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WO1997006179A1 - Procede permettant de produire des derives d'azidonucleoside - Google Patents

Procede permettant de produire des derives d'azidonucleoside Download PDF

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Publication number
WO1997006179A1
WO1997006179A1 PCT/JP1996/002197 JP9602197W WO9706179A1 WO 1997006179 A1 WO1997006179 A1 WO 1997006179A1 JP 9602197 W JP9602197 W JP 9602197W WO 9706179 A1 WO9706179 A1 WO 9706179A1
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Prior art keywords
group
reaction
derivative
halogen
toluoyl
Prior art date
Application number
PCT/JP1996/002197
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English (en)
Japanese (ja)
Inventor
Hiroyuki KYOMORI
Tomoyasu NAGASE
Ken-ichi TAKATSUKI
Haruhiro Yamashita
Original Assignee
Kobayashi Perfumery Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from JP7199755A external-priority patent/JPH0899990A/ja
Application filed by Kobayashi Perfumery Co., Ltd. filed Critical Kobayashi Perfumery Co., Ltd.
Priority to AU66309/96A priority Critical patent/AU6630996A/en
Publication of WO1997006179A1 publication Critical patent/WO1997006179A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • 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).
  • 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.
  • 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.
  • 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.
  • a leaving group 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.
  • 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
  • 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
  • X represents hydrogen, halogen, alkyl, aryl, alkenyl, or a halogen-substituted alkyl, aryl, or alkenyl group.
  • R 1 represents an aromatic acyl group.
  • 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;
  • 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.
  • 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) :
  • R 3 represents an alkylcarbonyl group or an arylcarbonyl group.
  • 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.
  • X represents a hydrogen, a halogen, an alkyl, an aryl, an alkenyl group or a halogen-substituted alkyl, an aryl, or an alkenyl group
  • R 3 represents an alkylcarbonyl group or an arylcarbonyl group.
  • 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
  • a 21-doxydizidine derivative represented by the following general formula (1) can be used as a raw material.
  • 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.
  • 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.
  • the compounds r or I can be suitably used as a compound for crushing (Bull. Chem.
  • a protecting group for the 5'-hydroxyl group of the above 2'-deoxyperidine derivative (1) Is preferably an aromatic acyl group.
  • aromatic acyl group examples 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.
  • 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.
  • an acid halide having the above-mentioned aromatic acyl 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.
  • R represents an aromatic acyl group
  • X has the same meaning as in the above general formula (1;).
  • 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.
  • a solvent may be used if necessary (in other words, the reagent may also serve as the solvent.
  • 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
  • a basic organic liquid such as pyridine can be suitably used.
  • 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
  • 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.
  • the reaction temperature is not more than room temperature (25 ° C), It is preferably below (especially 12 ⁇ or less).
  • the reaction temperature is not more than room temperature (25 ° C), It is preferably below (especially 12 ⁇ or less).
  • 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).
  • TLC thin layer chromatography; silica gel, alumina, etc.
  • HPLC high performance liquid chromatography
  • 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.
  • the isolation of the product from the reaction mixture of the above acylation reaction can be performed by a conventional method.
  • the reaction mixture may be subjected to an extraction operation using a suitable solvent,
  • the extraction solvent to be used at this time for example, ethyl acetate, chloroform, toluene, hexane and the like can be suitably used.
  • a crude product can be obtained. If necessary, the crude product may be used after further purification.
  • 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.
  • 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.
  • 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.
  • 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:
  • a solution may be used if necessary:
  • 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
  • an inorganic compound or a mixture of two or more such compounds can be used without any particular limitation.
  • a basic organic liquid such as pyridine can be suitably used.
  • 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 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.
  • 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).
  • 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.
  • 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.
  • 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):
  • a suitable extraction solvent preferably a low boiling point solvent such as toluene, ethyl acetate, chloroform, and hexane.
  • 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.
  • R 1 and X have the same meanings as in the general formula (1).
  • an inorganic or organic strong base can be suitably used as the base to be used in this hydrolysis.
  • 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.
  • DBU 1,8-diazabi Black [5.4.0] Pendecar 7-ene
  • strong organic bases such as the above-mentioned DBU can be suitably used.
  • 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).
  • the reaction between the above-mentioned 3′-sulfonyl compound (3) and a strong base may be carried out in an appropriate solvent, if necessary.
  • an appropriate solvent for example, acetonitrile, N, N-dimethylformamide (DMF), methanol, ethanol, 2-propanol and the like can be used.
  • 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.
  • 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.
  • 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.
  • a suitable 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.
  • 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).
  • instrumental means such as IR, NMR, or mass spectrometry (MS).
  • MS mass spectrometry
  • the purity of the product can be confirmed by TLC, HPLC, IR, NMR, melting point measurement and the like.
  • 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
  • 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.
  • 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 3 has the same meaning as in the above general formula (1).
  • 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.
  • ammonium chloride 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.
  • 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.
  • a reagent having an azide group (N :-) can be used without any particular limitation.
  • N 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.
  • sodium azide is particularly preferably used from the viewpoint of operability.
  • 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.
  • a solvent may be used if necessary.
  • 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
  • DMF is particularly preferably used from the viewpoint of the reaction yield.
  • 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
  • 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:
  • 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.
  • the above azidation product can be isolated, for example, by extraction from the reaction mixture using an appropriate solvent.
  • the extraction solvent for example, toluene, ethyl acetate, chloroform, hexane and the like 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.
  • 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.
  • a 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.
  • sodium hydroxide, and potassium hydroxide inorganic base preferably usable Demel c
  • 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).
  • 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. .
  • 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.
  • an appropriate acid such as hydrochloric acid
  • 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.
  • a 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 time when the spot corresponding to the raw material thymidine almost disappeared in the TLC was defined as the end of the reaction.
  • 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.
  • the melting point of the obtained white crystalline solid was 185 ° C (recrystallized from methylene chloride).
  • Example 1 was repeated except that 0-toluoyl chloride used in Example 1 was replaced with ⁇ -cuco benzobenzoyl chloride (7.94 g, 45.4 mmol) as an aromatic acyl halide.
  • ⁇ -cuco benzobenzoyl chloride 7.94 g, 45.4 mmol
  • X H
  • 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.
  • DBU 1,8-diazabicyclo [5,4,0] -17-denecene
  • dimethylforma-mide DMF
  • 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.
  • 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.
  • Example 7 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.
  • ammonium sulfate or ammonium bromide, tritylamine hydrochloride, or trimethylamine hydrochloride was used as a catalyst instead of ammonium chloride used in Example 7.
  • IR spectrum data 2-1 00 cm-1 (one 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.
  • 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).
  • 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.
  • 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.
  • 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.

