WO2023149487A1 - Procédé de production de pyrrole-imidazole polyamide - Google Patents

Procédé de production de pyrrole-imidazole polyamide Download PDF

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WO2023149487A1
WO2023149487A1 PCT/JP2023/003274 JP2023003274W WO2023149487A1 WO 2023149487 A1 WO2023149487 A1 WO 2023149487A1 JP 2023003274 W JP2023003274 W JP 2023003274W WO 2023149487 A1 WO2023149487 A1 WO 2023149487A1
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哲宏 根本
誠也 中島
篤志 金田
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国立大学法人千葉大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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
    • C07D207/42—Nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two 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
    • C07D233/91—Nitro radicals
    • C07D233/92—Nitro radicals attached in position 4 or 5
    • C07D233/95—Nitro radicals attached in position 4 or 5 with hydrocarbon radicals, substituted by nitrogen atoms, attached to other ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
    • C08G69/02—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids
    • C08G69/08—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids derived from amino-carboxylic acids
    • C08G69/12—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids derived from amino-carboxylic acids with both amino and carboxylic groups aromatically bound

Definitions

  • the present invention relates to a method for producing pyrrole-imidazole polyamide.
  • PIP Pyrrole-imidazole polyamide
  • Py N-methylpyrrole units
  • Im N-methylimidazole units
  • PIP enters the minor grooves of DNA, as expected from its molecular design, with Im-Py for GC base pairs, Py-Im for CG base pairs, and AT base pairs. Or Py-Py can bind to the TA base pair. Since PIP can specifically recognize and bind to the base sequence of DNA and strongly suppress the transcriptional activity of target genes, it is expected to be applied to epigenetic drug discovery to suppress the expression of target genes.
  • PIP synthesis methods include a solid phase synthesis method using a condensing agent developed by Dervan et al. have proposed a cross-coupling method using a metal catalyst (Patent Document 1).
  • Patent Document 1 a compound supported on a polymer is used to extend the peptide chain, so the atomic efficiency is very poor, and large-scale synthesis is difficult.
  • the purity of the crude purified product is low, and column chromatography is required for purification, which is time-consuming.
  • Liquid-phase synthesis methods using trichloroacetyl derivatives can only synthesize dimers, and trichloroacetyl derivatives having imidazole are unstable and difficult to handle. Furthermore, when the reaction is actually carried out, the solubility of the substrate is low, and large-scale synthesis is difficult.
  • the cross-coupling method does not require expensive condensing agents or polymers, but requires multistep processes for substrate synthesis.
  • Patent Literature 2 discloses sequence-selective pyrrole and imidazole polyamide metal complexes and methods for preparing the same.
  • Non-Patent Document 5 discloses monocyclic and multicyclic pyrrole containing N-formamides and imidazole-2-carboxylic acids for use in the preparation of polyamide molecules.
  • the present invention relates to the provision of a method for producing a pyrrole-imidazole polyamide that can produce a pyrrole-imidazole polyamide in a simple manner.
  • a method for producing a pyrrole-imidazole polyamide comprising the following steps A1 and A2.
  • Step A1 Reduction step of reducing compound 1 represented by the following formula (1) to obtain compound 2 represented by the following formula (2)
  • Step A2 compound 3 represented by the following formula (3)
  • X 0 each independently represents N or CH
  • R a is a hydrogen atom, an alkyl group having 1 to 12 carbon atoms, an alkoxy group having 1 to 12 carbon atoms, a aryl group, an aralkyl group having 7 to 25 carbon atoms, a nitrile group, —COOR p
  • R p represents a hydrogen atom, an alkyl group having 1 to 12 carbon atoms, or an aryl group having 6 to 20 carbon atoms.
  • R q and R r independently represent a hydrogen atom, an alkyl group having 1 to 12 carbon atoms, or an aryl group having 6 to 20 carbon atoms
  • n is 0 or 1 Represents an integer greater than or equal to .
  • each X 1 independently represents N or CH, and Y represents a halogen atom.
  • m represents an integer of 0 or 1 or more.
