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WO2016200210A1 - Dérivés de triphénylméthane présentant une solubilité sélective, et leur utilisation - Google Patents

Dérivés de triphénylméthane présentant une solubilité sélective, et leur utilisation Download PDF

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Publication number
WO2016200210A1
WO2016200210A1 PCT/KR2016/006194 KR2016006194W WO2016200210A1 WO 2016200210 A1 WO2016200210 A1 WO 2016200210A1 KR 2016006194 W KR2016006194 W KR 2016006194W WO 2016200210 A1 WO2016200210 A1 WO 2016200210A1
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mmol
peptide
equiv
added
solution
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Korean (ko)
Inventor
김재일
전용국
김대영
홍매화
박소영
윤현목
김종민
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Anygen Co Ltd
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Anygen Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C47/00—Compounds having —CHO groups
    • C07C47/38—Unsaturated compounds having —CHO groups bound to carbon atoms of rings other than six—membered aromatic rings
    • C07C47/42—Unsaturated compounds having —CHO groups bound to carbon atoms of rings other than six—membered aromatic rings with a six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C47/00—Compounds having —CHO groups
    • C07C47/52—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/782—Ketones containing a keto group bound to a six-membered aromatic ring polycyclic
    • C07C49/784—Ketones containing a keto group bound to a six-membered aromatic ring polycyclic with all keto groups bound to a non-condensed ring
    • C07C49/786—Benzophenone

Definitions

  • the present invention relates to triphenylmethane derivatives having selective solubility and uses thereof.
  • the usual methods include atmospheric pressure or reduced pressure distillation and crystallization. Atmospheric or vacuum distillation, however, is limited to materials having relatively low molecular weights and relatively low boiling points.
  • a multi-step reaction is used to obtain the target compound. In each step, a crystallization method is usually used. However, due to different properties and physical properties of each compound, it is difficult to purify by the same crystallization method, and a crystallization method corresponding to each compound is required.
  • the desired compound is sent in a special phase and other impurities are sent in another phase to separate.
  • the method is a quick and simple method, but the extraction method should be studied according to the properties and properties of each compound.
  • U.S. Patent Application Publication No. 2009299103 and U.S. Patent Application Publication No. 2010029904 have reported by Japanese researchers how to prepare and isolate a compound or peptide using a hydrophobic tag having a benzene ring backbone.
  • the tag since the tag has a three-dimensionally small structure, the binding between the tag and the compound or peptide is not stable and may be unstable and may be separated during the reaction.
  • the method has a disadvantage in that the peptide synthesis yield is low (whole crude yield 48% when synthesizing 3 mer peptides) and commercially available.
  • US Patent Application Publication No. 20140213761 reported a method for preparing and isolating a compound or peptide using a hydrophobic tag having a diphenylmethane backbone by Japanese researchers. However, the method is limited to peptide synthesis with C-terminal carboxyamide bonds.
  • Chemical methods for synthesizing peptides generally include solution-phase synthesis and solid-phase synthesis.
  • Liquid phase synthesis method has the advantage of low cost of reagents and materials as a conventional organic synthesis method, but has a disadvantage that the purification is difficult because the number of reaction steps, the intermediate should be advantageous for each step, and isomers may occur.
  • Solid phase synthesis methods liberate sequences from solid supports after completion of assembly by sequentially binding amino acid or 2-mer peptide fragments to a solid support. This method has the advantages of fast synthesis rate, low by-products, and easy automation, but it requires the use of excess raw material and implies the possibility of generation of deletion peptide impurities due to incomplete reaction. There is a problem that makes it difficult to attach the pieces to the solid support.
  • the present inventors have tried to develop a compound having a property of reversibly changing from a liquid state to a solid state according to a change in solution composition.
  • the present invention is completed by synthesizing the compound of Formula I and confirming that the novel compound has very excellent applicability in peptide and compound synthesis, separation process, and removal of impurities (e.g., deletion of a defective peptide in peptide synthesis). It was.
  • Another object of the present invention is to provide a method for separating or preparing a target compound or target peptide using a novel triphenylmethane derivative.
  • Still another object of the present invention is to provide a method for removing a deleted peptide in the synthesis of a desired peptide.
