JPH0311089A - Novel nucleosides and synthesis thereof - Google Patents

Abstract

NEW MATERIAL:Nucleosides containing a phosphosugar as a sugar component. EXAMPLE:2-Azido-3-hydroxy-3-methyl-1-phenylphosphorane-1-oxide of formula. USE:The compound has physiological activities such as carcinostatic, anti-AIDS, antiviral and antibacterial activities and is useful as a drug. PREPARATION:The objective nucleosides can be produced by trimethyl-silylating (A) a base compound having pyridine skeleton or analogous skeleton and bonding the silylated compound with (B) a deoxyhalo derivative through N- glucoside bond by Friedel-Crafts reaction. Preferably, the component A is 2- hydroxypyridine, the component B is converted to a phosphosugar N- glycosylazide compound by azidation and made to react with (C) alpha- cyanoacetamide and the obtained intermediate is treated with (D) ethyl acetate to construct an azapurine skeleton as a base and obtain the objective nucleosides.

Description

Detailed Description of the Invention (Field of Industrial Application) The present invention is directed to nucleosides, which are expected to have physiologically active applications in the fields of biochemistry, pharmaceuticals/medical care, agrochemicals, etc., and particularly phosphorus, which is a new substance. This invention relates to sugar N-nucleosides and their synthesis method.

In this document, "nucleosides" refers to nucleosides, which are N-glycosidic bonds of a base component having a purine or pyrimidine skeleton, which is a base component of a nucleic acid, and a sugar component, and base components having a purine-like or pyrimidine-like skeleton. It is understood that it includes a nucleoside structural analog consisting of and a sugar component.

(Prior Art) Many natural or synthetic glycosides have been confirmed to have antitumor, antiviral, and other physiological activities.Among them, nucleosides, such as amicetin, angestomycin, cordycepin, and gougelotin. , puromycin, 3'-deoxyadenosine, 2'-deoxyuridine and its derivatives, tegaflu, etc., and nucleoside structural analogs, such as brezinin, ribavirin, deazauridine, choudomycin, oxazinomycin, toyocamycin,
Many substances, such as 6-azauridine, 5-azacytidine, and coformycin, are known as useful physiologically active substances and are in practical use.

In addition, nucleosides using a heterosaccharide such as thiosaccharide in the sugar moiety, such as 1-(2-deoxy-4-thio α-D-
Although it has been reported that erythrobentofuranosyl)-5-fluorouracil and (±)-arysteromycin act as antibiotics, beta sugar nucleosides using phosphorus sugar have not yet been reported.

Phosphorous sugars are phosphorus derivatives of sugars, particularly compounds having a phosphorus atom in the hemiacetal ring of sugars.

Little is known about the physiological effects of phosphorus sugar, but it is a natural product with a C-P bond (-)-(IR,2S
) -1,2-Epoxypropylphosphonic acid is an antibiotic with antiviral activity, and cyclophosphamide, a phosphorus-containing cyclic compound, is an important anti-111i drug; furthermore, 5-deoxy-1 , 5-C-(ethylphosphinylidene)-β-D-glyose derivatives show weak but anticancer effects, and phosphorus sugar has important physiological effects such as anticancer and anti-AIDS effects. It is expected that there will be something that shows this.

Therefore, in view of the fact that existing heterosaccharide nucleosides exhibit physiological activity as mentioned above, nucleosides whose sugar component is phosphosaccharide, which itself is expected to be physiologically active, have been further increased or have new physiological activity. expected to show,
Their synthesis is also of great biochemical interest.

However, the conventional phosphorus sugar synthesis method uses sugar as a starting material, converts the hydroxyl group into a functional group and introduces a protective group to functionalize only the necessary reaction points, and then reacts with a phosphorus compound to functionalize only the necessary reaction points. This method introduced a carbon-phosphorus bond into the sugar skeleton, followed by functional group conversion on the phosphorus atom, and hydrolysis of the hemi-Secure ring to introduce a phosphorus atom into the hemi-Secure ring. A typical example is shown by the following series of reactions.

Conventional methods (1) have a long reaction path and are difficult to synthesize in large quantities;
2) Since aphrodisiacs are used as a starting material, the starting materials that can be used are severely restricted from an economic standpoint, (3) The types of phosphorus sugars that can be synthesized are limited, (4) The reaction of phosphorus and the functionality of phosphorus compounds Group conversion reactions are often accompanied by great difficulties and yields are low; (5) Reactions that utilize ozone decomposition progress as side reactions progress as the reaction time increases, making it difficult to scale up the reaction; (6) ) There were problems with industrialization, such as difficulties from an economic standpoint and a process standpoint. Therefore, there were few examples of phosphosaccharide being synthesized, and the yield of the compound was very small, so no attempt had been made in the past to convert phosphosaccharide into its important derivatives, nucleosides. .