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  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Saccharide Compounds (AREA)

Abstract

On peut protéger de manière sélective le groupe 5'-hydroxyle d'un dérivé de 2'-désoxyuridine au moyen d'un groupe acyle aromatique. Le dérivé protégé de manière sélective ainsi obtenu peut être utilisé pour produire un dérivé 3'-azido comprenant un ion d'azoture par l'introduction, par exemple, d'un groupe partant adéquat tel qu'un groupe sulfonyle dans le groupe 3'-hydroxyle du dérivé protégé de manière sélective et la formation d'un intermédiaire 2,3'-anhydro avec une base. On peut produire à haut rendement un dérivé d'azidonucléoside en éliminant le groupe protecteur du groupe 5'-hydroxyle protégé.
PCT/JP1996/002197 1995-08-04 1996-08-05 Procede permettant de produire des derives d'azidonucleoside WO1997006179A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU66309/96A AU6630996A (en) 1995-08-04 1996-08-05 Process for producing azido nucleoside derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP7/199755 1995-08-04
JP7199755A JPH0899990A (ja) 1994-08-05 1995-08-04 アジド化ヌクレオシド誘導体の製造方法

Publications (1)

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WO1997006179A1 true WO1997006179A1 (fr) 1997-02-20

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WO (1) WO1997006179A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100368422C (zh) * 2000-11-29 2008-02-13 三井化学株式会社 L-核酸衍生物及其合成方法
CN103864870A (zh) * 2013-11-28 2014-06-18 安徽一帆香料有限公司 一种齐多夫定的制备方法

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100368422C (zh) * 2000-11-29 2008-02-13 三井化学株式会社 L-核酸衍生物及其合成方法
CN103864870A (zh) * 2013-11-28 2014-06-18 安徽一帆香料有限公司 一种齐多夫定的制备方法

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