  • the invention provides triphenylmethane derivatives represented by the following formula (I):
  • A is a reactive active site comprising at least one atom of carbon, oxygen, sulfur, nitrogen and halogen atoms;
  • R 1 to R 15 are the same or different and are hydrogen, C 1-50 alkyl, C 3-10 cycloalkyl, C 1-50 alkoxy, C 6-30 aryl, C 6-30 aralkyl or C 6-30 alka Reel; At least one of R 1 to R 15 is C 12-50 alkyl or C 12-50 alkoxy.
  • the present inventors have tried to develop a compound having a property of reversibly changing from a liquid state to a solid state according to a change in solution composition. As a result, it was confirmed that the compound of formula I was synthesized, and this novel compound has very excellent applicability in peptide and compound synthesis, separation process, and removal of impurities (eg, deletion of a defective peptide in peptide synthesis).
  • A is a reactive active site including at least one atom among carbon, oxygen, sulfur, nitrogen, and halogen atoms, and may include several homogenous atoms.
  • A is a halogen group, hydroxyl group, sulfonyl group, thiol group, amino group, nitro group, carboxyl Groups, carbonate groups, carbamate groups or chloroformate groups, and the like, preferably halogen groups, hydroxyl groups, amino groups, Carboxyl group, carbonate group (e.g., p -nitrophenyl carbonate group), carbamate group, or chloroformate group.
  • halo refers to a halogen group element, including, for example, fluoro, chloro, bromo and iodo, specifically chloro.
  • R 1 to R 15 are the same or different and are hydrogen, C 1-50 alkyl, C 3-10 cycloalkyl, C 1-50 alkoxy, C 6-30 aryl, C 6-30 aralkyl or C 6-30 alkaryl; At least one of R 1 to R 15 is C 12-50 alkyl or C 12-50 alkoxy.
  • alkyl refers to a straight or branched, unsubstituted or substituted saturated hydrocarbon group.
  • C 1 -50 alkyl having a carbon number in the case where means an alkyl group that has an alkyl unit having a carbon number of 1 to 50, and the C 1-50 alkyl substituted with a substituent is not included.
  • cycloalkyl refers to a cyclic hydrocarbon radical, which includes cyclopropyl, cyclobutyl and cyclopentyl.
  • C 3 -10 cycloalkyl means a carbon number of 3-10 cycloalkyl, to form a ring structure and a carbon number in the case where the C 3-10 cycloalkyl substituted with a substituent is not included.
  • alkoxy means an —Oalkyl group.
  • aryl refers to a substituted or unsubstituted monocyclic or polycyclic carbon ring which is wholly or partially unsaturated.
  • C 6 -30 aryl group is not included in the carbon number of the substituent when the aryl group means a group having a carbon ring atom of a carbon number of 6 to 30, C 6-30 aryl is optionally substituted.
  • aryl is monoaryl or biaryl. It is preferable that monoaryl has 5-6 carbon atoms, and it is preferable that biaryl has 9-10 carbon atoms.
  • aralkyl refers to an alkyl group substituted with an aryl group.
  • C 6 -30 aralkyl group is not included in the carbon number of a substituent when the mean aralkyl having the aralkyl unit containing 6 to 30 carbon atoms, and, C 6-30 aralkyl are substituted.
  • alkaryl refers to an aryl group substituted with an alkyl group.
  • C 6 -30 alkaryl will not include the carbon number of a substituent when the mean alkaryl having an alkaryl unit containing 6 to 30 carbon atoms, and the C 6-30 alkaryl substituted.
  • any one of R 1 to R 5 is C 12-50 alkyl or C 12-50 alkoxy
  • any one of R 6 to R 10 is C 12-50 alkyl or C 12-50 alkoxy or Either R 11 to R 15 is C 12-50 alkyl or C 12-50 alkoxy.
  • C 12-50 alkyl or C 12-50 alkoxy is selected from R 3 , And may be located at R 8 and / or R 13 . More specifically, C 12-50 alkyl or C 12-50 alkoxy may be located at R 3 and R 8 .
