WO2013089168A1 - ノイラミン酸誘導体の製造方法 - Google Patents

ノイラミン酸誘導体の製造方法 Download PDF

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WO2013089168A1
WO2013089168A1 PCT/JP2012/082294 JP2012082294W WO2013089168A1 WO 2013089168 A1 WO2013089168 A1 WO 2013089168A1 JP 2012082294 W JP2012082294 W JP 2012082294W WO 2013089168 A1 WO2013089168 A1 WO 2013089168A1
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formula
compound represented
compound
acid
produce
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PCT/JP2012/082294
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English (en)
French (fr)
Japanese (ja)
Inventor
智仁 櫻井
工 中島
雅一 若山
鳥山　史彦
泰久 桑原
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第一三共株式会社
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Priority to CA2859296A priority Critical patent/CA2859296C/en
Priority to BR112014014635A priority patent/BR112014014635A2/pt
Priority to IN971MUN2014 priority patent/IN2014MN00971A/en
Priority to EP12858308.5A priority patent/EP2792676A4/en
Priority to US14/365,951 priority patent/US20140356625A1/en
Priority to CN201280062083.6A priority patent/CN103974945B/zh
Priority to JP2013549304A priority patent/JP6038808B2/ja
Priority to HK14112666.2A priority patent/HK1199034A1/en
Priority to KR1020147016077A priority patent/KR101971311B1/ko
Application filed by 第一三共株式会社 filed Critical 第一三共株式会社
Publication of WO2013089168A1 publication Critical patent/WO2013089168A1/ja
Priority to IL233124A priority patent/IL233124A0/en
Priority to IL236766A priority patent/IL236766A0/en
Priority to US15/401,665 priority patent/US20170114035A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/14—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • 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
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T428/00—Stock material or miscellaneous articles
    • Y10T428/29—Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
    • Y10T428/2982—Particulate matter [e.g., sphere, flake, etc.]

Definitions

  • the present invention relates to a method for producing a neuraminic acid derivative having a neuraminidase inhibitory action.
  • R 1 represents an alkyl group having 1 to 4 carbon atoms
  • R 2 and R 3 are the same or different and represent a hydrogen atom or an aliphatic acyl group having 2 to 25 carbon atoms
  • X represents Represents a hydroxyl group, an alkoxy group having 1 to 4 carbon atoms
  • Y represents NH 2 or the like
  • Z represents an oxygen atom or the like.
  • a pharmacologically acceptable salt thereof has an excellent neuraminidase inhibitory activity and is known to be useful as a therapeutic or prophylactic agent for influenza (Patent Document 1, 2, 3).
  • a compound represented by the formula (I) included in the compound represented by the above formula or a pharmacologically acceptable salt thereof (provided that the compound represented by the formula (I) is a regioisomer)
  • Compound represented by the formula (I) is a regioisomer
  • Method A may be contained (Patent Document 4).
  • R 1 represents a C 1 -C 19 alkyl group
  • R 2 represents a C 1 -C 4 alkyl group
  • R 3 , R 6 , and R 7 are independently A C 1 -C 6 alkyl group
  • R 4 and R 5 independently represent a hydrogen atom, a C 1 -C 6 alkyl group or a phenyl group
  • R 4 and R 5 together represent a tetra A methylene group, a pentamethylene group, or an oxo group may be formed.
  • a known compound (1) is reacted with an alcohol having the formula R 3 OH in the presence of an acid to produce compound (2) (step A-1), and compound (2) Is reacted with acetic anhydride in the presence of an acid to produce compound (3) (step A-2), compound (3) is reacted with a compound having the formula NaOR 3 to give compound (4).
  • Produced (step A-3), and compound (4) is reacted with compound (5) or compound (6) to produce compound (7) (step A-4).
  • Compound (7) is present in the presence of a base.
  • compound (8) is azidotrimethyl in the presence of Lewis acid.
  • step A-6 Reaction with silane produces compound (9) (step A-6), and compound (9) is converted to triphenylphosphine.
  • step A-9 (13) is reacted with compound (14) in the presence of an acid to produce compound (I) [however, a compound having formula (II) may be contained] (step A-10) Is the method.
  • the formula (13) the formula (13)
  • Non-Patent Document 1 or 2 It is known that the trifluoroacetate salt of the compound represented by the formula has an excellent neuraminidase inhibitory activity and is useful as a therapeutic or prophylactic agent for influenza (Non-Patent Document 1 or 2).
