WO2016035847A1 - Intermédiaire de dérivés de céphalosporine et son procédé de production - Google Patents

Intermédiaire de dérivés de céphalosporine et son procédé de production Download PDF

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WO2016035847A1
WO2016035847A1 PCT/JP2015/075042 JP2015075042W WO2016035847A1 WO 2016035847 A1 WO2016035847 A1 WO 2016035847A1 JP 2015075042 W JP2015075042 W JP 2015075042W WO 2016035847 A1 WO2016035847 A1 WO 2016035847A1
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compound
formula
group
solvate
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PCT/JP2015/075042
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麻由 福田
健朗 渡邊
貴教 栗田
優貴 横田
正敏 竹尾
耕一 野口
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塩野義製薬株式会社
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Priority to JP2016546689A priority Critical patent/JP6783497B2/ja
Priority to CN201580047736.7A priority patent/CN106661052B/zh
Publication of WO2016035847A1 publication Critical patent/WO2016035847A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
    • C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
    • C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
    • C07D501/48—Methylene radicals, substituted by hetero rings
    • 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 an intermediate of a cephalosporin derivative and a method for producing the same.
  • the cephalosporin derivative (hereinafter referred to as compound (I)) having a catechol group represented by the formula has a broad antibacterial spectrum and exhibits a strong antibacterial activity particularly against ⁇ -lactamase producing bacteria. It is described that it is useful as a preventive agent. Also included in Example 12 are the following compounds: (Hereinafter referred to as Compound (IA)).
  • the compound (IA) is synthesized according to a general synthesis method shown below or a specific synthesis method of an analogous compound, although a specific synthesis method thereof is not described.
  • Patent Document 1 describes the following scheme as a general synthesis method of compound (I).
  • Patent Document 1 discloses Compound 9 corresponding to Compound (IX) above: However, the sulfoxide group at the 1-position of the cephem nucleus is described in a racemic form, and there is no description regarding the optically active form of R-form or S-form. Patent Documents 2 to 4 and 6 include compounds: In addition, the sulfoxide group at the 1-position is described in a racemic form, and there is no description regarding the optically active substance. Further, Patent Documents 4 and 7 include the formula: Are disclosed, but none of them are crystals, and there is no description about crystals. Further, Patent Document 4 describes a method for producing the above S-form compound, but does not describe the production method of the present invention. Furthermore, there is no description regarding the S body and its advantages.
  • cephalosporin derivatives such as compound (IA)
  • IA cephalosporin derivatives
  • (Item 2) Item 2. The crystal according to item 1, wherein R 1 is a t-butoxycarbonyl group, R 2 is a t-butyl group, and R 3 is a p-methoxybenzyl group. (Item 3) In powder X-ray diffraction spectrum, 4.3 ⁇ 0.2 °, 10.9 ⁇ 0.2 °, 14.5 ⁇ 0.2 °, 18.3 ⁇ 0.2 ° and 21 3.
  • Crystal of methanol solvate according to item 2 having at least 3 peaks selected from 2 ⁇ 0.2 °. (Item 4) In powder X-ray diffraction spectrum, diffraction angles (2 ⁇ ): 4.8 ⁇ 0.2 °, 14.4 ⁇ 0.2 °, 14.9 ⁇ 0.2 °, 16.0 ⁇ 0.2 ° and 20 3. Solvate-free crystals according to item 2, having at least three peaks selected from 5 ⁇ 0.2 °.
  • Step 11 The following steps: (Step 3) A step of reacting compound (IV) with compound (X) in the presence of boric acid or boronic acid to obtain compound (III); (Step 4) Step of reducing Compound (III) to obtain Compound (II); and (Step 5) Step of deprotecting Compound (II) to obtain Compound (IA);
  • Step 12 The following steps: (Second Step) A step of reacting compound (V) with peracid to obtain compound (IV); (Step 3) A step of reacting compound (IV) with compound (X) in the presence of boric acid or boronic acid to obtain compound (III); (Step 4) Step of reducing Compound (III) to obtain Compound (II); and (Step 5) Step of deprotecting Compound (II) to obtain Compound (IA); Item 10. A method for producing a compound (IA) according to Item 10, a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • the present invention provides a synthetic intermediate useful for industrial production of various cephalosporin derivatives and a method for producing the same. Moreover, by using them, especially a compound (IA) can be manufactured with sufficient yield, simply, safely, and efficiently.
  • crystallization of compound (IV) obtained in Example 3 is shown.
  • the horizontal axis represents the diffraction angle 2 ⁇ (°), and the vertical axis represents the intensity (Count).
  • crystallization of compound (IV) obtained in Example 3 is shown.
  • reacting a compound with a compound includes reacting a salt thereof or a solvate thereof.
  • the following reaction may be performed “continuously in the process” without isolation.
  • Performing “steps continuously” includes performing the next step without isolating the compound produced by the reaction of the previous step. For example, performing two processes by one pot is mentioned. (Wherein each symbol is as defined above)
  • Compound (VIII) is obtained by reacting compound (VII) with mesyl chloride, optionally in the presence of a base.
  • the base is not particularly limited as long as it allows the above process to proceed efficiently.
  • An inorganic base such as an organic base or an inorganic carbonate can be used.
