WO2010150791A1 - Procédé de production de composé adénosine tétraphosphate - Google Patents

Procédé de production de composé adénosine tétraphosphate Download PDF

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WO2010150791A1
WO2010150791A1 PCT/JP2010/060577 JP2010060577W WO2010150791A1 WO 2010150791 A1 WO2010150791 A1 WO 2010150791A1 JP 2010060577 W JP2010060577 W JP 2010060577W WO 2010150791 A1 WO2010150791 A1 WO 2010150791A1
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compound
formula
group
added
mmol
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悟 向後
和臣 大沢
弘之 早川
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ヤマサ醤油株式会社
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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
    • C07H19/16—Purine radicals
    • C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to an efficient method for producing an adenosine tetraphosphate compound.
  • the adenosine tetraphosphate compound represented by the following formula (1) or a salt thereof is an agonist of the P2Y purine receptor and is expected to be developed as a therapeutic agent for cystic fibrosis, chronic obstructive pulmonary disease (COPD) and the like. It is a compound.
  • M represents a hydrogen atom or an ion such as Na + .
  • triphosphoric acid represented by the formula (5) is obtained by subjecting the compound of the formula (3) to a two-step phosphorylation reaction.
  • M represents a hydrogen atom or an ion such as Na + .
  • the total isolation yield until the compound of the formula (1) is obtained from the compound of the formula (2) is 0. 3%, 0.03 to 0.08% in the conventional method 2, which is not a practical method at all.
  • the conventional synthesis method of the compound of formula (1) has the following major problems (A) to (C).
  • the compound of formula (3) is obtained as a single isomer, and unlike conventional methods, it is industrially disadvantageous in silica gel column chromatography and preparative HPLC. It was revealed that the compound of the formula (3) can be obtained in a high yield of 69% in two steps only by crystallization without using an apparatus such as
  • Me represents a methyl group
  • Bz represents a benzoyl group
  • Ac represents an acetyl group.
  • Non-Patent Document 1 a method for synthesizing di (pyrimidine nucleoside 5'-) polyphosphate in the presence of a magnesium salt has already been reported (Patent Document 2).
  • Patent Document 2 a method for synthesizing di (pyrimidine nucleoside 5'-) polyphosphate in the presence of a magnesium salt.
  • adenosine 5′-cyclic triphosphoric acid and adenosine 5′-monophosphoric acid which is a reaction of a compound closer to the compound of the present invention
  • magnesium salt is inferior to zinc salt by several steps, and high yield cannot be achieved.
  • Non-Patent Document 1 it is not considered that the target compound can be obtained in high yield even if a magnesium salt is used instead of a zinc salt in the synthesis of adenosine tetraphosphate. It was unexpected.
  • the present invention is as follows. [1] After converting the compound of formula (XI) to the compound of formula (XIV) using a condensing agent (step A), in the presence of a metal salt selected from any of magnesium, manganese or iron, A process for producing an adenosine tetraphosphate compound, characterized in that a compound of formula (I) is obtained by reaction (step B).
  • Ar is an aryl group
  • X is a group selected from a sulfur atom, an oxygen atom or an imino group
  • R 1 and R 2 are groups selected from a hydrogen atom, an alkyl or an aralkyl group
  • M is Indicates hydrogen atom or ion.
  • the synthesis method of the present invention has a higher yield in each step leading to the compound of formula (I) (including the starting material (including the compound of formula (XI)), and crystallization is frequently used as a purification means.
  • the greatest feature is that refining is remarkably facilitated.
  • the total yield of the target compound of the formula (1) was as extremely low as about 0.03 to 0.3%. Even when the total amount is from the compound of formula (II), which is the starting compound of formula (XI) compound), the isolation yield is about 14%, and it can be synthesized very efficiently.
  • the present invention can synthesize an adenosine tetraphosphate compound with a high yield and a simpler method, and is a suitable method for industrial mass synthesis.
  • a compound of formula (I) is converted into a compound of formula (XIV) using a condensing agent (step A) and then reacted with the compound of formula (XIII) in the presence of a metal salt.
  • Step B The present invention relates to a method for producing an adenosine tetraphosphate compound characterized by comprising two steps.