  • compound (9) is produced by reacting compound (8) with azidotrimethylsilane in the presence of Lewis acid in step A-6. Excess azidotrimethylsilane needs to be decomposed, and a compound for decomposition is added as an aqueous solution.
  • Such a chelate compound is obtained when a polymer compound having a functional group capable of reacting with a titanium compound such as a hydroxy group, a carboxy group or an ester group, an acetate group, or an epoxy group in the molecule is modified with a titanium compound. Used to stabilize the polymer composition obtained. Further, the method A of Patent Document 4 described above has a problem that the reaction rate of the compound (10) and the compound (11) is not constant in the step A-8 and the production time is not constant.
  • the present inventors have intensively studied on a method for producing a neuraminic acid derivative having a neuraminidase inhibitory action, and found that the production method of the present invention is superior from a known production method from an industrial viewpoint, thereby completing the present invention. did.
  • the present invention provides a method for producing a neuraminic acid derivative. That is, the present invention [1] As shown in the following production scheme,
  • R 1 represents a C 1 -C 19 alkyl group.
  • the compound represented by the formula (1) is reacted with methanol in the presence of an acid and a compound represented by the formula HC (OMe) 3 to produce a compound represented by the formula (2).
  • the compound represented by the formula (2) is reacted with acetic anhydride in the presence of an acid to produce a compound represented by the formula (3).
  • the compound represented by the formula (3) is reacted with sodium methoxide to produce the compound represented by the formula (4).
  • the compound represented by the formula (4) is reacted with dimethyl carbonate to produce the compound represented by the formula (5).
  • the compound represented by the formula (5) is reacted with dimethyl sulfate in the presence of a base to produce the compound represented by the formula (6).
  • the compound represented by the formula (6) is reacted with azidotrimethylsilane in the presence of titanium (IV) isopropoxide to produce a compound represented by the formula (7).
  • the base is reacted with water to produce the compound represented by the formula (8).
  • the compound represented by formula (8) and the compound represented by formula (9) are reacted to produce a compound represented by formula (10),
  • the compound represented by the formula (10) is heated in water to produce the compound represented by the formula (11),
  • the compound of formula (11) the presence of an acid, a compound represented by the formula R 1 C (OMe) 3 (wherein, R 1 represents a C 1 -C 19 alkyl group) and Reacting to produce a compound represented by formula (12)
  • the compound represented by formula (12) is reacted with water to produce the compound represented by formula (I) or a pharmacologically acceptable salt thereof.
  • the present invention further provides the following production method.
  • the compound represented by the formula (6) is reacted with azidotrimethylsilane in the presence of titanium (IV) isopropoxide to crystallize the compound represented by the formula (7) in the resulting reaction solution.
  • a method for producing a compound represented by formula (I) or a pharmacologically acceptable salt thereof, comprising the production method according to [4] above, [6] A compound represented by formula (7) is reacted with triphenylphosphine, and then reacted with a base and water to produce a compound represented by formula (8), and then compound (8) is contained.
  • the 50% by weight particle size according to the laser diffraction / scattering particle size distribution measurement method is 5 to 15 ⁇ M, and the 90% particle size by the laser diffraction / scattering particle size distribution measurement method is 15 to 35 ⁇ M.
  • a compound represented by formula (I) or a pharmacologically acceptable salt thereof obtained by the production method according to any one of [3], [5], [7] and [8].
  • the “C 1 -C 19 alkyl group” in R 1 represents a linear or branched alkyl group having 1 to 19 carbon atoms, such as a methyl group, an ethyl group, a propyl group, In butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decanyl group, undecanyl group, dodecanyl group, tridecanyl group, tetradecanyl group, pentadecanyl group, hexadecanyl group, heptadecanyl group, octadecanyl group, or nonadecanyl group
  • it is a C 5 -C 19 alkyl group, more preferably a C 5 -C 17 alkyl group, and more preferably a pentyl group, a heptyl group, a nonyl group, an undecanyl
  • the “pharmacologically acceptable salt” means, for example, a hydrohalide salt such as a hydrofluoride salt, a hydrochloride salt, a hydrobromide salt, and a hydroiodide salt; Inorganic acid salts such as chlorates, sulfates, phosphates; alkane sulfonates such as methanesulfonate, ethanesulfonate, trifluoromethanesulfonate; benzenesulfonates, p-toluenesulfonic acid Aryl sulfonates such as salts; organic acid salts such as acetate, trifluoroacetate, citrate, tartrate, oxalate, maleate; glycine, lysine, arginine, ornithine, Amino acid salts such as glutamate and aspartate; alkali metal salts such as lithium salt, sodium salt and potassium salt; alkali such as calcium salt and
  • the above-mentioned compound (II) can coexist as positional isomers having different substitution positions of acyloxy groups.