On the other hand, one of the present inventors, together with another co-inventor,
Breaking away from the past fixed idea that "sugar derivatives are synthesized starting from sugar" and changing the way of thinking to "synthesizing t* derivatives from compounds other than sugar," we have developed a wide variety of inexpensive starting materials. From this, we succeeded in developing a method that can be mass-produced on a commercial scale to efficiently and economically synthesize many types of phosphosaccharides using a simplified process.
This was proposed as Japanese Patent Application Laid-Open No. 64-50891. This method involves treating an adduct resulting from the reaction between a conjugated diene and a dihalogenated phosphorus compound with a phosphorene oxytohalohydrination agent, which can be easily obtained by treating the adduct with water or alcohol. The present invention includes a method for obtaining deoxyhaloline sugar having a skeleton of phosphorane oxide. Deoxyhalophosphorus sugar can be chemically modified more easily by using a highly reactive halogen atom as a functional group. This makes it possible to obtain derivatives.

The present inventors have focused on various phosphosaccharides, which have been industrially obtained easily and economically advantageously through the above-mentioned invention, and their promising possibility of expressing biological activity, and have developed an unprecedented method using them. The present invention was achieved by attempting to synthesize phosphorus sugar nucleosites.

(Problems to be Solved by the Invention) The present invention aims to provide novel nucleosides industrially easily and economically.

The ultimate objective is to provide new nucleosides that are expected to exhibit increased physiological activity, such as anticancer, anti-AIDS, antiviral, and antibacterial effects, and can be developed for medical, medicinal, agricultural, and other uses. It is in.

Another object of the present invention is to provide novel nucleosides that can be used as intermediates for synthesizing physiologically active nucleoside compounds.

(Means for Solving the Problem) The above object is achieved by novel nucleosides containing phosphorus sugar as a sugar component.

The phosphorus sugars constituting the novel nucleosides are preferably phospholane derivatives.

Further, the base component preferably has a pyridine or a similar skeleton, or a purine or a similar skeleton.

The first synthetic method of the present invention for forming such novel nucleosides involves trimethylsilylation of pyridine or a basic compound having a similar skeleton, and then a Friedel-Crafts type reaction to form a deoxyhaloline sugar derivative and an N-glycoside. It consists of joining.

The basic compounds preferably used in the above synthesis method are 2
-Hydroxypyridine.

The second synthesis method of the present invention is to azidate a deoxyhalophosphorus sugar derivative to form a phosphorus In-glycosyl azide compound,
Next, the azide compound is treated with α-cyanoacetamide to convert the azide group into a triazole ring, and the triazole ring-containing intermediate thus obtained is treated with ethyl acetate to construct an azapurine skeleton as a base. Become.

The deoxyhaloline sugar derivative suitably applied to the above-mentioned synthesis method of the present invention is, for example, 2-halo-3-hydroxy-3-methyl-1-phenyl (or alkoxy)-phosphorane-1-oxide; The deoxyhaloline sugar derivative is preferably obtained by saturating the ethylene bond of phospholene oxide derived from a conjugated diene and a dihalogenated phosphorus compound by halohydrination.

Hereinafter, the structure of the present invention will be further explained along with its operation.

The deoxyhaloline sugar derivative used in the method of the present invention, preferably the 1-deoxy-1-bromoline'JMFa conductor having a bromo group at the α-position of phosphorus, is
According to the method described in Japanese Patent No. 50,891, phosphosines obtained by methanol decomposition of adducts of 3-dienes and trivalent phosphorus compounds are treated with a halohydrination agent, preferably N-bromoacetamide (NBA). It can be obtained by treating with and converting it into a halohydrin. Halohydrination readily proceeds at room temperature in an aqueous solvent such as a water-miscible organic solvent such as tetrahydrofuran (THF). This reaction is expressed, for example, by the following formula (1).

e However, R indicates OMe, OEt, Ph, etc.

The 1-deoxy-1-bromoline derivative thus obtained, namely 2-halo-3-hydroxy-3-methyl-1-alkoxy(phenyl)-phosphorane-1-
oxide, TMS-protected 2 in the presence of tin tetrachloride.
-Hydroxypyridine (2-pyridone) is reacted with Friedel-Crafts type reaction shown in the following formula (2),
Alkylated on the N atom of pyridone. Thus, the bromo group at the C1 position is substituted with 2-pyridone,
A nucleoside structure is obtained, namely 1-(3-hydroxy-3methyl-1-alkoxy-phosphorane-1-oxide)-1,2-dihydropyridin-2-one.

