JPH0753586A - Production of pyrimidine nucleoside derivative - Google Patents

Abstract

PURPOSE:To safely, efficiently and industrially obtain the subject derivative useful as an important intermediate for antitumor agents by successively reacting a compound of specific formula, etc. CONSTITUTION:A compound of formula I (R<1> is amino; R<2>, R<3> are hydroxyl group-protecting groups) is reacted with an oxidizing agent (preferably sodium hypochlorite-potassium bromide) in the presence of an alkali metal halide and TEMPO in an inactive solvent (preferably dichloromethane), and the obtained compound of formula II is reacted with acetonecyanhydrin to obtain the compound of formula III. The compound of formula III is reacted with 2- naphthylchlorothionoformate in the presence of a base (preferably triethylamine) in an inactive solvent (preferably toluene) to obtain the objective derivative of formula IV.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a process for producing a synthetic intermediate of a pyrimidine nucleoside derivative having excellent antitumor activity.

[0002]

As a method for producing compound (2), compound (3) and compound (4 ') which are important synthetic intermediates for obtaining a 2'-cyanodeoxynucleoside derivative having excellent antitumor activity. Is Japanese Patent Publication
A method described in Japanese Patent Laid-Open No. 4-235182 (hereinafter abbreviated as a conventional method) is known.

[0003]

[Chemical 7]

In the conventional method, manganese dioxide is used as an oxidizing agent in order to obtain the compound (2), that is, for the oxidation of the hydroxyl group at the 2'position. However, this method is not suitable for mass production because the reagent is required in large excess and the yield is poor. In addition, the treatment of waste manganese dioxide is not easy and causes environmental pollution.

Further, the publication also describes oxidation using PCC (pyridinium chlorochromate) and PDC (pyridinium dichromate).
It is not suitable for large-scale synthesis, because a target product must be purified using a celite-like residue and using Celite, molecular sieve and the like.

Further, in the conventional method, sodium cyanide is used for obtaining the compound (3), that is, for introducing a cyano group at the 2'position. However, in this method, hydrogen cyanide gas is generated from the system during the reaction, which poses a problem in safety in mass synthesis.

Further, in the conventional method, phenoxythiocarbonyl chloride is used for obtaining the compound (4 '), that is, for introducing the phenoxycarbonyl group. However, the crude product obtained by this method is oily, requires column operation for purification, and is not suitable for large-scale synthesis. It is also difficult at present to obtain a large amount of phenoxycarbonyl chloride.

[0008]

Therefore, the inventors of the present invention have conducted a long-term intensive study on a method for producing a synthetic intermediate thereof in order to improve the method for producing a pyrimidine nucleoside derivative having excellent antitumor activity. As a result, unlike the known method, a novel and excellent method for producing a synthetic intermediate, which is more practical and suitable for large-scale synthesis, was found, and the present invention was completed.

[0009]

The production method of the present invention is represented by the general formula (1)

[0010]

[Chemical 8]

[In the formula, R ¹ represents an amino group which may have a protecting group, and R ² and R ³ each independently or in combination represent a hydroxyl-protecting group. ] To the compound represented by, in a solvent, an alkali metal halide and TEMPO
Compound (2) obtained by reacting an oxidizing agent in the presence of (2,2,6,6-tetramethylpiperidinooxy)

[0012]

[Chemical 9]

[In the formula, R ¹ , R ² and R ³ have the same meanings as described above. ] To a compound (3) obtained by reacting acetone cyanohydrin with a solvent.

[0014]

[Chemical 10]

[Wherein R ¹ , R ² and R ³ have the same meanings as described above. ] To 2-naphthylchlorothionoformate in the presence of a base in a solvent to give compound (4)

[0016]

[Chemical 11]

[In the formula, R ¹ , R ² and R ³ have the same meanings as described above. ] It is a method of manufacturing.