  • an organic base can be used.
  • triethylamine, pyridine, dimethylaminopyridine, diazabicycloundecene, 1,8-bis (dimethylamino) naphthalene, diisopropylethylamine, N-methylimidazole, N-methylmorpholine and the like can be mentioned. Triethylamine is preferred.
  • the base may be reacted with about 1 to 2 molar equivalents relative to compound (VII).
  • the reaction solvent is not particularly limited as long as it allows the above steps to proceed efficiently.
  • amide solvents eg, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone, etc.
  • acetate solvents eg, ethyl acetate, Propyl acetate, etc.
  • hydrocarbon solvents eg, toluene, benzene, hexane, etc.
  • ether solvents eg, cyclopentyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,2-dimethoxyethane, etc.
  • nitrile solvents examples: One or more selected from acetonitrile, propionitrile, etc., halogen solvents (eg, dichlorome
  • the reaction temperature is not particularly limited, but is usually about ⁇ 20 to 100 ° C., preferably about ⁇ 10 to 0 ° C.
  • the reaction time is not particularly limited, but is usually 0.5 to 20 hours, preferably about 0.5 to 2 hours.
  • the ratio of mesyl chloride used is preferably about 1 to 5 molar equivalents, more preferably about 1 to 1.5 molar equivalents, relative to compound (VII).
  • Mesyl chloride may be added all at once or dropwise.
  • the obtained compound (VIII) may be used in the next step without isolation.
  • Compound (V) is obtained by reacting compound (VI) with compound (VIII), optionally in the presence of a base. What is necessary is just to perform the said reaction according to the conditions of normal amidation reaction.
  • the base is not particularly limited as long as it allows the above process to proceed efficiently.
  • An inorganic base such as an organic base or an inorganic carbonate can be used.
  • an organic base can be used.
  • triethylamine, pyridine, dimethylaminopyridine, diazabicycloundecene, 1,8-bis (dimethylamino) naphthalene, diisopropylethylamine, N-methylimidazole, N-methylmorpholine and the like can be mentioned.
  • N-methylmorpholine is preferred.
  • the base may be reacted with about 1 to 5 molar equivalents relative to compound (VII). Preferably about 1 to 2 molar equivalents.
  • the reaction solvent is not particularly limited as long as it allows the above steps to proceed efficiently.
  • amide solvents eg, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone, etc.
  • acetate solvents eg, ethyl acetate, Propyl acetate, etc.
  • hydrocarbon solvents eg, toluene, benzene, hexane, etc.
  • ether solvents eg, cyclopentyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,2-dimethoxyethane, anisole, etc.
  • nitriles One or more selected from a solvent (eg, acetonitrile, propionitrile, etc.), a halogen solvent (eg, dichloromethane, chloroform, etc.), a ketone solvent (eg, acetone, methyl ethyl ketone, etc.), di
  • the reaction temperature is not particularly limited, but is usually about ⁇ 20 to 100 ° C., preferably about ⁇ 10 to 0 ° C.
  • the reaction time is not particularly limited, but is usually 0.5 to 20 hours, preferably about 0.5 to 2 hours.
  • the ratio of compound (VIII) to be used is preferably about 0.8 to 5 molar equivalents, more preferably about 0.8 to 1.5 molar equivalents, relative to compound (VI). The obtained compound (V) may be used in the next step without isolation.
  • reaction solvent is not particularly limited as long as it allows the above steps to proceed efficiently.
  • alcohol solvents eg, methanol, ethanol, isopropanol, etc.
  • amide solvents eg, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolide Non-acetate
  • acetate solvents eg, ethyl acetate, propyl acetate, etc.
  • hydrocarbon solvents eg, toluene, benzene, hexane, etc.
  • ether solvents eg: cyclopentyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran) , 1,2-dimethoxyethane, anisole, etc.
  • the solvent can be used as a two-layer solvent with water or a water-containing solvent as necessary.
  • a halogen solvent, a nitrile solvent, an amide solvent or a mixed solvent of a nitrile solvent and an amide solvent is preferable. More preferred is dichloromethane, acetonitrile, N-methylpyrrolidone or N, N-dimethylacetamide. More preferred is acetonitrile or a mixed solvent of acetonitrile and N, N-dimethylacetamide or N-methylpyrrolidone.
  • the ratio of the mixed solvent is preferably 5: 1 to 5: 5, more preferably 5: 4 to 5: 5.
  • S-isomer selectivity can be improved.
  • the reaction temperature is not particularly limited, but is preferably about -80 to 10 degrees, more preferably about -40 to 0 degrees, and further preferably about -10 to 0 degrees.
  • the reaction temperature is preferably lower from the viewpoint of the selectivity of the S form, but can be set to an industrially controllable temperature (eg, about ⁇ 10 to 0 ° C.), for example, by selecting a solvent.
  • the reaction time is not particularly limited, but is preferably about 0.5 to 10 hours, more preferably about 1 to 3 hours.
  • the peracid examples include metachloroperbenzoic acid (mCPBA), perbenzoic acid, peracetic acid, aqueous hydrogen peroxide, magnesium monoperoxyphthalate hexahydrate, and the like. Peracetic acid is preferred.