  • the C 12-50 alkyl or C 12-50 alkoxy is C 12-40 alkyl or C 12-40 alkoxy, even more specifically C 12-30 alkyl or C 12-30 alkoxy, even more specifically C 12-20 alkyl or C 12-20 alkoxy, even more specifically C 12-18 alkyl or C 12-18 alkoxy, most specifically C 12-16 alkyl or C 12-16 alkoxy (eg C 12 Alkyl or C 12 alkoxy, C 14 alkyl or C 14 alkoxy, or C 16 alkyl or C 16 alkoxy).
  • the present invention provides a method for separating or preparing a target compound or peptide of interest comprising the following steps:
  • step (c) separating the target compound or target peptide tagged with the triphenylmethane derivative from the result of step (b);
  • the tag and the compound (or peptide) coupling reaction proceeds in the liquid phase, and after completion of the reaction is coupled to the tag from the reaction mixture by a change in solvent composition
  • the desired compound or target peptide can be easily isolated and also simply liberated in the tag to obtain the target compound or target peptide with high purity.
  • the triphenylmethane derivative as the tag is bonded to the functional group of the target compound or the target peptide through A of Formula I, wherein the bond is an amide bond, ester bond, ether bond, sulfide ( sulfide) bonds, amine bonds, urea bonds, carbonate bonds or carbamate bonds, specifically ether bonds, ester bonds, amine bonds or carbamate bonds, more specifically ester bonds , Amine bonds and carbamate bonds.
  • the step (a) is dichloromethane (dichloromethane), 1,2-dichloroethane (1,2-dichloroethane), chloroform (chloroform), N, N- dimethylformamide (N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidinone, tetrahydrofuran, dioxane, ethyl acetate ), Acetone or a mixed solvent thereof.
  • the chemical reaction temperature of the tag and the compound bond reaction or the tag and the compound represented by the formula (I) is not limited, but is preferably -80 to 150 ° C, more preferably 0 to 100 ° C. More preferably, it is 0-60 degreeC.
  • Solvents used to change the solvent composition are alcohols having 1-3 carbon atoms (eg, methanol and ethanol), acetonitrile, water (H 2 O), or a mixed solvent thereof.
  • step (a) is a triphenylmethane derivative-starter having a starting material covalently bonded to A, which is a reactive active site of the triphenylmethane derivative, and the triphenylmethane derivative-starter and a reactant. It is carried out using.
  • the final target compound or peptide may be obtained through several steps of chemical reaction in the state where the tag and the starting material (compound or amino acid) are combined. .
  • the chemical reaction in each stage proceeds in the liquid phase, and after completion of the reaction, the desired compound or peptide bound to the tag is easily separated from the reaction mixture by the change of solvent composition, and also after the completion of the last stage reaction, it is simply advantageous in the tag to obtain high purity.
  • the desired compound or peptide can be obtained.
  • each step of the chemical reaction may proceed to the next step without the separation process.
  • the reaction that releases the target compound or the target peptide bound to the tag represented by the formula (I) from the tag is not limited to acidic conditions, basic conditions, reduction reactions, hydrogen reactions, etc., but preferably in the presence of a solution showing acidity Conduct.
  • step (a) binds an amino acid or a peptide comprising 2-20 amino acid residues to the reactive active site A of the triphenylmethane derivative, followed by the amino acid linked to the reactive active site A. Or by continuously binding additional amino acids or peptides to the peptide.
  • the peptide fragment consisting of amino acids or two or more amino acids are sequentially linked to the tag to complete the assembly of the desired peptide.
  • the reaction of each stage proceeds in the liquid phase, and after completion of each stage reaction, the peptide composition bound to the tag from the reaction mixture is easily separated by filtration by changing the solvent composition, and after completion of the final stage reaction, simply tag It is advantageous in that the desired peptide can be obtained with high purity.
  • the bond of the tag represented by the formula (I) and the peptide fragment consisting of amino acids or two or more amino acids may be an ester bond, an amide bond, an ether bond, an amine bond, or a carbonate. ) Bonds, carbamate bonds, and the like, preferably ester bonds, amide bonds, carbamate bonds, and the like.