In the above-mentioned compounds (1), (2), (3) and (4), the protecting group for the amino group which may have a protecting group for R ¹ is "an amino group which may be protected". "Indicates a group in which the following protecting group protects one or two amino groups, and preferably formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, lauroyl, Alkylcarbonyl groups such as myristoyl, tridecanoyl, palmitoyl, stearoyl, chloroacetyl, dichloroacetyl, trichloroacetyl,
Aliphatic acyl groups such as halogeno lower alkylcarbonyl groups such as trifluoroacetyl, lower alkoxy lower alkylcarbonyl groups such as methoxyacetyl, unsaturated alkylcarbonyl groups such as (E) -2-methyl-2-butenoyl; Arylcarbonyl groups such as benzoyl, α-naphthoyl, β-naphthoyl, 2-bromobenzoyl, 4-
A halogenoarylcarbonyl group such as chlorobenzoyl, 2,4,6-trimethylbenzoyl, a lower alkyl-substituted arylcarbonyl group such as 4-toluoyl, a lower alkoxy-substituted arylcarbonyl group such as 4-anisoyl,
Nitro-substituted arylcarbonyl groups such as 4-nitrobenzoyl, 2-nitrobenzoyl, lower alkoxycarbonyl-substituted arylcarbonyl groups such as 2- (methoxycarbonyl) benzoyl, aryls such as 4-phenylbenzoyl Aromatic acyl groups such as substituted arylcarbonyl groups; lower alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, isobutoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl An alkoxycarbonyl group such as a halogen or a lower alkoxycarbonyl group substituted with a tri-lower alkylsilyl group; an alkenyloxycarbonyl group such as vinyloxycarbonyl, allyloxycarbonyl; benzyloxycarbonyl, 4-methoxybenzene The aryl ring is substituted with 1 to 2 lower alkoxy or nitro groups such as benzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl. There may be mentioned an aralkyloxycarbonyl group, more preferably an aliphatic acyl group and an aromatic acyl group.

As the protective group for the hydroxyl group of R ² and R ³ ,
For example, alkylcarbonyl groups such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, lauroyl, myristoyl, tridecanoyl, palmitoyl, stearoyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl. Aliphatic acyl groups such as halogeno lower alkylcarbonyl groups such as, lower alkoxy lower alkylcarbonyl groups such as methoxyacetyl, unsaturated alkylcarbonyl groups such as (E) -2-methyl-2-butenoyl; benzoyl, α -Arylcarbonyl group such as naphthoyl and β-naphthoyl, 2-bromobenzoyl, halogenoarylcarbonyl group such as 4-chlorobenzoyl, 2,4,6-trimethylbenzoyl, 4-toluoyl Lower alkyl-substituted arylcarbonyl group, lower alkoxy-substituted arylcarbonyl group such as 4-anisoyl, nitro-substituted arylcarbonyl group such as 4-nitrobenzoyl, 2-nitrobenzoyl, 2- (methoxy) Carbonyl) aromatic alkoxy groups such as lower alkoxycarbonyl-substituted arylcarbonyl groups such as benzoyl, aryl-substituted arylcarbonyl groups such as 4-phenylbenzoyl; tetrahydropyran-2-yl, 3-bromotetrahydro Pyran-2-yl,
Tetrahydropyranyl or tetrahydrothiopyranyl groups such as 4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran-2-yl, 4-methoxytetrahydrothiopyran-4-yl; tetrahydrofuran-2-yl, tetrahydrothiofuran A tetrahydrofuranyl or tetrahydrothiofuranyl group such as -2-yl; tri-lower alkyl such as trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-t-butylsilyl, triisopropylsilyl Silyl groups, such as tri-lower alkylsilyl groups substituted by 1 to 2 aryl groups such as silyl groups, diphenylmethylsilyl, diphenylbutylsilyl, diphenylisopropylsilyl, phenyldiisopropylsilyl; Various protecting groups,
More preferably, it is a lower trialkylsilyl group or an aliphatic acyl group.

When R ² and R ³ together represent a hydroxyl-protecting group, it is particularly preferred that 1,1,3,3-
A tetraisopropyldisiloxane-1,3-diyl group may be mentioned.

Next, the manufacturing method of the present invention will be described in more detail.

[0022]

[Chemical 12]

(Step I) In this step, compound (1) is mixed with an alkali metal halide and TEMP in an inert solvent.
O (2,2,6,6-tetramethylpiperidinooxy)
In the presence of, a compound (2) is obtained by reacting with an oxidizing agent.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but preferably, aromatic hydrocarbons such as benzene, toluene and xylene, Dichloromethane, 1,2-
Halogenated hydrocarbons such as dichloroethane and chloroform, esters such as ethyl acetate and methyl acetate, ethers such as ether, tetrahydrofuran and dioxane.
Examples thereof include ters, amides such as dimethylformamide and dimethylacetamide, sulfoxides such as dimethylsulfoxide, and more preferably halogenated hydrocarbons (particularly dichloromethane).