  • mCPBA metachloroperbenzoic acid
  • perbenzoic acid peracetic acid
  • aqueous hydrogen peroxide magnesium monoperoxyphthalate hexahydrate
  • Peracetic acid is preferred.
  • the ratio of the peracid to be used is preferably about 1 to 2 molar equivalents, more preferably about 1 to 1.2 molar equivalents, relative to compound (V).
  • additives other than peracid may be added as necessary.
  • the additive include nitric acid, sulfuric acid, 3,5-dihydroxybenzoic acid, 2-methyl-2-butene, resorcinol, sulfamic acid and the like.
  • Preferred additives include sulfuric acid and 3,5-dihydroxybenzoic acid.
  • the compound (IV) obtained as a high proportion of S form may be used in the next step without isolation, but is preferably isolated as a salt, solvate or crystal thereof. If desired, an extremely high purity S form can be obtained by purification by such a method as crystallization.
  • the crystallization method (method for transitioning to a supersaturated state) is not particularly limited, and for example, an evaporation method (a method for evaporating a crystallization solvent from a crystallization system), a cooling method (a crystallization system (or compound (IV) solution) Cooling method), poor solvent addition method (method of adding poor solvent of compound (IV) to crystallization system), seed crystal addition method (method of adding seed crystal containing compound (IV) to crystallization system) Etc. can be exemplified.
  • an evaporation method a method for evaporating a crystallization solvent from a crystallization system
  • a cooling method a crystallization system (or compound (IV) solution) Cooling method
  • poor solvent addition method method of adding poor solvent of compound (IV) to crystallization system
  • seed crystal addition method method of adding seed crystal containing compound (IV) to crystallization system
  • an evaporation method (a crystallization system (or solution) containing a compound (IV) and a crystallization solvent is used to evaporate the crystallization solvent to a supersaturated state and crystallize from this supersaturated state) or a cooling method (compound)
  • a seed crystal obtained from the compound (IV) is obtained. It can be crystallized by a seed crystal addition method in which a seed crystal is added to a solution dissolved in a crystallization solvent and / or an acid for crystallization.
  • an alcohol solvent eg, methanol, ethanol, isopropanol, etc.
  • a mixed solvent of an alcohol solvent and water can be used.
  • it is methanol, ethanol, or a mixed solvent thereof with water.
  • the corresponding solvate crystals can also be obtained.
  • the obtained solvate can also be converted into a solvate by natural drying, ventilation drying or drying under reduced pressure.
  • the drying temperature may be, for example, room temperature to warming, preferably 20 to 60 degrees.
  • the drying time may be, for example, about 0.5 to 48 hours, preferably about 0.5 to 24 hours (for example, 2 to 18 hours).
  • the S-form Since the R-form and S-form of 1-sulfoxide are different in solubility in various solvents, the S-form has higher isolation yield of 1-sulfoxide due to crystallization or the like than the R-form. In addition, since the S-form has higher stability such as storage stability than the R-form, it can be stably stored as an intermediate for a long period of time by increasing the purity of the S-form. . In addition, S-form crystals have higher stability such as storage stability and coloring stability than S-form amorphous bodies, and the generation of decomposition products is also suppressed. Furthermore, the yield of compound (III) is preferably improved by about 10% or more by using the S form rather than the R form of 1-sulfoxide in the reaction of the next step. Therefore, the crystal of compound (IV) which is the S form of 1-sulfoxide of the present invention is very useful as an industrial intermediate.
  • Compound (III) is obtained by reacting compound (IV) with compound (X).
  • Compound (III) is also an S form of 1-sulfoxide.
  • the reaction solvent is not particularly limited as long as it allows the above steps to proceed efficiently.
  • Amide solvents eg, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone, etc.
  • acetate ester solvents eg, ethyl acetate, propyl acetate) Etc.
  • hydrocarbon solvents eg toluene, benzene, hexane etc.
  • ether solvents eg cyclopentyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,2-dimethoxyethane, anisole etc.
  • nitrile solvents examples: One or more selected from acetonitrile, propionitrile
  • the reaction temperature is not particularly limited, but is usually about 0 to 100 ° C., preferably about ⁇ 5 to 15 ° C.
  • the reaction time is not particularly limited, but is usually about 0.5 to 36 hours, preferably about 3 to 24 hours.
  • This reaction may be carried out in the presence of an alkali metal halide (for example, an alkali metal iodide (eg, NaI, KI, etc.), an alkali metal bromide (eg, NaBr, KBr, etc.), if necessary.
  • an alkali metal halide for example, an alkali metal iodide (eg, NaI, KI, etc.), an alkali metal bromide (eg, NaBr, KBr, etc.), if necessary.
  • an alkali metal iodide for example, an alkali metal iodide (eg, NaI, KI, etc.), an alkali metal bromide (eg, NaBr, KBr, etc.), if necessary.
  • an alkali metal iodide for example, an alkali metal iodide (eg, NaI, KI, etc.), an alkali metal bromide (eg, NaBr,
  • This reaction is preferably boronic acid or its derivative boronic acid (: R—B (OH) 2 ); R is a substituent such as alkyl, substituted or unsubstituted carbocycle, substituted or unsubstituted heterocycle ),
  • R is a substituent such as alkyl, substituted or unsubstituted carbocycle, substituted or unsubstituted heterocycle ),
  • the yield is improved by, for example, about 5% or more.
