WO1997006179A1

WO1997006179A1 - Process for producing azido nucleoside derivatives

Info

Publication number: WO1997006179A1
Application number: PCT/JP1996/002197
Authority: WO
Inventors: Hiroyuki KYOMORI; Tomoyasu NAGASE; Ken-ichi TAKATSUKI; Haruhiro Yamashita
Original assignee: Kobayashi Perfumery Co., Ltd.
Priority date: 1995-08-04
Filing date: 1996-08-05
Publication date: 1997-02-20
Also published as: AU6630996A

Abstract

The 5'-hydroxyl group of a 2'-deoxyuridine derivative can selectively be protected by an aromatic acyl group. The selectively protected derivative thus produced is suitably utilizable for producing a 3'-azido derivative with an azide ion by, for example, introducing an appropriate leaving group such as a sulfonyl group into the 3'-hydroxyl group of the selectively protected derivative and forming a 2,3'-anhydro intermediate with a base. An azido nucleoside derivative can be produced in a high yield by removing the protective group from the protected 5'-hydroxyl group.

Description

^ ίΒ%

Method for producing azidolated nucleoside derivative

Technical field

The present invention relates to a method for producing an azido nucleoside derivative and a method for producing an intermediate that can be suitably used for producing the derivative.

Azido nucleoside derivatives are important as intermediates and the like for the production of azido nucleoside compounds represented by AZT (azido thymidine).

Conventionally, as a general method for synthesizing azido nucleoside derivatives, a method comprising several steps as shown in FIG. 1 has been known. In the method shown in FIG. 1, the 5′-hydroxyl group of the 2′-deoxyperidine derivative is protected by an appropriate protecting group (R), and an appropriate leaving group (R ¹ ) is introduced into the monohydroxyl group. It consists of 2,3'-anhydrolation with a strong base, 3'-azidation with an azide ion, and finally, removal of the 5'-hydroxyl protecting group (R) above (for example, , Matsuda et al., Nucleosides and Nucleotides, 9 (4) ゝ See 587-59, 199, 990) _c

In the first step of the above method (FIG. 1), in which the 5′-hydroxyl group is protected by an applicable protecting group, a protecting reagent used in the reaction, for example, t-butyldimethylsilyl cucolide-trityl chloride Is very expensive because it takes time to prepare or purify it. Therefore, the use of such a protective reaction reagent increases the difficulty of the reaction for producing the target 3, -azido 2 ′, 3′-dideoxyperidine derivative, and as a result, the dideoxyperidine This will be a major factor in the cost of derivative production. C More effective use of such dideoxyperidine derivatives In view of the above, there is a strong need for the development of a protection reaction that can achieve the same effects as described above by using a simpler and more inexpensive protection reagent (for example, Matsuda et al., Nucleosides and Nucleotides, 9 (4), 587—5 9 7, 1 990

Glinski et al., Org. Chem., 19 7-3, 38 (25), 429 9-430.

5).

On the other hand, the protecting group (bivaloyl group) introduced by pivaloyl chloride (trimethylacetyl chloride), which has been widely used as a reagent for selective 5'-hydroxyl-based acyl protection, is strong for deprotection. Basic conditions are required. Therefore, the deprotection reaction of the pivaloyl group requires a long time, and the above-mentioned strong basic conditions have an unfavorable effect on the reaction product (for example, decrease in yield, decrease in optical purity). May be obtained. From such a viewpoint, development of a protection reaction capable of deprotection under milder reaction conditions has been desired.

In addition, one step (hydrolysis reaction) of the conventional method shown in FIG. 1 described above involves the introduction of a leaving group into the 3′-hydroxyl group for preparing an intermediate for synthesizing an hydroisomer with a base. However, in terms of selectivity, yield, and operability of the introduction reaction, it is considered difficult to set conditions such as reagents for introducing a leaving group into the 3'-hydroxyl group. ing. From such a viewpoint, development of a leaving group introduction reaction that is highly selective, has high yield, and is easy to operate has been desired.

Furthermore, in the azidation reaction of the anhydro compound, several methods shown in FIGS. 2 to 4 (hereinafter, only the method using 5′-hydroxyl protected 1,2,3′-anhydro thymidine as a raw material are described. However, in these methods, the leaving group (aglycone moiety) is not necessarily capable of leaving in the azidation reaction using azideion (Ν _3- ), and the reaction proceeds selectively. Therefore, there is a tendency for impurities to be easily generated: Therefore, the generation of such impurities not only hinders the improvement of the synthesis yield, but also requires a complicated purification step for removing the impurities. Shall be assumed. From this point of view, the azide method that is more selective and produces less impurities The development of the law is eagerly awaited.

① 5 '- 0- Torichiru 2, 3, - Anhi Dorochimijin and N a N ₃ by reaction with 3' - azido one 3, - Dokishi 5, -〇 one trityl thymidine synthesis method (J. Org Chem,.. 1 973, 38-(25), 42 9 9-4305 (Glinski et al.)).

② 5 '-〇 one Torichiru 2, 3' - Anhi Dorochimijin and L i N ₃ reaction with by 3, - Ajido 3 '- Dokishi one 5, -〇 over trityl thymidine synthesis method (Nucleosides & Nucleotides, 1 9 90 , 9 (5), 629-637

(Watanabe, etc.)).

③ presence benzoate, 5 '- O-t-heptyl dimethylsilyl one 2, 3, - 3 by reaction with Anhi Dorochimijin and L i N _3' - Ajido 5 one O-t-butyldimethylsilyl one 3 'single Deoxythymidine synthesis method (Nucleosides & Nucleotides, 1990, 9 (5), 587-597 (Matsuda et al.))

Accordingly, an object of the present invention is to provide a method capable of highly selectively producing an azido nucleoside derivative and an intermediate for producing the derivative.

Another object of the present invention is to provide a method capable of producing an azido nucleoside derivative and an intermediate for producing the derivative in high yield. Disclosure of the invention

As a result of diligent research, Hoshikisha et al. Used an aromatic acyl group as a selective protecting group for the 5'-hydroxyl group in a peridine derivative in which the 3'-position and the 5'-position are free hydroxyl groups. Gave an extremely efficient 5′-aromatic acyl compound useful as an intermediate for the production of 3′-azido-perziridine derivatives.

₅ of the present MizunotoAkira '- aromatic Ashiru of - 2' - method of manufacturing Dokishiurijin derivatives is based on the above discovery, and more specifically, as represented by the following general formula, 2 'over de O carboxymethyl © lysine The derivative is reacted with an aromatic acylating reagent to give the derivative. 5 lysine derivative '- _c be of the is characterized by selectively aromatic Ashiru the hydroxyl group

(In the above formula, X represents hydrogen, halogen, alkyl, aryl, alkenyl, or a halogen-substituted alkyl, aryl, or alkenyl group. R ¹ represents an aromatic acyl group.)

Based on the above findings, the present Kiyoshi et al. Conducted further studies. After sulfonylating the 3'-hydroxyl group of the 5'-aromatic acyl compound obtained above, the compound was subjected to 2,3 in the presence of a base. 'The ability to monohydrogenate was found to be extremely effective for the production of 2,3 hydrodeoxyperidine derivatives.

The method of the present invention for producing 2,3′-anhydro-2′-deoxyperidine derivative is based on the above-mentioned findings, and more specifically, as shown by the following general formula, 2′-deoxyperidine derivative Protecting the 3'-hydroxyl group with an alkyl or aryl'sulfonyl group;

It is characterized in that a base is reacted with the sulfonylation product to obtain a 2,3′-monohydro compound.

(In the above formula, X represents hydrogen, halogen, alkyl, aryl, alkenyl, or halogen-substituted alkyl, aryl, or alkenyl. R ¹ represents an aromatic acyl group. R ² represents alkyl or aryl. 'Represents a sulfonyl group.) Based on the above findings, the present researchers have conducted further studies and found that the 2,3-anhydro form obtained above can be treated with azide ion in the presence of an ammonium salt as a catalyst. Was found to be extremely effective for highly selective azidation of the anhydro compound.

The method for producing the azido nucleoside derivative of the present invention is based on the above findings. More specifically, as shown in the following general formula, a 2,3′-anhydro 2′-doxyduridine derivative is added to an ammonium salt. Reacting an azide ion in the presence of a compound to obtain a 3'-azide compound represented by the following general formula (5) _:

(In the above formula, represents a hydrogen, a halogen, an alkyl, an aryl, an alkenyl group, or a halogen-substituted alkyl, aryl, or alkenyl group, and R 3 represents an alkylcarbonyl group or an arylcarbonyl group. )

According to the present invention, further, as shown in the following general formula, a 3′-azidoxydoxydidine derivative is reacted with a base to deprotect the 5′-hydroxyl group, and 3′-azidoxydoxy. A method for producing a lysine derivative is provided.