  • Solvents used in the coupling reaction for attaching the peptide fragment consisting of two or more amino acids to the tag represented by the formula (I) include dichloromethane, 1,2-dichloroethane, chloroform ( chloroform), N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidinone, tetrahydrofuran ), Dioxane, ethyl acetate, acetone, and the like, or one or more solvents selected from the group consisting of dichloromethane, tetrahydrofurane, N, N-dimethylformamide, N-methylpyrrolidinone or a mixed solvent thereof.
  • the binding reaction temperature for binding the peptide fragment consisting of amino acids or two or more amino acids to the tag represented by the formula (I) is not limited, but is preferably -50 to 100 ° C, more preferably 0 to 60 ° C, More preferably, it is 0-40 degreeC.
  • the solvent used to change the solvent composition after the completion of the coupling reaction for attaching the peptide fragment consisting of amino acids or two or more amino acids to the tag represented by the formula (I) includes alcohols having 1-3 carbon atoms (eg, methanol and ethanol), acetonitrile (acetonitrile), water (H 2 O), or a mixed solvent thereof.
  • the target peptide bound to the tag After the completion of the binding reaction to attach the peptide fragment consisting of amino acids or two or more amino acids to the tag represented by the formula (I), the target peptide bound to the tag from the reaction mixture by reducing the volume of the solvent used in the reaction to change the solvent composition It can also be easily removed.
  • the present invention provides a method for removing a deleted peptide in the synthesis of a desired peptide comprising the following steps:
  • step (a) synthesizing a target peptide comprising reactions that sequentially attach an N-protected amino acid to a solid support;
  • the result of step (a) is a mixture comprising the target peptide and a deletion peptide of the target peptide;
  • Said step (a) comprises acetylating the N-terminus of the peptide bound to said solid support after each of said reactions or after some steps of said reactions;
  • the acetylation reaction acetylates the N-terminus of the deleted peptide;
  • step (b) contacting the triphenylmethane derivative of any one of claims 1 to 5 as a tag (i-1) with the product of step (a);
  • the target peptide binds to the reactive active site A of the triphenylmethane derivative;
  • (i-2) applying the result of step (i-1) to the solid support removal process;
  • (ii-1) applying the result of step (a) to the solid support removal process;
  • the target peptide binds to the reactive active site A of the triphenylmethane derivative;
  • step (d) removing the deleted peptide from the product of step (c).
  • impurities are small molecule impurities produced in the deprotection reaction of the missing peptide and side chain protecting groups due to incomplete solid phase reaction. Impurities of small molecules generated in the deprotection reaction of the latter side chain protecting group are removed during peptide crystallization, but deletion peptide impurities due to incomplete reaction are difficult to remove during crystallization because they have similar physical properties to the target peptide. The proximity to the desired peptide peak makes the purification difficult. Therefore, it greatly affects the decrease in final synthesis yield and purity.
  • the present invention provides a new method for removing defective peptide impurities generated in solid phase peptide synthesis using a tag represented by the above formula (I) having a property of reversibly changing from a liquid state to a solid state in accordance with a change in solution composition.
  • the tag and the peptide bond is made of an amine bond, carbamate bond, etc., preferably carbamate ) Combined.
  • the solvent used in the tag and peptide binding reaction is dichloromethane, 1,2-dichloroethane (1,2-dchloroethane), chloroform (chloroform), N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidinone, tetrahydrofuran ( one or more solvents selected from the group consisting of tetrahydrofurane, dioxane, ethyl acetate, acetone, and the like, preferably dichloromethane, tetrahydrofurane, N, N -Dimethylformamide (N, N-dimethylformamide), N-methylpyrrolidinone alone or a mixed solvent thereof.
  • the tag and peptide bond reaction temperature is not limited, but preferably -50 ⁇ 100 °C, more preferably 0 ⁇ 60 °C, More preferably, it is 0-40 degreeC.
  • the solvent used to change the solvent composition after the tag and peptide binding reaction is completed, the alcohol having 1-3 carbon atoms (for example, methanol and ethanol), acet Nitrile (acetonitrile), water (H 2 O) or a mixed solvent thereof.
  • the target compound bound to the tag from the reaction mixture through a solvent composition change after reducing the volume of the solvent used in the reaction Can be easily removed.