  • Step B1 A reduction step to obtain a compound 5 represented by the following formula (5) by reducing the compound 4 obtained by the production method according to any one of [1] to [9] above
  • Step B2 The following formula Elongation step of reacting compound 6 represented by (6) with compound 5 to obtain compound 7 represented by the following formula (7)
  • X 2 each independently represents N or CH
  • Y represents a halogen atom
  • R b represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 12 carbon atoms, a It represents an alkoxy group of 1 to 12 or an aryl of 6 to 10 carbon atoms.
  • p represents an integer of 0 or 1 or more;
  • a method for producing a pyrrole-imidazole polyamide is provided by which a pyrrole-imidazole polyamide can be produced in a simple manner.
  • the method for producing a pyrrole-imidazole polyamide of the present invention includes the following steps A1 and A2.
  • Step A1 Reduction step of reducing compound 1 represented by the following formula (1) to obtain compound 2 represented by the following formula (2)
  • Step A2 compound 3 represented by the following formula (3)
  • X 0 each independently represents N or CH
  • R a is a hydrogen atom, an alkyl group having 1 to 12 carbon atoms, an alkoxy group having 1 to 12 carbon atoms, a aryl group, an aralkyl group having 7 to 25 carbon atoms, a nitrile group, —COOR p
  • R p represents a hydrogen atom, an alkyl group having 1 to 12 carbon atoms, or an aryl group having 6 to 20 carbon atoms.
  • R q and R r independently represent a hydrogen atom, an alkyl group having 1 to 12 carbon atoms, or an aryl group having 6 to 20 carbon atoms
  • n is 0 or 1 Represents an integer greater than or equal to .
  • each X 1 independently represents N or CH, and Y represents a halogen atom.
  • m represents an integer of 0 or 1 or more.
  • step A1 compound 1 represented by the above formula (1) is reduced to obtain compound 2 represented by the above formula (2).
  • Compound 1 which is the starting compound of Step A1, is a monomer of N-methylpyrrole or N-methylimidazole having a nitro group, or a pyrrole-imidazole polyamide having a nitro group, and is represented by the above formula (1).
  • Each X 0 in the above formula (1) independently represents N or CH. When X 0 represents N, the nitrogen-containing 5-membered ring containing X 0 is a pyrrole ring, and when X 0 represents CH, the nitrogen-containing 5-membered ring containing X 0 is an imidazole ring.
  • n represents an integer of 0 or 1 or more. n is preferably an integer of 0 to 3, more preferably 0 or 1, still more preferably 0, from the viewpoint of reactivity.
  • R a is a hydrogen atom, an alkyl group having 1 to 12 carbon atoms, an alkoxy group having 1 to 12 carbon atoms, an aryl group having 6 to 20 carbon atoms, an aralkyl group having 7 to 25 carbon atoms, a nitrile group, —COOR p (R p represents a hydrogen atom, an alkyl group having 1 to 12 carbon atoms, or an aryl group having 6 to 20 carbon atoms.), or —CONR q R r (R q and R r are independently a hydrogen atom, a carbon represents an alkyl group having 1 to 12 carbon atoms or an aryl group having 6 to 20 carbon atoms.).
  • the alkyl group is preferably a linear or branched alkyl group having 1 to 6 carbon atoms. Specifically, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, neopentyl group, tert-pentyl group, n-hexyl group and isohexyl group.
  • the alkyl group may have 1 or more and 3 or less substituents.
  • the alkoxy group is preferably a linear or branched alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy. group, sec-butoxy group, tert-butoxy group, n-pentyloxy group, isopentyloxy group, n-hexyloxy group, isohexyloxy group and the like. Among them, an alkoxy group having 1 or more and 3 or less carbon atoms is preferable.
  • the aryl group is preferably an aryl group having 6 or more and 10 or less carbon atoms.
  • aryl group may have 1 or more and 3 or less substituents.
  • a halogen atom, an alkyl group, an alkoxy group, etc. are mentioned as said substituent.
  • the alkyl group is the above alkyl group
  • the aryl group is the above aryl group.
  • a benzyl group is mentioned as an aralkyl group.
  • Compound 1 can be obtained as a commercial product or from a commercial product by a known organic synthesis reaction.
  • R a is, among others, preferably a hydrogen atom or —COOR p , more preferably —COOR p .
  • the compound 2 obtained in step A1 is an N-methylpyrrole or N-methylimidazole monomer having an amino group, or a pyrrole-imidazole polyamide having an amino group, and is represented by the above formula (2).