(In the above formula, X represents a hydrogen, a halogen, an alkyl, an aryl, an alkenyl group or a halogen-substituted alkyl, an aryl, or an alkenyl group, and R 3 represents an alkylcarbonyl group or an arylcarbonyl group. Brief description of the drawings

FIG. 1 is a diagram for explaining each step of conventional synthesis of an azidonucleotide derivative _c

FIG. 2 is a diagram for explaining an example of an azidation step of a conventional anhydrolated nucleoside derivative:

FIG. 3 is a diagram for explaining another example of the conventional azidation step of an anhydrated nucleoside derivative.

FIG. 4 is a view for explaining still another example of the azidation step of a conventional anhydrated nucleoside derivative. The best form for carrying out KIKI

Hereinafter, the present invention will be described in detail with reference to the drawings as necessary.

(2'-deoxyperidine derivative)

In the present invention, a 21-doxydizidine derivative represented by the following general formula (1) can be used as a raw material.

In the general formula (1), the substituent X is not particularly limited as long as it does not hinder the 5′-protecting group, the hydrophilization, and / or the 3′-azidation reaction.

As such X, for example, a hydrogen atom, a halogen atom, or an alkyl group (preferably having 1 to 6 carbon atoms) which may be substituted by a halogen atom, an alkenyl group (preferably having 1 to 6 carbon atoms) Alternatively, an aryl group (preferably having 6 to 12 carbon atoms) or the like can be used. In terms of avoiding reaction inhibition and steric hindrance, X = a hydrogen atom, a halogen atom, or a methyl group can be suitably used: χ = When a halogen atom, x = F, Cl, B The compounds r or I can be suitably used as a compound for crushing (Bull. Chem. So Jpn., 6_0_ (1987), 2073-2077). When X is Cl, Br, or I, the reaction conditions in each step for producing the azido-nucleoside derivative of the present invention may be appropriately adjusted according to the respective substituents.

(Protection of δ 'monohydroxy group)

As a protecting group for the 5'-hydroxyl group of the above 2'-deoxyperidine derivative (1) Is preferably an aromatic acyl group. Examples of such an aromatic acyl group include a benzoyl group, a p-tonoleoyl group, an o-toluoyl group, a 2,4,6-trimethylbenzoyl group, a p-chlorobenzoyl group, and a 0-chlorobenzoyl group. An aromatic acyl group having about 7 to 10 carbon atoms, such as a group, a P-methoxybenzoyl group or a 0-methoxy-benzoyl group, can be suitably used. Among these protecting groups, a benzoyl group can be particularly preferably used from the viewpoint of ease of production or cost. Further, from the viewpoint of stability in the azidation reaction described later, a 0- or p-toluoyl group can be particularly preferably used.

As a reagent for imparting the above-mentioned aromatic acyl group to the above-mentioned 5′-hydroxyl group, for example, an acid halide having the above-mentioned aromatic acyl group, an acid anhydride and the like can be used, but there is no particular limitation. Not done. From the viewpoint of reactivity, the above-mentioned acid halide having an aromatic acyl group is preferable as the reagent, and among them, acid chloride is particularly preferably used from the viewpoint of easy production.

By the aromatic acylation of the 5′-hydroxyl group, a 5′-monoaromatic acylated dexperidine derivative represented by the following general formula (2) is obtained.

In the above general formula (2), R ^: represents an aromatic acyl group, and X has the same meaning as in the above general formula (1;).

(Reaction conditions for 5'-monoaromatic acylation)

In the above 5'-aromatic acylation reaction, an acylating reagent (aromatic acylhala The amount of amide, aromatic acid anhydride, etc.) used is 0.5 to 1.5 moles per 1 mole of the starting material 21-deoxyduridine derivative (1), from the viewpoint of 5, -hydroxyl selectivity. Is preferably about 0.9 to 1.2 mol.

(Solvent)

In the above-mentioned aromatic acylation, a solvent may be used if necessary (in other words, the reagent may also serve as the solvent. The same applies to the following description). When a solvent is used in the above 5′-hydroxyaromatic acylation, the solvent may be an organic or inorganic compound that is substantially inert to the acylation reaction and is liquid at the reaction temperature of the reaction (or , mixture) can be used without limitation of two or more of the compounds _c

From the viewpoint of the solubility of the reaction raw materials and the acceptance of acids produced as a by-product of the reaction, a basic organic liquid such as pyridine can be suitably used. From the viewpoint of improving the reactivity, an organic or inorganic base such as triethylamine or sodium carbonate may be appropriately mixed with the above solvent and used.

The amount of the solvent to be used is not particularly limited. However, from the viewpoint of reaction efficiency and ease of stirring, about 0.5 to 4 L (liter) is used per 1 mol of the starting material 2-deoxyperidine derivative (1). It is preferable to use

(Reaction conditions)

The above-mentioned acylation reaction is performed, for example, by dissolving or suspending the raw material 2′-deoxyperidine derivative (1) in the above-mentioned solvent, and then dropping the above-mentioned acylation reagent and reacting it. Is preferred. Further, if necessary, the above acylating reagent may be diluted with the above solvent, and then may be dropped and reacted with the 2, -deoxyperidine derivative (1). The time required for dropping is preferably about 15 minutes to 2 hours. The reaction temperature (the temperature of the anti-mixture during the reaction) can be about 120 to 50 ° C from the viewpoint of the balance between reaction efficiency and suppression of side reactions. From the viewpoint of the property, the reaction temperature is not more than room temperature (25 ° C), It is preferably below (especially 12 ^ or less). After cooling the above-mentioned acylating reagent with ice or the like, it is added dropwise to the 2'-deoxyperidine derivative (1) (since the above-mentioned acylation reaction is a hot-hot reaction), the reaction at about 8 to 12 ° C. Temperature is easily obtained.

(Confirmation of acylation)

The progress and completion of the acylation reaction can be monitored or confirmed by ordinary means such as TLC (thin layer chromatography; silica gel, alumina, etc.) and high performance liquid chromatography (HPLC). In addition, the infrared absorption spectrum

(IR) confirms the formation of an ester group. Since the reaction time of the acylation reaction may also depend on the above-mentioned reaction temperature, the kind of the acylation reagent, and the like, the progress of the reaction is monitored by the above-described method, and at least 90% or more of the reaction proceeds. It is desirable to terminate the reaction after confirming that the reaction has been performed. The reaction time of the acylation reaction is usually 5 hours or less, preferably about 10 minutes to 3 hours.

(Product isolation, etc.)

The isolation of the product from the reaction mixture of the above acylation reaction can be performed by a conventional method. For example, the reaction mixture may be subjected to an extraction operation using a suitable solvent, As the extraction solvent to be used at this time, for example, ethyl acetate, chloroform, toluene, hexane and the like can be suitably used. After removing the extraction solvent from the obtained extract, a crude product can be obtained. If necessary, the crude product may be used after further purification. As such a purification means, for example, a silica gel column, preparative HPLC and the like can be suitably used.

The structure of the acylated product can be confirmed by IR, nuclear magnetic resonance (NMR), or mass spectrometry (MS). The purity of the product can be confirmed by melting point measurement or the like in addition to TLC, HP LC, IR and NMR described above. (Sulfonylation reaction)

In the present invention, the above-mentioned 5'-hydroxyl-aromatic acylated-2 deoxyperidine derivative (2) is a derivative of the 3'-hydroxyl sulfonyl derivative represented by the following formula (3). It is preferable to subject it to the production and subsequent hydrolysis reaction.

R '

In the general formula (3), the leaving group R ^{2 at the} 3′-position represents an alkyl or arylsulfonyl group represented by a methanesulfonyl group, a p-toluenesulfonyl group, and the like.

R ¹ and X have the same meanings as in the general formula (2).

R ² as a protecting group for the above 3′-hydroxyl group is an alkyl (preferably having 1 to 12 carbon atoms) or aryl (preferably having carbon number) represented by a methanesulfonyl group, a p-toluenesulfonyl group and the like. 6-30) A sulfonyl group can be suitably used.

(Sulfonylation reagent)

The sulfonylation reagent for the sulfonylation is not particularly limited, but from the viewpoint of reactivity, for example, ', a sulfonyl halide can be suitably used. Among them, sulfonyl colloid is particularly preferred from the viewpoint of ease of production;

The amount of the sulfonylating reagent used is 0.8 with respect to 1 mol of the starting material 5—hydroxy-aromatic acylated 1-2-deoxyperidine derivative (2) from the viewpoint of selectivity to 3′-hydroxyl group selection. It is preferred to use about 4 moles:

(Solvent: '

In the above sulfonylation reaction, a solution may be used if necessary: When a solvent is used in the above 3′-hydroxyl sulfonylation, the solvent is substantially inert to sulfonylation. : An organic liquid which is liquid at the opposite reaction temperature Alternatively, an inorganic compound (or a mixture of two or more such compounds) can be used without any particular limitation.

The amount of the above solvent is not particularly limited. However, the solvent is used in an amount of 0.5 to 4 L (relative to 1 mol of the 3′-hydroxy derivative (2) as a raw material). It is preferable to use a degree.