  • the compound related to the present invention has an asymmetric carbon in the molecule and has stereoisomers (including enantiomers and diastereomers). These stereoisomers and mixtures in any proportions (including racemates) are encompassed by the compounds relevant to the present invention.
  • Compound (I) is a compound (11) produced when an acyloxy group at the 3-position of the side chain is converted to a hydroxyl group by metabolic reaction such as hydrolysis when administered to a warm-blooded animal.
  • Patent Document 1 Is known to exhibit pharmacological activity (Patent Document 1, etc.).
  • compound (II) When compound (II) is administered to a warm-blooded animal, the acyloxy group at the 2-position of the side chain is converted to a hydroxyl group by metabolic reaction such as hydrolysis, and similarly compound (11) is produced.
  • compound (I) and compound (II) are converted to the same compound (11) which is an active metabolite, and therefore a mixture of compound (I) and compound (II) is used. From the viewpoint of use as a medicine, any compound can be considered as an active ingredient.
  • the chemical purity of the compound, the content of the compound as an impurity, the composition ratio of the stereoisomers, or the composition ratio in the mixture of the compound (I) and the compound (II) is a method well known in the field of organic chemistry.
  • high performance liquid chromatography, weight%, etc. preferably, can be determined by the peak area ratio in high performance liquid chromatography (hereinafter also referred to as HPLC).
  • HPLC measurement conditions can be selected as appropriate, but are preferably those shown below.
  • the peak area ratio of the compound (I) and the compound (II) detected from 0 minutes to a time approximately 2.3 times the retention time of the compound (I) is measured.
  • the peak area ratio of the compound as an impurity detected from 0 minute to about 1.8 times the retention time of the compound (I) is measured.
  • the peak of the compound as an impurity is detected from all the peaks detected as 0.01% or more when the peak of the compound (I), the peak of the compound (II), and only the solvent are injected.
  • the peak is excluded (for example, solvent peak, noise-derived peak, etc.).
  • the chemical purity (%) of compound (I) can be calculated according to the following formula.
  • Chemical purity of compound (I) 100-sum of peak area ratio (%) of compound as impurity
  • compound (II) may also be produced together with compound (I) by the production method of the present invention.
  • the chemical purity is calculated as a mixture of compound (I) and compound (II).
  • the peak area ratio of the compound (I) and the compound (II) can be measured according to the above HPLC measurement condition (1).
  • the composition ratio (%) of the mixture of compound (I) and compound (II) can be calculated according to the following formula.
  • the manufacturing method of the present invention described above is superior in, for example, the following points as compared with Method A described in Patent Document 4 which is a known and excellent manufacturing method.
  • the starting material is a dihydrate of compound (1).
  • the starting compound (1) uses an anhydride.
  • the production method of the present invention uses a dihydrate.
  • the dihydrate has a smaller specific volume than the anhydride.
  • the specific volume of the anhydride is 6 to 8 [cm 3 / g], whereas the specific volume of the dihydrate is 1 to 2 [cm 3 / g]. Therefore, when a dihydrate is used as a starting material, it is more excellent in operability and workability at the time of manufacture than an anhydride.
  • the solvent amount used at the 1st process can be reduced compared with the case where an anhydride is used. Since the amount of the solvent can be reduced, the concentration of the reaction substrate in the first step increases, and the reactivity of the first step can be improved as compared with the case where an anhydride is used. For this reason, the reaction temperature of a 1st process can be made low and reaction time can also be shortened. Moreover, since reaction temperature can be lowered
  • the compound (8) and the compound (9) which are the reaction raw materials of the above, and the compound (10) which is the reaction product of the eighth step are the reaction raw materials of the A-8 step of Method A described in Patent Document 4.
  • Compounds (10) and (11) are compounds corresponding to the compound (12) which is the reaction product of step A-8.
  • Step A-8 of Example 1 of Patent Document 4 a specific production method of compound (12) is disclosed. According to this manufacturing method, [1] N, N′-bis (tert-butoxycarbonyl) -1H-pyrazole-1-carboxyimidamide is added to the aqueous solution of the compound (10) obtained in the step A-7 at room temperature and stirred at the same temperature. did.
  • the production method of the present invention is superior in operability to handle starting materials, and as a result of relaxation of reaction temperature, shortening of reaction time, etc., it is excellent as an industrial production method on an actual production scale. .
  • a highly pure neuraminic acid derivative can be obtained in high yield.
