <IMAGE> in which one of R<7> and R<8> is a metal ion and the other is a protective group which can be eliminated by reduction, with a glycoside halide and reduction. The compounds have an antitumour activity.

Description

The present invention relates to a process for the preparation of a new class of 5-fluorouracil derivatives containing a glycoside residue 25.

Certain 5-fluorouracil derivatives are known as anti-tumor agents. E.g. it was claimed that 5-fluorouracil itself (hereinafter referred to as "5-FU") and N '- (2-tetra-hydrofuryl) -5-fluorouracil (hereinafter referred to as "FT-207" 3o) show a good anti-tumor effect [R. Duschinsky et al., J. Amer. Chem. Soc. 79.4559 (1957) and S.A. Hiller et al., Doc. Akad. Nauk. (USSR) 176, 332 (1967)]. However, there is a need for an agent with anti-tumor activity that is as good as or better than that of 35 5-FU and FT-207, but with fewer side effects and less toxicity.

The 5-fluorouracil derivatives obtainable according to the invention correspond to the formula:

45

means, where R5 and R6 are the same or different and each represents hydrogen or an unbranched or branched alkyl group having 1 to 5 carbon atoms.

15. A process for the preparation of 5-fluorouracil derivatives of the formula I, in which one of the symbols R1 and R2 denotes hydrogen and the other a glycoside residue of the formula:

(I)

wherein one of the symbols R1 and R2 represents hydrogen and the other a glycoside residue of the formula:

H

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or represents wherein R represents an acyl group, R3 represents a group of the formula -OR or an amino group and R4 represents an alkoxy group, a cycloalkoxy group, an aralkoxy group, an aryloxy group or an amino group of the For-. mei:

> 5

R-

R

\

6 /

N-

20th

OR

N

(II)

means, where R5 and R6 are the same or different and are each hydrogen atoms, alkyl groups, cycloalkyl groups, 25 in which one of the symbols R7 and R8 denotes a metal ion

Aralkyl groups or aryl groups or R5 and R6 together with the nitrogen atom to which they are attached form a 5- to 7-membered cyclic amino group and, if R3 represents an amino group, the pharmaceutically acceptable acid addition salts thereof.

According to the invention, the 5-fluorouracil derivatives and the other represents a reductively removable hydroxyl protecting group, with a compound of the formula:

R9-X

(III)

30th

where X is a halogen atom, e.g. Chlorine or bromine

Formula I prepared by using a compound of the formula: and R9 is a glycoside residue of the formula:

RO-ÇH

R-

R -CÔ

or represents, in which R and R4 have the above meanings and R3 'represents a group of the formula -OR or a protected amino-60 group, to a compound of the formula:

65

OR11

(IV)

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wherein one of the symbols R10 and R "represents a reductively removable hydroxyl protecting group and the other represents a group R9 as defined above, and the compound of formula IV is subjected to the reduction.

Preferred examples of hydroxyl protecting groups which can be represented by R7 or R8 in the compounds of formula II above are benzyl groups which may be unsubstituted or whose phenyl radical may be substituted by one or more nitro groups and / or one or more halogen atoms, e.g. Benzyl itself, o-nitrobenzyl, m-nitrobenzyl, p-nitrobenzyl, o-chlorobenzyl, m-chlorobenzyl, p-chlorobenzyl, o-bromobenzyl, m-bromobenzyl, p-bromobenzyl, o-fluorobenzyl, m-fluorobenzyl or p -Fluorobenzyl, as well as ß-Halogenäthylgruppen, for example 2,2,2-trichloroethyl, 2,2,2-tribromoethyl, 2,2-dichloroethyl or 2,2-dibromoethyl.

The acyl group R is preferably an aliphatic acyl group with 2 to 4 carbon atoms, e.g. Acetyl, n-propionyl, n-butyryl or isobutyryl, or an aromatic acyl group having 7 to 11 carbon atoms, e.g. Benzoyl, p-nitrobenzoyl, p-methylbenzoyl, p-methoxybenzoyl or naphthoyl.

If R3 'represents a protected amino group, this is preferably easily removed by reduction. Such protecting groups are e.g. : Benzyloxycarbonyl groups, which may be unsubstituted or whose phenyl radical may have one or more nitro and / or halogen substituents, e.g. Benzyloxycarbonyl, o-nitrobenzyloxycarbonyl, m-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, o-chloro-benzyloxycarbonyl, m-chlorobenzyloxycarbonyl, p-chlorobenzyloxycarbonyl, o-bromobenzyloxycarbonyl, m-bromobenzyl-oxycarbonyl, p-bromobenzyloxycarbonyl, p-bromobenzyloxycarbonyl m-fluorobenzyloxycarbonyl or p-fluorobenzyl-oxycarbonyl, or ß-halogenoethoxycarbonyl groups, for example 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl, 2,2-dibromoethoxycarbonyl or 2,2-dichloroethoxycarbonyl.

R4 preferably represents a straight or branched alkoxy group with 1 to 8 carbon atoms, e.g. Methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobu-toxy, n-pentyloxy, isopentyloxy, n-hexyloxy, sec.-hexyloxy, n-heptyloxy, n-octyloxy or 2-ethylhexyloxy, a cycloalkoxy group with 5 to 7 ring carbon atoms, e.g. Cyclopentyloxy, cyclohexyloxy or cycloheptyloxy, an aralkoxy group with 7 to 12 carbon atoms, the aromatic ring of which may be unsubstituted or may have one or more substituents consisting of alkyl groups of 1 to 4 carbon atoms, e.g. Methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl, alkoxy groups with 1 to 4 carbon atoms, e.g. Methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy or isobutoxy, or halogen atoms, e.g. Chlorine, bromine or fluorine are selected, e.g. Benzyloxy or phenylethyloxy, or an aryloxy group of 6 to 10 carbon atoms, the aromatic ring of which may be unsubstituted or may have one or more substituents consisting of alkyl groups of 1 to 4 carbon atoms, e.g. Methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl, alkoxy groups with 1 to 4 carbon atoms, e.g. Methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy or isobutoxy, or halogen atoms, e.g. Chlorine, bromine or fluorine are selected, e.g. Phenyloxy.

If R4, an amino group of the formula:

R5 and R6 are the same or different and each preferably represents hydrogen, an unbranched or branched alkyl group having 1 to 5 carbon atoms, e.g. Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl or isopentyl, a cycloalkyl group with 5 to 7 ring carbon atoms, e.g. Cyclopentyl, cyclohexyl or cyclo-heptyl, an aralkyl group with 7 to 12 carbon atoms, e.g. Benzyl or phenylethyl, the aromatic ring of which may be unsubstituted or may have one or more substituents selected from alkyl of 1 to 4 carbon atoms, e.g. Methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl, alkoxy with 1 to 4 carbon atoms, e.g. Methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy or isobutoxy, or halogen atoms, e.g. Chlorine, bromine or fluorine are selected, an aryl group with 6 to 10 carbon atoms, e.g. Phenyl, the aromatic ring of which may be unsubstituted or may have one or more substituents selected from alkyl groups of 1 to 4 carbon atoms, e.g. Methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl, alkoxy groups with 1 to 4 carbon atoms, e.g. Methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy or isobutoxy, or halogen atoms, e.g. Chlorine, bromine or fluorine are selected, or R5 and R6 together with the nitrogen atom to which they are attached can form a cyclic amino group with 5 or 6 ring atoms, e.g. 1-pyrrolidinyl, piperidino or morpholino.