(Reaction conditions)

In the above sulfonylation reaction, for example, the 3′-hydroxy group derivative (2) as a raw material is dissolved or suspended in the above solvent, and then the above sulfonylation reagent is added dropwise to cause a reaction. It is preferable from the viewpoint of selectivity. Further, if necessary, the above sulfonylating reagent may be diluted with the above solvent and then added dropwise to the 3-hydroxy group derivative (2) for reaction. The time required for dropping is preferably about 15 minutes to 2 hours.

The reaction temperature can be about 120 to 50 ° C. from the viewpoint of the balance between the reaction efficiency and the suppression of side reactions, but from the viewpoint of the selectivity of 3′-hydroxyl sulfonylation, the reaction temperature should be room temperature. (25 ° C) or lower, more preferably 15 ° C or lower (especially 12 or lower).

(Confirmation of sulfonylation)

The progress and completion of the sulfonylation reaction can be monitored or confirmed by ordinary means such as TLC, HPLC and the like, as in the case of the above acylation reaction. Further, the formation of a sulfonic acid ester group can be confirmed by IR. Since the reaction time of the sulfonylation reaction may depend on the above-mentioned reaction temperature, the kind of the sulfonylation reagent, and the like, the progress of the reaction is monitored by the above-mentioned method, and at least 90% or more is monitored. After confirming that the reaction has progressed, terminate the reaction. Is desirable. The reaction time for the sulfonylation reaction is usually 5 hours or less, preferably about 10 minutes to 3 hours.

(Product isolation, etc.)

The above sulfonylation product (3) can be isolated once, but from the viewpoint of yield, use the crude product extracted with a suitable solvent for the next hydrolysis reaction. According to the findings of the present inventors, even if the sulfonylation product (3) is not once isolated, there is no substantial disadvantage in the subsequent steps.

When the sulfonylation product (3) is not isolated, for example, the reaction mixture is extracted with a suitable extraction solvent (preferably a low boiling point solvent such as toluene, ethyl acetate, chloroform, and hexane). Then, the extraction solvent is removed from the extract to obtain a crude 3′-sulfonyl compound (3):

(Hydrogenation reaction)

The 3′-sulfonyl compound (3) obtained as described above can then be converted to an anhydro compound represented by the following general formula (4) by the action of a base or the like.

In the general formula (4), R ¹ and X have the same meanings as in the general formula (1). As the base to be used in this hydrolysis, an inorganic or organic strong base can be suitably used. Such strong bases include, for example, 1,8-diazabi Black [5.4.0] Pendecar 7-ene (DBU), sodium hydroxide, potassium hydroxide, sodium phthalate, potassium phthalate, etc. can be used. Above all, from the viewpoint of nucleophilicity or suppression of side reactions, strong organic bases such as the above-mentioned DBU can be suitably used.

In the above-mentioned hydrolysis, the amount of the above-mentioned strong base used depends on the amount of the starting material 5′-hydroxyl-aromatic acyl-acylated 13′-sulfonyl-substituted 1 2′-deoxyperidine derivative

The amount is preferably about 0.8 to 1.5 mol (more preferably about 1.0 to 1.3 mol) per 1 mol of (3).

(Solvent)

The reaction between the above-mentioned 3′-sulfonyl compound (3) and a strong base may be carried out in an appropriate solvent, if necessary. As the solvent at this time, for example, acetonitrile, N, N-dimethylformamide (DMF), methanol, ethanol, 2-propanol and the like can be used. Among these, acetonitrile and DMF can be particularly preferably used from the viewpoint of the stability of the 5'-aromatic acyl-protecting group.

The amount of the solvent used is not particularly limited, but may be about 0.5 to 4 L based on 1 mol of the 3'-sulfonyl compound (3) as a raw material in consideration of reaction efficiency and ease of stirring. I like it.

(Reaction conditions)

The above-mentioned hydrolysis is carried out, for example, by dissolving or suspending the raw material 3, -sulfonyl compound (3) in the above-mentioned solvent, followed by dropping the above-mentioned base and reacting it. It is preferable from the viewpoint of the selectivity of the drolation reaction. If necessary, the base may be diluted with the solvent and then added dropwise to react. The time required for the drop is preferably about 15 minutes to 2 hours. The reaction temperature is preferably about 10 to 80 ° C (more preferably about 40 to 80 ° C) from the viewpoint of the balance between the reaction efficiency and the side reaction suppression.

(Confirmation of hydrodehydration) The progress and termination of the hydrolysis reaction are determined in the same manner as in the aromatic acylation described above.

It can be confirmed by ordinary means such as TLC and HP LC. The reaction time may also depend on the reaction temperature and the base described above.Therefore, the reaction progress is monitored by the above method, and after confirming that at least 9_0% of the reaction has progressed, the reaction is performed. Is preferably terminated. The reaction time is usually 5 hours or less, preferably about 10 minutes to 3 hours.

The product can be isolated from the reaction mixture by extraction with a suitable solvent. As the extraction solvent at this time, a low-boiling solvent such as toluene, chloroform, hexane and the like can be suitably used. A crude product can be obtained by removing the extraction solvent from the obtained extract. However, if necessary, the crude product may be further purified. As such a purification means, for example, silica gel column chromatography, preparative HPLC and the like can be suitably used.

The structure of the hydrolyzed product (4) can be confirmed by instrumental means such as IR, NMR, or mass spectrometry (MS). The purity of the product can be confirmed by TLC, HPLC, IR, NMR, melting point measurement and the like.

(Azidation reaction)

The above 2,3′-anhydro form (4) is then suitably used for an azide reaction. In this azidation, the protecting group R ³ is not particularly limited as long as it is a group capable of protecting the 5′-hydroxyl group. Azido nucleoside derivatives as products

In view of the ease of deprotection of (5), R ³ may be a weakly acidic (pH = about 1 to 4) or weakly basic (pH = about 9 to 13) eliminable group. preferable.

Examples of such a protecting group R ³ include a trityl group (C ₆ H ₅ ) ₃ C—, a pivaloyl group (CH ₃ ) C—CO—, a 1-adamantoyl group, a benzoyl group, a p-toluoyl group, — Toluoyl group, 2,4,6-trimethylbenzoyl group, p-cococobenzoyl group, 0-cocolobenzoyl group, p-methoxybenzoyl group, 0-methoxybenzoyl group, etc. can be suitably used. Above all, under weakly acidic conditions From the viewpoint of ease of deprotection in the present invention, a trityl group is particularly preferable, and from the viewpoint of ease of deprotection under weakly basic conditions, a 0- or p-toluoyl group is particularly preferably used.

R

In the above K general formula (5), R ³ has the same meaning as in the above general formula (1).

(Ammonium salt)

As the ammonium salt used as the azidation reaction catalyst, any of an inorganic ammonium salt and an organic ammonium salt (for example, a tetraalkyl ammonium salt containing a lower alkyl group having 1 to 4 carbon atoms) can be used. In terms of operability, inorganic ammonium salts are preferably used.

In the azidation, as the above-mentioned inorganic ammonium salt, for example, ammonium chloride NH ₄ Cl, ammonium sulfate (NH ₄ ) ₂ SO., Ammonium bromide Br can be used, but the reaction yield is high. From the point of view, ammonium chloride is particularly preferably used.

From the viewpoint of the balance between the reaction efficiency and the ease of post-treatment, the above-mentioned ammonium salt as a catalyst is 0.2 mol or more with respect to 1 mol of the raw material 2,3'-ammonium (4). Further, it is preferable to use about 1 to 2 mol.

(Azide reagent)

As the azide reagent that gives the azide ion for the azide reaction, a reagent having an azide group (N :-) can be used without any particular limitation. , For example azide Natoriumu N a N _3, lithium azide L i N _3, azide trimethylsilyl _{(CH 3) 3 S i -} N 3 ( i.e. TMS-N ₃₎ and the like are suitably used. Among them, sodium azide is particularly preferably used from the viewpoint of operability.

From the viewpoint of the balance between the reaction efficiency and the ease of post-treatment, the azide reagent is used in an amount of 0.8 mol or more, and more preferably 1. mol, per 1 mol of the raw material 2,3'-anhydro derivative (4). It is preferable to use about 2 to 6 mol.

(Solvent)

In this azidation reaction, a solvent may be used if necessary. Examples of such a solvent include an organic or inorganic compound (or a mixture of two or more compounds) that is substantially inert to the azidation reaction and is liquid at the reaction temperature of the reaction. It can be used without any particular restrictions. From the viewpoint of solubility of raw materials and azide reagents, DMF (dimethylformamide), dioxane, diglyme, HMPA

(Hexamethylphosphorus.triamide), DMA (dimethylacetamide), DMI (1,3-dimethyl-12-imidazolidone), DMSO (dimethylsulfoxide), 1-methyl-12-pyrrolid Don and the like are preferably used. Among them, DMF is particularly preferably used from the viewpoint of the reaction yield. In addition, in order to improve the solubility of the azide reagent, the solubility of the raw materials should not be impaired.