  • the neuraminic acid derivative is produced by the production method shown below.
  • R 1 is, R 1 represents a C 1 -C 19 alkyl group.
  • the first step is a step of producing a compound (2) by reacting a known compound (1) with methanol in the presence of an acid and a compound represented by the formula HC (OMe) 3 (trimethyl orthoformate). It is.
  • the order of adding the acid and trimethyl orthoformate is not limited. Preferably, acid, then trimethyl orthoformate.
  • the acid used is not limited as long as it is used for the esterification reaction of a carboxyl group using alcohols, for example, an organic acid such as acetic acid, propionic acid, trifluoroacetic acid, pentafluoropropionic acid, It can be an organic sulfonic acid such as p-toluenesulfonic acid, camphorsulfonic acid, trifluoromethanesulfonic acid, or an inorganic acid such as hydrogen chloride, hydrogen bromide, hydrogen iodide, phosphoric acid, sulfuric acid, nitric acid. Is an inorganic acid, most preferably sulfuric acid.
  • the reaction temperature is 0 to 60 ° C., preferably 20 to 40 ° C.
  • the reaction time is 30 minutes to 10 hours, preferably 1 to 4 hours.
  • compound (2) is synthesized as a monohydrate.
  • the reverse reaction of the first step can occur due to the presence of the acid added in the first step.
  • the residual amount of compound (1) as a starting material in compound (2) increases.
  • the reverse reaction by the acid can be stopped or the reverse reaction can be accelerated.
  • the compound (2) can be crystallized while the stability of the compound (2) solution is improved, and the content of the compound (2) in the resulting crystal is improved.
  • the amount of triethylamine added to the reaction solution is 0.01 to 1.00 equivalent, preferably 0.01 to 0.20 equivalent, relative to compound (1).
  • the dropping temperature of ethyl acetate is 0 to 60 ° C, and preferably 10 to 40 ° C.
  • the dropping time is 10 minutes to 10 hours, preferably 30 minutes to 4 hours.
  • the second step is a step of producing compound (3) by reacting compound (2) with acetic anhydride in the presence of an acid.
  • the acid is preferably added gradually in the vicinity of room temperature until the compound (2) is dissolved in the presence of the compound (2) and acetic anhydride. This is because the reaction rate can be controlled.
  • the acids used are the acetylation of hydroxyl groups in the 1, 2 and 3 positions of the side chain, the formation of carbon-carbon double bonds in the 2 and 3 positions of the tetrahydropyran ring, the oxazolines in the 4 and 5 positions of the tetrahydropyran ring
  • organic acids such as acetic acid, propionic acid, trifluoroacetic acid, and pentafluoropropionic acid, p-toluenesulfonic acid, camphorsulfonic acid, and trifluoromethanesulfonic acid.
  • an organic acid such as hydrogen chloride, hydrogen bromide, hydrogen iodide, phosphoric acid, sulfuric acid, nitric acid, preferably an inorganic acid, most preferably sulfuric acid.
  • the solvent used is preferably a hydrocarbon, preferably toluene.
  • the reaction temperature is ⁇ 20 to 100 ° C., preferably ⁇ 20 to 60 ° C.
  • the reaction time is preferably 30 minutes to 60 hours, and more preferably 1 to 20 hours.
  • the third step is a step for producing compound (4) by reacting compound (3) with sodium methoxide.
  • the solvent used is preferably methanol.
  • the reaction temperature is preferably ⁇ 20 to 70 ° C., and more preferably 0 to 50 ° C.
  • the reaction time is preferably 1 minute to 5 hours, and more preferably 5 minutes to 1 hour.
  • the fourth step is a step of producing compound (5) by reacting compound (4) with dimethyl carbonate.
  • Compound (5) crystallizes out as crystals.
  • a further base can be used.
  • Such a base is not particularly limited as long as it is used for the conversion reaction of 1,2-diol to a cyclic carbonate, and is preferably an alkali metal alkoxide, more preferably sodium methoxide. .
  • the solvent used is preferably methanol.
  • the reaction temperature is preferably ⁇ 30 to 80 ° C., and more preferably 0 to 50 ° C.
  • the reaction time is preferably 30 minutes to 60 hours, and more preferably 1 to 20 hours.
  • the purity of the crystals of the obtained compound (5) is not sufficiently high, the purity can be increased by re-slurry in methanol and purify. Specifically, the crystal of compound (5) is added to methanol, heated to 20 to 60 ° C., stirred for 1 hour, then cooled to room temperature, stirred and the crystallized crystal was filtered and washed with methanol. By doing this, a highly pure compound (5) can be obtained.