The oxidizing agent used is preferably m
-Chloroperbenzoic acid, electrode oxidation (electrolytic oxidation), sodium hypochlorite-potassium bromide, cupric chloride-oxygen, sodium bromine, bromine, chlorine, and more preferably,
Sodium hypochlorite-potassium bromide.

The amount of oxidant used is generally
It is preferably 1.1 equivalents to 1.2 equivalents with respect to the starting material.

The amount of TEMPO used is generally 0.1 to 2.0 equivalents, preferably 0.2 to 0.3 equivalents, relative to the starting materials. Examples of the alkali metal halide used include potassium chloride and potassium bromide, with potassium bromide being preferred.

The reaction is generally carried out neutral or alkaline, usually in the range of pH 7.0 to 11.0, preferably pH 8.0 to 10, and more preferably pH 8. .5 to 9.5. The buffer used to adjust the liquidity is preferably sodium hypochlorite-sodium hydrogen carbonate. The reaction temperature is usually -20 to 100 ° C, preferably 0 to 10 ° C.

The reaction time is usually 5 minutes to 5 hours, preferably 30 minutes to 2 hours, varying mainly depending on the reaction solvent, the reaction temperature and the amount of the oxidizing agent used.

After completion of the reaction, a small amount of 2-propanol was added, the organic layer was washed with an aqueous solution of sodium thiosulfate and saturated saline in this order, and the solvent was distilled off to obtain the compound (2). be able to.

(Step II) In this step, in an inert solvent,
In this method, compound (3) is obtained by reacting compound (2) with acetone cyanohydrin.

The solvent used in the reaction is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but is preferably an aromatic hydrocarbon such as benzene, toluene or xylene. , Dichloromethane, 1,
Halogenated hydrocarbons such as 2-dichloroethane and chloroform, esters such as ethyl acetate and methyl acetate, ethers such as ether, tetrahydrofuran and dioxane, amides such as dimethylformamide and dimethylacetamide. , Sulfoxides such as dimethyl sulfoxide, and the like, and more preferably,
Halogenated hydrocarbons (especially dichloromethane).

This reaction is generally carried out in a neutral or weakly alkaline solution, preferably in the pH range of 7.5 to 8.0. A buffer is used to adjust the pH. The buffer used is not particularly limited, but preferably potassium dihydrogen phosphate-sodium hydroxide, sodium hydrogen carbonate-sodium hydroxide, disodium hydrogen phosphate-potassium dihydrogen phosphate, boric acid- Examples thereof include potassium chloride-sodium hydroxide, and potassium dihydrogen phosphate-sodium hydroxide is preferable.

The reaction temperature is 0 ° C to 50 ° C, preferably 20 ° C to 30 ° C.

The reaction time varies depending on the reaction solvent, the starting compound, the reaction temperature, etc., but is usually 30 minutes to 10 hours, and preferably 1 hour to 4 hours.

After completion of the reaction, the reaction solution is poured into water, extracted with a solvent immiscible with water such as benzene, ether, ethyl acetate, dichloromethane and the like, and the solvent is distilled off to obtain the compound (3). .

If necessary, the compound thus obtained is further subjected to, for example, an adsorption chromatography method using various carriers such as activated carbon and silica gel, or n-hexane, ether, ethyl acetate, chloroform and the like. It can be performed by a recrystallization method or the like using an organic solvent, and preferably,
By recrystallizing with ethyl acetate: n-hexane = 1: 10, white crystals can be obtained in good yield.

(Step III) This step is a step of reacting compound (3) with 2-naphthylchlorothionoformate in the presence of a base in an inert solvent to obtain compound (4). .

The solvent used is not particularly limited as long as it does not inhibit the reaction, but amides such as dimethylformamide and dimethylacetamide, nitriles such as acetonitrile, benzene, toluene and xylene. Aromatic hydrocarbons can be mentioned, but aromatic hydrocarbons (particularly toluene) are preferable.

The base to be used is not particularly limited as long as it is used as a base in a usual reaction, but alkali metal such as sodium carbonate, potassium carbonate and lithium carbonate is preferred. Carbonates; alkali metal hydrogencarbonates such as sodium hydrogencarbonate, potassium hydrogencarbonate, lithium hydrogencarbonate; alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride; sodium hydroxide, potassium hydroxide , Inorganic bases such as alkali metal hydroxides such as barium hydroxide and lithium hydroxide; sodium methoxide, sodium ethoxide, potassium t-butoxide,
Alkali metal alkoxides such as lithium methoxide; mercaptan alkali metals such as methyl mercaptan sodium, ethyl mercaptan sodium; triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (dimethylamino) pyridine, N , N-Dimethylaniline, N, N-
Diethylaniline, 1,5-diazabicyclo [4.3.0] nona-5
-Ene, 1,4-diazabicyclo [2.2.2] octane (DABCO)
, 1,8-Diazabicyclo [5.4.0] undec-7-ene (DBU)
And organic metal bases such as butyllithium and lithium diisopropylamide, and preferably an organic base (particularly triethylamine).