  • X 0 , R a and n in formula (2) are the same as defined in formula (1).
  • step A1 the nitro group of compound 1 is reduced to lead to an amino group to obtain compound 2.
  • a reduction reaction of a nitro group can be performed by a known method. For example, catalytic reduction in which hydrogen gas is reacted in the presence of a palladium carbon catalyst, nickel catalyst, etc.; Bechamp reduction in which an acid such as ammonium chloride, hydrochloric acid, acetic acid, etc. hydride reduction, etc., in which metal oxides are reacted.
  • the reduction reaction is preferably carried out in the presence of a palladium carbon catalyst. From the viewpoint of reaction progress, the reduction reaction is preferably carried out in a solvent.
  • solvents examples include aqueous solvents such as water; alcohol solvents such as methanol and ethanol; ether solvents such as diethyl ether and tetrahydrofuran; Aprotic polar solvents such as dimethylsulfoxide (DMSO), hexamethylphosphoric triamide (HMPA), N-methylpyrrolidone (NMP), acetonitrile, acetone, and the like.
  • DMSO dimethylsulfoxide
  • HMPA hexamethylphosphoric triamide
  • NMP N-methylpyrrolidone
  • acetonitrile acetone, and the like.
  • a solvent can be used individually by 1 type or in mixture of 2 or more types.
  • the alcoholic solvent is preferably methanol.
  • the aprotic polar solvent is preferably N,N-dimethylformamide (DMF), tetrahydrofuran (THF), or a mixed solvent of DMF and THF.
  • the reduction reaction is carried out in an alcoholic solvent, for example, from the viewpoint of being widely used in reduction reactions carried out in the presence of a palladium carbon catalyst.
  • the pyrrole-imidazole polyamide is highly soluble, and the reduction reaction is performed in an aprotic polar solvent from the viewpoint of further improving the reaction rate, reaction progress, reproducibility of the reaction, and the like.
  • the solubility of pyrrole-imidazole polyamide (polymer) is lower than that of N-methylpyrrole or N-methylimidazole monomers, which may reduce the reactivity and reaction reproducibility of step A1.
  • the reduction reaction of the pyrrole-imidazole polyamide (polymer) having a nitro group is preferably carried out in an aprotic polar solvent.
  • n is an integer greater than or equal to 1 (eg, 1, 2 or 3)
  • the reduction reaction is performed in a polar aprotic solvent.
  • the solvent may be either a single solvent or a mixture of two or more solvents.
  • the amount of the catalyst to be used is preferably 0.1 equivalent to excess amount, more preferably 0.2 equivalent to 5 equivalents, still more preferably 0.5 to 2 equivalents, relative to compound 1.
  • the reaction temperature is preferably 0° C. to 100° C., and the reaction time is preferably 0.5 to 24 hours.
  • Step A1 may be either a batch method using a flask or the like or a flow reaction using a flow microreactor or the like. In one preferred embodiment, it is a flow reaction.
  • Step A2 is an elongation step of reacting compound 3 represented by the above formula (3) with compound 2 to obtain compound 4 represented by the above formula (4).
  • the compound 3 to be reacted with the compound 2 in step A2 is an acid halide compound represented by the above formula (3).
  • Each X 1 in the above formula (3) independently represents N or CH.
  • Y represents a halogen atom.
  • a halogen atom is a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, or the like, and preferably a chlorine atom from the viewpoint of availability.
  • m represents an integer of 0 or 1 or more. From the viewpoint of reactivity, m is preferably an integer of 0 to 3, more preferably 0 or 1, still more preferably 0.
  • compound 3 is represented by the following formula (3').
  • Compound 3 can be obtained as a commercial product or from a commercial product by a known organic synthesis reaction.
  • a specific example is a method of reacting a carboxylic acid compound with a halogenating agent such as thionyl chloride or oxalyl chloride.
  • the reaction with the halogenating agent is preferably carried out in a solvent.
  • the solvent is preferably an ether solvent such as diethyl ether or tetrahydrofuran.
  • the solvent may be either a single solvent or a mixture of two or more solvents.
  • the amount of the halogenating agent to be used is preferably 0.1 equivalent to excess, more preferably 0.2 to 5 equivalents, still more preferably 0.5 to 2 equivalents, relative to the carboxylic acid compound.