Water) may be mixed with the above solvent.

The amount of the solvent used is not particularly limited, but from the viewpoint of the balance between the reaction efficiency and the ease of stirring, the raw material 2,3'-anhydro derivative (4) is 3.5 m on a 7.5-millimol scale. 1 or more, and more preferably used in an amount of about 5 to 50 m 1 _c

(Reaction conditions)

In the azidation, the reaction conditions for obtaining an azido nucleoside derivative (Ihi 5) by reacting an azide ion with a raw material 2,3'-anhydride-1'-deoxyduridine derivative in the presence of the above ammonium salt are as follows: As long as phase reactions are possible There is no particular limitation. From the viewpoint of the balance between reaction efficiency and suppression of side reactions, the reaction temperature is preferably 80 or more, and more preferably about 100 to 150 ° C.

The completion of the azidation reaction can be confirmed by ordinary means such as IR, NMR, TLC, and HP LC. The reaction time depends on the above-mentioned reaction temperature, but is usually 30 hours or less, preferably about 30 minutes to 15 hours. _C (Isolation of product)

The above azidation product can be isolated, for example, by extraction from the reaction mixture using an appropriate solvent. As the extraction solvent at this time, for example, toluene, ethyl acetate, chloroform, hexane and the like can be suitably used. A crude product can be obtained by removing the extraction solvent from the obtained extract. If necessary, the crude product may be further purified. In this purification, for example, silica gel ′ column chromatography (for example, ethyl acetate z hexane (volume ratio = 1 _: 1) as a mobile phase, preparative HPLC) can be suitably used.

The structure of the azidation formation can be confirmed by IR, NMR, MS or the like. The purity of the product can be confirmed by TLC, HPLC, IR, NMR measurement and the like, and can be confirmed by TLC, HPLC, IR, NMR measurement and the like.

(Deprotection of 5 'monohydroxy group)

The technique for deprotection of the 5′-protecting group of the azide derivative (5) obtained above is not particularly limited, but, for example, hydrolysis using a base can be suitably used. As the base, for example, inorganic bases such as sodium hydroxide, potassium hydroxide, and ammonia; and organic bases such as alkylamine, sodium methoxide, and sodium methoxide can be preferably used. Particularly, in the present invention, from the viewpoint of easy of the reaction operation, sodium hydroxide, and potassium hydroxide inorganic base preferably usable Demel _c

(Base)

In the above deprotection reaction, the amount of the base used is, from the viewpoint of suppressing reaction by-products, It is preferably used in an amount of about 0.05 to 2.0 mol, more preferably about 0.2 to 1.0 mol, per 1 mol of the starting azide compound (5).

(Solvent)

Solvents usable in the deprotection reaction include organic or inorganic compounds which are substantially inert to the hydrolysis reaction and are liquid at the reaction temperature of the reaction (or two or more kinds of the compounds). Mixture) can be used without particular limitation. From the viewpoint of the solubility of the raw material (5), alcohol (particularly, methanol) is preferably used.

The amount of the solvent to be used is not particularly limited, but is preferably about 0.5 to 4 L per 1 mol of the starting azide compound (5) in consideration of reaction efficiency and ease of stirring. .

(Reaction conditions)

In the deprotection reaction, it is preferable that the starting azide compound (5) is dissolved or suspended in the above-mentioned solvent, and then the above-mentioned base is added thereto for the reaction. The temperature is preferably about 40 to 80 ° C. (for example, the reflux temperature of methanol) from the viewpoint of the balance between reaction efficiency and side reaction suppression.

The progress and completion of the deprotection reaction can be confirmed by ordinary means such as TLC and HPLC, similarly to the above-mentioned acylation and the like. The reaction time may also depend on the deacylation reagent, the reaction temperature, and the type of protecting group as described above, but the progress of the reaction was monitored by the method described above, and at least 90% or more of the reaction proceeded. It is preferred to terminate the reaction later. The reaction time is generally 5 hours or less, preferably about 10 minutes to 3 hours.

(Isolation of product)

The isolation of the product can be performed as follows. For example, the reaction mixture obtained by the above deprotection is cooled, neutralized with an appropriate acid (such as hydrochloric acid), the solvent is removed, the obtained aqueous solution is washed with ether, and the aqueous solution is concentrated. _ε The concentrated aqueous solution is cooled (approximately 10 ° C), and the desired 3'-azide 2 ' 'White crystals of one dideoxyperidine derivative (R ³ = H in general formula (5)) precipitate.

The structure of the above deprotected product (5) can be confirmed by instrumental analysis such as IR, NMR, and MS. The purity of the product can be confirmed by TLC, IR, HPLC, NMR, melting point measurement and the like.

(Example)

Hereinafter, the present invention will be described more specifically based on examples.

Example 1

(Synthesis of 5'100-throylthymidine from thymidine)

In a reaction flask, 40 ml of pyridine was placed, and thymidine (10. Og, 41.3 mmol; X = H in the above formula (1)) as a raw material was dissolved therein. To the raw material solution thus obtained, while stirring at a reaction temperature of 0 to 5 ° C while cooling, 0-toluoyl chloride (7.02 g, 45.4 mmol) as an aromatic acylating reagent was added. It was added dropwise over 1 hour. At this time, the above reaction temperature was monitored while the thermometer was immersed in the reaction mixture (the immersion depth of the monitor part (tip) of the thermometer-mm). After the completion of the dropping of the reagent, the acylation reaction was completed by further stirring at 0 to 5 ° C for 2 hours.

The above acylation reaction was carried out while monitoring by TLC (developing solvent: ethyl acetate / n-hexane // triethylamine, volume ratio = 5: 1: 0.2). The time when the spot corresponding to the raw material thymidine almost disappeared in the TLC was defined as the end of the reaction.

After completion of the above acylation reaction, the obtained reaction mixture was poured into 40 ml of water containing sodium hydrogen carbonate (4.20 g, 49.9 mmol), and 4 Oml of toluene was added thereto. Extraction was performed using a separating funnel. This toluene extraction operation was performed twice, and the separated toluene organic layer was collected.

5.0 g of anhydrous sodium sulfate was added to the toluene organic layer obtained by the extraction operation. In addition, it was dried by standing at 25 ° C for 1 hour. Next, when toluene was distilled off under reduced pressure using a rotary evaporator from the toluene organic layer separated by filtration, a white solid residue was obtained.

The resulting solid residue is dissolved in 30 ml of a mixed solvent of ethyl acetate Zn—hexane = 2Z1, and silica gel column chromatography (developing solvent: mixed solvent of ethyl acetate / n—hexane = 2/1) is used. And purified. When the solvent was distilled off from the eluate of the silica gel column under reduced pressure using a rotary evaporator, 5′-〇10-toluoylthymidine was obtained as white crystals (yield 12.08 g). , Yield: 85.0 //; in the general formula (2), Rl = 0-toluoyl, X = H).

The melting point of white crystalline solid obtained by the above is 1 1 5 ° C (after recrystallization from methylene chloride), TLC (developing solvent: silica gel, acetic acid Echiru Z _n - hexane =

5/1) showed a single spot, and the Rf value of the spot was 0.3. The data of 1 H-NMR (DMSO-d6, standard substance: tetramethylsilane) were as follows.

5 1. 5 7 (s, 3 Η, heterocyclic CH3), 52.28 (t, 2 H, J = 72 Η ζ, Η—2 '), 5 2.57 (s, 3 H. ο-toluene CH3), 6 4.00 to 4.33 (m, 1 H, H-3), δ 4 35 to 4.75 (m, 3 H, H—4 ′, H—5 ′), δδ.5 δ (d, 1 Η. J = 5.0Η ζ, Η— 3'OH), 56.35 (ΐ, 1H, J = 7.2Hz Η— 1 '), δ7.20-7 65 (m, 4H, o-toluene, H-6) δ 7.80〜8.15

(m, 1 H, o—toluene), δ 1 1.32 (s 1 Η, 3-ΝΗ).

Substantially the same as the reaction conditions of the above-mentioned Example, even when X is hydrogen, alkyl, or halogen (F, C 1, Br, I), the corresponding product 5′-0 It is possible to obtain 0-toluoyl-1 2'-deoxyperidine derivatives. Example 2 (Synthesis of 5′-Op-toluoyl thymidine from thymidine) Instead of o-toluoyl chloride used in Example 1, p-toluoyl chloride (7.02 g) was used as an aromatic acyl halide. , 45.4 mmol) in the same manner as in Example 1 except that 5 ′ — 0—toluoyl thymidine (Rl = p—toluoyl in the general formula (2), white crystal of X = H) was used. A solid was obtained (yield 12.08 g, 85.0% yield).

The melting point of the obtained white crystalline solid was 185 ° C (recrystallized from methylene chloride). TLC (silica gel, eluent: ethyl diethyl hexane = 51) showed a single spot. Had an R f value of 0.30.