The reaction temperature is -20 ° C to 50 ° C,
It is preferably 0 ° C to 10 ° C.

The reaction time varies depending on the compound, the reaction temperature and the like, but is usually 30 minutes to 5 hours, and preferably 1
Hours to 2 hours.

In order to carry out the reaction more efficiently, 4-
It is desirable to use organic amines such as (dimethylamino) pyridine and triethylamine.

After completion of the reaction, for example, the reaction solution is poured into water,
Water-immiscible solvents such as toluene, ethyl acetate,
By extracting with ether, etc., and distilling off the solvent,
An oily crude product is obtained. Crystallization becomes possible by adding diisopropyl ether, and it can be easily purified.

[0045]

Industrial Applicability According to this method, compound (4), which is an important intermediate of a useful antitumor agent, can be produced safely, efficiently, and industrially.

Using the compound (4), the compound (5) can be produced by a method similar to the method described in JP-A-4-235182 (the following fourth step). Furthermore, using this compound (5), the compound (6) which is an antitumor agent can be produced by the method described in Japanese Patent Publication No. 4-235182.

[0047]

[Chemical 13]

(Step IV) This step is a step of reductively removing the naphthyl 0 oxythiocarbonyloxy group at the 2'position of the compound (4) obtained in the third step to obtain the compound (5). is there. The solvent to be used is not particularly limited as long as it does not inhibit the reaction, but it is hexane, heptane, ligroin, aliphatic hydrocarbons such as petroleum ether, aromatic hydrocarbons such as benzene, toluene and xylene. , Diethyl ether, diisopropyl ether,
Tetrahydrofuran, dioxane, dimethoxyethane,
Examples thereof include ethers such as diethylene glycol dimethyl ether. Suitable reagents used include trialkyltin hydrides such as tributyltin hydride. The reaction temperature is usually 50 ° C to 2 ° C.
It is 50 ° C., preferably the boiling point of the solvent used. The reaction time is usually 30 minutes to 10 hours, preferably 30 minutes to 3 hours. Further, in order to carry out the reaction efficiently, a radical initiator such as azoisobutyronitrile can be used as a catalyst. The target compound thus obtained can be collected, separated and purified by appropriately combining various methods. For example, the reaction solution is poured into water, extracted with a solvent immiscible with water, such as benzene, ether, ethyl acetate,
It is obtained by distilling the solvent from the extract. If necessary, the compound thus obtained is further subjected to adsorption or ion exchange chromatography using various carriers such as activated carbon and silica gel, or gel filtration using a Sephadex column, and organic compounds such as ether, ethyl acetate and chloroform. It is performed by recrystallization using a solvent.

Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.

In the examples, (1,1,3,3, -tetraisopropyldisiloxane-1,3-diyl) was added to T
Abbreviated as IPDS.

[0051]

【Example】

Example 1 N ⁴ -Acetyl-1- (3,5-O-TIPDS-β-
Erythro - Pentofuran 2- Uroshiru) cytosine emissions N ⁴ - acetyl -1- (3,5-O-TIPDS- β-
D-ribofuranosyl) cytosine (10.0 g) was dissolved in dichloromethane (50 ml) and water (2 ml) to prepare 2,2,6,6-tetramethylpiperidinooxy (0.74 g) and potassium bromide (0.45).
g) was added and cooled to 0-5 ° C.

On the other hand, a 9% aqueous solution of sodium hypochlorite (1
Sodium hydrogen carbonate was added to 7.1 ml) to adjust the pH to 8.8-
It was adjusted to 9.0. This solution is used as a reaction solution at a temperature of 0 to 10
While maintaining the temperature at 0 ° C, the mixture was added dropwise. After that, the reaction temperature is 0 to 5
The mixture was stirred for about 30 minutes while maintaining the temperature at 0 ° C. After the reaction, 2
-Propanol (13.0 ml) was added, and the reaction was stopped by stirring at room temperature for 30 minutes. The aqueous layer was separated and removed, and the dichloromethane layer was added with 20% sodium thiosulfate solution, separated and extracted, and washed with 5% saline. After distilling off the solvent under reduced pressure and drying under reduced pressure in the presence of phosphorus pentoxide, 9.9 g of the title compound was obtained (yield 98%).