  • the fifth step is a step of producing compound (6) by reacting compound (5) with dimethyl sulfate in the presence of a base.
  • a base By controlling the reaction rate of the compound (5) and dimethyl sulfate, the production of by-products can be suppressed. That is, it is preferable to gradually add a base to the compound (5) and dimethylsulfuric acid because the reaction rate can be controlled efficiently, and the production of by-products can be suppressed. As a result, the purity of the compound (7) obtained through the sixth step of the next step can be increased.
  • the base used is not limited as long as it is used for alkylation of a hydroxyl group, and may be, for example, the base shown in the fourth step, preferably an alkali metal hydride, and most preferably Is sodium hydride.
  • the solvent used is preferably an ether, amide, or a mixture thereof, more preferably tetrahydrofuran, N, N-dimethylacetamide, or a mixture thereof, most preferably. , Tetrahydrofuran and N, N-dimethylacetamide.
  • the base is added to the reaction solution at a reaction temperature of preferably ⁇ 20 to 20 ° C., more preferably ⁇ 15 to 15 ° C.
  • a solvent immiscible with water is added to the reaction solution containing the compound (6), and the mixture is washed with an aqueous sodium hydrogen carbonate solution. It is preferable to separate the layers and wash the resulting organic layer again with an aqueous sodium bicarbonate solution.
  • the solvent used is preferably toluene.
  • the sixth step is a step of producing compound (7) by reacting compound (6) with azidotrimethylsilane in the presence of titanium (IV) isopropoxide.
  • the compound (7) which is the target compound, can be synthesized with high selectivity from stereoisomers depending on the orientation of the groups.
  • the solvent used is preferably an aromatic hydrocarbon, an alcohol, or a mixture thereof, more preferably 2-propanol, 2-methyl-2-propanol, toluene, or a mixture thereof.
  • the reaction temperature is preferably ⁇ 20 to 80 ° C., and more preferably 0 to 30 ° C.
  • the reaction time is preferably 1 to 100 hours, and more preferably 5 to 30 hours.
  • titanium (IV) isopropoxide After reacting compound (6) and azidotrimethylsilane in the presence of titanium (IV) isopropoxide to produce compound (7), after adding hydroxycarboxylic acid to the reaction solution as a post-treatment of the reaction Sodium nitrite is preferably added as an aqueous solution. Titanium (IV) isopropoxide is in a liquid state at room temperature, but in the presence thereof, compound (6) is reacted with azidotrimethylsilane to produce compound (7). In order to decompose excess azidotrimethylsilane, When sodium nitrate is added as an aqueous solution, a hardly soluble insoluble matter derived from titanium (IV) isopropoxide is produced.
  • the separation operation of the compound (7) and the compound derived from titanium (IV) isopropoxide or titanium (IV) isopropoxide is preferable only by filtration operation. Since it is possible to avoid the formation of hardly soluble insoluble matter derived from titanium (IV) isopropoxide, the compound (7) having a high content can be produced.
  • the hydroxycarboxylic acid include lactic acid, tartaric acid, and citric acid, preferably lactic acid or tartaric acid, and more preferably lactic acid.
  • Hydroxycarboxylic acid can be used in any of L-form, D-form, and DL-form.
  • the reaction temperature is ⁇ 20 to 80 ° C., preferably 0 to 30 ° C.
  • the reaction time is 10 minutes to 100 hours, preferably 30 minutes to 10 hours.
  • the solvent used for washing the crystals of the obtained compound (7) is preferably methanol. When methanol is used, the crystals are difficult to be colored.
  • the seventh step includes (step 7a) a step of treating compound (7) with triphenylphosphine; (step 7b) a step of treating the compound obtained in step 7a with a base and water.
  • the solvent used is preferably tetrahydrofuran or ethyl acetate, more preferably tetrahydrofuran. It is preferable to add the compound (7) after dissolving triphenylphosphine with a solvent for easy operation.
  • the reaction temperature is preferably ⁇ 30 to 100 ° C., more preferably 10 to 60 ° C.
  • the reaction time is preferably 30 minutes to 100 hours, more preferably 1 hour to 10 hours.
  • the base to be used is not limited as long as it causes the hydrolysis reaction of the ester group and the removal reaction of the cyclic carbonate group, and is preferably an alkali metal hydroxide, more preferably sodium hydroxide. Or it is potassium hydroxide, Especially preferably, it is sodium hydroxide.
  • the solvent used is preferably tetrahydrofuran, methanol or ethanol, more preferably tetrahydrofuran.