  • the reaction temperature is preferably 0° C. to 100° C., and the reaction time is preferably 0.5 to 24 hours.
  • Compound 4 obtained in step A2 is a pyrrole-imidazole polyamide and is represented by the above formula (4).
  • X 0 , X 1 , R a , n and m in formula (4) are the same as defined in formulas (1), (2) and (3) above.
  • step A2 compound 4 is obtained by reacting the acid halide group of compound 3 with the amino group of compound 2 to form an amide bond.
  • the elongation reaction can be carried out in the presence of preferably 0.1 to excess mol, more preferably 0.5 to 10 mol of base relative to 1 mol of compound 3, if necessary.
  • the base include organic bases such as pyridine, triethylamine and N,N-diisopropylethylamine (DIPEA). From the viewpoint of reaction progress, the reaction is preferably carried out in a solvent.
  • solvents examples include organic solvents such as ethyl acetate, N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), 1,4-dioxane, tetrahydrofuran (THF), acetonitrile and dichloromethane.
  • organic solvents such as ethyl acetate, N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), 1,4-dioxane, tetrahydrofuran (THF), acetonitrile and dichloromethane.
  • the solvent may be either a single solvent or a mixture of two or more solvents.
  • Step A2 may be either a batch method using a flask or the like or a flow reaction using a flow microreactor or the like.
  • step A2 is a flow reaction, more preferably the reaction is carried out in a microreactor.
  • both steps A1 and A2 are flow reactions from the viewpoint of easy mass synthesis.
  • a flow reaction which is a preferred embodiment of the present invention, is a reaction in which multiple components are mixed in a channel.
  • the inner diameter of the channel in the flow reaction is not particularly limited.
  • the inner diameter of the channel is preferably 0.05-2 mm, more preferably 0.1-1 mm.
  • the cross-sectional shape of the channel is, for example, circular or rectangular.
  • the channel length in the flow reaction is preferably 0.5 m or more and 10 m or less, more preferably 0.9 m or more and 8 m or less.
  • the mode of mixing in the flow reaction may be either laminar mixing or turbulent mixing. Flow reactions are preferably carried out in microreactors.
  • the microreactor is not particularly limited as long as it has a diameter on the order of micrometers, that is, 1000 ⁇ m or less, and examples of the microreactor include T-shaped or Y-shaped micromixers. It is preferable to use a pump such as a plunger pump, a gear pump, a rotary pump, a diaphragm pump, a syringe pump, or the like to transfer the liquid in the flow reaction. Preferably, the reaction temperature in the microreactor is controlled.
  • each component in the flow reaction is controlled so that the reaction time (residence time) is the above reaction time, and each component is independently preferably 0.01 mL/min to 100 mL/min, more preferably is 0.05 mL/min to 50 mL/min.
  • the concentration of each component in the flow reaction is preferably 0.005M to 0.5M, more preferably 0.01M to 0.1M for each component independently.
  • the compound 4 is used as the compound 1 in the next step A1 to continuously extend the pyrrole-imidazole polyamide to obtain a desired sequence and desired length of pyrrole • It is possible to produce imidazole polyamides.
  • Step B1 Reduction step of reducing compound 4 obtained by the above production method to obtain compound 5 represented by the following formula (5)
  • Step B2 Compound 6 represented by the following formula (6) and compound 5 above Elongation step of obtaining compound 7 represented by the following formula (7) by reacting
  • X 2 each independently represents N or CH
  • Y represents a halogen atom
  • R b represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 12 carbon atoms, a It represents an alkoxy group of 1 to 12 or an aryl of 6 to 10 carbon atoms.
  • p represents an integer of 0 or 1 or more;
  • a pyrrole-imidazole polyamide having no terminal nitro group or amino group can be produced.
  • Step B1 can be carried out in the same manner as Step A1 above, except that Compound 4 obtained by the above production method is used in place of Compound 1.
  • compound 5 is represented by the following formula (5').
  • Step B2 can be performed in the same manner as Step A2 above, except that Compound 5 obtained in Step B1 above and Compound 6 above are used instead of Compound 3.
  • the compound 6 to be reacted with the compound 5 in step B2 is an acid halide compound represented by the above formula (6).
  • Compound 6, unlike compound 3, does not have a nitro group.
  • Each X 2 in the above formula (6) independently represents N or CH.