Mass spectrum m / e; 525 (M +
_{C 23 H 39 O 7 N 3} Si 2) Nuclear magnetic resonance spectrum; (400 MHz, DMSO
-D ₆ , δppm) 11.0 (1H, s), 8.15
(1H, d, J = 7.33), 7.25 (1H, d, J
= 7.81), 4.10 to 3.95 (3H, m), 3.
3 (2H, s), 2.15 (3H, d), 1.5 (28
H, m) (Example 2) N ⁴ - acetyl-1- (2'-cyano -3 ', 5'-O
-TIPDS-β-D-arabinofuranosyl) cytosine The compound of Example 1 (10.0 g) was dissolved in dichloromethane (50 ml), and acetone cyanohydrin (3.5 ml) and
0.2M KH ₂ PO ₄ -NaOH buffer solution (25 ml) was added, and the mixture was stirred for 4 hours. After completion of the reaction, the aqueous layer was separated and extracted, and the dichloromethane layer was concentrated under reduced pressure. Crystallization was performed by adding ethyl acetate (10 ml) and n-hexane (100 ml) to obtain 7.5 g of the title compound as white crystals (yield 70%).

Mass spectrum m / e; 552 (M +
C ₂₄ H ₄₀ O ₇ N ₄ Si ₂ ) Nuclear magnetic resonance absorption spectrum; (400 MHz, DMSO
−d ₆ , δppm) 11.0 (1H, d, J = 14.
4), 8.05 (1H, d, J = 7.33), 7.82
(1H, d, J = 7.65), 7.25 (1H, J =
7.81), 6.33 (1H, s), 4.25 (1H,
m), 4.10 (2H, m), 3.94 (1H, m),
2.11 (3H, s), 4.27 (28H, m) ( Example 3) N ⁴ - acetyl-1- (2'-cyano-2'-Nafutoki
Cythiocarbonyl-3 ', 5'-O-TIPDS-β-
D-arabinofuranosyl) cytosine The compound of Example 2 (10.0 g) was dissolved in toluene (100 ml) to prepare 4,4-dimethylaminopyridine (0.22 g), 24%.
2-Naphthyl chlorothionoformate (toluene solution) (26.1 ml) and triethylamine (3.8 ml) are added, and the mixture is stirred for 1 hour under cooling. After completion of the reaction, diisopropyl ether
Crystallization was performed using tell (50 ml) to obtain 12.0 g (yield 90.0%) of the title compound as white crystals.

Mass spectrum m / e; 739 (M +
_{C 35 H 46 O 8 N 4} SSi 2) Nuclear magnetic resonance spectrum; (400 MHz, DMSO
-D ₆ , δppm) 11.2 (1H, s), 8.0 (1
H, d), 8.0-7.5 (7H, m), 7.1 (1
H, dd), 4.24 (1H, m), 4.1-4.0.
(2H, m), 3.3 (2H, s), 2.5 (3H,
s), 1.1 (28H, m)

Claims (3)

[Claims] 1. A general formula (1): [In the formula, R ¹ represents an amino group which may have a protecting group,
R ² and R ³ independently or together represent a hydroxyl-protecting group. ] To the compound represented by
Alkali metal halide and TEMPO (2, 2,
6,6-tetramethylpiperidinooxy) is reacted with an oxidizing agent to give a compound represented by the general formula (2): [Wherein R ¹ , R ² and R ³ have the same meanings as described above. ] The method of manufacturing the compound represented by these. 2. A general formula (2): [In the formula, R ¹ represents an amino group which may have a protecting group,
R ² and R ³ independently or together represent a hydroxyl-protecting group. ] To the compound represented by
By reacting with acetone cyanohydrin, general formula (3): [Wherein R ¹ , R ² and R ³ have the same meanings as described above. ] The method of manufacturing the compound represented by these. 3. A general formula (3): [In the formula, R ¹ represents an amino group which may have a protecting group,
R ² and R ³ independently or together represent a hydroxyl-protecting group. ] To the compound represented by
2-naphthylchlorothionoformate is reacted in the presence of a base to give a compound of the general formula (4): [Wherein R ¹ , R ² and R ³ have the same meanings as described above. ] The method of manufacturing the compound represented by these.