  • the acid used to adjust the pH of the reaction mixture to the acidic side is preferably hydrochloric acid.
  • the reaction temperature is preferably ⁇ 30 to 100 ° C., and more preferably 0 to 70 ° C.
  • the reaction time is preferably 10 minutes to 20 hours, and more preferably 30 minutes to 10 hours.
  • this step is a pre-step of the eighth step by first adding an acid to the aqueous solution containing the compound (8) obtained after the synthesis of the compound (8) to adjust the pH of the aqueous solution to the acidic side. It is preferable to release the carbon dioxide by-produced in the seventh step as carbon dioxide gas.
  • a base is added to return the pH of the reaction solution to the alkali side.
  • the acid used to adjust the pH of the reaction mixture to the acidic side is preferably hydrochloric acid.
  • the base used to return the pH of the reaction mixture to the alkaline side is preferably sodium hydroxide.
  • the solvent used is preferably a mixture of water and alcohols, more preferably a mixture of water and methanol.
  • the reaction temperature is preferably ⁇ 30 to 80 ° C., and more preferably 0 to 50 ° C.
  • the reaction time is preferably 1 to 160 hours, and more preferably 5 to 80 hours.
  • the ninth step is a step of producing the compound (11) by heating the compound (10) in water.
  • the solvent used is preferably water.
  • the reaction temperature is preferably 30 to 100 ° C, and more preferably 50 to 100 ° C.
  • the reaction time is preferably 30 minutes to 20 hours, and more preferably 1 to 10 hours.
  • slurry purification with water alone is preferred. Since the compound (11) can be produced as crude crystals with low purity, water is added to the crude crystals, heated and stirred, cooled, the obtained crystals are filtered off, washed, and dried. Crystals of the compound (11) with high purity are obtained.
  • the temperature of the stirring operation is preferably 30 to 100 ° C, and more preferably 50 to 100 ° C.
  • the stirring time is preferably 1 to 20 hours, and more preferably 2 to 10 hours.
  • the purity of the obtained compound (11) can be increased by recrystallization by adjusting the pH of the reaction solution containing the compound (11).
  • an acid such as hydrochloric acid is added and dissolved, and then neutralized with a base such as sodium hydroxide to crystallize compound (11). be able to.
  • a purification method of the compound (11) slurry purification with water alone is more preferable.
  • R 1 C (OMe) 3 [wherein R 1 represents a C 1 -C 19 alkyl group] in the presence of an acid to give compound (12). It is a manufacturing process.
  • the compound represented by the formula R 1 C (OMe) 3 is preferably 1,1,1-trimethoxyoctane.
  • the acid used is not limited as long as it allows the cyclic orthoesterification reaction of hydroxyl group using orthoester, and is preferably organic sulfonic acid or inorganic acid, and more preferably p- Toluenesulfonic acid, sulfuric acid, or hydrogen chloride is preferable, and hydrogen chloride is particularly preferable.
  • the solvent used is preferably methanol.
  • the reaction temperature is preferably ⁇ 30 to 80 ° C., and more preferably 0 to 50 ° C.
  • the reaction time is preferably 5 minutes to 20 hours, and more preferably 10 minutes to 5 hours.
  • compound (I) can be produced as well as compound (I)
  • compound (I) is highly selective compared to compound (II) by adjusting the pH of the reaction solution as described above. And can be produced in high yield.
  • the acid used is preferably hydrochloric acid.
  • the base used for adjusting the pH of the reaction solution to the basic side is preferably sodium carbonate.
  • the reaction temperature is preferably ⁇ 30 to 80 ° C., and more preferably 0 to 50 ° C.
  • the reaction time is preferably 1 minute to 100 hours, and more preferably 10 minutes to 5 hours.
  • Compound (I) and a pharmacologically acceptable salt thereof produced by the production method of the present invention have a 50% by weight particle size of 5 to 15 ⁇ M and a 90% by weight particle size by a laser diffraction scattering type particle size distribution measurement method. 15 to 35 ⁇ M.
  • the laser diffraction scattering type particle size distribution measurement method Particle size analysis. Laser diffraction methods
  • irradiates a particle group with laser light and calculates the particle size distribution by calculation from the intensity distribution pattern of the diffracted / scattered light emitted therefrom. It is a method to seek.
  • the measurement method is defined in ISO 13320 issued by the International Organization for Standardization and is internationally standardized.
  • the particle diameters at 50% and 90% of the weight-based cumulative particle size distribution curve obtained by the laser diffraction / scattering particle size distribution measurement method are 50% by weight and 90% by weight, respectively.