  • Ar is an aryl group
  • X is a group selected from a sulfur atom, an oxygen atom or an imino group
  • R 1 and R 2 are groups selected from a hydrogen atom, an alkyl or an aralkyl group
  • M is It represents a hydrogen atom, a metal ion such as Na + or a substituted ammonium ion.
  • step A as a condensing agent for converting the compound of formula (XI) to the compound of formula (XIV), carbodiimides such as dicyclohexylcarbodiimide, water-soluble carbodiimide, diisopropylcarbodiimide, and phosphoric acid halides such as diphenylphosphorochloridate, Known condensing agents such as sulfonic acid halides such as toluenesulfonyl chloride and carbonyldiimidazole can be used, and carbodiimides are particularly preferred.
  • the reaction differs depending on the condensing agent used, for example, 1 to 5 mol of condensing agent is used per 1 mol of the compound of formula (XI) in a single or mixed solvent such as dimethylformamide, dimethylacetamide, formamide, dimethyl sulfoxide and the like.
  • the reaction can be carried out at 0 to 50 ° C., preferably 15 to 30 ° C. for about 1 to 24 hours.
  • diisopropylcarbodiimide when diisopropylcarbodiimide is used as the condensing agent, 1 to 5 mol, preferably 1.2 to 2 mol, of diisopropylcarbodiimide is used in 1 mol of the compound of formula (XI) in dimethylformamide. It can be carried out by reacting at about 50 ° C., preferably 20-30 ° C. for about 1 to 3 hours.
  • Step B the compound of formula (I) is synthesized by reacting with the compound of formula (XIII) in the presence of a metal salt.
  • the metal salt coexisting in the reaction is not particularly limited as long as it is a metal salt selected from any of magnesium, manganese and iron.
  • magnesium fluoride, magnesium chloride, magnesium bromide, magnesium iodide, manganese chloride, ferric chloride and other metal halides, magnesium, manganese, iron sulfate, nitric acid, phosphoric acid, perchloric acid examples thereof include metal inorganic acid salts such as tetrafluoroborate, magnesium, manganese, and iron trifluoromethanesulfonic acid, methanesulfonic acid, toluenesulfonic acid, acetic acid, trifluoroacetic acid, stearic acid, and citrate. .
  • a magnesium salt is preferable from the viewpoint of synthesis yield and ease of handling, and a magnesium halide such as magnesium chloride is particularly preferable.
  • the metal salt used may be an anhydride or a hydrate.
  • reaction 1 to 5 mol, preferably 1 to 2 mol, and 1 to 5 mol, preferably 1 to 2 mol of a metal salt are added to 1 mol of the compound of formula (XIV),
  • the reaction can be carried out at 0 to 100 ° C., preferably 15 to 30 ° C. for about 1 to 24 hours.
  • the compound of formula (I) for the purpose of synthesis is a method used for isolation and purification of general nucleotides (for example, recrystallization method, ion exchange column chromatography, adsorption column chromatography, activated carbon column chromatography, etc.) Can be separated and purified by combining them as appropriate, and can be converted into a salt form as necessary.
  • general nucleotides for example, recrystallization method, ion exchange column chromatography, adsorption column chromatography, activated carbon column chromatography, etc.
  • the compound of formula (XI) is preferably prepared from the three steps described below.
  • Ar represents an aryl group
  • X represents a group selected from a sulfur atom, an oxygen atom or an imino group
  • R 3 represents a protecting group
  • R 4 represents an acyl group.
  • Second step By selectively protecting the 5-position hydroxyl group of the compound of formula (V) and protecting the 2,3-position hydroxyl group with a protecting group different from the 5-position protecting group, and then selectively removing the 5-position protecting group A step of obtaining a compound of formula (VII), phosphorylating the compound in the presence of a base to give a compound of formula (VIII), and removing a protecting group at positions 2 and 3 to obtain a compound of formula (IX).
  • Ar represents an aryl group
  • X represents a group selected from a sulfur atom, an oxygen atom or an imino group
  • R 5 and R 6 represent a protecting group
  • M represents a hydrogen atom or an ion.
  • Third step A step of obtaining a compound of the formula (XI) by converting a phosphate group of the compound of the formula (IX) into a compound of the formula (X) and then reacting with a pyrophosphate.