1 H-NMR (DMS 0-d6, tetramethylsilane) Data were as _follows.c

δ 1.57 (s, 3Η, heterocycle CH3), δ 2.28 (t, 2H, J = 7.2Hz, H—2 '), 52.57 (s, 3H, p-toluoyl CH3), δ 4.00 to 4.33 (m, 1 H, H-3 ′), 54.35 to 4.75 (m, 3H, H-4 ′, H-), 5 δ.55 (d, 1 H, J = 5.0 Hz, H-3'OH), δ 6.35 (t, 1H, J = 7.2Hz, H-l '), 57.22 (d, 2H, J = 7. 2Hz, p-torr oil), δ7.51 (s, 1H, Η-6), δ7.76 (d, 2Η, J = 7.2Ηζ, ρ-torr oil), δ11.30 (s, 1 Η, 3 -ΝΗ)

Example 3

(Synthesis of 5'-Ο-ρ- wolfberry benzoyl thymidine from thymidine)

Example 1 was repeated except that 0-toluoyl chloride used in Example 1 was replaced with ρ-cuco benzobenzoyl chloride (7.94 g, 45.4 mmol) as an aromatic acyl halide. In the same manner, a white crystalline solid of 5′—0—p—clo-mouth benzoylthymidine (Rl = p-crocobenzoyl in general formula (2), X = H) was obtained (yield 11.17 g). , Yield 73.7%). The melting point of the above white crystalline solid was 184 ° C (recrystallized from methylene chloride), and it showed a single spot by TLC (silica gel, eluent: ethyl acetate = 5: 1). The value was ◦.30.

1 H-NMR (DMS 0-d6, tetramethylsilane) Data were as follows _c

51.70 (s, 3Η, heterocycle CH3), 52.20 (t, 2H, J = 7.2HzH-2 ') δ4.00 to 4.30 (m , 1 HH— 3 '), δ 4.3.5 5 4.75 (m 3 H H- 4', H— 5 '), 5 5.55 (d, 1 HJ = δ .0 Hz H- 3 'OH), 56.35 (t, 1H, J = 7.2HzH-1'), 57.20 (s1HH-6), δ7.35 (d2H , J = 7.2 H zp—chlorobenzyl), 5 7.95 (d, 2 Η, J = 7.2 H zp—clon benzoyl), 51.1.00 (sl H 3— NH)

Example 4

(Synthesis of 5'-O-o-tonoleoyl-1,2,3-hydroxythymidine from 5'-O-o-tonoleoylthymidine)

In a reaction flask, pyridine was added to 40 ml, and 5′-O—0—toluylthymidine obtained in Example 2 (1.208 g 35.1 mmol (Rl = p-toluoyl in the general formula (2)) , X = H) The resulting raw material solution was stirred under cooling at 55 ° C., and 30 ml of methanesulfonyl chloride (13.5 g, 121 mmol) as a sulfonylation reagent was added. After the completion of the dropwise addition, the mixture was further stirred for 2 hours at 05 ° C. to complete the sulfonylation reaction. The reaction was terminated when the spot of o-toluoyl thymidine almost disappeared.

After the completion of the above sulfonylation reaction, the obtained reaction mixture was treated with sodium hydrogen carbonate.

(16.6 g, 198 mmol) was added to water (40 ml), and toluene (4 Om1) was added to the obtained product, followed by extraction to separate an organic layer. This extraction The operation was repeated twice, and the organic layers were combined, and 5.0 g of anhydrous sodium sulfate was used. C, The solvent was distilled off from the organic layer obtained by e-filtration after drying for 1 hour under reduced pressure using a monotary evaporator to obtain a white solid residue.

The obtained white solid residue (5'-0-o_-toluoyl thymidine 3, -sulfonylide; R3-0-toluoyl, R2 = sulfonyl, X = H in the above general formula (3)) is acetonitrile. Ril was dissolved in 100 ml, and the resulting solution was heated and maintained at 50 ° C. Then, 1,8-diazabicyclo [5,4,0] -17-denecene (DBU) (7.5 g) , 49.2 mmol) was slowly added dropwise. After the addition of the DBU was completed, stirring was continued at 50 at 2 hours for 2 hours to complete the 2,3-hydrogenation reaction of the 3, -sulfonylation product.

The above-mentioned anhydration reaction was carried out while monitoring with TLC, and the reaction was terminated when the spot of the above-mentioned intermediate (3′-sulfonylated compound) almost completely disappeared.

After the completion of the above-mentioned hydrolysis reaction, the solvent was distilled off from the obtained reaction mixture under reduced pressure using a single evaporator, and a white solid residue (2,3′-hydrochloride) was obtained. Obtained.

After adding and dissolving 50 ml of chloroform and 50 ml of water to the white solid residue, crocoform extraction was performed to separate an organic layer. This extraction operation was performed twice, the obtained organic layers were combined, and dried at 25 ^DC for 1 hour using 5.0 g of anhydrous sodium sulfate. From the organic layer separated by filtration, the solvent was distilled off under reduced pressure using a rotary evaporator.

The residue obtained after distilling off the solvent is recrystallized from acetonitrile 10 Om 1 to give 5'-0-o-toluoyl-1,3'-anhydrothymidine (in the above formula (4), R3 = 0- Toluoyl, X = H) was obtained (yield 10.60 g, yield 88.2 ° /.).

The melting point of the white crystalline solid obtained above was 194 ° C, and TLC (silica gel And a developing solvent: black form / methanol = 7: 1), showing a single spot, and the Ri value of the spot was 0.35.

1 H-NMR (DMS O-d6, tetramethylsilane) data were as follows.

δ1.53 (s, 3Η, hetero CH3), δ2.35 to 2.70 (m, 5H, H-2 '; o-toluoyl CH3), 54.30 to 4. 75 (m, 3H, H-4 ';H-5'), 55.35 to 5.65 (m, 1H, H-3 '), 55.90 to 6.0 5 (m, 1 Η, Η- 1 '), 5 7. 3 5~ 7. 5 5 (m, 3 H, o one toluoyl), 5 7. 6 3 (s , 1 H N H- 6), 5 7.75 to 7.95 (m, 1H, o—Torr oil)

Substantially in the same manner as the reaction conditions described above in this example, even when X is hydrogen, alkyl, or halogen (F, CI, Br, I), the corresponding product 5′—〇1 o — Toluoyl — 2 ′ —Doxy 2,3 ′ —Anhydrodolidine derivative (general formula (4), X-hydrogen, alkyl, halogen (F, C 1, Br, I)) can be obtained .

Example 5

(Synthesis of 5'-O-p-toluoyl-1,2 ', 3'-anhydrodochymidine from 5 "-0-p-toluoinothymidine)

Instead of 5'-O-0-toluoylthymidine used in Example 4, 5'-0-p-toluoylthymidine (1.208 g; R3 = p-toluoyl in the general formula (2)) 5 ′ —O—p—toluoyl-1,2,3′—anhydrothymidine (in the general formula (4), except that R3 = p− (Yield: 10.88 g, 90.0% yield): Melting point of this solid was 217 ° C, TLC (silica gel, developing solvent: Mouth form / methanol 7: 1) showed a single spot, and the Rf value of the spot was 0.35. The 1 H-NMR (DMS O-d6, tetramethylsilane) data was as follows.

δ1.53 (s, 3H, heterocycle CH3), 52.35-2.70 (m, δΗ, Β-2 '; ρ-toluoyl CH3)., δ4.30- 4.75 (m, 3Η, Η-4 '; Η_5'), δ 5.35 to 5.6.5 (m, 1Η, Η—3 '), δ 5.90.6.0 5 (m, 1Η, Η— 5 7.2 2 (d, 2 Η, J = 7.2 Η 2 ρ—toluoyl), δ 7.5 1 (s, 1 1, Η— 6), δ 7 . 7 6 (d 2Η, J = 7.2 Η ζ, ρ—toluoyl)

Example 6

(Synthesis of 5'-Ο-ρ-black benzoinolethymidine, et al.

The procedure was performed in the same manner as in Example 4, except that 5′-0-ρ-monobenzoyl thymidine (1 1.I 7 _g ) was used as a raw material instead of 5′-Ο-0-toluoyl thymidine used in Example 4. in the same manner as example 4, 5 'to give a crystal of -〇 one p- black port base Nzoiru 2, 3 ¹ one Anhi Dorochi spermidine (in the general formula (4) R3 = p- black port base Nzoiru, X = H) (10.11 g, yield 91.0%). The melting point of this crystalline solid was 21 3, and it showed a single spot by LC (silica gel, developing solvent: chloroform / methanol 7: 1), and the Rf value of the spot was 0.3. Was.