Preferred examples of compounds obtainable according to the invention are listed below. The numbers with which the connections in the following list are designated are used in the following to identify these connections.

1.1 -0- (5-Fluoro-1 H-2-oxopyrimidin-4-yl) -ß-D-glucopyra nuronamide.

2. 1- 0- (5-fluoro-lH-4-oxopyrimidin-2-yl) -ß-D-glucopyra nuronamide.

3. 04- (3,4,6-Tri-0-acetyl-2-amino-2-deoxy-ß-D-glucopy-ranosyl) -5-fluorouraciI.

4.02- (3,4,6-tri-0-acetyl-2-amino-2-deoxy-β-D-glucopy-ranosyl) -5-fluorouracil.

5. 1- 0- (5-Fluoro-1 H-2-oxopyrimidin-4-yl) -2,3,4-tri-0-acetyl-β-D-glucopyranuronic acid, methyl ester.

6. 02- (2,3,4,6-tetra-0-acetyl-β-D-glucopyranosyl) -5-fluoro-uracil.

7. 04- (2,3,4,6-tetra-0-acetyl-β-D-glucopyranosyl) -5-fluoro-uracil.

8.1 -0- (5-Fluoro-1 H-4-oxopyrimidin-2-yl) -2,3,4-tri-0-acetyl β-D-glucopyranuronic acid, methyl ester.

9. 04- (3,4,6- (Tri-0-acetyl-2-amino-2-deoxy-β-D-glucopy-ranosyl) -5-fluorouracil hydrochloride.

10. 02- (3,4,6-Tri-0-acetyI-2-amino-2-deoxy-β-D-glucopy-ranosyl) -5-fluorouracil hydrochloride.

In connection with the formula:

one of the symbols R7 and R8 means a metal ion and the other a hydroxyl protecting group. The metal ion can be any monovalent ion that contains a metal, and the metal itself can be monovalent or multivalent. If

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the metal is monovalent, the metal ion preferably consists of the metal alone, e.g. a silver ion, a mercuroion (Hg +) or an alkali metal ion, e.g. a sodium or potassium ion. If the metal is multivalent, the metal ion contains the metal and one or more anionic ligands so that the metal ion itself is monovalent. Examples are HgCl + and HgBr +. If the metal is multivalent, the compound of formula II may also contain more than one residue of a 5-fluorouracyl derivative, and the metal ion is then considered to consist of the metal and all of these residues except one.

Instead of adding the metal salt of formula II to the reaction mixture on its own, the metal salt can be formed in situ from the corresponding free 5-fluorouracil derivative. E.g. the reaction can be carried out e.g. Mercuricyanid to a solution of the corresponding free 5-fluorouracil derivative and then add the compound of formula III.

The compound of formula III is an a-glycosyl halide, the halogen atom preferably being chlorine or bromine. When this α-glycosyl halide reacts with the compound of formula II, the corresponding β-glycoside of the 5-fluorouracil derivative is formed.

The reaction of the compounds of the formula II and III with one another is preferably carried out in the presence of a solvent. Any solvent can be used so long as it has no adverse effect on the reaction. Examples of suitable solvents are aromatic hydrocarbons, e.g. Toluene or xylene, dialkylamides of aliphatic acids, e.g. N, N-dimethylformamide or N, N-dimethylacetamide, dialkyl sulfoxides, e.g. Dimethyl sulfoxide, phosphoric acid amides, e.g. Hexamethylphosphoric triamide, nitroalkanes, e.g. Nitromethane and nitriles, e.g. Acetonitrile. Although there is no particular limitation on the reaction temperature, the reaction is generally carried out at a temperature of 0 to 150 ° C. If a non-polar solvent is used, the preferred reaction temperature is 100 to 150 ° C. If a polar solvent is used, a reaction temperature of approximately ambient temperature is preferred. The time required for the reaction depends mainly on the reaction temperature and the solvent used, but is generally between 5 minutes and 20 hours.

After the reaction has ended, the resulting compound of the formula IV can be separated off from the reaction mixture by conventional methods. E.g. After filtering off insoluble substances, the solvent can be removed from the reaction mixture by distillation under reduced pressure, after which the residue can be extracted with an organic solvent such as chloroform. The extract can then be washed with water and dried, after which the solvent can be removed from the extract by distillation. The residue so obtained can be mixed with an organic liquid such as ethanol, after which the mixture is cooled in the cold, e.g. can stand in a refrigerator to obtain the desired compound of formula IV in the form of crystals.

The compounds of the formula IV are intermediates in the synthesis of the antitumor agents of the formula I and are easily converted into such antitumor agents by reduction.

The hydroxyl protecting group in the pyrimidine residue and / or the amino protecting group in the glycoside residue are removed by reduction by contacting the compound of formula IV with a reducing agent, preferably in the presence of a solvent. The reducing agent used can be selected to achieve the best results, taking into account the type of protective group to be removed. When the hydroxyl protecting group is an optionally substituted benzyl group or the amino protecting group is an optionally substituted benzyloxycarbonyl group, the reducing agent is preferably hydrogen and a catalyst such as palladium on carbon. When the hydroxyl protecting group is a ß-haloethyl group or the amino protecting group is a ß-haloethoxycarbonyl group, the reducing agent is preferably metallic zinc with an acid, e.g. Acetic acid, or an alcohol, e.g. Methanol or ethanol. The type of solvent used is not critical unless it has an adverse effect on the reaction. Suitable solvents are alcohols, such as methanol or ethanol, and ethers, such as tetrahydrofuran and dioxane. The reaction temperature also plays no decisive role; For convenience, the reaction is therefore preferably carried out at about ambient temperature. The time required for the reaction depends mainly on the type of reducing agent, but is generally in the range of 5 to 60 minutes.

After completion of the implementation, the product can be obtained using conventional methods. E.g. After filtering off the insoluble substances, the solvent can be removed from the reaction mixture by distillation under reduced pressure, and an organic liquid such as ethanol can be added to the resulting residue, whereupon the mixture can be left to obtain the desired product in crystalline form.

5-Fluorouracil derivatives of the formula I, in which R3 denotes an amino group, can be converted into pharmaceutically acceptable acid addition salts in a conventional manner. Examples of suitable salts are the acid addition salts with mineral acids, e.g. Hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid, or with organic acids, e.g. Oxalic acid, succinic acid, maleic acid or citric acid.

The antitumor activity of the 5-fluorouracil derivatives obtainable according to the invention was tested according to the method described in Gann 61,485 to 493 (1970), Japan. The results of these tests are shown in Table I below. In each case, BDFi strain mice were used as test animals and the tests were carried out by intraperitoneally inoculating the mice with L-1210 leukemia cells (1 x 105). The day of administration of the agent given in the table means the number of days after vaccination with the leukemia cells.

Table I

Medium Dose Day of Type of Medium Improvement Administering- Overloading of mg / kg / handing Life Time Length of Day (Days) Life Time (%)

Connection 2

500

1

i.p.

10.2

20th

FT-207

250

1

i.p.

10.4

22

comparison

-

-

-

8.5

-

Connection 3

500

1

i.p.

13.0

78

5-FU

100

1

i.p.

13.2

81

FT-207

400

1

i.p.

9.2

26

comparison

-

-

-

7.3

-

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65

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Medium Dose Day of Type of Medium Improvement Administering- Overloading of mg / kg / handing Life Time Length of Day (Days) Life Time (%)

Connect

500

1

i.p.

10.6

33

exercise 10

5-FU

100

1

i-p.

13.8

73

FT-207

400

1

i.p.

11.0

38

comparison

-

-

8.0

-

It is thus proven that the compounds obtainable according to the invention have valuable antitumor activity.