...(2) Here, R represents an alkoxyl group such as OMe or OEt or a phenyl group.

Further, phosphorus sugar N-nucleosides consisting of a base having a purine type skeleton can be synthesized by the following method.

First, phosphosine, such as phosphorene oxide having a phenyl group on the phosphorus atom, produced from 1,3-dienes such as isoprene and a trivalent phosphorus compound such as dichlorophenylphosphine in the same manner as above, is treated with NBA as above. 2-bromo-3-hydrolex-3-methyl-1-phenylphosphorane-1-oxide having a phenyl group on the phosphorus atom is obtained by bromohydrination. This bromohydrin phosphorane derivative is azidated by reacting sodium azide, for example, in a dimethylformamide (DMF) solvent, resulting in a phosphorus sugar N-glycoside with an azide group bonded to the α-position of phosphorus, 2-azido-
3-Hydroxy-3-methyl-1-phenylphosphorane-
1-oxide is obtained.

The azidation reaction is shown by the following formula (3).

It is known that azido groups give various cyclized products through 1,3-dipolar cycloaddition reactions.

In the method of the present invention, this reaction is utilized to react α-cyanoacetamide on the phosphorus sugar N-glycoside having an azide group at the 01-position in the presence of sodium ethoxide.
The azide group is cyclized to form a triazole ring, and the triazole ring-containing intermediate thus obtained is treated with ethyl acetate to construct an azapurine skeleton. The phosphorus WN-nucleoside structural analog obtained by the above formula (4) is expressed as follows:
phenylphosphorane-1-oxide)-2-methyl-8
-Azapurin-6-one.

As is clear from the above explanation, the deoxyhaloline #M derivative, which is one of the starting materials for the method of the present invention, is produced from a 1,3-diene compound and a trivalent phosphorus compound, unlike the conventional method, which is derived from sugar. Since synthesized phosphorene is used as a raw material, it is easy to convert functional groups and introduce substituents due to the high reactivity of phosphorene's double bonds and allyl positions. Furthermore, since the halogen atom of halophosphorus sugar is a highly reactive functional group, it can be easily chemically modified. Therefore, it is possible to synthesize a wide variety of arbitrary phosphorus sugar N-nucleosides.
-(3-hydroxy-3-methyl-1-methoxyphosphorane-1-oxide)-1゜2-dihydropyridine-2
-one and its similar compounds, and 9-(3-hydroxy-3-methyl-1-phenylphosphorane-1-oxide)-2-methyl-8-azapurin-6-one and its similar compounds only. First, it is easy to see that the products of the present invention can include nucleosides with modified phosphorus sugar structures, and phosphorus nucleosides made of purines, pyrimidines, or various bases having skeletons similar to those mentioned above. be understood.

(Example) The present invention will be explained in more detail by way of Examples below.

Synthesis of 2-azido-3-hydroxy-3-methyl-1-phenylphosphorane-1-oxide on carbon 5.0 g (14 mmo
f) and 1.38 g (20 mmo
1) was dissolved in 25m DMF and reacted at 80'C for 24 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in chloroform and washed with water (15 dx 2 ).

After drying with anhydrous sodium sulfate, it was concentrated under reduced pressure to obtain phosphorus tJ.
! 2.04 g of N-glycoside is obtained (yield 58%).

The following structure was confirmed by MS, IR, and 'H-NMR.

MS (m/e): 251 (MtrR (cm-'
): 2100 (Nl) 3300 (OH) 11 NMR (ppm): 1.5 (s, 3
11. CH3) 1.7-2.9 (m, 411.
Cll2C112) 4.0 (d, 18.
CI-I+) 4.6 (bs, IH, Of+)
7.3~8.0 (m, 511. C6118
) Sous 11 Fresh% 1-(3-Hydroxy-3-methyl-1-methoxyphosphorane-1-oxide)-1,2-dihydropyridine-
Synthesis of 2-one Bromohydrin with methoxy group on the phosphorus atom 1.4
6g (6,01mmoj2) and 1.05g (6,29mm) of 2-(trimethylsilyloxy)pyridine
oj2) in 30 m2 of acetonitrile solution under a nitrogen stream at 0°C. ]M 5nC1n solution in 1.2-dichloroethane 2.5+nj! Add little by little and stir for 30 minutes. The temperature is further increased to 80°C and the reaction is continued for about 24 hours. After neutralizing the reaction solution with saturated sodium bicarbonate solution, the undissolved material is filtered through Celite and the mother liquor is concentrated under reduced pressure. Pour the remaining solution into chloroform 30n/! After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 0.432 g of phosphorus sugar nucleoside (
yield 28%). The structure of the product was confirmed by 'H-NMR and IR.