  • the compound of formula (II) is reacted with a phenol compound in the presence of Lewis acid and molecular sieves to obtain a compound of formula (III) which is a stereoisomer mixture, and from the obtained compound of formula (III)
  • the ⁇ -form compound of formula (IV)
  • the compound is deprotected under alkaline conditions to obtain the compound of formula (V).
  • the hydroxyl-protecting group represented by R 3 may be any one commonly used as a hydroxyl-protecting group, such as an ether-based protecting group, an acyl-based protecting group, a silyl-based protecting group, an acetal-based protecting group, etc. It can be illustrated. More specifically, examples of the ether protecting group include methyl ether, tertiary butyl ether, benzyl ether, methoxybenzyl ether, and trityl ether. Examples of the acyl protecting group include acetyl, benzoyl, p-chlorobenzoyl, and pivaloyl.
  • Silyl protecting groups such as t-butyldimethylsilyl, t-butyldiphenylsilyl, trimethylsilyl, triethylsilyl, etc., and acetal protecting groups such as isopropylidene, ethylidene, methylidene, benzylidene, tetrahydropyranyl, methoxymethyl, etc.
  • acetal protecting groups such as isopropylidene, ethylidene, methylidene, benzylidene, tetrahydropyranyl, methoxymethyl, etc.
  • an acyl protecting group such as a benzoyl group having good crystallinity is preferable.
  • R 4 may be an acyl group, and examples thereof include acetyl, benzoyl, and pivaloyl groups.
  • Such a raw material compound may be a commercially available product or may be prepared by a known method (such as Helvetica Chimica Acta, 42, 1171-1173 (1959)). Moreover, it can also use for reaction, without refine
  • the reaction from the compound of the formula (II) to the compound of the formula (III) is carried out by reacting the compound of the formula (II) in an organic solvent such as dichloromethane, 1,2-dichloroethane, toluene, etc. with respect to 1 mol of the compound of the formula (II).
  • an organic solvent such as dichloromethane, 1,2-dichloroethane, toluene, etc.
  • 01 to 2 mol of Lewis acid 1 to 10 mol, preferably 1.2 equivalents of phenolic compound and 0 to 50 ° C., preferably 20 to 20 mol in the presence of 2 g or more of molecular sieves per 1 g of the compound of formula (II)
  • the reaction can be carried out at 30 ° C. for 1 to 24 hours.
  • Lewis acid used in the reaction examples include trimethylsilyl trifluoromethanesulfonate, boron trifluoride ether complex, tin tetrachloride, zinc chloride, zinc iodide, and anhydrous aluminum chloride. Trimethylsilyl trifluoromethanesulfonate is exemplified. Most preferred.
  • molecular sieves can be used as appropriate. Of these, the molecular sieve 4A is particularly suitable.
  • phenol compound examples include phenol, thiophenol, and C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, C 1-4 at the 2-position and 4-position thereof.
  • substituents such as dialkylamino, C 1-4 alkylsulfonyl, halogeno, nitro, cyano, amino, hydroxyl and the like.
  • the compound of formula (III) obtained is acetone, -It may be dissolved in a ketone-based organic solvent such as butanone and / or a halogen-based solvent such as dichloromethane or chloroform, and methanol, ethanol or isopropanol may be added thereto as a poor solvent for crystallization.
  • a ketone-based organic solvent such as butanone and / or a halogen-based solvent such as dichloromethane or chloroform
  • methanol, ethanol or isopropanol may be added thereto as a poor solvent for crystallization.
  • the 5-position hydroxyl group of the compound of formula (V) is selectively protected, the 2-position hydroxyl group is protected with a protecting group having a different removal method from the 5-position protecting group, and then the 5-position protecting group is selectively treated.
  • a compound of formula (VII) which is phosphorylated in the presence of a base to give a compound of formula (VIII), and the protecting groups at positions 2 and 3 are removed to give a compound of formula (IX). It is a process to obtain.
  • the protecting group for the 5-position hydroxyl group represented by R 5 may be any one commonly used as a selective protecting group for the primary hydroxyl group, and specifically includes dimethoxytrityl, methoxytrityl, trityl, tert-butyl. Examples thereof include dimethylsilyl and tert-butyldiphenylsilyl groups.