1 H-NMR (DMS O- d6 , tetramethylsilane) data rarely _c at follows

51.70 (s3Η, heterocycle CH3), δ2.35-2.70 (m, 2H, H-2 '), δ4.30—4.75 (m, 3 Η, Η-4 '; Η-5'), δ 5.35 to 565 (m, 1 Η, Η— 3 '), 5 5.9 0 to 6.05 (m, 1 Η , Η- I ') δ 7.20 (s, 1 Η, Η-6), δ 7.35 (d, 2

Η, J = 7.2 Η ζ, ρ-chlorobenzyl), 5 7.95 (d, 2 H, J = 7.2 ζ ζ, _p _ Example 7

(5'-O- trityl-2,3'- 3'-azide from anhydrothymidine

3 1 Deoxy 5'-〇- Synthesis of trityl thymidine)

In a reaction flask, dimethylforma-mide (DMF) was added to 35 ml of 5′-〇-trityl-1-2,3′-anhydrothymidine (3.50 g, 7.5 mmol; in the general formula (4) R3 = trityl, X = H)) was dissolved. Sodium azide (1.75 g, 27 mmol) as an azide reagent and ammonium chloride (0.60 g, 11.3 mmol) as a catalyst were added to the obtained raw material solution. The mixture was stirred for about 11 hours while heating at C. The progress of the azidation reaction is monitored by TLC, etc., and the reaction is terminated when the spots of the starting material, 5'-0-trityl-1,2,3,-anhydrothymidine, have almost completely disappeared. Was. After the completion of the above azidation reaction, the obtained reaction mixture was cooled to room temperature, 30 ml of water was added thereto, and the mixture was extracted with ethyl diperoxide (150 ml). The extraction is performed twice, and the organic solvent layers are combined.The organic layer is washed three times with 30 ml of water, and dried at 25 ° C. for 1 hour using 10.0 g of anhydrous sodium sulfate. did. From the organic layer separated by filtration, the organic solvent was distilled off under reduced pressure using a single-port evaporator to obtain a residue.

The resulting residue was purified by silica gel column chromatography (developing solvent: Nityl Zirconate Zinc-Hexane = 1/1) to obtain 3'-azide 3'-doxy-1 5'-O-tritylthymidine (general formula In (5), R3 = trityl, X = H) was obtained as an oil (yield 3.60 g, 94.0%). The oil showed a single spot by TLC (silica gel, developing solvent: ethyl acetate / n-hexane = 5Zl), and the Rf value of the spot was 0.6.

1 H-NMR (CD C 13, tetramethylsilane) data were as follows.

6 1.52 (s, 3Η, hetero 澴 CH3), δ 2.4 1 to 2.50 (m, 2 H, H-2 '), 53.34 (m, H, H-5'), 53.55 (m, 1H, H-5 '), 53.98 (m, H, H-4') , 64.34 (m, 1H, H-3 '), 56.25 (t, H, J = 6.4Hz, H-1') δ 7.

20-7.50 (m, 15H, trityl), δ7.55 (s, 1Η, Η-6), δ8.42 (s, 1Η, 3—ΝΗ). IR spectrum data: 2100 cm—1 (-N3)

Example 8

In the same manner as in Example 7 except that the amount (equivalent) of ammonium chloride was changed as shown in the following (Table 1) with respect to 5'-O-triter-1,2,3'-hydrothymidine. When the azidation reaction was performed, the results shown in the following (Table 1) were obtained. <Table 1>

<1 equivalent of NH4C>

(Unused) 80.3%

0.1 equivalent 79 5%

0.2 89 5%

0.δ 89 9%

1. 0 92 5%

1.δ (Example 7) 94 0%

2. 0 93 2%

3.0 88 5%

As shown in Table 1 above, the addition of ammonium chloride in an amount of 0.2 equivalent or more (particularly when 1.0 to 2.0 equivalents were added) increased the reaction yield. Example 9

Same as Example 7 except that ammonium sulfate or ammonium bromide, tritylamine hydrochloride, or trimethylamine hydrochloride was used as a catalyst instead of ammonium chloride used in Example 7. When the azidation reaction was performed by the method, The results shown in the following (Table 2) were obtained.

Table 2>

(Reaction yield using other ammonium salt)

Ammonia salt> Reaction yield>

Ammonium sulfate 5 equivalents 8 9 9 ° λ

Ammonium bromide 5 equivalents 86, 0%

Triethylamine hydrochloride 5 equivalents 88,

Trimethylamine hydrochloride 5 equivalents 89.2%

As shown in Table 2 above, when any of the ammonium salts was used, an increase in the reaction yield was observed as compared with the data of Example 8 (without catalyst).

Comparative Example 1

In the azidation reaction using benzoic acid as a catalyst, in the case of using 0.2 equivalents according to the above-mentioned reference (3); Nucleosides k Nucleotides 1 990, 9 (5), 587-597 (Matsuda et al.) The reaction yield was 77.6%, and no increase in the reaction yield was observed. On the other hand, when 1.0 equivalent of benzoic acid was used, the reaction yield was 85.7%, indicating an increase in the reaction yield.

Example 10

(Synthesis of 5'-0-0-toluoyl-1,2,3-anthrothymidine from 3'-azide-3'-doxy-5'-0-0-toluoylthymidine)

In place of 5′-Ο—ο-trityl-1,2,3′-anhydrothymidine used in Example 7, 5′—0_0—toluoyl-1,2,3′—anhydrothymidine (2.57 g, 7.5 mmol; 3′-azido 3′-doxy-5 ′ under the same reaction conditions as in Example 7 except that R3 = o-toluoyl, X = H) in the general formula (4) was used. — O— 0—toluoyl thymidine (R3 = 0-toluoyl, X = H in formula (5)) was obtained as an oil (yield 2.75 g, yield 95.5).

0%). The obtained oil showed a single spot by TLC (silica gel, developing solvent: ethyl acetate n-hexane = 5/1), and the Rf value of the spot was 0.4.

1H—NMR (CDC 13, tetramethylsilane) data were as follows:

δ 1.57 (s, 3Η, heterocyclic CH3), 5 2.25 to 2.75 (m, 5H, H-2 '; toluene oil CH3), 64.00 to 4.80 (m, 4H, H -3 '; H—4'; H-5 '), δ 6.26 (ΐ, 1H, J = 6.4Ηζ, Η—1'), 57.10 to 7.70 (m, 4Η, ο —Tolu oil; Η— 6), δ 7.80 to 8.15 (m, 1H, o-toluiol), 5 10.40 (s, lH, 3- 3).

IR spectrum data: 2100 cm-1 (-N3).

Substantially in the same manner as the reaction conditions of the above-mentioned Example, even when X is an alkyl group, the corresponding product 3'-azido 5'-〇0-toluoyl-1 2 ', 3' It is possible to obtain dideoxyperidine derivatives (R3 = o-toluoyl, X = alkyl in the general formula (5)).

Example 1 1

(Synthesis of 5'-0-p-toluoyl-2,3'-anhydrothymidine to 3'-azide 3'-doxy-5'-0-p-toluoylthymidine)

Instead of 5′-O—0—trityl-2,3′—anhydrothymidine used in Example 7, 5′—O—p—toluoyl-1,2,3′-anhydrothymidine (2.57 g) was used as a raw material. 3′-Azido 3′-dexoxy, using the same reaction conditions as in Example 7 except that in formula (4), R3 = p-toluoyl, X = H) was used. 5 ′ —〇-I p-toluoyl thymidine (R 3 = p-toluoyl in general formula (5), χ = Η) was obtained as an oil (yield 2.62 g, 91.0% yield) ₌

The obtained oil was purified by TLC (silica gel, developing solvent: ethyl acetate n-hexane). Down = 5 1) in showed a single spot, R f value of the spot was 0. 4 _c

1 H-NMR (CD C 13, tetramethylsilane) data were as follows.

δ 1.57 (s, 3H, heterocycle CH3), 62.25-2.75 (m, 5H, H-2 '; toluoyl CH3), 64.00-4.8 0 (m, 4H, H—3 '; H-4'; H-5 '), δ6.20 (t, 1H, J = 6.4Hz, H—), δ7.1 0 ~ 7.45 (m, 3H, p-toluoyl; H-6), 67.80 ~ 8.15 (d, 2H, J = 7.8Hz, p-toluoyl), δ 1 0

2 8 (s, 1 H, 3—NH) _c IR spectrum data: 210 m cm_l (— N

3) _c

Example 1 2

(Synthesis of 3'-Azido 3'-deoxy-1 5'-O-p-chlorobenzoylthymidine from 5'-O-p-chlorobenzoyl 2,3'-anhydrothymidine) Used in Example 7 Instead of 5'-O-0-trityl-2,3'-anhydrothymidine, as a raw material, 5'-0-p-chlorobenzoyl-1,2'-anhydrothymidine (2.72 g, 7. 5 mmol; 3′-azide-1 3′-deoxy-1 5 under the same conditions as in Example 7 except that R3 = p-chlorobenzoyl in the general formula (4), 、 = Η) was used. '— Ο— ρ-clo mouth benzoyl thymidine (general formula

In (5), R3 = ρ-crocobenzoyl, X = H) was obtained as an oil (yield 2.59 g, yield 8δ0.0%). _C

The obtained oil showed a single spot by TLC (silica gel, developing solvent: ethyl acetate n-hexane = 5Z1), and the Rf value of the spot was 0.35 ₌ 1 H—NMR (CD C 13, tetramethylsilane) data are as follows:

61.60 (s, 3Η, heterocycle CH3), 52.4-1 to 2.50 (m, 2H, H—2 '), δ4.00 to 4.95 (m , 4 Η, Η— 3 ';Η-4'; Η -5 '), 5 6.26 (ΐ, 1Η, J = 6.4Η, Η-1'), 57.41 (d, 2Η, J = 7.2Η ρρ Benzoyl), 5 7.80-8.10 (m, 3H p—black mouth Benzoyl; H-6), δ 10.20 (s, 1Η, 3-ΝΗ). IR spectrum data: 2-1 00 cm-1 (one N3).