  • the neuraminic acid derivative (I) of the present invention has an excellent neuraminidase inhibitory activity, and is known to be useful as a therapeutic or prophylactic agent for influenza (see the aforementioned Patent Document 1 or 2). *
  • the neuraminic acid derivative (I) of the present invention is used as a medicine, particularly as a therapeutic or prophylactic agent for influenza, it is mixed with itself or appropriate pharmacologically acceptable excipients, diluents and the like. It can be administered orally or parenterally, but it is preferred that the active ingredient Compound (I) be administered by a method that can be delivered directly to the lungs or respiratory tract (including intraoral and intranasal). These preparations are produced by known methods using additives such as excipients and diluents.
  • the amount used varies depending on the symptom, body weight, age, etc. of the administered person (warm-blooded animal, preferably human), but the neuraminic acid derivative (I) as an active ingredient is 5 to 120 mg per dose in terms of anhydride.
  • 20 to 80 mg, specifically 20 mg, 40 mg, or 80 mg is preferably administered according to body weight and age. *
  • Example 1 First step: methyl N-acetylneuraminate monohydrate N-acetylneuraminic acid dihydrate (150 g), methanol (450 mL), trimethyl orthoformate (138.3 g), concentrated sulfuric acid (3.4 g) Was added at room temperature and stirred at 30 ° C. for 2 hours.
  • the reaction mixture was cooled to 20 ° C., triethylamine (1.8 g) and water (53 mL) were added, and ethyl acetate (2100 mL) was added dropwise over 1 hour, followed by stirring for 1 hour.
  • the suspension was further cooled to 5 ° C. and stirred at the same temperature for 1 hour, and then the crystals were filtered.
  • Example 2 Fifth step: (3aR, 4R, 7aR) -4- ⁇ (S) -methoxy [(4R) -2-oxo-1,3-dioxolan-4-yl] methyl ⁇ -2-methyl-3a, 7a- Methyl dihydro-4H-pyrano [3,4-d] [1,3] oxazole-6-carboxylate Compound (60 g) obtained according to Example 1, Step A-4 described in Patent Document 4 was added to tetrahydrofuran (240 mL). ), N, N-dimethylacetamide (60 mL) was added and suspended, and cooled to 5 ° C. or lower.
  • Dimethyl sulfuric acid (31.8 g) was added to the suspension, and 60% sodium hydride (10.2 g) was gradually added thereto, followed by stirring at 3 ° C. for 3 hours.
  • Acetic acid (11.5 g) and toluene (540 mL) were added to the reaction solution, and the mixture was washed with about 7% aqueous sodium hydrogen carbonate solution (240 mL), and the organic layer 1 and the aqueous layer 1 were separated.
  • the organic layer 1 was washed with about 2% aqueous sodium hydrogen carbonate solution (240 mL), and the organic layer 2 and the aqueous layer 2 were separated.
  • the aqueous layer 1 was extracted with toluene (180 mL) to separate the organic layer 3, the aqueous layer 2 was extracted with the organic layer 3, the organic layer 4 was separated, and matched with the organic layer 2.
  • the matched organic layer was evaporated under reduced pressure until the liquid volume reached 180 mL to obtain a toluene solution of the title compound.
  • Step 6 (2R, 3R, 4S) -3-acetamido-4-azido-2- ⁇ (S) -methoxy [(4R) -2-oxo-1,3-dioxolan-4-yl] methyl ⁇ - Methyl 3,4-dihydro-2H-pyran-6-carboxylate
  • 2-methyl-2-propanol 60 mL
  • titanium (IV) isopropoxide 16.3 g
  • azidotrimethylsilane (37.5 g) were added and the mixture was stirred at 18 ° C. for 15 hours.
  • aqueous sodium hydroxide solution (166.4 g) was added to the reaction solution to reach 40 ° C., and the mixture was stirred at the same temperature for 2 hours.
  • the reaction mixture was cooled to 25 ° C. or lower, concentrated hydrochloric acid (28.6 g) and ethyl acetate (150 mL) were added, and after standing, the aqueous layer was separated to obtain an aqueous solution of the title compound.
  • N, N′-bis (tert-butoxycarbonyl) -1H-pyrazole-1-carboxyimidamide (46.1 g) and methanol (300 mL) were added to the aqueous solution, and the suspension was brought to 23 ° C. at the same temperature for 46 hours. Stir. The solvent was distilled off under reduced pressure until the liquid volume reached about 400 mL, ethyl acetate (165 mL) was added, and the solvent was distilled off under reduced pressure until the liquid volume reached about 400 mL.