  • the protective group for the hydroxyl group at the 2- and 3-positions represented by R 6 may be any one that is usually used for protecting a hydroxyl group, such as an acyl-based protective group, an ether-based protective group, a silyl-based protective group, An acetal type protective group etc. can be illustrated.
  • examples of the ether protecting group include methyl ether, tertiary butyl ether, benzyl ether, methoxybenzyl ether, and trityl ether.
  • examples of the acyl protecting group include acetyl, benzoyl, p-chlorobenzoyl, pivaloyl, and the like.
  • Silyl protecting groups such as tert-butyldimethylsilyl, tert-butyldiphenylsilyl, trimethylsilyl, triethylsilyl, etc., and acetal protecting groups such as isopropylidene, ethylidene, methylidene, benzylidene, tetrahydropyranyl, methoxymethyl, etc. Each can be used.
  • the removal of the protecting group at the 5-position hydroxyl group may be appropriately selected from ordinary treatment methods such as acidic hydrolysis, alkaline hydrolysis, tetrabutylammonium fluoride treatment, and catalytic reduction according to the protecting group used.
  • the obtained compound of formula (VII) can be used in the next step without purification.
  • an acyl protecting group such as p-chlorobenzoyl group having high crystallinity is selected as the protecting group represented by R 6 , and the compound of formula (VII)
  • the crude product may be crystallized from an organic solvent such as ethanol.
  • the compound of formula (IX) can be obtained by phosphorylating the 5-position hydroxyl group of the formula (VII) compound and then removing the protective groups at the 2- and 3-positions.
  • the compound of formula (VII) is used in an organic solvent such as pyridine, acetonitrile, toluene, trialkyl phosphate, etc. with respect to 1 mol of the compound of formula (VII).
  • the reaction may be carried out in the presence of ⁇ 10 mol, preferably 1.5 mol of base, with 1 to 5 mol, preferably 1.2 equivalents of a phosphorylating agent at ⁇ 30 to 30 ° C. for 1 to 24 hours.
  • Examples of the base used include trialkylamines such as triethylamine and tributylamine, and heterocyclic amines such as pyridine, dimethylaminopyridine and N-methylimidazole. Phosphorus oxychloride, tetrachloropyrophosphate as phosphorylating agents And various amidite reagents.
  • the removal of the protecting group may be appropriately selected from ordinary treatment methods such as acidic hydrolysis, alkaline hydrolysis, tetrabutylammonium fluoride treatment and catalytic reduction according to the used protecting group.
  • the compound of formula (VIII) may be treated with concentrated aqueous ammonia at 0 ° C. to room temperature for 1 to 3 days. .
  • the produced compound of formula (IX) precipitates, and the compound of formula (IX) can be obtained simply by filtering and drying.
  • the third step is a step of obtaining the compound of formula (XI) by reacting with a pyrophosphate after converting the phosphate group of the compound of formula (IX) to the compound of formula (X).
  • the N-methylimidazolidate method when used as the activation method, 1 to 10 mol of dimethylaniline and 1 to 10 mol of triethylamine are present in 1 mol of the compound of formula (IX) in an organic solvent such as acetonitrile.
  • the compound of formula (IX) is activated by reacting with 1 to 10 mol of trifluoroacetic anhydride at ⁇ 20 to 30 ° C. for 10 to 60 minutes with 1 to 10 mol of N-methylimidazole for 10 to 60 minutes. Can be made.
  • the activation by the imidazolidate method is carried out by using a compound of formula (IX) in an organic solvent such as dimethylformamide, dimethylacetamide, etc., in an amount of 1 to 5 mol, preferably 3 mol, of carbonyl This can be achieved by reacting with diimidazole at 0 to 30 ° C. for 1 to 24 hours.
  • the obtained compound of the formula (X) can be used for the next step without isolation.
  • the compound of formula (X) can be converted to the compound of formula (XI) by reacting with 1 to 10 mol of pyrophosphate per 1 mol of the compound of formula (X).
  • 1 to 10 mol of pyrophosphate per 1 mol of the compound of formula (X) For example, when activated by the N-methylimidazolidate method, about 2 moles of pyrophosphate and 0 ° C. to room temperature for 10 to 60 minutes, and for imidazolidation, about 5 moles of pyrophosphate and room temperature.