Example 13

(Synthesis of δ'-110-toluoyl-1,2'-anhydro 2'-doxydziridine to 3'-azido 23'-dideoxy 5'-0-ο-toluoylpyridine)

Instead of 5'-Ο-0-trityl-2, '-anhydrothymidine used in Example 7, 5'-〇-0-toluoyl-1,2,3'-anhydrodraw-21-deoxydiridine (2. 46 g 7.5 mmol; using the same conditions as in Example 7 except that R3 = 0-toluoyl, X == H) in the general formula (4) was used. '— Didoxy 1 5' -0- 0 -Toluoylperzine

(In formula (5), R3 = o-toluoyl, X = H) was obtained as an oil.

(Yield 2.65 g, Yield 95.0%)

The obtained oil showed a single spot by TLC (silica gel, developing solvent: ethyl acetate n hexane = 51), and the Rf value of the spot was 0.30.

1 H-NMR (CD C 13, tetramethylsilane) data are as follows.

δ 2.25 2.75 (m 5H H-2; o-toluoyl CH3) δ 4.00 4.80 (m, 4H H-3 '; H-4'; H-5 '), 5 5.40 (d, 1H, J = 7.8HzH—5), δ6.20 (t, 1H, J = 6.OHzH—l '), δ7.107.70 (m, 4 H, o-tolu oil; H_6) δ 7.80 8.15 (m, 1 H o—tolu oil), δ 10.60 (s, 1 Η 3-ΝΗ).

IR spectrum data: 2100 cm-1 (—N3). Example 14

(5'-O-o-Tonole oil 1, 3'-anhydro 5 -Funoleo 1 2'-Doxydziridine 3 1 Azide 1 2 ', 3'-Dideoxy 5-Fluoro 1 5' -0-0 -Torr Oil-lysine synthesis)

In place of 5′-〇0-trityl-2,3′-anhydrothymidine used in Example 7, 5′—O— was used as a raw material. Toluoyl per 1,3'-anhydro-5-fluoro-2-doxydziridine (2.60 g, 7.5 mimol; R3 = o-toluoyl, X = F in general formula (4)) Using the same conditions as in Example 7, 3′-azido 2,2,3′-dideoxy-5-fluoro-5′1-to-0-toluoylpyridine (R3 = o-toluoyl in the general formula (5), X = F) was obtained as an oil (yield 2.77 g, yield 95.0%) _c

The resulting oil showed a single spot by TLC (silica gel, developing solvent: ethyl acetate n-hexane = 5 to 1), and the Rί value of the spot was 0.50.

1 H-NMR (CD C 13, tetramethylsilane) data was obtained as follows.

5 2.25 to 2.75 (m, 5H, H-2; toluoyl CH3), 54.00 to 4.80 (m, 4H, H-3 ';H-4', H-5 ') , 56.20 (ΐ, 1Η, J = 6.6Hz, H-1 '), 57.10 to 7.65 (m, 3H, o torr oil), 57.80 ( d, 1 H, J = 6.6 Hz; H—6), δ 7.80 to 8.15 (m, 1 H, o—toluoyl), δ ΐ θ. 50 (s, 1H, 3—NH) _c

IR spectrum data: 2100 cm-1 (-N3).

The product 3'-azide 5'-O-o-toluoyl is preferably used in substantially the same manner as in the above-mentioned reaction conditions of the present example even when X is Cl, Br, or I. It is possible to obtain 2 ,, 3'-dideoxyperidine derivatives.

Example 15 (Synthesis of 3'-azido 3'-deoxythymidine from 3'-azido 3'-doxy 5'-0-o-toluoylthymidine)

In a reaction flask, 3′-azido 3′-dexoxy 5′—0—0—toluoyl thymidine obtained in Example 10 (60 ml of methanol) (11.56 g, 30.0 mmol; general formula (5 )), Dissolved R3 = 0-toluoyl, X = H). A solution of sodium hydroxide (1.00 g) in methanol (20 ml) was added to the obtained raw material solution, and the mixture was refluxed for 2 hours.

The progress of the above deprotection reaction is carried out while monitoring with TLC, etc., and the reaction is carried out at the time when the sbot of 3'-azide 3'-dexoxy 5'-0-0-toluoylthymidine almost completely disappears. It was the end point.

After the completion of the above deprotection reaction, the obtained reaction mixture was cooled to room temperature, and the pH of the reaction mixture was adjusted to 6.5 to 7.0 using 1N hydrochloric acid. After addition of 16 Oml of water, methanol was distilled off under reduced pressure using a rotary evaporator. The aqueous solution obtained by the above operation was washed twice with getyl ether (80 ml). Next, the obtained aqueous solution was concentrated to 4 Om 1 under reduced pressure using a tally evaporator, and then cooled to 10 ° C., whereupon 3′-azido-3-doxythymidine (in the general formula (5) R3 = X = H) was precipitated as white crystals (yield 6.31 g, 78.7% yield).

The above crystals showed a single spot by TLC (silica gel, getyl ether), and the Rf value of the spot was 0.2. The melting point of this crystalline solid was 122-3 ° C (recrystallized from water). The recrystallized product was purified by HPLC (column: InertsilOD S-2, manufactured by GL Sciences; mobile phase-ayatonitrile: water: triethylamine: acetic acid mixed solvent (volume ratio: 400: 600: 2: 1)). It was confirmed that it was 5% or more. The maximum absorption wavelength of the crystals in the absorption spectrum in methanol was 265.8 nm, and the maximum absorption wavelength in the absorption spectrum in water was 266.6 nm. Further, the optical rotation is [a] D + 48.8 ° (25 ° C, C = 0.δ; Water) + 59.7 ° (20 ° C, C = 0.8; methanol).

The 1 H-NMR (DMSO-d6, tetramethylsilane) data of the product was as follows.

δ 1.80 (s, 3H, heterocycle CH3), 52. 20-2.45 (m, 2H′H-2 ′), δ 3.55 to 4.05 (m, 3H, H—4 ′); Η-5 '), 54.25 to 4.65 (m, 1H, H-3'), δ 5.24 (t, 1Η, J = 5Hz, 5'-OH), δ 6.18 (t , 1Η, J = 7.2Η ζ, Η-1 '), 5 7.76 (bs, 1Η, Η—6), δ 11.33 (bs, 1Η, 3—ΝΗ).

IR spectrum data: 2090 cm-l.

These physicochemical measurement data are based on literature values (eg, Tetrahedoron, 44 ゝ 2 (1988) 625-636; J. Pharm. Sci., 7_9_6 (1990) 531-533; J. Heterocycl. Chem. ., 30 ゝ δ (1993) 1445-52; see J. Am. Chera. Soc. 115, 15 (1993) 6730-6737). Substantially the same as the reaction conditions of the above-mentioned Example, even when X is an alkyl group, the corresponding product 3′-azido 2 ′, 3′-dideoxydiridine derivative is obtained. Is possible.

Example 16

(Synthesis of 3'-azide-3'-deoxythymidine from 3'-azide-3'-deoxy-5'-0-p-toluoylthymidine)

In a reaction flask, in 60 ml of methanol, 3′-azido-3′-dexoxy-5′-0-p-toluoylthymidine obtained in Example 11 (11.56 g, 30.0 mmol; In the general formula (5), R3 = p-toluoyl, X = H) was dissolved. A solution of sodium hydroxide (1.00 g) in methanol (20 ml) was added to the obtained raw material solution, and the mixture was heated under reflux for 30 minutes.

Except for using the reaction mixture obtained above, 3′-azido 3′-deoxythymidine (in the general formula (5), R3 = X = H) was crystallized (yield 6.35 g, yield 79.2%).

Example 17

(Synthesis of 3,2, -azido 3'-deoxythymidine from 3'-azide-3'-deoxy 5'-0-p-chlorobenzoylthymidine)

In a reaction flask, 6 ′ of methanol was added to 6 ml of 3′-azido 3′-dexoxy-5′-〇p-clo-benzoyl thymidine obtained in Example 12 (12.17 g, 30.0 Mmol; in formula (5), R3 = p-chlorobenzene, X = H). Sodium hydroxide (1.00 g) in methanol

(20 ml) solution was added and heated under reflux for 10 minutes.