  • Ethyl acetate (355 mL) was added to the obtained liquid, and the aqueous layer was separated after standing, and ethyl acetate (250 mL) was added again, and the aqueous layer was separated after standing.
  • Ethyl acetate (350 mL) was added to the obtained aqueous solution, the pH was adjusted to 2.7 with concentrated hydrochloric acid, and the mixture was allowed to stand to separate the organic layer 1 and the aqueous layer 1.
  • Ethyl acetate (175 mL) was added to the aqueous layer 1 and allowed to stand, and then the organic layer 2 was separated.
  • the obtained organic layer 1 and organic layer 2 were matched, and the solvent was distilled off under reduced pressure until the liquid volume became about 200 mL. Water (150 mL) was added to the concentrate, and the solvent was distilled off under reduced pressure until the liquid volume reached about 150 mL, and water (100 mL) was added to obtain an aqueous solution of the title compound.
  • Step 10 (2R, 3R, 4S) -3-acetamido-4-guanidino-2- ⁇ (S)-[(2RS, 4R) -2-heptyl-2-methoxy-1,3-dioxolane- 4-yl] (methoxy) methyl ⁇ -3,4-dihydro-2H-pyran-6-carboxylic acid
  • methanol 50 mL
  • 1,1,1-trimethoxyoctane trimethyl orthooctanoate
  • 9.2% hydrogen chloride methanol solution 13.64 g
  • the solvent was distilled off under reduced pressure until the liquid volume reached about 35 mL to obtain a methanol solution of the title compound.
  • Step 11 (2R, 3R, 4S) -3-Acetamido-4-guanidino-2-[(1R, 2R) -2-hydroxy-1-methoxy-3- (octanoyloxy) propyl] -3,4 -Dihydro-2H-pyran-6-carboxylic acid monohydrate [compound (I)] and (2R, 3R, 4S) -3-acetamido-4-guanidino-2-[(1S, 2R) -3hydroxy- 1-methoxy-2- (octanoyloxy) propyl] -3,4-dihydro-2H-pyran-6-carboxylic acid monohydrate [compound (II)] Water (100 mL) was added to the methanol solution of the compound obtained in the 10th step, and the reaction solution was washed twice with ethyl acetate (50 mL), and then the aqueous layer was separated.
  • reaction solution was adjusted to pH 7.2 with 17% aqueous sodium carbonate solution, and the reaction solution was stirred for 30 minutes, then adjusted to pH 8.8 with 17% aqueous sodium carbonate solution and stirred for 3 hours.
  • reaction solution was adjusted to pH 5.3 with concentrated hydrochloric acid, cooled to 5 ° C. or lower, stirred for 1 hour, and the crystals were filtered.
  • the crystals were washed with water (50 mL) and dried under reduced pressure to give the crude title compound as white crystals (13.59 g, yield 95.9%).
  • Methanol 60 mL was added to the crude title compound (10 g) to dissolve, and water (120 mL) was gradually added to the 25 ° C. solution, cooled to 5 ° C.

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HK14112666.2A HK1199034A1 (en) 2011-12-16 2012-12-13 Method for producing neuraminic acid derivative
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EP12858308.5A EP2792676A4 (en) 2011-12-16 2012-12-13 PROCESS FOR PREPARING NEURAMINE ACID DERIVATIVES
US14/365,951 US20140356625A1 (en) 2011-12-16 2012-12-13 Method for Manufacturing Neuraminic Acid Derivatives
CN201280062083.6A CN103974945B (zh) 2011-12-16 2012-12-13 用于制备神经氨酸衍生物的方法
CA2859296A CA2859296C (en) 2011-12-16 2012-12-13 Method for manufacturing neuraminic acid derivatives
BR112014014635A BR112014014635A2 (pt) 2011-12-16 2012-12-13 método para fabricar um composto, e, composto
JP2013549304A JP6038808B2 (ja) 2011-12-16 2012-12-13 ノイラミン酸誘導体の製造方法
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IL233124A IL233124A0 (en) 2011-12-16 2014-06-15 Production method for neuraminic acid derivatives
IL236766A IL236766A0 (en) 2011-12-16 2015-01-18 Production method for neuraminic acid derivatives
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CN113801138B (zh) * 2020-06-12 2024-11-29 博瑞生物医药（苏州）股份有限公司 一种一锅法制备辛酸拉尼米韦中间体的方法
KR102405310B1 (ko) * 2020-07-08 2022-06-02 가톨릭대학교 산학협력단 유체의 압력을 이용한 인공 요도괄약근
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