  • the carbocycle or heterocycle is preferably a 3- to 10-membered ring, more preferably a 5- to 6-membered ring.
  • the carbocyclic or heterocyclic ring may be a saturated ring or an unsaturated ring.
  • Examples of the substituent of the carbocycle or heterocyclic ring include lower alkyl (eg, methyl, ethyl, isopropyl, t-butyl), halo lower alkyl (eg, trifluoromethyl, chloromethyl), halogen (eg, fluorine, chlorine) , Hydroxy, carboxy, amino, lower alkoxy (eg, methoxy, ethoxy, t-butoxy), cyano, nitro, sulfamoyl, imino, hydroxyimino, carbamoyl, lower alkylcarbamoyl (eg, methylcarbamoyl, dimethylcarbamoyl), acyl (eg, : Acetyl, benzoyl).
  • lower alkyl eg, methyl, ethyl, isopropyl, t-butyl
  • halo lower alkyl eg, trifluoromethyl, chloromethyl
  • the ratio of boric acid or boronic acid to be used is preferably about 0.1 to 0.4 molar equivalent, more preferably about 0.1 to 0.3 molar equivalent, relative to compound (IV).
  • the obtained compound (III) may be used in the next step without isolation.
  • the reaction solvent is not particularly limited as long as it allows the above steps to proceed efficiently.
  • Amide solvents eg, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone, etc.
  • acetate ester solvents eg, ethyl acetate, propyl acetate) Etc.
  • hydrocarbon solvents eg toluene, benzene, hexane etc.
  • ether solvents eg cyclopentyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,2-dimethoxyethane, anisole etc.
  • nitrile solvents Examples: One or more selected from acetonitrile, propionitrile, etc., halogen solvents (eg, dichloromethane, chloroform, etc.),
  • Amide solvents are preferred. Of these, N, N-dimethylacetamide or N-methylpyrrolidone is preferable, and N-methylpyrrolidone is more preferable.
  • the reaction temperature is not particularly limited, but is usually about ⁇ 40 ° C. to about 30 ° C., preferably about ⁇ 10 to 10 ° C.
  • the reaction time is not particularly limited, but is usually about 1 to 10 hours, preferably about 1 to 5 hours.
  • the reducing agent include phosphorus trichloride, phosphorus tribromide, acetyl chloride and sodium iodide, sodium borohydride, iodine and the like, preferably phosphorus trichloride or phosphorus tribromide.
  • the reducing agent is preferably dissolved in a solvent and added dropwise as necessary.
  • peracid By dropping, peracid can be reacted with compound (III) at the same time as dropping, and the reaction heat can be controlled safely, so that dangers such as explosion during mass production can be avoided.
  • each protecting group of compound (II), compound (IA), a pharmaceutically acceptable salt thereof, or a solvate thereof can be obtained.
  • the reaction may be performed according to conditions for each deprotection reaction of amino group, hydroxy group or carboxy group well known to those skilled in the art.
  • Each protecting group may be sequentially deprotected. However, it is preferable that deprotection is sequentially performed without going through an isolation step in a one-pot reaction, or all protecting groups may be removed in one reaction.
  • the reaction solvent is not particularly limited as long as it allows the above steps to proceed efficiently.
  • Acetate solvents eg, ethyl acetate, propyl acetate, etc.
  • hydrocarbon solvents eg, toluene, benzene, hexane, etc.
  • ether solvents eg, cyclopentyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 2 -One or more selected from dimethoxyethane, anisole, etc., halogen solvents (eg, dichloromethane, chloroform, etc.), ketone solvents (eg, acetone, methyl ethyl ketone, etc.) can be used.
  • the solvent a two-layer solvent with water or a water-containing solvent can be used as necessary. Ketone solvents and / or ether solvents are preferred. Of these, anisole and methyl ethyl ketone are preferable, and a mixed solvent of anisole and methyl ethyl ketone is more preferable.
  • the reaction temperature is not particularly limited, but is usually about ⁇ 10 to 30 ° C., preferably about 10 to 20 ° C.
  • the reaction time is not particularly limited, but is usually about 0.5 to 5 hours, preferably about 0.5 to 2 hours.
  • Examples of the deprotecting reagent include hydrochloric acid, sulfuric acid, p-toluenesulfonic acid and the like. Preferably, it is sulfuric acid.
  • Examples of protecting groups (amino protecting group, hydroxy protecting group, carboxy protecting group and the like) that can be used in the above reaction include Protective Groups in Organic Synthesis, T. et al. W. By Greene, John Wiley & Sons Inc. (1991) and the like. The introduction and removal of protecting groups are carried out in accordance with methods commonly used in organic synthetic chemistry (for example, see Protective Groups in Organic Synthesis, TW Greene, John Wiley & Sons Inc. (1991)) and the like. It can be carried out.
  • the reaction solution containing the obtained compound (IA) may be post-treated or purified according to methods well known to those skilled in the art.
  • the crude product containing the compound (IA) is subjected to column treatment with a mobile phase (for example, acetonitrile-water or the like, and optionally an acid such as formic acid, acetic acid, hydrochloric acid, sulfuric acid, etc. may be added).