  • Y represents a halogen atom.
  • a halogen atom is a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, or the like, and preferably a chlorine atom from the viewpoint of availability.
  • R b represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 12 carbon atoms, an alkoxy group having 1 to 12 carbon atoms, or an aryl group having 6 to 20 carbon atoms.
  • Halogen atoms include fluorine, chlorine, bromine and iodine atoms. Examples of the alkyl group, the alkoxy group, and the aryl group include the same modes as those for Ra described above.
  • p represents an integer of 0 or 1 or more; p is preferably an integer of 0 to 3, more preferably 0 or 1, still more preferably 0, from the viewpoint of reactivity.
  • compound 6 is represented by the following formula (6').
  • compound 6 can be obtained as a commercial product or from a commercial product by a known organic synthesis reaction.
  • the reaction can be stopped by means such as changing the temperature or pH, adding water, a solvent, a saturated aqueous solution of sodium hydrogen carbonate, or the like, if necessary.
  • the target compound can be obtained through isolation steps such as filtration, concentration, and extraction, if necessary.
  • the solvent used in the next step can be exchanged.
  • Obtainment of the desired compound in each step can be confirmed by known means such as 1 H-NMR measurement, 13 C-NMR measurement and mass spectrometry.
  • Compound 7 obtained in step B2 is a pyrrole-imidazole polyamide and is represented by the above formula (7).
  • X 0 , X 1 , X 2 , R a , n, m, and p in formula (7) are the same as defined in formulas (5) and (6) above.
  • compound 7 is represented by the following formula (7').
  • a pyrrole-imidazole polyamide is produced.
  • a pyrrole-imidazole polyamide in which pyrrole rings and imidazole rings are arranged in a desired order can be produced freely and simply.
  • the compounds used in the present invention can be easily synthesized from commercially available compounds, and are economical because they do not use condensing agents that tend to be expensive.
  • the production method of the present invention does not require a condensing agent or a support (polymer used for solid-phase synthesis), and can be carried out without purification such as column chromatography, so that waste is generated during production. very little quantity.
  • the reaction efficiency is high and the formation of by-products such as branched structures can be prevented.
  • the production method using a flow microreactor has a very short reaction time compared to the batch production method, and can easily produce a large amount of pyrrole-imidazole polyamide.
  • the pyrrole or imidazole derivative monomer (iii) was dissolved in tetrahydrofuran (THF) to make a 0.058 M solution, and under an argon atmosphere, 3.0 equivalents of N,N-diisopropylethylamine (DIPEA) was added to the monomer (iii). ) was added at room temperature.
  • DIPEA N,N-diisopropylethylamine
  • the target dimers (iv-a) to (iv-d) were obtained with a yield of 53-75% by performing the reaction for 24 hours. This reaction was very fast, and dimers 4a to 4d could be produced even in 30 seconds.
  • the content of the PyPy dimer (iv-a) in the insoluble matter was 99% by mass or more.
  • the dimer (iv) obtained in Synthesis Example 1 was reduced using 10% Pd/C in a hydrogen atmosphere in the same manner as in Synthesis Example 1 to obtain dimer (v). Yields are shown in Table 2. In the table, “quant” indicates that the reaction proceeded quantitatively. The reduction of dimers (iv-a)-(iv-c) to dimers (va)-(vc) proceeded in high yields.
  • Trimer (vii) was obtained in the same manner as in Synthesis Example 1 above, except that monomer (iii) was replaced with dimer (v). Yields are shown in Table 3. Compounds (vii-a) to (vii-d) were obtained in yields of 12 to 71% in a reaction time as short as 30 seconds.
  • FIG. 1 shows a schematic diagram of synthesis using a flow microreactor.
  • a T-shaped micromixer having an inner diameter of 0.25 mm in the mixing section was used, and a tube made of PTFE (polytetrafluoroethylene) having an inner diameter of 0.8 mm was used.
  • the concentration of solution A containing monomer (ii) obtained in the same manner as in Synthesis Example 1 was 0.035 M, the flow rate was 2.0 mL/min, and the monomer (iii) obtained in the same manner as in Synthesis Example 1.
  • the concentration of solution B containing was set to 0.058 M, and the flow rate was set to 1.2 mL/min.