The compounds of formula I can be administered by any of the methods commonly used for the administration of anti-tumor agents, e.g.

by parenteral administration, intravenous injection or oral administration in the form of e.g. Tablets, capsules, granules, powders or syrups. The amount to be administered depends on the symptoms, age and body weight of the patient, but is generally in the range of 5 to 50 mg per kg and per day for an adult when administered intravenously and between 200 and 2000 mg per day for one Adults when administered orally. The compound can be administered in divided doses one to four times a day.

U. Bicker in Nature 252, 726 (1974) reported that combining glucose with an antitumor agent generally results in an increase in antitumor activity. It has been found that this combination with the 5-fluorouracil derivatives of the formula I is particularly effective. To demonstrate this effect, female mice from the DBA / 2 strain can be

535-539 (1970), Japan, are subcutaneously inoculated using a trocar in the armpit with a piece of lymphoma LS-1 tissue approximately 2 mm in diameter. The anti-tumor agent is administered intraperitoneally daily on the first, third, fifth, seventh and ninth days after vaccination with the lymphoma tissue. Glucose in the form of a 10% aqueous solution in an amount of 1 ml is administered on the same day as the anti-tumor agent. The glucose is preferably administered with or before the administration of the 5-fluorouracil derivative of the formula I. The amount of glucose administered is preferably 400 to 4000 mg per kg per day for an adult.

The invention is further illustrated by the following preparation, which explains the production of a starting material used in the present method, and by the following examples.

preparation

Silver salt of 02-benzyl-5-fluorouracil

2nd

5.387 g (24.5 mmol) of 02-benzyl-5-fluorouracil were suspended in 90 ml of water and then completely dissolved by adding 29.4 ml of an aqueous sodium hydroxide solution. A solution of 4.17 g (24.5 mmol) of silver nitrate in 30 ml of water was then added dropwise to this solution and the mixture was then stirred at room temperature for a further 15 minutes. After the reaction has ended, the precipitate is collected by filtration, washed with water and dried.

Further drying at 60 ° C. in the presence of phosphorus pentoxide for 7 hours gave 7.9 g of the desired silver salt of 02-benzyl-5-fluorouracil.

Elemental analysis for CnHgChNîFAg-OjSHaO:

Calculated: C 39.31 H 2.70 N8.34 F 5.65% Found: C 39.14 H 2.48 N8.41 F 5.78%

Other metal salts of 5-fluorouracil derivatives can be prepared in a similar manner.

example 1

1 -0- (5-Fluoro-1 H-2-oxopyrimidin-4-yl) -2,3,4-tri-0-acetyl-β-D-glucopyranuronic acid methyl ester a) 1--0 (2-benzyloxy-5 -fluoropyrimidin-4-yl) -2,3,4-tri-0-acetyl-β-D-glucopyranuronic acid methyl ester

> COCH

OOC-CH

7.9 g (24.2 mmol) of the silver salt of 02-benzyl-5-fluorouracil (obtained according to the above preparation) were suspended in 320 ml of dry xylene, after which approximately 90 ml of the solvent were removed by distillation Removing the water in the suspension used a water separator. The resulting mixture was then allowed to cool. 9.1 g (24.2 mmol) of 2,3,4-tri-O-acetyl-1-bromo-1-deoxy-aD-glucopyranuronic acid methyl ester were added to the suspension thus obtained and the mixture was then refluxed for 5 minutes Boiling heated. The mixture was then allowed to cool and the insolubles were filtered off. The solvent was distilled off under reduced pressure and the residue was dissolved in chloroform. The chloroform solution was washed successively with 5% by weight aqueous sodium hydrogen carbonate solution and 20% by weight aqueous sodium chloride solution. The wash water was extracted with chloroform. After the chloroform phases were combined and dried, the solvent was distilled off to obtain a caramel-like residue. Then ethanol was added to the residue and the mixture was left to stand at 4 ° C. overnight, 7.3 g of the desired 1 -0- (2-benzyloxy-5-fluoropyrimidin-4-yl)

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-2,3,4-tri-O-acetyl-β-D-glucopyranuronic acid methyl ester in the form of crystals which melt at 120 to 121 ° C, was obtained.

Elemental analysis for C24H25O11N2F:

Calculated: C 53.73 H 4.70 N5.22 F 3.54% Found: C 53.94 H 4.56 N5.19 F 3.48%

Ultraviolet absorption spectrum:

^ • max (0> In-HCl, CH3OH) 271 nm (s = 8000);

WCHsOH) 271 nm (s = 7300);

X.max (0, In-NaOH, CH3OH) 270 nm (e = 9000).

b) l-0- (5-Fluoro-1H-2-oxopyrimidin-4-yl) -2,3,4-tri-0-acetyl-β-D-glucopyranuronic acid methyl ester lOCCH

OOC-CH

1.2 g of methyl l-0- (2-benzyloxy-5-fluoropyrimidin-4-yl) -2,3,4-tri-0-acetyl-β-D-glucopyranuronate was dissolved in 120 ml of anhydrous methanol. The atmosphere in the reaction container containing the solution was replaced with nitrogen, and 240 mg of 10% by weight palladium-on-carbon catalyst was added to the solution. The atmosphere was replaced again with fresh nitrogen gas and the mixture was subsequently stirred for 15 minutes, hydrogen gas being introduced at the same time under atmospheric pressure. After the reaction was completed, the insoluble matters were removed from the reaction mixture, and the solvent was removed by distillation under reduced pressure. Finally, the resulting residue was mixed with ethanol and the precipitated crystals were collected by filtering, whereby 891 mg of the desired l-0- (5-fluoro-1H-2-oxopyrimidin-4-yl) -2,3,4-tri -O-acetyl-ß-D-glucopyranuronic acid methyl ester in the form of white crystals of melting point 115 to 117 ° C. A further 106 mg of crystals from Hessen are obtained from the mother liquor.

Elemental analysis for CnHisOnNiF-HïO:

Calculated: C 43.97 H 4.56 N6.03 F 4.10% Found: C 44.70 H 4.55 N 5.89 F 4.26%

Ultraviolet absorption spectrum:

^ max (H20) 288 nm (e = 4800).

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Example 2

02- (2,3,4,6-tetra-0-acetyl-ß-D-glucopyranosyl) -5-fluorouracil a) 02- (2,3,4,6-tetra-0-acetyl-ß-D- glucopyranosyl) -04-benzyl-5-fluorouracil

6H

AcOÇH,

OAc1

OAc

Ac = acetyl

1.95 g (6.1 mmol) of the silver salt of 04-benzyl-5-fluorouracil were suspended in 100 ml of anhydrous xylene, which had previously been dehydrated with calcium hydride and then distilled. The mixture was heated to reflux to remove approximately 10 ml of the solvent. The water was removed by azeotropic distillation. After the resulting mixture had been cooled, 2.51 g (6.1 mmol) of 2,3,4,6-tetra-O-acetyl-cc-D-glucopyranosylbromide were added and the mixture was heated to boiling under reflux for 5 minutes . After the reaction had ended, the insoluble materials were filtered off and the filtrate was distilled under reduced pressure, giving a caramel-like residue which was dissolved in 30 ml of ethyl acetate and then once with an aqueous 5% by weight sodium hydrogen carbonate solution and twice with 20 ml of water each time was washed. The wash water was extracted with 15 ml of ethyl acetate. The combined ethyl acetate solutions were dried over anhydrous magnesium sulfate and distilled under reduced pressure to obtain a caramel-like substance which was dissolved in 15 ml of ethanol. The solution was left to stand, whereupon white crystals separated out. These crystals were recrystallized from a mixture of 15 ml of ethanol and 4 ml of benzene, 1.986 g of 02- (2,3,4,6-tetra-0-acetyl-β-D-glucopyranosyl) -04-benzyl-5- fluorouracil, melting point 140-141 ° C, was obtained.