  • a mobile phase for example, acetonitrile-water or the like, and optionally an acid such as formic acid, acetic acid, hydrochloric acid, sulfuric acid, etc. may be added.
  • the eluate containing the resulting compound (IA) is optionally concentrated, crystallized, etc. to give an acid addition salt (eg, hydrochloride, sulfate, p-toluenesulfonate, or a mixed salt thereof) ) May be isolated.
  • an acid addition salt eg, hydrochloride, sulfate,
  • the acid addition salt may be a crystal such as a hydrate.
  • the acid addition salt may be converted to an alkali metal salt (eg, sodium salt) by a salt exchange reaction. That is, for example, to a solution containing the acid addition salt of compound (IA) or a hydrate thereof, an aqueous solution of sodium hydroxide or sodium source such as sodium bicarbonate is added to adjust the pH to about 5 to 6.5,
  • the sodium salt of compound (IA) can be obtained by lyophilization.
  • Examples of the pharmaceutically acceptable salt include acid addition salts and metal salts.
  • the acid of the acid addition salt is, for example, selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, maleic acid, citric acid, tartaric acid, p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, or these acids.
  • Examples include mixed acid of seeds.
  • Examples of the metal salt include sodium salt, potassium salt, calcium salt, magnesium salt and the like.
  • Examples of solvates include hydrates and acetonitrile solvates.
  • amino protecting group various amino protecting groups that can be generally used in the field of ⁇ -lactam antibacterial agents can be used. Specific examples thereof include t-butyldimethylsilyl group, benzyloxycarbonyl group, t-butoxycarbonyl group, allyl group, 9-fluorenylmethyloxycarbonyl group, benzyl group, p-methoxybenzyl group, methoxymethyl group, Examples include benzyloxymethyl group, benzhydryl group, trityl group and the like.
  • R 1 is preferably a t-butoxycarbonyl group or a benzyloxycarbonyl group, more preferably a t-butoxycarbonyl group.
  • hydroxy protecting group various hydroxy protecting groups that can be generally used in the field of ⁇ -lactam antibacterial agents can be used. Specific examples thereof include benzyl group, p-methoxyphenylbenzyl group, p-methoxybenzyl group, acetyl group, formyl group, benzoyl group, chloroacetyl group, pivaloyl group, methyl carbonate group, isobutyl carbonate group, benzyl carbonate group, Vinyl carbonate group, phenyl carbonate group, mesyl group, tosyl group, trimethylsilyl group, triethylsilyl group, t-butyldimethylsilyl group, methoxymethyl group, benzyloxymethyl group, methoxyethoxymethyl group, 2- (trimethylsilyl) ethoxymethyl group, Examples include propenyl group, phenacyl group, tetrahydropyranyl group, prenyl group and the like.
  • carboxy protecting group various carboxy protecting groups that can be generally used in the field of ⁇ -lactam antibacterial agents can be used. Specific examples thereof include lower alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl), lower alkanoyloxy (lower) alkyl, (eg, acetoxymethyl, propionyloxymethyl, Butyryloxymethyl, valeryloxymethyl, pivaloyloxymethyl, hexanoyloxymethyl), lower alkanesulfonyloxy (lower) alkyl (eg 2-mesylethyl), mono (or di or tri) halo (lower) alkyl (Example: 2-iodoethyl, 2,2,2-trichloroethyl), lower alkoxycarbonyloxy (lower) alkyl (Example: methoxycarbonyloxy
  • R 2 and R 3 are preferably each independently a t-butyl group, a p-methoxybenzyl group or a benzhydryl group. More preferably, R 2 is a t-butyl group, R 3 is a p-methoxybenzyl group or a benzhydryl group, and more preferably, R 3 is a p-methoxybenzyl group.
  • the crystals are preferably methanol solvate, methanol-hydrate, hydrate or solvate-free.
  • the crystals preferably exhibit the powder X-ray pattern shown below.
  • the crystal showing the pattern is preferably a methanol solvate.
  • the crystal showing the above pattern is preferably a solvate.
  • the present invention includes not only a crystal in which the diffraction angle of the peak in powder X-ray diffraction completely coincides but also a crystal in which the diffraction angle of the peak coincides with an error of about ⁇ 0.2 °.
  • the absolute and relative intensities of the peaks shown in the tables and figures below are a number of factors, such as the effect of selective orientation of the crystal on the x-ray beam, the influence of coarse particles, the purity of the substance being analyzed or the sample. It is known that it can vary depending on the degree of crystallinity.
  • the peak position can also be shifted based on the variation in sample height.
  • a characteristic diffraction peak as used herein is a peak selected from the observed diffraction pattern.
  • a peak that is seen in the crystal and not seen in other crystals is a preferable characteristic peak for specifying the crystal, rather than the size of the peak. With such characteristic peaks, even one or two peaks can characterize the crystal.
  • the diffraction peak may be one sharp peak (singlet shape), one gentle peak (broad shape), or about 2 to 5 multiple peaks (tablet). Shape, triplet shape, quartet shape, quintet shape), etc., but usually one sharp peak in many cases.