  • the reaction is preferably carried out for 1 to 3 days.
  • pyrophosphoric acid can be used as a tertiary ammonium such as triethylammonium and tributylammonium, and as a quaternary ammonium salt such as tetraethylammonium, tetrabutylammonium and benzyltriethylammonium.
  • R 1 and R 2 are a hydrogen atom, a group selected from alkyl or aralkyl, and M represents a hydrogen atom or an ion.
  • the hydroxyl group of the compound of formula (XII) is protected with an appropriate protecting group, then alkylated or aralkylated, and then the protecting group is removed.
  • the protecting group may be any one that is usually used for protecting a hydroxyl group, and examples thereof include an acyl protecting group, an ether protecting group, a silyl protecting group, and an acetal protecting group.
  • examples of the ether protecting group include methyl ether, tertiary butyl ether, benzyl ether, methoxybenzyl ether, and trityl ether.
  • examples of the acyl protecting group include acetyl, benzoyl, p-chlorobenzoyl, pivaloyl, and the like.
  • Silyl protecting groups such as tert-butyldimethylsilyl, tert-butyldiphenylsilyl, trimethylsilyl, triethylsilyl, etc., and acetal protecting groups such as isopropylidene, ethylidene, methylidene, benzylidene, tetrahydropyranyl, methoxymethyl, etc. Each can be used.
  • the compound of formula (XII) in which the hydroxyl group is protected with a protecting group is subsequently reacted with an alkylating agent or an aralkylating agent.
  • an alkylating agent such as 10-100 mol of methyl iodide, dimethyl sulfate, methyl methanesulfonate, diazomethane, trimethylsilyldiazomethane, etc. is added to the above reaction solution and reacted at 0-50 ° C. for 1-7 days. Good.
  • the removal of the protective group for the hydroxyl group may be appropriately selected from ordinary treatment methods such as acidic hydrolysis, alkaline hydrolysis, tetrabutylammonium fluoride treatment, and catalytic reduction according to the protective group used.
  • formula (XI) compound and formula (XIII) compound are converted from a free form into a salt form (for example, metal salt such as sodium salt, substituted ammonium salt such as tetrabutylammonium salt, etc.) as necessary. Thus, it may be used as a raw material compound.
  • a salt form for example, metal salt such as sodium salt, substituted ammonium salt such as tetrabutylammonium salt, etc.
  • dimethylformamide 20 mL
  • diisopropylcarbodiimide 940 ⁇ L, 6.07 mmol
  • a dimethylformamide solution of compound 12 and a dimethylformamide solution of magnesium chloride were added thereto, and the mixture was stirred at room temperature for 18 hours.
  • the dimethylformamide solution of Compound 12 was prepared by dissolving Compound 12 (2.63 g, 7.28 mmol) in deionized water (50 mL) and adjusting the pH to 8. with 10% tetra-n-butylammonium hydroxide under ice cooling.
  • a dimethylformamide solution of magnesium chloride was prepared by dissolving a residue obtained by azeotroping magnesium chloride hexahydrate (1.48 g, 7.28 mmol) three times with 20 mL of dimethylformamide in 10 mL of dimethylformamide.
  • the pH was adjusted to 7.0 with a 1N sodium hydroxide aqueous solution, followed by purification by DEAE Sephadex column chromatography (eluted with DEAE Sephadex 150 mL, 0.10 to 0.15 M lithium chloride). After concentrating the fraction containing the desired product, the residue was dissolved in methanol (40 mL), acetone (160 mL) was added, and the resulting precipitate was collected by filtration and dried. The obtained lithium salt was dissolved in deionized water, passed through a cation exchange resin column (PK216 (manufactured by Mitsubishi Chemical), sodium type, 20 mL), and the resin after passing was washed with deionized water. The combined flow-through and washings were concentrated and the residue was dissolved in deionized water, pre-frozen and then lyophilized overnight. A white powdery compound 1 was obtained.