  • the reaction that liberates the peptide bound to the tag from the tag is not limited to acidic conditions, hydrogen reactions, etc., but preferably a solution that exhibits acidity. Is carried out in the presence of, and more preferably, in a solution containing 0.1-95% of trifluoroacetic acid.
  • the present invention provides a new method for preparing and separating compounds and peptides using the tag represented by the above formula (I), which has a property of reversibly changing from a liquid state to a solid state according to a change in solution composition.
  • the present invention also uses a tag represented by the above formula (I), which has a property of reversibly changing from a liquid state to a solid state in accordance with a change in solution composition, to remove defective peptide impurities generated in solid phase peptide synthesis. Provides a new way to remove
  • the present invention has the advantage that the separation and purification of the synthesized compound or peptide is easy, commercial mass production is possible.
  • the present invention exhibits a very economical effect in terms of production cost since it is possible not only to use an inexpensive tag but also to recover and reuse the tag.
  • Trp tryptophan
  • EDCHCl N- (3-dimethylaminopropyl) -ene-ethylcarbodiimide hydrochloride N- (3-Dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride
  • % used to indicate the concentration of a particular substance is% solids / solids (w / w, weight / weight) and solids / liquids (w / v , Weight / volume)%, and liquid / liquid is (v / v, volume / volume)%.
  • Phenylbis (4-tetradecyloxyphenyl) methanol (3.43 g, 5 mmol) was dissolved in dichloromethane (90 mL, large purified gold), acetyl chloride (10 mL, Aldrich) was added at room temperature, and then 12 Stirred for time. The reaction mixture was then reduced to 1/3 by volume under reduced pressure, followed by crystallization by addition of acetonitrile (100 mL) to phenylbis (4-tetradecyloxyphenyl) methyl chloride (Compound 4). 3.16 g (yield 90%) were obtained.
  • Phenylbis (4-tetradecyloxyphenyl) methanol (3.43 g, 5 mmol) and 4-nitrophenylchloroformate (4-nitrophenylchloroformate) (1.26 g, 6.25 mmol, 1.25 equiv., Aldrich) were added to dichloromethane (100 mL). It melt
  • NH 4 Cl 10% ammonium chloride
  • Phenylbis (4-tetradecyloxyphenyl) methyl chloride (Compound 4) (1.4 g, 2 mmol) and Fmoc-Leu-OH (1.06 g, 3 mmol, 1.5 equiv., GL Biochem Ltd.) were diluted with dichloromethane (20 mL ), And then N, N-diisopropylethylamine (1.05 mL, 6 mmol, 3 equiv., Aldrich) was added thereto, followed by stirring at room temperature for 3 hours. The reaction solution was reduced to 1/3 volume by distillation under reduced pressure, and then acetonitrile (30 mL) was added to crystallize.
  • the obtained solid was subjected to a Fmoc removal reaction for 20 minutes with a 5% diethylamine / dichloromethane solution (20 mL). After distilling under reduced pressure to reduce the volume of the solution by 1/3, acetonitrile (30 mL) was added to crystallize. The obtained solid was dissolved in dichloromethane (15 mL), and then acetonitrile (45 mL) was added and recrystallized to obtain Crude H-Leu-phenylbis (4-tetradecyloxyphenyl) methane.
  • the organic layer was reduced to 1/3 volume by distillation under reduced pressure, and then acetonitrile (30 mL) was added to crystallize.
  • the obtained solid was subjected to Fmoc removal reaction with 5% diethylamine / dichloromethane solution (20 mL) for 1 hour. After distilling under reduced pressure to reduce the volume of the solution by 1/3, acetonitrile (30 mL) was added to crystallize.
  • the obtained solid was dissolved in dichloromethane (15 mL), and then acetonitrile (45 mL) was added and recrystallized to obtain crude H-Phe-Leu-phenylbis (4-tetradecyloxyphenyl) methane.
  • the obtained solid was subjected to a Fmoc removal reaction for 20 minutes with a 5% diethylamine / dichloromethane solution (20 mL). After distilling under reduced pressure to reduce the volume of the solution by 1/3, acetonitrile (30 mL) was added to crystallize. The obtained solid was dissolved in dichloromethane (15 mL) and acetonitrile (45 mL) was added and recrystallized to obtain Crude H-Leu-4-methoxyphenylbis (4-tetradecyloxyphenyl) methane.