  • the NMR analysis obtained in the examples was performed at 300 MHz or 400 MHz and measured using DMSO-d 6 , CDCl 3 or the like.
  • Step 1 Synthesis of Compound 10
  • Compound 9 (25.0 kg, 164.3 mol) was dissolved in methanol (125 L) under a nitrogen atmosphere and cooled to ⁇ 7 ° C.
  • Aqueous sodium hypochlorite (11-12%) (135 L, 261.1 mol) was added dropwise at ⁇ 7 ° C. over 2 hours 30 minutes, and the mixture was stirred at ⁇ 7 ° C. for 3 hours.
  • the reaction solution was added to a mixed solution of sulfuric acid water and methanol at 40 ° C., stirred for 1 hour and 30 minutes, and the precipitated solid was collected by filtration to obtain an undried solid.
  • the undried solid was recrystallized from methanol-water and dried to obtain Compound 10 (46.0 kg, content 57.3%, yield 86.1%).
  • Step 2 Synthesis of Compound 11 Under a nitrogen atmosphere, compound 10 (26.0 kg in terms of content), 139.3 mol) is dissolved in DMA (130 L), pyridine (30.9 kg, 391.2 mol) is added, and the mixture is heated to 50 ° C. did. A solution of aluminum chloride (26.0 kg, 195.0 mol) in anisole (78 L) was added dropwise at 53 ° C. over 2 hours and stirred at 53 ° C. for 2 hours. The reaction mixture was extracted with dilute hydrochloric acid and tetrahydrofuran, and the aqueous layer was extracted with tetrahydrofuran. The organic layers were combined and concentrated under reduced pressure.
  • Step 3 Synthesis of Compound 12 Under a nitrogen atmosphere, p-methoxybenzyl chloride (23.0 kg, 147.1 mol) was added to Compound 11 (content conversion: 12.0 kg, 69.5 mol). This solution was suspended in DMF (47 L) of potassium carbonate (22.1 kg, 159.8 mol), sodium iodide (0.516 kg, 3.4 mol), p-methoxybenzyl chloride (1.1 kg, 6.8 mol). It added at 40 degreeC to the liquid, and stirred at 40 degreeC for 2 hours and 30 minutes.
  • Step 4 Synthesis of Compound 13 Under a nitrogen atmosphere, Compound 12 (32.0 kg, 77.5 mol) was dissolved in DMF (320 L), and sodium dihydrogen phosphate dihydrate (3.0 kg, 19.3 mol) was dissolved. 35% aqueous hydrogen peroxide (9.1 kg, 93.9 mol) was added at 27 ° C. The mixture was cooled to 20 ° C., an aqueous solution of sodium hypochlorite (10.5 kg, 116.4 mol) was added dropwise at 20 ° C. over 1 hour and 45 minutes, and the mixture was stirred for 2 hours and 25 minutes. The temperature was raised to 30 ° C., water and dilute hydrochloric acid were added, and the mixture was stirred at 30 ° C.
  • Step 5 Synthesis of Compound 4 Under a nitrogen atmosphere, Compound 13 (32.0 kg, 74.6 mol) was suspended in tetrahydrofuran (160 L), and triethylamine (12.2 kg, 120.2 mol) was added at 27 ° C. over 30 minutes. Dropped and dissolved. This solution was added dropwise to a tetrahydrofuran solution of methanesulfonyl chloride (11.2 kg, 97.8 mol) at ⁇ 10 ° C. over 4 hours and stirred for 20 minutes. This reaction solution was added dropwise to a tetrahydrofuran solution of compound 14 (10.2 kg, 89.7 mol) at ⁇ 5 ° C. over 2 hours and stirred for 2 hours.
  • Step 1 Synthesis of Seed A of Solvate of Compound 3
  • Compound 6 (120.00 g, 154 mmol) was dissolved in dichloromethane (600 mL) under a nitrogen atmosphere and cooled to ⁇ 20 ° C. 39% peracetic acid (29.99 g, 154 mmol) was added dropwise over 50 minutes, and the mixture was stirred at ⁇ 20 ° C. for 30 minutes.
  • the reaction solution was added to an aqueous sodium hydrogen sulfite solution and extracted. The organic layer was washed with water and then concentrated under reduced pressure.
  • the solution was added dropwise over a period of time and stirred at ⁇ 5 ° C. for 30 minutes.
  • the reaction solution was added to a mixed solution of methyl ethyl ketone, sodium bisulfite and sodium chloride aqueous solution and extracted.
  • the organic layer was washed with a mixed solution of aqueous sodium hydrogen carbonate solution and aqueous ammonia, and then washed with brine.
  • the solvent was concentrated under reduced pressure, methanol was added to the resulting residue, seed crystal A (5.1 mg) was added to precipitate crystals, methanol-water was added, and the mixture was cooled to ⁇ 10 ° C. and collected by filtration. As a result, crystals of methanol solvate of Compound 3 were obtained.
  • the diffraction angle 2 ⁇ showing a characteristic diffraction peak is 4.3 ⁇ 0.2 °, 10.9 ⁇ 0.2 °, 12.7 ⁇ 0.2 °, 14.5 ⁇ 0.2 °, 16. 2 ⁇ 0.2 °, 18.0 ⁇ 0.2 °, 18.3 ⁇ 0.2 °, 21.2 ⁇ 0.2 °, 25.6 ⁇ 0.2 ° and 26.5 ⁇ 0.2 °.
