WO2017018835A1 - Procédé de préparation de tdm-621 - Google Patents

Procédé de préparation de tdm-621 Download PDF

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Publication number
WO2017018835A1
WO2017018835A1 PCT/KR2016/008306 KR2016008306W WO2017018835A1 WO 2017018835 A1 WO2017018835 A1 WO 2017018835A1 KR 2016008306 W KR2016008306 W KR 2016008306W WO 2017018835 A1 WO2017018835 A1 WO 2017018835A1
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ala
group
asp
arg
formula
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Inventor
Jong Yun Choi
Yeon Gun LEE
Woo Young Jang
Hee Kyoon Yoon
Seung Woo Kim
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Daewoong Pharmaceutical Co Ltd
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Daewoong Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids

Definitions

  • the present invention relates to a method of preparing TDM-621.
  • TDM-621 which is a substance extracted from a snail, has 16 amino acid sequences (Arg-Ala-Asp-Ala-Arg-Ala-Asp-Ala-Arg-Ala-Asp-Ala-Arg-Ala-Asp-Ala-Arg-Ala-Asp-Ala).
  • TDM-621 is a medicine registered in European Medicines Agency (EMEA), as a topical hemostatic agent used in a surgical operation.
  • EMEA European Medicines Agency
  • the solid-phase synthesis method is characterized by completing the synthesis of amino acid sequences by attaching amino acids to a solid supporter and isolating the synthesized amino acid sequences from the support, thereby obtaining desired peptides.
  • the solid-phase synthesis method has advantages such a rapid reaction rate, less by-products, and easy automation.
  • the solid-phase synthesis method is disadvantageous in that a large amount of raw material is required upon peptide synthesis, synthesis difficulty increases with increasing sequence length, related substances increase, and synthesis time and the amount of a used raw material exponentially increase.
  • the solution-phase synthesis method as a common organic synthesis method, has advantages such as less expensive reagents and materials, but also disadvantages such as many reaction steps and added complexity.
  • the solution-phase synthesis method is employed, intermediates should be released according to each step and isomers may be generated during a synthesis step, whereby there are difficulties in purification.
  • TDM-621 is also prepared by the solid-phase synthesis method.
  • sequence length is long as in TDM-621, synthesis difficulty increases, and related substances, which have the same structure as that of TDM-621 and, accordingly, difficulties upon isolation thereof, are massively generated, thus having great difficulties in purification.
  • the present invention is directed to a method of preparing TDM-621 in high-purity and high-yield, to solve the technical problem described above.
  • a method of preparing TDM-621 which is comprise obtaining a peptide represented by Formula VII by coupling reaction of a peptide represented by Formula II below with a peptide represented by Formula VI below with a solution-phase synthesis method and deprotecting the obtained peptide:
  • R 1 is hydrogen or a protective group for an amine
  • R 2 is hydrogen or a protective group for a guanidine
  • R 3 is hydrogen or a protective group for a hydroxyl group
  • R 4 is hydrogen or a protective group for a hydroxyl group
  • R 5 is hydrogen or a protective group for an amine.
  • the present invention it is able to prepare the TDM-621 in high purity and high yield in a relatively simple way by solving conventional problems according to the solid-phase synthesis method.
  • the new method for preparing TDM-621 according to the present invention has an advantage for commercial mass production.
  • FIG. 1 illustrates NMR data of a peptide represented by Formula II as an intermediate prepared according to an example below;
  • FIG. 2 illustrates mass data of a peptide represented by Formula II as an intermediate prepared according to an example below;
  • FIG. 3 illustrates NMR data of a peptide represented by Formula VI as an intermediate prepared according to an example below;
  • FIG. 4 illustrates mass data of a peptide represented by Formula VI as an intermediate prepared according to an example below;
  • FIG. 5 illustrates NMR data of TDM-621 prepared according to an example below.
  • FIG. 6 illustrates mass data of TDM-621 prepared according to an example below.
  • the present inventors have conducted research into methods for solving conventional problems of a solid-phase synthesis method used upon preparation of TDM-621. As a result, they confirmed that, by using solid-phase and solution-phase synthesis methods, high-purity TDM-621 can be prepared in a high yield, thus completing the present invention.