  • the organic layer was reduced to 1/3 volume by distillation under reduced pressure, and then acetonitrile (30 mL) was added to crystallize.
  • the obtained solid was subjected to Fmoc removal reaction with 5% diethylamine / dichloromethane solution (20 mL) for 1 hour. After distilling under reduced pressure to reduce the volume of the solution by 1/3, acetonitrile (30 mL) was added to crystallize.
  • the obtained solid was dissolved in dichloromethane (15 mL), acetonitrile (45 mL) was added and recrystallized to obtain Crude H-Phe-Leu-4-methoxyphenylbis (4-tetradecyloxyphenyl) methane.
  • Chlorophenylbis (4-tetradecyloxyphenyl) methane (Compound 4) (0.7 g, 1 mmol) and Fmoc-Ala-Phe-Leu-OH (0.86 g, 1.5 mmol, 1.5 equiv.) Were converted to dichloromethane (10 mL). It was dissolved in and then N, N-diisopropylethylamine (0.52 mL, 3.0 mmol, 3.0 equiv) was added, followed by stirring at room temperature for 2 hours. The reaction solution was reduced to 1/3 volume by dark distillation, and then acetonitrile (15 mL) was added to crystallize.
  • the obtained solid was subjected to a Fmoc removal reaction with a 5% diethylamine / dichloromethane solution (10 mL) for 1 hour. The solution was reduced to 1/3 by distillation under reduced pressure, and then acetonitrile (15 mL) was added to crystallize. The obtained solid was dissolved in dichloromethane (10 mL) and acetonitrile (30 mL) was added and recrystallized to obtain crude H-Ala-Phe-Leu-phenylbis (4-tetradecyloxyphenyl) methane.
  • the organic layer was reduced to 1/3 volume by distillation under reduced pressure, and then acetonitrile (15 mL) was added to crystallize.
  • the obtained solid was subjected to a Fmoc removal reaction with a 5% diethylamine / dichloromethane solution (10 mL) for 1 hour. The solution was reduced to 1/3 by distillation under reduced pressure, and then acetonitrile (15 mL) was added to crystallize.
  • the obtained solid was dissolved in dichloromethane (5 mL), and then acetonitrile (20 mL) was added to recrystallize the crude H-Ala-Phe-Leu-Ala-Phe-Leu-phenylbis (4-tetradecyloxyphenyl) methane. Got it.
  • dichloromethane 60 mL, large purified gold
  • reaction product was filtered under reduced pressure to remove the reaction solution, and the resin was washed twice with N, N-dimethylformamide to obtain 9-fluorenyloxycarbonyl-Asn (Trt) -Phe-2-chlorotrityl resin. .
  • the acetyl capping reaction was further performed after the coupling reaction as described above.
  • reaction was carried out at room temperature for 4 hours.
  • the reaction product was filtered under reduced pressure to remove the reaction solution, and the resin was washed twice with N, N-dimethylformamide, followed by acetic anhydride (3.78 mL, 40 mmol, 20 equivalents, Aldrich) and N, N -N, N-dimethylformamide solution (24 mL) containing diisopropylethylamine (10.4 mL, 60 mmol, 30 equiv) was added, followed by reaction at room temperature for 30 minutes.
  • the peptide represented by Formula IV obtained above is dissolved in 1% trifluoroacetic acid / dichloromethane solution (25 mL) and stirred for 30 hours.
  • the distillation under reduced pressure reduced the volume of solvent to 1/3, and added acetonitrile (30 mL) to crystallize.
  • the solid was removed by filtration, the filtrate was concentrated to 5 mL by distillation under reduced pressure, and ethyl ether (30 mL) was added to crystallize to obtain the peptide represented by the formula (III) in a solid state.