  • they are 4.3 ⁇ 0.2 °, 10.9 ⁇ 0.2 °, 14.5 ⁇ 0.2 °, 18.3 ⁇ 0.2 ° and 21.2 ⁇ 0.2 °.
  • Diffraction angles 2 ⁇ showing characteristic diffraction peaks are 4.8 ⁇ 0.2 °, 14.1 ⁇ 0.2 °, 14.4 ⁇ 0.2 °, 14.9 ⁇ 0.2 °, 16. 0 ⁇ 0.2 °, 17.1 ⁇ 0.2 °, 17.6 ⁇ 0.2 °, 20.5 ⁇ 0.2 °, 25.2 ⁇ 0.2 ° and 33.1 ⁇ 0.2 °.
  • Preferred are 4.8 ⁇ 0.2 °, 14.4 ⁇ 0.2 °, 14.9 ⁇ 0.2 °, 16.0 ⁇ 0.2 °, and 20.5 ⁇ 0.2 °.
  • Step 1 Synthesis of seed crystal B
  • Compound (IA) was prepared according to the method described in WO2010 / 050468.
  • Compound (IA) (100 mg) was dissolved in 1.0 mol / L p-toluenesulfonic acid aqueous solution (2 mL) at room temperature using ultrasound, and allowed to stand at 4 ° C. for 4 days. The precipitate was filtered to obtain seed crystal B (73 mg). It was confirmed to be a needle-like crystal by a microscope.
  • Process 2 Seed crystal C Seed B (50 mg) is dissolved in 6 mol / L H 2 SO 4 (3 mL) at room temperature on an ultrasonic bath and allowed to stand at 4 ° C. for 2 days. The precipitated crystalline solid was filtered and washed with ice-cold water to obtain seed crystal C (23 mg).
  • Step 3 Synthesis of Compound 3
  • Compound 2 (35.0 kg, 81.42 mol) was dissolved in DMA (90 L) under a nitrogen atmosphere and cooled to ⁇ 5 ° C.
  • Methanesulfonyl chloride (10.2 kg, 88.82 mol) was added, and triethylamine (10.5 kg, 103.63 mmol) was added dropwise at ⁇ 5 ° C. over 80 minutes, followed by stirring at ⁇ 5 ° C. for 30 minutes.
  • reaction solution was added to a mixed solution of methyl ethyl ketone, sodium bisulfite and sodium chloride aqueous solution and extracted.
  • the organic layer was washed with a mixed solution of aqueous sodium hydrogen carbonate solution and aqueous ammonia, and then washed with brine.
  • Step 4 Synthesis of Compound (IA) Boric acid (0.4 kg, 6.78 mol) was dissolved in NMP (50 L) under a nitrogen atmosphere, sodium iodide (10.2 kg, 67.80 mol) was added, and the temperature was 0 ° C. Cooled to. Compound 3 (18.0 kg, 22.60 mol) and compound 4 (13.1 kg, 24.86 mol) were added, and the mixture was stirred at 0 ° C. for 6 hours. After heating up to 7 degreeC and stirring for 16 hours, the production
  • the measuring method was tested from the Japanese Pharmacopoeia General Test Method Moisture (coulometric titration). However, Aquamicron (registered trademark) AX manufactured by Mitsubishi Chemical was used as the anolyte, and Aquamicron (registered trademark) CXU was used as the catholyte. Since the water measurement by the Karl Fischer method may cause an error within a range of ⁇ 0.3%, the value of the water content needs to be understood as including a numerical value within a range of about ⁇ 0.3%.
  • Step 1 Preparation of sample solution About 40 mg of a sample was accurately weighed and dissolved in a sample dilution solvent to make exactly 25 mL. 2 mL of this solution was accurately weighed and a sample dilution solvent was added to make exactly 20 mL.
  • Step 2 Preparation of standard solution About 25 mg of standard p-toluenesulfonate standardized at 25 ° C / 60% RH was accurately weighed and dissolved in the sample dilution solvent to make exactly 100 mL.
  • Step 3 Measurement and Quantification The above sample solution and standard solution were measured by liquid chromatography under the following test conditions, and the peak area of p-toluenesulfonic acid was measured by an automatic integration method.
  • dehydrated equivalent is a value calculated by subtracting the water content from the total amount as 100%.
  • Mobile phase A 0.1% trifluoroacetic acid solution
  • Mobile phase B Acetonitrile gradient program for liquid chromatography The content of p-toluenesulfonic acid in the sample was determined using the following calculation formula.