  • PK216 cation exchange resin column
  • Triethylamine (418 ⁇ L, 3.00 mmol) was added to compound 5 (1.00 mmol), and azeotroped three times with dimethylformamide (10 mL). The residue was dissolved in dimethylformamide (5 mL), diisopropylcarbodiimide (232 ⁇ L, 1.50 mmol) was added, and the mixture was stirred at room temperature for 3 hr. To this, a dimethylformamide solution of compound 12, magnesium chloride, or a dimethylformamide solution of zinc chloride was added and stirred at room temperature for 24 hours. The reaction solution was adjusted to 250 mL with deionized water, 5 ⁇ L was analyzed by HPLC (260 nm), and the synthesis yield of Compound 1 was calculated.
  • the dimethylformamide solution of Compound 12 was prepared by dissolving Compound 12 (592 mg, 1.64 mmol) in deionized water (20 mL) and adjusting the pH to 8.0 with 10% tetrabutylammonium hydroxide under ice cooling. Was concentrated at 40 ° C., the residue was azeotroped three times with 10 mL of dimethylformamide, and then dissolved in 2.5 mL of dimethylformamide.
  • a solution of zinc chloride in dimethylformamide was obtained by subjecting magnesium chloride hexahydrate (305 mg, 1.50 mmol) or zinc chloride (204 mg, 1.50 mmol) to dimethylformamide 2. Prepared by dissolving in 5 mL. The results are shown in Table 1.
  • the crude silyl ether was dissolved in pyridine (50 mL), benzoyl chloride (13.0 mL, 112 mmol) and dimethylaminopyridine (248 mg, 2.03 mmol) were added under ice cooling, and the mixture was stirred at room temperature for 24 hours.
  • Deionized water (20 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour and then concentrated.
  • the residue was dissolved in ethyl acetate (300 mL).
  • the organic layer was washed with water (300 mL) and saturated aqueous sodium bicarbonate (200 mL ⁇ 2), and then the organic layer was dried over anhydrous magnesium sulfate and concentrated.
  • the residue was azeotroped with toluene (50 mL ⁇ 3) to obtain a crude benzoyl ester.
  • the tributylamine salt of the obtained compound 4 was dissolved in dimethylformamide (350 mL), carbonyldiimidazole (17.3 g, 107 mmol) was added, and the mixture was stirred at room temperature for 3 hours in an argon atmosphere. Methanol (2.9 mL) was added to the reaction solution, and the mixture was stirred for 10 minutes, and then a dimethylformamide solution (750 mL) of 3 tributylamine salt of pyrophosphate (5 equivalents) was added, and the mixture was stirred at room temperature for 15 hours. After filtration of the reaction solution, the filtrate was concentrated.
  • the residue was dissolved in deionized water to a total volume of 800 mL and the pH was adjusted to 1.5 with 1N hydrochloric acid. This was adsorbed on an activated carbon column (1 L), washed with water (5 L), and eluted with 0.2 N aqueous ammonia and 20% ethanol-0.2 N aqueous ammonia. After concentrating the eluate, the residue was dissolved in 0.2N aqueous ammonia and treated overnight at room temperature. After the reaction solution was concentrated, water was added to make a total volume of 800 mL, and the mixture was purified by a DEAE Sephadex column (eluted with 500 cc, 50 to 75 to 100 to 200 to 300 mM ammonium bicarbonate).
  • the residue was azeotroped with water (100 mL ⁇ 5). Water was added to the residue to make a total volume of 600 mL, and the solution was passed through a cation exchange resin column (PK216 (manufactured by Mitsubishi Chemical), proton type, 200 mL), and the resin after passing was washed with deionized water. The passing solution and the washing solution were received by triethylamine (26.0 mL, 109 mmol), neutralized, and concentrated.
  • PK216 manufactured by Mitsubishi Chemical
  • the passing solution and the washing solution were received by triethylamine (26.0 mL, 109 mmol), neutralized, and concentrated.
  • N-methylimidazole (1.20 mL) and an acetonitrile solution (5 mL) of triethylamine (3.50 mL) were added, followed by stirring at 0 ° C. for 1 hour.
  • Deionized water 100 mL was added to the reaction mixture, and the mixture was stirred, adjusted to pH 10.0 with 7.5N aqueous sodium hydroxide solution, and extracted three times with chloroform (50 mL).
  • the aqueous layer was adjusted to pH 7.0 with 1N hydrochloric acid and concentrated, and then made up to 500 mL with deionized water (synthesis yield 81.6% in the analysis by HPLC).