  • Phenylbis (4-tetradecyloxyphenyl) methyl chloride (Compound 4) (1.4 g, 2 mmol) and Fmoc-Ser (tBu) -OH (1.15 g, 3 mmol, 1.5 equiv., GL Biochem Ltd.) It was dissolved in (20 mL), and then N, N-diisopropylethylamine (1.05 mL, 6 mmol, 3 equivalents, Aldrich) was added thereto, followed by stirring at room temperature for 3 hours. The reaction solution was reduced to 1/3 volume by distillation under reduced pressure, and then acetonitrile (30 mL) was added to crystallize.
  • the obtained solid was subjected to a Fmoc removal reaction for 20 minutes with a 5% diethylamine / dichloromethane solution (20 mL). After distilling under reduced pressure to reduce the volume of the solution by 1/3, acetonitrile (30 mL) was added to crystallize. The obtained solid was dissolved in dichloromethane (15 mL), and then acetonitrile (45 mL) was added and recrystallized to obtain H-Ser (tBu) -phenylbis (4-tetradecyloxyphenyl) methane.
  • Phenylbis (4-tetradecyloxyphenyl) methyl chloride (Compound 4) (1.4 g, 2 mmol) and Fmoc-Arg (Pbf) -OH (1.95 g, 3 mmol, 1.5 equiv., GL Biochem Ltd.) It was dissolved in (20 mL), and then N, N-diisopropylethylamine (1.05 mL, 6 mmol, 3 equivalents, Aldrich) was added thereto, followed by stirring at room temperature for 3 hours. The reaction solution was reduced to 1/3 volume by distillation under reduced pressure, and then acetonitrile (30 mL) was added to crystallize.
  • the obtained solid was subjected to a Fmoc removal reaction for 20 minutes with a 5% diethylamine / dichloromethane solution (20 mL). After distilling under reduced pressure to reduce the volume of the solution by 1/3, acetonitrile (30 mL) was added to crystallize. The obtained solid was dissolved in dichloromethane (15 mL), and then acetonitrile (45 mL) was added and recrystallized to obtain H-Arg (Pbf) -phenylbis (4-tetradecyloxyphenyl) methane.
  • the obtained solid was subjected to a Fmoc removal reaction for 20 minutes with a 5% diethylamine / dichloromethane solution (20 mL). After distilling under reduced pressure to reduce the volume of the solution by 1/3, acetonitrile (30 mL) was added to crystallize. The obtained solid was dissolved in dichloromethane (15 mL), and then acetonitrile (45 mL) was added and recrystallized to obtain crude H-Leu-bis (4-tetradecyloxyphenyl) methane.
  • the organic layer was reduced to 1/3 volume by distillation under reduced pressure, and then acetonitrile (30 mL) was added to crystallize.
  • the obtained solid was subjected to Fmoc removal reaction with 5% diethylamine / dichloromethane solution (20 mL) for 1 hour. After distilling under reduced pressure to reduce the volume of the solution by 1/3, acetonitrile (30 mL) was added to crystallize.
  • the obtained solid was dissolved in dichloromethane (15 mL), and then acetonitrile (45 mL) was added and recrystallized to obtain crude H-Phe-Leu-bis (4-tetradecyloxyphenyl) methane.
  • Example 14 Comparative Example, it was found that the crude yield is reduced by 10% or more than the example according to the present invention.
  • Phenylbis (4-dodecyloxyphenyl) methanol (3.15 g, 5 mmol) was dissolved in dichloromethane (90 mL, large purified gold), acetyl chloride (10 mL, Aldrich) was added at room temperature, and then 12 Stirred for time. Subsequently, the reaction mixture was reduced to 1/3 by volume under reduced pressure, and then acetonitrile (100 mL) was added to crystallize to obtain phenylbis (4-dodecyloxyphenyl) methyl chloride (Compound 13). 2.65 g (yield 82%) were obtained.
  • Phenylbis (4-dodecyloxyphenyl) methyl chloride (Compound 13) (1.29 g, 2 mmol) and Fmoc-Leu-OH (1.06 g, 3 mmol, 1.5 equiv., GL Biochem Ltd.) were diluted with dichloromethane (20 mL ), And then N, N-diisopropylethylamine (1.05 mL, 6 mmol, 3 equivalents, Aldrich) was added thereto, followed by stirring at room temperature for 3 hours. The reaction solution was reduced to 1/3 volume by distillation under reduced pressure, and then acetonitrile (30 mL) was added to crystallize.