The mother liquor was further concentrated and dried, and the residue was subjected to column chromatography using silica gel using chloroform as an eluent to obtain various fractions, which were purified. In this way, 274 mg of the desired crystalline product were obtained.

Elemental analysis for C25H27OÌ1N2F:

Calculated: C 54.55 H 4.94 N 5.09 F 3.45% Found: C 54.34 H 5.08 N5.04 F 3.30%

Ultraviolet absorption spectrum:

^ max (0.1 HCl in CH3OH) 264 nm (e = 5200);

Àmax (CH3OH) 264 nm (e = 5100);

? w (0.1n NaOH in CH3OH) 265 nm (e = 5500).

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b) 02- (2,3,4,6-Tetra-0-acetyl-β-D-glucopyranosyI) -5-fluorouracil

AcOÇH,

OAc

OAc

OAc

Ac = acetyl

550 mg (1 mmol) of 02- (2,3,4,6-tetra-0-acetyl-β-D-glucopy-ranosyl) -04-benzyl-5-fluorouracil were dissolved in 30 ml of anhydrous methanol. The atmosphere in the reaction vessel containing the solution was replaced with dry nitrogen gas, after which 100 mg of a 10% by weight palladium-on-carbon catalyst was added. Then hydrogen gas was bubbled into the solution at normal pressure and at room temperature, shaking the container until 24 ml of hydrogen was absorbed. When the reaction was complete, the atmosphere in the container was replaced by fresh nitrogen gas and the catalyst was filtered off. The filtrate was concentrated by evaporation under reduced pressure and then dried to give a crystalline residue. This was dissolved in 45 ml of anhydrous ethanol while heating. The ethanolic solution was left in a refrigerator overnight, with crystals separating. These were filtered off and gave 373 mg of white crystals of the desired 02- (2,3,4,6-tetra-0-acetyl-β-D-glucopyrano-syl) -5-fluorouracils (compound 6). These crystals melted at 140 to 142 ° C and decomposed at 197 to 212 ° C.

Elemental analysis for C18H21O11N2F:

Calculated: C 46.96 H 4.60 N6.09 F 4.13% Found: C 47.23 H 4.90 N 5.73 F 3.95%

Ultraviolet absorption spectrum:

Xn, ax (CH30H) 266 nm (s = 6200).

Example 3

04- (2,3,4,6-tetra-0-acetyl-ß-D-glucopyranosyl) -5-fluorouracil a) 04- (2,3,4,6-tetra-0-acetyl-ß-D- glucopyranosyl) -02-benzyl-5-fluorouracil c

ACOCH2

OAc

CAc

OAc where Ac = acetyl

4.91 g (15 mmol) of the silver salt of 02-benzyl-5-fluorouracil were suspended in 220 ml of dry xylene; then 20 ml of xylene was distilled off to remove all water. Then 6.17 g (15 mmol) of 2,3,4,6-tetra-O-acetyl-a-D-glucopyranosyl bromide was added to the suspension and the mixture was heated to reflux for 5 minutes. When the reaction was over, a grayish yellow insoluble material was filtered off, and the solution was concentrated under reduced pressure and dried. The residue was dissolved in 100 ml of ethyl acetate and the solution was washed once with 70 ml of a 5% by weight aqueous sodium hydrogen carbonate solution and twice with 70 ml of water. The aqueous washes were extracted several times with 50 ml of ethyl acetate and the combined ethyl acetate solutions were dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure to obtain a caramel-like substance, which was then dissolved in ethanol. By adding isopropanol to the ethanol solution, crystals precipitated, which were filtered off and dried, and 5.795 g of the desired 04- (2,3,4,6-tetra-0-acetyl-β-D-glu-copyranosyl) -02 -benzyl -5-fluorouracils in the form of white crystals with a melting point of 95 to 96 ° C.

Elemental analysis for C25H27O11N2F:

Calculated: C 54.54 H 4.94 N5.09 F 3.26% Found: C 54.33 H 4.92 N 4.70 F 3.26%.

Ultraviolet absorption spectrum:

A. max (0.1 normal HCl in CHIOH) 270 nm (e = 7200); A. max (CH30H) 270 nm (e = 7100);

^ max (0.1 normal NaOH in CH3OH) 270 nm (s = 8300).

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b) 04- (2,3,4,6-Tetra-0-acetyl-β-D-glucopyranosyl) -5-fluoro-uracil

ACOCH2

OAc

OAC

where Ac = acetyl

5.795 g (10.5 mmol) of 04- (2,3,4,6-tetra-0-acetyl-β-D-glucopyranosyl) -02-benzyl-5-fluorouracil were dissolved in 130 ml of distilled tetrahydrofuran; the atmosphere in the vessel containing the solution was then replaced with nitrogen gas, and 526 mg of 10% by weight palladium on carbon was added to the solution. Hydrogen was introduced into the vessel and the mixture was reduced with shaking at ambient temperature and pressure until 254 ml of hydrogen had been absorbed. The atmosphere in the vessel was then replaced with nitrogen gas, whereupon another 52 mg of palladium on carbon was added and another 14 ml of hydrogen gas was absorbed. When the reaction was completed, the atmosphere in the vessel was replaced with nitrogen gas and the catalyst was filtered off. The filtrate was concentrated by evaporation under reduced pressure and then dried to give a crystalline residue to which methanol was added. The resulting crystals were filtered off to give 4.318 g of the desired 04- (2,3,4,6-tetra-0-acetyl-β-D-glucopyranosyl) -5-fluorouracils (Compound 7) of melting point 154 to 155 ° C .

Elemental analysis for C25H27O11N2F:

Calculated: C 54.54 H 4.94 N5.09 F 3.26% Found: C 54.33 H 4.92 N4.70 F 3.26%.

Ultraviolet absorption spectrum:

A.max (0.1 normal HCl in CH3OH) 270 nm (s = 7200); ^ max (CHîOH) 270 nm (e = 7100);

^ max (0.1 normal NaOH in CH3OH) 270 nm (e = 8300).

Example 4

l-0- (5-fluoro-lH-4-oxopyrimidin-2-yl) -2,3,4-tri-0-acetyl-β-D-glucopyranuronic acid methyl ester a) l-0- (4-benzyloxy-5- fluoropyrimidin-2-yl) -2,3,4-tri-0-acetyl-β-D-glucopyranuronic acid methyl ester

C.

OAc

OAc

OAc

5.23 g (16 mmol) of the silver salt of 04-benzyl-5-fluorine-uracil were suspended in 250 ml of dry xylene, whereupon the suspension was heated to reflux. Then about 50 ml of xylene was removed by azeotropic distillation to remove the water. The remaining suspension was mixed with 6.35 g (16 mmol) of 2,3,4-tri-O-acetyl-1-bromo-1-deoxy-a-D-glucopyranuronic acid methyl ester and the mixture was heated to reflux for 12 minutes. After the completion of the reaction, the mixture was allowed to cool, whereupon insoluble substances which failed on standing left

were removed by filtration. The filtrate was then evaporated to dryness by distillation under reduced pressure, leaving a residue which was dissolved in 100 ml of ethyl acetate. The ethyl acetate solution was washed in turn with 50 ml of a 5% aqueous sodium bicarbonate solution, 50 ml of a saturated aqueous sodium chloride solution and 50 ml of water. The washed solution was then dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure, leaving a caramel-like material. A mixture of benzene and ethanol was added to this material, causing the material to crystallize. 7.107 g of the desired 1-0- (4-benzyloxy-5-fluoropy-rimidin-2-yl) 2,3,4-tri-0-acetyl-β-D-glucopyranuronic acid, methyl ester were obtained in the form of white powdery crystals receive. A further 450 mg of crystals were obtained from the mother liquor. The melting point of the product was 141 ° C.