  • ImPy dimer (iv-c) Synthesis of ImPy dimer (iv-c) Using imidazole derivative as monomer (ii) and pyrrole derivative as monomer (iii), ImPy dimer is prepared in the same manner as in 3-1 above. Synthesis of body (iv-c) was carried out. Table 6 shows the yield under each condition.
  • Synthesis Example 4 Trimer Synthesis Using Flow Microreactor 4-1: Synthesis 1 of PyPyPy Trimer (vii-a) Using the flow microreactor used in Synthesis Example 3 above, using a pyrrole derivative as the monomer (ii) and a PyPy dimer (va) as the monomer (iii), after liquid A and liquid B are merged Synthesis of PyPyPy trimers (vii-a) was carried out by setting various tube lengths and reaction temperatures. The content of the PyPyPy trimer (vii-a) in the insoluble matter obtained by synthesis under the conditions of a tube length of 410 cm and a reaction temperature of 0° C. was 99% by mass or more. Table 8 shows the yield under each condition.
  • ImPyPy trimer (vii-d) Synthesis of ImPyPy trimer (vii-d) Using an imidazole derivative as monomer (ii) and a PyPy dimer (va) as monomer (iii), ImPyPy trimer (vii-d ) was synthesized. Table 12 shows the yield under each condition.
  • Synthesis Example 5 Tetramer synthesis using a flow microreactor 5-1: Synthesis of PyPyPyPy tetramer (ix-a) The PyPyPy trimer (vii-a) obtained in 4-1 above was added to 10% Reduction with Pd/C gave the PyPyPy trimer. Reduction proceeded quantitatively.
  • Synthesis Example 6 Tetramer synthesis by flow method 6-1: Synthesis of PyPyPyPy tetramer (ix-a) The PyPy dimer (iv-a) obtained in 3-1 above was treated with 10% Pd /C to give the PyPy dimer (va). Reduction proceeded quantitatively. The PyPy dimer (iv-a) obtained in 3-1 above was suspended in a 1:1 mixed solution of H 2 O and EtOH, and then 5 equivalents of sodium hydroxide was added under ice-cooling. Stir in the bath for 1 hour. Thereafter, the mixture was ice-cooled again, and 10 equivalents of a 1 mol/l hydrochloric acid aqueous solution was added. The resulting yellow precipitate was filtered using a Kiriyama funnel to obtain PyPy-CO 2 H(xa) with a yield of 50%.
  • Test Examples 1 to 4 differences in hydrogenation reduction reaction efficiency due to differences in solvents (DMF or methanol) were evaluated.
  • palladium carbon catalyst Pd/C
  • palladium-activated carbon was used, and the amount was 10 parts by mass with respect to 100 parts by mass of NO 2 Py 4 OMe (ix-a).
  • concentration of NO2Py4OMe (ix-a) in DMF was 0.1M .
  • NO 2 Py 4 OMe was completely dissolved in DMF from the beginning of the reaction, and the reduction reaction proceeded well in the solution. After the reaction, disappearance of the raw material was confirmed by thin layer chromatography (TLC). Ethyl acetate was used as the developing solvent for TLC.
  • the inside of the flask was replaced with argon to remove hydrogen, 7 mL of tetrahydrofuran (THF) was added to the reaction solution, and the mixture was stirred for 15 minutes.
  • the reaction solution was passed through a column packed with 4.9 g of amino-modified silica gel to adsorb the product, and 49 mL of ethyl acetate was passed through to elute the product. After that, the eluate was concentrated under reduced pressure.
  • the amount of amino-modified silica gel used was 0.7 g per 1 mL of DMF used in the reaction.
  • the amount of ethyl acetate used was 7 times the amount of DMF used in the reaction.
  • Test Example 2 Hydrogenation reduction of PyPyPyPy tetramer in methanol
  • a hydrogenation reduction reaction was performed in the same manner as in Test Example 1 except that the solvent was changed from DMF to methanol, and the reaction was performed for 41 hours in the same manner as in Test Example 1. reacted. NO 2 Py 4 OMe did not completely dissolve in methanol and the reaction proceeded in a suspended state. The suspended state was not resolved even at the end of the reaction.
  • Column purification and concentration were performed in the same manner as in Test Example 1. 0.115 g (0.68 mmol) of 1,1,2,2-tetrachloroethane was added to the concentrated residue, diluted with heavy chloroform to obtain a homogeneous solution, and 1 H-NMR was measured.