By the same operation as in Example 15 except that the reaction mixture obtained above was used, white crystals of 'monoazide 3'-deoxythymidine (R3 = X = H in the general formula (5)) were crystallized. (Yield 6.36 g, yield 79.3%).

Example 18

(Synthesis of 3'-azido 2 ', 3'-dideoxyperidine from 3'-azido 2', 3'-dideoxy 5'-0-0-toluoyl peridine)

In a reaction flask, add 60 ml of methanol to 3,3-azide-2 ′, 3′-dideoxy-5′-0-0-0-toluoyl pyridine obtained in Example 13 (11.14 g). , 30.0 mmol; R3 = o-toluoyl, X = H) in the general formula (5). The resulting raw material solution of sodium hydroxide in methanol (2 0 m l) of (1. 00 g) After the solution was added, the mixture was heated to reflux for 2 hours _e

Except for using the reaction mixture obtained above, 3′-azido 2 ′, 3′-dideoxydiridine (in the general formula (5), R3 = X = White crystals of H) crystallized out (yield 6.08 g, yield 80.0%).

The melting point of the crystals obtained by further recrystallizing the above white crystals with acetone was 164 to 5 ° C, and showed a single spot by TLC (silica gel, getyl ether). The value was 0.15. 1H-NMR (DMS〇, tetramethylsilane) Data were as follows.

52.20-2.45 (m, 2H, H—2 '), 5 3.50 to 4.05 (m, 3H, H-4'; H-5 '), 54.25 to 4.65 ( m, 1 H, H 3 '), δ δ .20 (bs, 1H, 5'-H)-, δ 5.60 (d, 1 Η, J = 7.8 Η ζ, Η-5), δ 6.10 (ΐ, 1Η, J = 7.2 Η ,, Η-1 '), 5 7.80 (d, 1Η, J = 7.8 Η ζ, Η-6), δ 1 1. 30 (bs, 1Η, 3Ν) _c IR spectrum data: 2100 cm-1 (-N3).

Example 19

(Synthesis of 3, azido 2 ', 3' didoxy-5 fluoroperidine from 3'-azido 2 ', 3' didoxy-5 fluoro-5'-0-0-0-toluoylperidine)

In a reaction flask, 3 azide-2 ′, 3′-dideoxy-5-fluoro-5′-0-o-toluoylpyridine (1.68 g, 30.0 ml) obtained in Example 14 was added to 60 ml of methanol. In the formula (5), R3-o-toluyl (X = F) is dissolved, and a solution of sodium hydroxide (1.00 g) in methanol (20 ml) is added to the obtained solution. The mixture was refluxed for 2 hours.

Except that the reaction mixture obtained above was used, the same operation as in Example 15 was carried out to obtain 31-azido-2,2,3, -dideoxy-5-fluoroperidine (general formula

In (5), white crystals of R3 = H, X = F) were crystallized (yield: 6.35 g, yield: 80.0%).

The crystals obtained by further recrystallizing the above white crystals with 2-propanol show a single spot at a melting point of 148 to 9 ° C and TLC (silica gel, jet ether), and the R i value of the spot Was 0.25.

1 H- MR (DMS_〇, tetramethylsilane) data was as follows _c

62.20-2.45 (m, 2H, H-2 '), 53.50-4.05 (m, 3H, H-4'; H-5 '), 54.25-4.65 ( m, 1 H, H— 3 '), 5 5.10 (bs, 1H, 5'-OH), 56.20 (t, 1H, J = 6.6Hz, H-l '), δ 8.20 (d, 1H, J = 6 6Hz, H-6), 5 1 1.

40 (bs, 1 H, 3-NH).

IR spectrum data: 2100 c -1 (-N3).

Substantially in the same manner as the reaction conditions of this example described above, even when X is C 1, Br, I, the corresponding product 3′-azido 2 ′, 3′-dideoxydidine derivative It is possible to get.

Comparative Example 2

(Synthesis of 3'-Azido-3'-deoxythymidine from 3'-Azido 3'-deoxy-5'-0-Trimethylacetylthymidine)

In a reaction flask, add 3 — azido 3'-doxy

5′-O-trimethylacetylthymidine (10.54 g, 30 mmol; R 3 = trimethylacetyl, X = H in the general formula (5)) was dissolved. When a methanol solution (20 ml) of sodium hydroxide (1.00 g) was added to the obtained raw material solution to carry out a deprotection reaction, it took 20 hours to complete the reaction.

The same operation as in Example 15 was carried out except for using the reaction mixture obtained as described above, and it was found that 3′-azido 3′-deoxythymidine (R3 = X = H in the general formula (5)) was slightly colored. Crystals precipitated (yield 6.14 ^, yield 76.5%), industrial applicability

As described above, according to the present invention, it is possible to selectively protect the 5′-hydroxyl group of a 2′-deoxyperidine derivative. The product in which the 5′-hydroxyl group is selectively protected in this way can be obtained, for example, by introducing an appropriate leaving group such as a sulfonyl group into the 3′-hydroxyl group of the product, and adding 2,3 ^; It can be suitably used for 3'-azidation with azideion via a droylated intermediate. The azidated product is finally removed in a high yield by removing the above 5′-hydroxyl protecting group. It becomes possible to produce an oside derivative.

Claims

¾¾ ^ ¾ ® The following general formula (1)

(In the above formula, X represents hydrogen, halogen, alkyl, aryl, alkenyl, or a halogen-substituted alkyl, aryl, or alkenyl group). A method for producing a 5′-monoaromatic acylated 1 2′-deoxyperidine derivative, which comprises reacting a 5′-hydroxyl group of the deoxyperidine derivative with an aromatic acyl reagent by reacting the 5′-hydroxyl group.

2. The aromatic acyl group is a benzoyl group, a p-toluoyl group, an o-toluoinole group, a 2,4,6-trimethinolebenzoyl group, a p-chlorobenzoyl group, or a 0-chlorobenzoyl group. 2. The production method according to claim 1, wherein the production method is selected from the group consisting of, a p-methoxybenzoyl group and a 0-methoxybenzoyl group.

3. The following general formula (2)

(In the above formula, X represents hydrogen, halogen, alkyl, aryl, alkenyl, or halogen-substituted alkyl, aryl, or alkenyl. R ¹ represents an aromatic acyl group.) Protecting the 3′-hydroxyl group of the deoxyperidine derivative with an alkyl or arylsulfonyl group;

The sulfonylation product is reacted with a base to give 2,3 ′ represented by the following formula (4).

—A method for producing a 2,3′-anhydro-1′-doxyperidine derivative, which comprises obtaining an hydroisomer.

R 〇

(In the above formula, X represents hydrogen, halogen, alkyl, aryl, alkenyl, or a halogen-substituted alkyl, aryl, or alkenyl group. R ′ represents an aromatic acyl group.)

4. The method according to claim 3, wherein the sulfonyl group is a methanesulfonyl group or a p-toluninsulfonyl group.

5. The method according to claim 3, wherein the base is selected from the group consisting of diazabicycloundecene (DBU), sodium hydroxide, potassium hydroxide, sodium phthalate, and potassium phthalate.

6. The following general formula (4)

(In the above formula, X represents a hydrogen, a halogen, an alkyl, an aryl, an alkenyl group or a halogen-substituted alkyl, an aryl, or an alkenyl group, and R 3 represents an alkylcarbonyl group or an arylcarbonyl group. )) Is reacted with an azide ion in the presence of an ammonium salt with a 2,3'-anhydride 2'-deoxyduridine derivative to obtain a 3'-azide compound represented by the following general formula (5). A method for producing an azido nucleoside derivative, characterized in that:

(In the above formula, X and R 3 are the same as those in the general formula (1).)

7. The above R 3 force; trityl group, bibacoyl group, 1-adamantoyl group, benzoyl group, p-toluoyl group, or 0-toluoyl group, p-chlorobenzoyl group, 0-crocobenzoyl group, p-methoxybenzoyl group 7. The method for producing an azido nucleoside derivative according to claim 6, wherein the group is selected from the group consisting of 1, 0-methoxybenzoyl group and 2, 4, 6-trimethylbenzoyl group.

8. The method for producing an azido-nucleoside derivative according to claim 7, wherein R3 is a trityl group.

9. The process according to claim 7, wherein R3 is a 0- or p-toluoyl group.

10. The method for producing an azido nucleoside derivative according to claim 6, wherein the ammonium salt is ammonium chloride.

1 1. The method for producing an azide nucleoside derivative according to claim 6, wherein the azide reagent that gives the azide ion is sodium azide.

1 2. The following general formula (5)

(In the above formula, X represents a hydrogen, a halogen, an alkyl, an aryl, an alkenyl group, or a halogen-substituted alkyl, aryl, or alkenyl group, and R3 represents an alkylcarbonyl group or an arylcarbonyl group. A method for producing a 3'-azidodidoxydziridine derivative, comprising reacting a base with the 3'-azididoxydziridine derivative represented by the formula (1) to deprotect the 5'-hydroxyl group .