Elemental analysis for C24H25O11N2F:

Calculated: C 53.73 H 4.70 N5.22 F 3.54% Found: C 54.03 H 4.68 N5.03 F 3.56%

Ultraviolet absorption spectrum:

A, max (50% 0.1 normal HCl, 50% CH3OH) 264 nm (e = 8200); ? wx (50% CH3OH, 50% H2O) 264 nm (e = 8000);

A. max (50% 0.1 normal NaOH, 50% CH3OH) 265.5 nm (e = 8200).

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b) 1 -0- (5-Fluoro-1 H-4-oxopyrimidin-2-yl) -2,3,4-tri-0-acetyl-β-D-glucopyranuronic acid, methyl ester

CH-.0-C0

OAc

OAc

OAc

0.55 g (1.04 mmol) of l-0- (4-benzyloxy-5-fiorpyrimidin-2-yl) -2,3,4-tri -O-acetyl-β-D-glucopyranuronic acid methyl ester were dissolved in 40 ml of anhydrous Dissolved methanol, whereupon the atmosphere in the reaction vessel containing the solution was replaced by nitrogen gas. Then 0.11 g of 10 wt% palladium on carbon was added to the solution and the mixture was stirred in a stream of hydrogen gas for 7 minutes. After the completion of the reaction, the catalyst was filtered off and the solvent was then distilled off under reduced pressure, leaving a residue. This residue was crystallized by adding anhydrous ethanol and gave 378 mg of the desired 1- 0- (5-fluoro-1H-4-oxopyrimidin-2-yl) -2,3,4-tri-O-acetyl-β-D -glucopyranuronic acid methyl ester (compound 8) in the form of white crystals with a melting point of 165 to 167 ° C.

Elemental analysis for C17H19O11N2F:

Calculated: C 45.75 H 4.29 N6.28 F 4.26% Found: C 45.35 H 4.35 N6.32 F 4.02%

Ultraviolet absorption spectrum:

^ max (CH30H) 266 nm (e = 6400).

Example 5

1 -0- (5-Fluoro-1 H-4-oxopyrimidin-2-yl) -ß-D-glucopyranuron acid amide

P

N

OH

OH

OH

357 mg (0.8 mmol) of l-0- (5-fluoro-1H-4-oxopyrimidin-2-yl) -2,3,4-tri-0-acetyl-β-D-glucopyranuronic acid methyl ester were dissolved in 27 ml anhydrous methanol dissolved, whereupon the solution was saturated with ammonia by introducing dry ammonia. The resulting mixture was allowed to stand in a refrigerator overnight. When the reaction was completed, the solvent was removed by distillation under reduced pressure, and the residue was dissolved in a small volume of methanol. 10 ml of chloroform was added to the solution to form a precipitate, which was isolated by filtration and then suspended in chloroform. The suspension was stirred for 30 minutes and then filtered to give 270 mg of a powder which gave a single spot on thin layer chromatography on silica gel developed with chloroform containing 50% by volume of methanol. The melting point was 120 to 125 ° C (with decomposition).

Elemental analysis for CioHhOtNjF-HîO:

Calculated: C 37.16 H 4.37 N 13.00 F 5.88% Found: C 37.05 H 4.23 N 12.85 F 5.66%

Ultraviolet absorption spectrum:

Àmax (0.02 molar phosphate buffer, pH 6.86) 268 nm (e = 6700).

Example 6

04- (3,4,6-tri-0-acetyl-2-amino-2-deoxy-ß-D-glucopyrano-syl) -5-fluorouracil a) 02-benzyl-04- (3,4,6- tri-0-acetyl-2-deoxy-2-trichloro-thoxy carbonylamino-β-D-glucopyranosyl) -5-fluorouracil c

NH-CO-OCH "CCl

23.1 g (71 mmol) of the silver salt of 02-benzyl-5-fluorouracil was suspended in 710 ml of anhydrous toluene, which had been dehydrated and distilled with calcium hydride; the suspension was then distilled until 50 ml of toluene was removed to remove water by azeotropic distillation. The suspension was then cooled to room temperature. A solution of 33.6 g (71 mmol) of 3,4,6-tri-O-acetyl-2-deoxy-2-trichloroethoxycarbonylamino-2-aD-glucopyranosyl bromide in 100 ml of dry toluene was added to the suspension, whereupon the mixture was heated to reflux with stirring for 15 minutes. When the reaction was over, insoluble substances were filtered off, and the filtrate was concentrated by evaporation under reduced pressure and dried. A caramel-like residue formed, which was dissolved in 500 ml of ethyl acetate and then in succession with 300 ml of a 5% strength by weight aqueous solution

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643 272

Sodium hydrogen carbonate solution and 500 ml of a saturated aqueous sodium chloride solution. After filtering off insoluble substances, the organic phase was dried with anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. 43.2 g of the desired 02-benzyl-04- (3,4,6-tri-0-acetyl-2-deoxy-2-trichlorätho-xycarbonylamino-ß-D-glucopyranosyl) -5-fluorouracil were obtained as a caramel-like substance receive. This substance was used in the following step without further purification, but for analysis it was purified by column chromatography on silica gel using chloroform containing 1% by volume of methanol as an eluent.

Ultraviolet absorption spectrum:

Λ max (0.1 normal HCl in CH3OH) 270 nm (e = 6950); A max (CH30H) 271 nm (e = 7260);

Àmax (0.1 normal NaOH in CH3OH) 272 nm (e = 7310).

Nuclear Magnetic Resonance Spectrum (CDCb), 5 (ppm): 6.30 (doublet, H in the 1 'position, Jr_2' = 8.5 Hz)

Elemental analysis for C26H270iiN3C13F-1 / 3CHC13: Calculated: C 43.77 H 3.81 N5.81 F 2.56% Found: C 43.88 H 3.66 N6.04 F 2.56%

b) 02-benzyl-04- (3,4,6-tri-0-acetyl-2-amino-2-deoxy-β-D-glucopyranosyl) -5-fluorouracil

C6H5CH2V ^ (K

nAf

AcOCHp I

U-0

v i yoAc y

NH2

where Ac = acetyl

43.2 g (63.0 mmol) of the crude 02-benzyl-04- (3,4,6-tri-0-acetyl-2-deoxy-2-trichloroethoxycar bonylamino-β-D) obtained in step (a) -glucopyranosyl) -5-fluorouracils were dissolved in 200 ml of 80% acetic acid. In the meantime, 20.4 g (31.5 mmol) of zinc dust were suspended in 330 ml of 80% acetic acid, stirred for about 5 minutes and cooled to about 20 ° C. with ice. The solution was then added to the suspension with stirring and the mixture was stirred for a further 70 minutes after the addition of 80% acetic acid. After the completion of the reaction, insoluble substances were filtered off, and the solvent was evaporated under reduced pressure. A residue was obtained, which was dissolved in 300 ml of ethyl acetate and then washed in turn with 300 ml of ice water, with 500 ml of 5% by weight aqueous sodium hydrogen carbonate solution, with 200 ml of water and with 200 ml of saturated saline. Each of the aqueous washes was extracted with 100 ml of ethyl acetate, after which all of the ethyl acetate solutions were combined and then dried over anhydrous magnesium sulfate; the solvent was then distilled off. The residue was dissolved in 200 ml of ethanol and the solution was distilled to reduce its volume to about 100 ml; then the solution was left to stand at about 5 ° C. overnight. The crystals that precipitated were filtered off and dried to give 14.38 g of the desired 02-benzyl-04- (3,4,6-tri-0-acetyl-2-amino-2-deoxy-β-D-glucopyranosyl ) -5-fluorouracils in the form of colorless crystals with a melting point of 141 to 142 ° C.