  • the yield of NH 2 Py 4 OMe (xi-a) is calculated from the integral ratio of an arbitrary peak of NH 2 Py 4 OMe (xi-a) and the peak of 1,1,2,2-tetrachloroethane. The calculated yield was 11%.
  • a reduction reaction and quantification of the product were carried out in the same manner as in Test Example 1 except that the PyPyPyPy tetramer (ix-a) was replaced with the PyPyPy trimer (vii-a) obtained in Synthesis Example 4-1 above. gone. NO 2 Py 3 OMe was completely dissolved in DMF from the start of the reaction, and the reduction reaction proceeded well in the solution. The reaction was completed in 15 hours and the yield of NH2Py3OMe (vii-b) was 100%.
  • the reaction solvent is methanol
  • the PIP substrate containing the nitro group has low solubility in methanol. going to start.
  • the reaction solvent is methanol
  • the PIP substrate containing the nitro group has low solubility in methanol. going to start.
  • the reaction proceeded without problems after stirring for one day (Synthesis Example 1), but the longer the PIP length, the lower the solubility in the MeOH solvent. Decreased.
  • DMF is used as a solvent
  • the PIP substrate containing a nitro group is highly soluble, and the reduction reaction can be initiated with the entire amount of the substrate dissolved. Admitted.

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Abstract

La présente invention concerne un procédé de production d'un pyrrole-imidazole polyamide, le procédé comprenant les étapes A1 et A2 suivantes. Étape A1 : une étape de réduction pour réduire le composé 1 pour obtenir le composé 2 ; Étape A2 : une étape d'extension consistant à faire réagir le composé 3 avec le composé 2 pour obtenir le composé 4 (les composés 1-4 sont tels que définis dans la description).
PCT/JP2023/003274 2022-02-02 2023-02-01 Procédé de production de pyrrole-imidazole polyamide WO2023149487A1 (fr)

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Citations (6)

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Publication number Priority date Publication date Assignee Title
JPH0692933A (ja) * 1992-09-17 1994-04-05 Taiho Yakuhin Kogyo Kk オリゴ−ｎ−メチルピロールカルボキサミド誘導体又はその塩
JPH0827146A (ja) * 1994-07-15 1996-01-30 Mitsui Toatsu Chem Inc ２，６−ジ置換インドール誘導体
WO2003000683A1 (fr) * 2001-06-25 2003-01-03 Japan Science And Technology Agency Procede de synthese en phase solide de polyamides de pyrrole-imidazole
JP2004517830A (ja) * 2000-11-28 2004-06-17 フアルマシア・イタリア・エツセ・ピー・アー ジスタマイシン誘導体の調製方法
JP2006509027A (ja) * 2002-12-10 2006-03-16 オーシェント ファーマシューティカルズ コーポレーション （ピロールカルボキサミド）−（ベンズアミド）−（イミダゾールカルボキサミド）モチーフを有する抗菌化合物
US20070265240A1 (en) * 2003-10-07 2007-11-15 University Of Western Sydney Sequence Selective Pyrrole and Imidazole Polyamide Metallocomplexes

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JPH0692933A (ja) * 1992-09-17 1994-04-05 Taiho Yakuhin Kogyo Kk オリゴ−ｎ−メチルピロールカルボキサミド誘導体又はその塩
JPH0827146A (ja) * 1994-07-15 1996-01-30 Mitsui Toatsu Chem Inc ２，６−ジ置換インドール誘導体
JP2004517830A (ja) * 2000-11-28 2004-06-17 フアルマシア・イタリア・エツセ・ピー・アー ジスタマイシン誘導体の調製方法
WO2003000683A1 (fr) * 2001-06-25 2003-01-03 Japan Science And Technology Agency Procede de synthese en phase solide de polyamides de pyrrole-imidazole
JP2006509027A (ja) * 2002-12-10 2006-03-16 オーシェント ファーマシューティカルズ コーポレーション （ピロールカルボキサミド）−（ベンズアミド）−（イミダゾールカルボキサミド）モチーフを有する抗菌化合物
US20070265240A1 (en) * 2003-10-07 2007-11-15 University Of Western Sydney Sequence Selective Pyrrole and Imidazole Polyamide Metallocomplexes

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