  • the obtained solid was subjected to a Fmoc removal reaction for 20 minutes with a 5% diethylamine / dichloromethane solution (20 mL). After distilling under reduced pressure to reduce the volume of the solution by 1/3, acetonitrile (30 mL) was added to crystallize. The obtained solid was dissolved in dichloromethane (15 mL), and then acetonitrile (45 mL) was added thereto, followed by recrystallization to obtain crude H-Leu-phenylbis (4-dodecyloxyphenyl) methane.
  • the organic layer was reduced to 1/3 volume by distillation under reduced pressure, and then acetonitrile (30 mL) was added to crystallize.
  • the obtained solid was subjected to Fmoc removal reaction with 5% diethylamine / dichloromethane solution (20 mL) for 1 hour. After distilling under reduced pressure to reduce the volume of the solution by 1/3, acetonitrile (30 mL) was added to crystallize.
  • the obtained solid was dissolved in dichloromethane (15 mL), acetonitrile (45 mL) was added and recrystallized to obtain crude H-Phe-Leu-phenylbis (4-dodecyloxyphenyl) methane.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Peptides Or Proteins (AREA)

Abstract

La présente invention concerne des dérivés de triphénylméthane représentés par la formule chimique (I), et leur utilisation. La présente invention a pour effet de permettre une séparation aisée et la purification de composés ou de peptides préparés, présentant ainsi l'avantage de permettre une production industrielle à grande échelle. En outre, la présente invention utilise des étiquettes bon marché pouvant être récupérées et réutilisées, et a pour effet d'être vraiment économique en termes de coût de production.
PCT/KR2016/006194 2015-06-12 2016-06-10 Dérivés de triphénylméthane présentant une solubilité sélective, et leur utilisation Ceased WO2016200210A1 (fr)

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KR20150083477 2015-06-12

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Cited By (1)

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CN114409564A (zh) * 2022-01-24 2022-04-29 广州同隽医药科技有限公司 一种含三苯甲基结构的化合物及其应用

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WO1998047910A1 (fr) * 1997-04-21 1998-10-29 Proligo Llc Synthese d'oligonucleotides en solution
US5874532A (en) * 1997-01-08 1999-02-23 Nexstar Pharmaceuticals, Inc. Method for solution phase synthesis of oligonucleotides and peptides
US20040116685A1 (en) * 1995-10-19 2004-06-17 Proligo Llc Method for solution phase synthesis of oligonucleotides
US20090299103A1 (en) * 2006-03-24 2009-12-03 National University Corporation, Tokyo University Reagent for Organic Synthesis and Method of Organic Synthesis Reaction with the Reagent
US20100029904A1 (en) * 2005-09-20 2010-02-04 Kazuhiro Chiba Carrier for Separation, Method for Separation of Compound, and Method for Synthesis of Peptide Using the Carrier

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040116685A1 (en) * 1995-10-19 2004-06-17 Proligo Llc Method for solution phase synthesis of oligonucleotides
US5874532A (en) * 1997-01-08 1999-02-23 Nexstar Pharmaceuticals, Inc. Method for solution phase synthesis of oligonucleotides and peptides
WO1998047910A1 (fr) * 1997-04-21 1998-10-29 Proligo Llc Synthese d'oligonucleotides en solution
US20100029904A1 (en) * 2005-09-20 2010-02-04 Kazuhiro Chiba Carrier for Separation, Method for Separation of Compound, and Method for Synthesis of Peptide Using the Carrier
US20090299103A1 (en) * 2006-03-24 2009-12-03 National University Corporation, Tokyo University Reagent for Organic Synthesis and Method of Organic Synthesis Reaction with the Reagent

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114409564A (zh) * 2022-01-24 2022-04-29 广州同隽医药科技有限公司 一种含三苯甲基结构的化合物及其应用
CN114409564B (zh) * 2022-01-24 2024-04-26 广州同隽医药科技有限公司 一种含三苯甲基结构的化合物及其应用

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KR20160147235A (ko) 2016-12-22
KR101889893B1 (ko) 2018-08-22

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