Ultraviolet absorption spectrum:

Xmax (0.1 normal HCl in CH3OH) 270 nm (e = 6900); A ™ ax (CH30H) 271 nm (e = 6990);

? 4nax (0.1 normal NaOH in CH3OH) 270 nm (e = 6880).

Nuclear Magnetic Resonance Spectrum (CDCb), 8 (ppm): 8.24 (doublet, H in 6-position, J6H_F = 2.0 Hz); 5.90 (doublet, H in the 1 'position, Jr_2 <= 8.5 Hz); 5.40 (singlet, -Cth-CsHs).

Elemental analysis for C23H26O9N3F;

Calculated: C 54.44 H 5.16 N 8.28 F 3.74% Found: C 54.18 H 5.44 N 8.28 F 3.45%

c) 04- (3,4,6-Tri-0-acetyl-2-amino-2-deoxy-ß-D-glucopy-ranosyl) -5-fluorouracil where Ac = acetyl

517 mg of 02-benzyl-04- (3,4,6-tri-0-acetyl-2-amino-2-deoxy-β-D-glucopyranosyl) -5-fluorouracil were dissolved in 50 ml of anhydrous ethanol; the atmosphere in the reaction vessel containing the solution was then replaced with dry nitrogen gas. 50 mg of 10% by weight palladium on carbon was added, and the solution was stirred while introducing hydrogen gas at atmospheric pressure until 20 ml of hydrogen gas was absorbed. When the reaction was over, the catalyst was filtered off and the filtrate was concentrated by evaporation under reduced pressure. The residue was dissolved in 5 ml of anhydrous methanol. 20 ml of anhydrous ethanol was added and the solution was concentrated by evaporation under reduced pressure. Crystals formed which were filtered off and dried. 250 mg of the desired 04- (3,4,6-tri-0-acetyl-2-amino-2-deoxy-β-D-glucopyranosyl) 5-fluorouracil (compound 3) with a melting point of 129 to 130 ° C. ( with decomposition).

Ultraviolet absorption spectrum:

^ max (CH3OH) 291 nm (e = 5010).

Magnetic nuclear magnetic resonance spectrum (dimethyl sulfoxide-dö), 5 (ppm):

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8.13 (doublet, H in 6-position, J6h-f = 5.5 Hz); 6.06 (doublet, H in the 1 'position, J | <_2' = 8.0 Hz).

Elemental analysis for Ci6H2oOçN3F- H2O:

Calculated: C 44.14 H 5.09 N9.65 F 4.36% Found: C 44.05 H 4.77 N9.39 F 3.87%

Example 7

04- (3,4,6-tri-0-acetyl-2-amino-2-deoxy-ß-D-glucopyrano-syl) 5-fluorouracil hydrochloride a) 02-benzyl-04- (3,4,6 -tri-0-acetyl-2-amino-2-deoxy-β-D-glucopyranosyl) -5-fluorouracil hydrochloride

3.04 g (6 mmol) 02-benzyl-04- (3,4,6-tri-0-acetyl-2-amino-2-deoxy-ß-D-glucopyranosyl) -5-fluorouracil, which is as in Example 6b) was obtained, were dissolved in 160 ml of acetone; a solution of 1.96 ml of diethyl ether, which contained 0.95 equivalents of hydrogen chloride, in 40 ml of acetone was added dropwise. When the reaction was complete, the white precipitate produced was filtered off, washed with acetone and dried and gave 2.67 g of the desired product in the form of white crystals with a melting point of 171 to 172 ° C. (with decomposition). The filtrate was concentrated, leaving a crystalline residue to which 200 ml of acetone were added. A further 378 mg of the desired product were obtained by filtering off the residue, washing with acetone and drying. This product also had a melting point of 171 to 172 ° C (with decomposition).

Ultraviolet absorption spectrum:

^ max (CH30H) 270 nm (b = 7030).

Nuclear Magnetic Resonance Spectrum (Dimethylsulfoxyd-d «), S (ppm):

8.63 (doublet, H in 6-position, J6h_f = 2.7 Hz); 6.78 (doublet, H in the 1 'position, Jr_2' = 8.5 Hz).

Elemental analysis for C23H2609N3F-HCl:

Calculated: C 50.79 H 5.00 N7.73 C16.52 F 3.49%

Found: C 50.84 H 4.98 N7.80 C16.55 F 3.30%

b) 04- (3,4,6-Tri-0-acetyl-2-amino-2-deoxy-β-D-glucopy-ranosyl) -5-fluorouracil hydrochloride

54.4 mg of 02-benzyl-04- (3,4,6-tri-0-acetyl-2-amino-2-deoxy-β-D-glucopyranosyl) -5-fluorouracil hydrochloride was dissolved in 50 ml of anhydrous methanol ; the atmosphere in the vessel containing the solution was then replaced with dry nitrogen gas. 50 mg of 10 wt% palladium on carbon was added and hydrogen gas was bubbled through the solution with stirring at atmospheric pressure until 20 ml of hydrogen gas was absorbed. When the reaction was over, the catalyst was filtered off and the filtrate was concentrated to form crystals, which were filtered off, washed with anhydrous ethanol and then dried. White crystals of the desired 04- (3,4,6-tri-0-acetyl-2-amino-2-deoxy-β-D-glucopyranosyl) -5-fluorouracil hydrochloride of melting point 112 to 116 ° C. (below Decomposition).

Elemental analysis for C16H20O9N3F • HCl • H2O:

Calculated: C 40.73 H 4.70 N8.91 Cl 7.51 F 4.03%.

Found: C 40.66 H 4.67 N9.55 Cl 7.23 F 3.57%

Example 8

02- (3,4,6-tri-0-acetyl-2-amino-2-deoxy-ß-D-glucopyrano-syl) 5-fluorouracil a) 04-benzyl-02- (3,4,6-tri -0-acetyl-2-deoxy-2-trichloro-thoxycarbonylamino-β-D-glucopyranosyl) -5-fluorouracil

6h

ACOCH,

OAc

NH-CO-OCHoCCl where Ac = acetyl

10.8 g (33 mmol) of the silver salt of 04-benzyl-5-fluorouracil were suspended in 330 ml of anhydrous toluene, which had been dehydrated with calcium hydride and then distilled. The suspension was then heated to distill off about 30 ml of toluene and thus remove water by azeotropic distillation; the suspension was then cooled to room temperature. A solution of 17.9 g (33 mmol) of 3,4,6-tri-O-acetyl-2-deoxy-2-trichloroethoxycarbonylamino-aD-glucopyrano-sylbromide in 30 ml of anhydrous toluene was then added to the suspension, whereupon the The mixture was heated to reflux for 30 minutes. When the reaction was over, the crystalline precipitate was filtered off and the filtrate was distilled under reduced pressure. The residue was dissolved in 200 ml of ethyl acetate and washed once with 150 ml of 5% by weight aqueous sodium hydrogen carbonate solution and twice with 200 ml of water. Each of the aqueous washes was extracted with 50 ml of ethyl acetate, whereupon the ethyl acetate solutions were combined and dried over anhydrous magnesium sulfate. The solvent was then distilled off, 26.3 of the desired 04-benzyl-02- (3,4,6-tri-0-acetyl-2-deoxy-2-trichloroethoxycarbonylamino-β-D-glucopyra-nosyl) -5- fluoruracils were obtained as a raw caramel-like product. For identification, this crude product was purified by chromatography on silica gel using chloroform containing 1% by volume of methanol as the eluent. However, it was used as the starting material in the following step without further purification.