  • Amount of p-toluenesulfonic acid (%) M S : Weighed amount of standard sodium p-toluenesulfonate (mg) M T : Weighed sample (mg) P: Purity of standard sodium p-toluenesulfonate (%) W T : Sample moisture (%) A T : Peak area of p-toluenesulfonic acid obtained from the sample solution A S : Peak area of p-toluenesulfonic acid obtained from standard solution 172.20: Molecular weight of p-toluenesulfonic acid 194.18: Molecular weight of sodium p-toluenesulfonate
  • Step 1 Preparation of standard solution About 50 mg of anhydrous sodium sulfate was accurately weighed and dissolved in the mobile phase to make exactly 25 mL. 2 mL of this solution was accurately weighed, and the mobile phase was added to make exactly 50 mL. Furthermore, 2 mL of this solution was accurately weighed and the mobile phase was added to make exactly 20 mL. Step 2: Preparation of sample solution About 30 mg of the sample was accurately weighed and dissolved in the mobile phase to make exactly 25 mL. 2 mL of this solution was accurately weighed and the mobile phase was added to make exactly 20 mL.
  • Step 3 Measurement and Quantification
  • the sample solution and standard solution were measured by liquid chromatography (ion chromatography) under the following test conditions, and the peak area of sulfate ions was measured by an automatic integration method.
  • Detector Electrical conductivity detector (Non-suppressor system)
  • Mobile phase Bis-Tris about 0.67 g, boric acid about 3.09 g, and ground p-hydroxybenzoic acid about 1.11 g accurately weighed and dissolved in water to make exactly 1000 mL. The content of sulfuric acid in the sample was determined.
  • Amount of sulfuric acid (%) M S / M T ⁇ 100 / (100-W T ) ⁇ A T / A S ⁇ 98.08 / 142.04 ⁇ 1/25 ⁇ 100 M S : Weighed amount of anhydrous sodium sulfate (mg) M T : Weighed sample (mg) W T : Sample moisture (%) A S : Peak area of sulfate ion obtained from standard solution A T : Peak area of sulfate ion obtained from the sample solution 98.08: Molecular weight of sulfuric acid 142.04: Molecular weight of anhydrous sodium sulfate 1/25: Dilution factor (result) Water content (KF method): 13.3% p-Toluenesulfonic acid: 21.5 ⁇ 0.2% (dehydrated equivalent) Sulfuric acid: 4.9 ⁇ 0.1% (dehydrated equivalent)

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Abstract

La présente invention concerne des composés représentés par la formule (IV) (dans la formule, R1 est un groupe protecteur d'un groupe amino, et R2 et R3 sont chacun indépendamment un groupe protecteur d'un groupe carboxy), des sels pharmaceutiquement acceptables de ceux-ci, des solvates de ceux-ci, ou des cristaux de ceux-ci, un procédé de production de ceux-ci. La présente invention concerne en outre un procédé nouveau et utile de production de composés céphem à l'aide de la formule (IV).
PCT/JP2015/075042 2014-09-04 2015-09-03 Intermédiaire de dérivés de céphalosporine et son procédé de production WO2016035847A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021147986A1 (fr) 2020-01-22 2021-07-29 上海森辉医药有限公司 Composé céphalosporine antibactérien et son application pharmaceutique
WO2022025091A1 (fr) 2020-07-28 2022-02-03 塩野義製薬株式会社 Formulation lyophilisée contenant de la céphalosporine possédant un groupe catéchol, et son procédé de production
WO2022152146A1 (fr) 2021-01-12 2022-07-21 上海森辉医药有限公司 Composé antibactérien de céphalosporine et son procédé de préparation

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CN113698365A (zh) * 2021-08-30 2021-11-26 成都大学 一种头孢地尔侧链的制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010050468A1 (fr) * 2008-10-31 2010-05-06 塩野義製薬株式会社 Céphalosporine possédant un groupe catéchol
WO2011125967A1 (fr) * 2010-04-05 2011-10-13 塩野義製薬株式会社 Composé de céphème comprenant un groupe catéchol
WO2011125966A1 (fr) * 2010-04-05 2011-10-13 塩野義製薬株式会社 Composé céphème who portant un groupe pseudocatéchol
WO2013052568A1 (fr) * 2011-10-04 2013-04-11 Glaxo Group Limited Composés antibactériens

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104854113A (zh) * 2012-10-29 2015-08-19 盐野义制药株式会社 2-烷基头孢烯化合物的中间体的生产方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010050468A1 (fr) * 2008-10-31 2010-05-06 塩野義製薬株式会社 Céphalosporine possédant un groupe catéchol
WO2011125967A1 (fr) * 2010-04-05 2011-10-13 塩野義製薬株式会社 Composé de céphème comprenant un groupe catéchol
WO2011125966A1 (fr) * 2010-04-05 2011-10-13 塩野義製薬株式会社 Composé céphème who portant un groupe pseudocatéchol
WO2013052568A1 (fr) * 2011-10-04 2013-04-11 Glaxo Group Limited Composés antibactériens

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
YAMAWAKI, K. ET AL., BIOORGANIC & MEDICINAL CHEMISTRY, vol. 15, 2007, pages 6716 - 6732 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021147986A1 (fr) 2020-01-22 2021-07-29 上海森辉医药有限公司 Composé céphalosporine antibactérien et son application pharmaceutique
WO2022025091A1 (fr) 2020-07-28 2022-02-03 塩野義製薬株式会社 Formulation lyophilisée contenant de la céphalosporine possédant un groupe catéchol, et son procédé de production
WO2022152146A1 (fr) 2021-01-12 2022-07-21 上海森辉医药有限公司 Composé antibactérien de céphalosporine et son procédé de préparation

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