OH IR (cm-’): 1040 220 650 400 'H-N gate R (ppm): (P-0-C) (P = 0) (2-pyri (011”) 1.5 (s, 31 (.

1.6-2.6 (Ya.

3.85 (dX2゜ 4.0 (d, LH.

5.9 (bs, IH.

6.1-7.2 (m.

t) CH3) 4H, C) ItGHz) JpocH=10.5+1z, 311. POC)11)
CIH) OH) 4H12-pyridone) Synthesis of 9-(3-hydroxy-3-methyl-1-phenylphosphorane-1-oxide)-2-methyl-8-azapurin-6-one in 5 ito To the prepared ethanol solution of sodium ethoxide was added 0.42 g of α-cyanoacetamide (5
mlIlol) and 1.26 g (5 mmol) of the phosphosaccharide N-glycosyl azide compound obtained in Example 1 were added and stirred for 1 hour. Furthermore, 112 ml of anhydrous ethyl acetate was added and the reaction was continued at 70°C for 24 hours. The solvent was distilled off under reduced pressure, the residue was diluted with water, and then neutralized with frugal acid. The solution is concentrated under reduced pressure, extracted with chloroform, the organic phase is dried over anhydrous sodium sulfate, and the solvent is distilled off to obtain 0.423 g of a crude product. The structure of the product was confirmed by 'H-NMR and IR.

IR (cm-'): 1705 (C=O)'HN
MR (ppm): 1.65 (s, 3B,
Cz Me) 1.95 (s, 3H, C-C
-Me) 2.85 (d, LH, C, -H) (Effects of the Invention) The heroline sugar derivative, which is a precursor of the novel phosphorus sugar nucleosides of the present invention, uses sugar as a starting material. Unlike conventional methods, it is obtained by functional group conversion of phosphorene synthesized from inexpensive conjugated dienes and a trivalent phosphorus compound. By the way, the double bond, allyl position, etc. of phosphorene are highly reactive, so it is easy to convert functional groups and introduce substituents, and furthermore, the halogen atom of halophosphorus sugar is a highly reactive functional group, so it is easy to convert the functional groups and introduce substituents. Since chemical modification can be carried out, it is possible to synthesize a wide variety of new phosphosugar N-nucleosides in high yields and in a short route.
Conversion into nucleosides can be carried out on a large scale, and low-cost industrialization is easy in terms of raw materials and processes.

In addition, the novel phosphorus sugar nucleosides obtained by the method of the present invention have anticancer, anti-AIDS, antiviral, antibacterial, etc. that nucleosides originally have or are expected to have due to the physiological activity expected from phosphorus sugar itself. It is expected that this will lead to an increase in the physiological activity or new expression of . Furthermore, it is expected to be useful as an intermediate for the synthesis of new physiologically active substances with more complex chemical structures, and is useful for pharmaceutical, medical, and medical purposes.
It is believed that this will pave the way for the development of applications in the biochemical field, such as agricultural chemicals.

Claims (1)

[Claims] 1. Novel nucleosides containing phosphorus sugar as a sugar component. 2. The novel nucleosides according to claim 1, wherein the phosphosaccharide is a phospholane derivative. 3. The novel nucleosides according to claim 2, comprising a base component having pyridine or a similar skeleton. 4. The novel nucleosides according to claim 2, comprising a base component having a purine or a skeleton similar thereto. 5. A method for synthesizing novel nucleosides using phosphorus sugar as a sugar component, which comprises trimethylsilylating pyridine or a basic compound having a similar skeleton, and then forming an N-glycosidic bond with a deoxyhaloline sugar derivative through a Friedel-Crafts type reaction. . 6. The synthesis method according to claim 5, wherein the basic compound is 2-hydroxypyridine. 7. Azidation of deoxyhalophosphorus sugar derivative to produce phosphorus sugar N
- a glycosyl azide compound, then the azide group is reacted with α-cyanoacetamide to convert the azide group into a triazole ring, and the triazole ring-containing intermediate thus obtained is reacted with ethyl acetate to form a base. A method for synthesizing novel nucleosides using phosphosaccharide as a sugar component by constructing an azapurine skeleton. 8. The synthesis method according to claim 5 or 7, wherein the deoxyhaloline sugar derivative is 2-halo-3-hydroxy-3-methyl-1-phenyl (or alkoxy)-phosphorane-1-oxide. 9. The synthesis method according to claim 5 or 7, wherein the deoxyhaloline sugar derivative is obtained by saturating the ethylene bond of phospholene oxide derived from a conjugated diene and a dihalogenated phosphorus compound by halohydrination.