Ultraviolet absorption spectrum:

^ max (0J normal HCl in CH3OH) 265 nm (s = 6900); A. max (H20 / CH30H) 265 nm (e = 8200);

Ä-max (0.1 normal NaOH in CH3OH) 266 nm (e = 8000).

Nuclear Magnetic Resonance Spectrum (CDCb), S (ppm): 8.48 (doublet, H in 6-position, J6H_F = 2.6 Hz); 6.18 (doublet, H in the 1'-position, Jrj '= 9.0 Hz); 5.55 (singlet, -CH2-C6H5).

Elemental analysis for C26H27O11N3CI3F • '/ sCHCh • 0.5CH3ÛH:

Calculated: C 44.80 H 4.11 N 5.89 Cl 16.76 F 2.66%

Found: C 44.63 H 3.82 N 5.57 Cl 16.72 F 2.41%

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b) 04-benzyl-02- (3,4,6-tri-0-acetyl-2-amino-2-deoxy-ß-D-glucopyranosyl) -5-fluorouracil c) 02- (3,4,6- Tri-0-acetyl-2-amino-2-deoxy-β-D-glucopy-ranosyl) -5-fluorouracil

15

where Ac = acetyl

9.8 g (150 mmol) of zinc dust were suspended in 250 ml of 80% acetic acid, whereupon the mixture was stirred at room temperature and cooled to about 20 ° C. The resulting suspension was washed with a solution of 20.5 g (30 mmol) of the crude 04-benzyl-02- (3,4,6-tri-0-acetyl-2-deoxy-2- trichloroethoxycarbonylamino-β-D-glucopyranosyl) -5-fluorouracils in 80 ml of 80% acetic acid; then the mixture was stirred at room temperature for 2 hours. After the completion of the reaction, insoluble substances were filtered off, and the solvent was distilled off under reduced pressure, leaving a caramel-like residue. This residue was dissolved in 350 ml of ethyl acetate and washed once with 300 mm of ice water, 300 ml of an aqueous sodium hydrogen carbonate solution or 300 ml of ice water. Each of the aqueous washes was extracted with 100 ml of ethyl acetate, and the ethyl acetate solutions were combined. The combined solutions were dried over anhydrous magnesium sulfate and the solvent was distilled off. A residue was obtained which was dissolved in ethanol. The ethanol solution was concentrated to give crystals, which were filtered off and 10.7 g of the desired 04-benzyl-02- (3,4,6-tri-0-acetyl-2-amino-2-deoxy-β-D -glucopyranosyl) -5-fluorouracils with a melting point of 61 to 62 ° C.

Ultra violet absorption spectrum:

A max (0, normal HCl in CHbOH) 263.5 nm (e = 8300); àraax (H20 / CH30H) 265 nm (e = 8200);

Àmax (0.1 normal NaOH in CH3OH) 265 nm (£ = 8200).

Nuclear magnetic resonance spectrum (dimethyl sulfoxide-ds), 5 (ppm):

8.49 (doublet, H in 6-position, J6h_f = 2.6 Hz); 5.94 (doublet, H in the 1'-position, Jr_v = 8.5 Hz); 5.58 (singlet, -CH2-C6H5).

Elemental analysis for C23H2609N3F-0.5C2H50H: Calculated: C 54.34 H 5.51 N7.92 F 3.58% Found: C 53.91 H 5.31 N 8.00 F 3.50%

25 where Ac = acetyl

507 mg (1 mmol) of 04-benzyl-02- (3,4,6-tri-0-acetyl-2-amino-2-deoxy-β-D-glucopyranosyl) -5-fluorouracil were dissolved in 30 ml of anhydrous methanol ; the atmosphere in the vessel containing the solution was replaced with dry nitrogen gas. 50 mg of 10% by weight palladium on carbon was then added to the solution, and hydrogen gas was bubbled through at room temperature until 23 ml of hydrogen gas had been absorbed). When the reaction was over, the catalyst was filtered off, and the solvent was distilled off under reduced pressure. Anhydrous methanol was added to the residue thus obtained, and the mixture was concentrated by evaporation under reduced pressure to obtain a precipitate. This precipitate was filtered off, washed 40 with anhydrous ethanol and then dried to give 283 mg of the desired 02- (3,4,6-tri-0-acetyl-2-amino-2-deoxy-ß-D-glucopyranosyl) -5 -fluorouracils (compound 4) as a white powder with a melting point of 103 to 104 ° C.

45 ultraviolet absorption spectrum:

A. max (CH30H) 267 nm (e = 6000).

Magnetic nuclear magnetic resonance spectrum (dimethyl sulfoxide-d <0, S (ppm):

7.84 (doublet, H in 6-position, J6h-f = 3.7 Hz); so 5.97 (doublet, H in the 1 'position, Jv.2 <= 8.3 Hz). Elemental analysis for Ci6H2o09N3F-0,5H20:

Calculated: C 45.07 H 4.96 N9.86 F 4.46% Found: C 45.33 H 5.33 N9.93 F 3.92%

55 Example 9

02- (3,4,6-tri-0-acetyl-2-amino-2-deoxy-ß-D-glucopyrano-syl) 5-fluorouracil hydrochloride a) 04-benzyl-02- (3,4,6 -tri-0-acetyl-2-amino-2-deoxy-β-D-glucopyranosyl) -5-fluorouracil hydrochloride 60 9.3 g (18.3 mmol) 04-benzyl-02- (3,4,6 tri-0-acetyl-2-amino-2-deoxy-β-D-glucopyranosyl) -5-fluorouracil (obtained as described in Example 8b) were dissolved in a mixture of 60 ml of acetone and 30 ml of diethyl ether. Then an ethereal solution containing one equivalent of hydrogen chloride was added to the solution while cooling with ice. When the reaction was over, about 80 ml of acetone was added to the reaction mixture, whereby crystals precipitated. These crystals were crushed, filtered off, with acetone

643 272

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washed and then dried to give 8.5 g of the desired 04-benzyl-02- (3,4,6-tri-0-acetyI-2-amino-2-deoxy-ß-D-glucopyranosyl) -5-fluorouracil hydrochloride in Form of white crystals with a melting point of 157 to 159 ° C (with decomposition).

Ultraviolet absorption spectrum:

A. max (CH30H) 263 nm (e = 7600).

Nuclear Magnetic Resonance Spectrum (Dimethylsulfoxyd-de), 8 (ppm):

8.55 (doublet, H in 6-position, J6h-f = 2.5 Hz); 6.57 (doublet, H in the 1'-position, J | ._r = 8.0 Hz); 5.61 (singlet, -CH2-C6H5).