  • This solution was adsorbed on an activated carbon column (Nimura activated carbon 300cc), washed with water, and eluted with 0.2N aqueous ammonia.
  • the fraction containing the target product was concentrated to 250 mL, passed through a cation exchange resin (PK216 (manufactured by Mitsubishi Chemical), proton type, 10 mL), and the resin after passing was washed with deionized water.
  • the passing liquid and the washing liquid were neutralized with triethylamine (5 mL) and concentrated.
  • the residue was azeotroped with acetonitrile (20 mL ⁇ 3) to obtain pale yellow candy-like compound 5 (quantity by HPLC: yield 3.86 mmol, yield 77.2%) as a triethylamine salt.
  • the obtained precipitate was dissolved in water (2500 mL), passed through an anion exchange resin column (IRA67 (Rohm & Haas), formic acid type, 200 mL), and the resin after passing was washed with deionized water.
  • the combined flow-through solution and washing solution were concentrated, ethanol (300 mL) was added, and the resulting precipitate was collected by filtration and washed with cold ethanol (50 mL). After vacuum drying, white powdered compound 12 (15.4 g, 42.6 mmol as a free acid, yield 74.0%) was obtained.
  • 1-Op-methoxy which is a mixture of stereoisomers, is reacted with a 1-O-acetyl- ⁇ -D-ribo-pentofuranose protector and a phenol compound in the presence or absence of Lewis acid and molecular sieves.
  • a phenyl-D-ribo-pentofuranose protector was synthesized, and the abundance ratios of ⁇ and ⁇ stereoisomers were examined.
  • Entry 1 As the 1-O-acetyl- ⁇ -D-ribo-pentofuranose protector, compound 2 in which R is acetyl was used, and the reaction was carried out according to the method described in the known literature (WO08 / 060632). After the reaction solution was diluted, it was analyzed by HPLC, and the abundance ratio and ⁇ : ⁇ ratio of each of ⁇ and ⁇ stereoisomers were calculated.
  • Entries 2-5 As the 1-O-acetyl- ⁇ -D-ribo-pentofuranose protector, compound 8 in which R is benzoyl was used, and compound 8 and 4-methoxyphenol (1.2 equivalents) were added to an organic solvent (10 mL / 1 g of Dissolve in Compound 8), add Molecular Sieves 4A (Wako, 2 g / 1 g of Compound 8 or in the absence), stir at room temperature for 1 hour, and then trimethylsilyl trifluoromethanesulfonate (0.4 mL / 1 g of compound). 8) was added and stirred at room temperature for 24 hours. The reaction solution was diluted and then analyzed by HPLC, and the ⁇ : ⁇ ratio was calculated as in entry 1.
  • Table 1 shows the ⁇ : ⁇ ratio under each condition.
  • TMSOTf represents trimethylsilyl trifluoromethanesulfonate
  • MS4A represents molecular sieves 4A.

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Abstract

L'invention porte sur un nouveau procédé pour la production d'une adénosine tétraphosphate, par lequel une adénosine tétraphosphate peut être synthétisée plus facilement dans un rendement accru par comparaison à des procédés classiques. Dans le nouveau procédé, la synthèse d'un composant de formule générale (I) à partir d'un composé de formule générale (XI) est menée par conversion d'un composé de formule générale (XI) en le composé triphosphate cyclique correspondant de formule générale (XIV) à l'aide d'un carbodiimide en tant qu'agent de condensation, puis réaction du composé triphosphate cyclique avec un composé de formule générale (VIII) en présence d'un sel d'un métal choisi parmi le magnésium, le manganèse et le fer. Dans les formules, Ar représente aryle, X est un atome de soufre, un atome d'oxygène ou un groupe imino ; R1 et R2 représentent chacun un atome d'hydrogène ou un groupe choisi parmi des groupes alkyles et des groupes aralkyles ; et M est un atome d'hydrogène ou un ion.
PCT/JP2010/060577 2009-06-23 2010-06-22 Procédé de production de composé adénosine tétraphosphate WO2010150791A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102659856A (zh) * 2012-04-10 2012-09-12 常州康丽制药有限公司 1-O-乙酰基-2，3，5-三-O-苯甲酰基-β-D-呋喃核糖的制备工艺

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