Elemental analysis for C23H26O9N3F • HCl:

Calculated: C 50.48 H 5.00 N7 / 73 Cl 6.51 F 3.49%

Found: C 50.48 H 5.03 N 7.55 Cl 6.50 F 3.28%

b) 02- (3,4,6-Tri-0-acetyl-2-amino-2-deoxy-β-D-glucopyranosyl) -5-fluorouracil hydrochloride

544 mg (1 mmol) of 04-benzyl-02- (3,4,6-tri-0-acetyl-2-amino-2-deoxy-ß-D-glucopyranosyI) -5-fluorouracil hydrochloride were obtained in 50 ml of anhydrous methanol dissolved; the atmosphere in the vessel containing the solution was then replaced with dry nitrogen gas. 50 mg 10

% by weight palladium on carbon was added to the solution, and the mixture was stirred at ambient temperature while bubbling hydrogen gas until 21 ml of hydrogen gas was absorbed. When the reaction 5 was completed, the catalyst was filtered off, and the filtrate was concentrated by evaporation under reduced pressure to form crystals. A small volume of anhydrous ethanol was then added and the distillation continued. The crystals obtained were filtered off, washed with anhydrous ethanol and then dried to give 304 mg of the desired 02- (3,4,6-tri-0-acetyl-2-amino-2-deoxy-β-D-glucopyrano -syl) 5-fluorouracil hydrochloride in the form of white crystals with a melting point of 140 to 148 ° C (with decomposition). 15 ultraviolet absorption spectrum:

• ^ max (phosphate buffer, pH 6.86) 266 nm (e = 6000).

Magnetic nuclear magnetic resonance spectrum (dimethyl sulfoxide-d <0, S (ppm):

7.94 (doublet, H in 6-position, J6h-f = 3.5 Hz); 20 6.32 (doublet, H in the l'-position, Ji'_2 '= 8.0 Hz).

Elemental analysis for Ci6H2oC> 9N3F-HCl:

Calculated: C 42.35 H 4.66 H 9.26 Cl 7.81 F 4.19%

Found: C 42.03 H 4.56 N9.00 Cl 7.77 25 F 3.83%

Claims (12)

643 272 2nd PATENT CLAIMS 1. Process for the preparation of 5-fluorouracil derivatives of the formula: (X) wherein one of the symbols R1 and R2 represents hydrogen and. the other a glycoside residue of the formula: RO-ÇH or MR- MR- MR- where R is an acyl group, R3 is a group of the formula -OR or an amino group and R4 is an alkoxy group, a cycloalkoxy group, an aralkoxy group, an aryloxy group or an amino group of the form 50: R R \ 6 / N- a) a compound of the formula ,8th R70 (II) means, where Rs and R6 are identical or different and each represent hydrogen, an alkyl group, a cycloalkyl group, an aralkyl group or an aryl group or Rs and R6 together with the nitrogen atom to which they are attached form a 5- to 7-membered cyclic amino group, or, if R3 represents an amino group, of acid addition salts thereof, characterized in that one of the symbols R7 and R8 represents a metal ion and the other represents a reductively removable hydroxyl protective group, with a compound of the formula: 65 R9-X (III) wherein X represents a halogen atom and R9 represents a glycoside residue of the formula: 643 272 or MR- where R and R4 have the meanings given above and R3 'represents a group of the formula -OR or a protected amino group, to a compound of the formula: (IV) 10 R 0 in which one of the symbols R10 and R "denotes a reductively removable hydroxyl protective group and the other represents the group R9, b) subjecting the compound of Formula IV to reduction to produce the compound of Formula I, and c) subjecting the compound of Formula I to salt formation, if necessary, to an acid addition salt. 2. The method according to claim 1, characterized in that the metal ion is a silver, mercuro, sodium or potassium ion or an ion of the formula HgCl + or HgBr +. 3. The method according to claim 1 or 2, characterized in that stage a is carried out in the presence of an aromatic hydrocarbon, a dialkyl amide, an aliphatic acid, a dialkyl sulfoxide, a phosphoric acid reamide, a nitroalkane or a nitrile as a solvent. 4. The method according to any one of claims 1 to 3, characterized in that one carries out the reaction at a temperature of 0 to 150 ° C. 5. The method according to claim 4, characterized in that a non-polar solvent is used in stage a and this stage is carried out at a temperature of 100 to 150 ° C. 6. The method according to claim 4, characterized in that step a is carried out in the presence of a polar solvent and at a temperature of about ambient temperature. 3o 7. The method according to any one of claims 1 to 6, characterized in that the reduction in stage b is carried out with the aid of hydrogen and a catalyst. 8. The method according to claim 7, characterized in that palladium on carbon is used as the catalyst. 35 9. The method according to any one of claims 1 to 6, characterized in that one carries out the reduction in stage b with the aid of metallic zinc and an acid or an alcohol. 10. The method according to claim 9, characterized in that to use acetic acid as the acid. 11. The method according to claim 9, characterized in that methanol or ethanol is used as the alcohol. 12. The method according to any one of claims 1 to 11, characterized in that the salt formation in step c 45 with the help of hydrochloric acid. 13. The method according to any one of claims 1 to 12, characterized in that one of the symbols R10 and R11 is benzyl, a substituted benzyl group with one or more nitro and / or halogen substituents in the phenyl radical or a β-halogenoethyl group and the other represents a glycoside radical of the formula given in connection with formula III, where R is an aliphatic acyl group with 2 to 4 carbon atoms or an aromatic acyl group with 7 to 11 carbon atoms, 55 R3 'is a group of the formula -OR, a benzyloxycarbonylamino group, a substituted benzyloxycarbonylamino group with one or more nitro and / or halogen substituents in the phenyl radical or represents a β-halogenoethoxycarbonylamino group and R4 is a straight-chain or branched-chain alkoxy group having 1 to 8 carbon atoms, a cycloalkoxy group having 5 to 7 ring carbon atoms, an aralkoxy group having 7 to 12 carbon atoms, a substituted aralkoxy group having 7 to 12 carbon atoms , wherein the aromatic ring has one or more substituents selected from alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or halogen atoms, an aryloxy group of 6 to 10 carbon atoms, a substituted aryloxy group of 6 to 10 carbon atoms. 643 272 4th len atoms, wherein the aromatic ring has one or more substituents selected from alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms or halogen atoms, or an amino group of the formula: s R \ N— or MR- means, where R5 and R6 are the same or different and each hydrogen, an unbranched or branched alkyl group having 1 to 5 carbon atoms, a cycloalkyl group having 5 to 7 ring carbon atoms, an aralkyl group having 7 to 12 carbon atoms, a substituted aralkyl group having 7 to 12 Carbon atoms, wherein the aromatic ring has one or more substituents selected from alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms or halogen atoms, an aryl group having 6 to 10 carbon atoms or a substituted aryl group having 6 to 10 carbon atoms, wherein the aromatic ring has one or more substituents selected from alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or halogen atoms, or R5 and R6 together with the nitrogen atom to which they are attached are 5 to 7-membered form cyclic amino group. 14. The method according to any one of claims 1 to 13, characterized in that one of the symbols R10 and R "denotes a benzyl group or a β-halogenoethyl group and the other represents a glycoside residue of the formula given in connection with formula III, where R denotes an acetyl group, R3 'a group of the formula -OR, a Benzyloxycarbonylamino group or a ß-Halogenätoxy-carbonylamino group and R4 represents a straight or branched alkoxy group having 1 to 8 carbon atoms or an amino group of the formula: R: R \ 6 / N- 20th represents, where R is hydrogen, R3 is hydroxy or an amino group and R4 is an amino group or, if R3 is an amino group, acid addition salts thereof, characterized in that a corresponding compound of the formula I is obtained by the process according to claim 1, but R4 is means an alkoxy group, produces and reacts this compound with ammonia.