  • novel intermediates are prepared by using solid-phase and solution-phase synthesis methods and a final product TDM-621 are prepared by reacting the intermediates via solution-phase synthesis method
  • R types as functional groups and protecting groups (protective groups) used in the present specification are as follows:
  • R 1 Hydrogen, or amine protecting group (protective group for amine)
  • R 2 Hydrogen or guanidine protecting group (protective group for guanidine)
  • R 3 Hydrogen, or hydroxyl protecting group (protective group for hydroxyl group)
  • R 4 Hydrogen, or hydroxyl protecting group (protective group for hydroxyl group)
  • R 5 Hydrogen, or amine protecting group (protective group for amine)
  • a peptide represented by Formula I below may be prepared using a solid-phase synthesis method commonly used in the art (Merrifield, R. B., J. Am. Chem. Soc. , 85:2149-2154(1963), Kaiser, E., Colescot, R. L., Bossinger, C. D., Cook, P. I., Anal. Biochem., 34:595-598(1970)).
  • a peptide of desired sequences may be synthesized by binding a resin with an amino acid having a protected amino group and then removing the protective group for the amino group, followed by synthesizing amino acids having a protected amino group.
  • the resin may be a general resin that can be easily decomposed under an acidic condition which is mild enough such that a protective group for a side chain of the prepared peptide having the sequence can be conserved.
  • protecting groups for amino acids or protecting groups for side chain functional groups When protecting groups for amino acids or protecting groups for side chain functional groups are selected, a condition, under which the protecting group is exposed during reaction, and functional groups in a molecule should be considered.
  • Each of the protecting groups and the functional groups of the molecules should be stable under a condition and in the presence of reagents, which are selected to remove different protecting groups thereof, and deprotection should not occur in coupling reaction.
  • the protecting groups and the functional groups should be stable under a condition and in the presence of reagents, which are used to isolate the synthesized sequences from a resin after synthesis of desired sequences.
  • a peptide represented by Formula II may be obtained by removing a resin from a peptide obtained in Step (1) under a mild acidic condition.
  • the acidic condition should be mild enough such that side-chain-protecting groups of the amino acid sequences can be conserved.
  • the resin may be removed in the presence of a mixture including an organic solvent and an acid under a mild acidic condition.
  • the acid and the organic solvent may be an acid and an organic solvent commonly used in the art.
  • the acid may include various acetic acids (such as dichloroacetic acid, aminooxyacetic acid, and trifluoroacetic acid, etc.), hydrochloric acids, nitric acids, sulfuric acids, and the like.
  • the organic solvent may be dichloromethane, dichloroethane, tetrahydrofuran, ethyl acetate, methanol, and ethanol, etc.
  • a peptide which is represented by Formula III below and to which a resin is attached may be synthesized using a solid-phase synthesis method as in Step (1):
  • a peptide represented by Formula IV below may be synthesized by removing the resin from the peptide represented by Formula III as in Step (2):
  • a peptide represented by Formula V may be prepared by using a solution-phase synthesis method.
  • the peptide represented by Formula V may be synthesized by reacting a peptide represented by Formula IV, which is obtained according to Step (4), with H-Ala-NHR 5 using a coupling agent:
  • the coupling reaction may be carried out at -5 to 45°C in the presence of a coupling agent and an organic solvent.
  • the coupling reaction may be additionally carried out in the presence of a base.
  • a peptide including seven amino acid sequences (peptide represented by Formula IV) is prepared via a solid-phase synthesis method. Then, via a solution-phase synthesis method Ala having NHR 5 as a C-terminal is introduced into the prepared peptide, and the peptide represented by Formula V including eight amino acid sequences is synthesized.
  • a peptide represented by Formula VI may be synthesized by deprotecting the peptide represented by Formula V, which is obtained according to Step (5), i.e., by removing an N-terminal protecting group:
  • the deprotection may be carried out in the presence of a common base, particularly an organic base.
  • the base may be, without being limited to, one or more selected from the group consisting of piperidine, N,N'-diisopropylethylamine (DIPEA) and 1,8-diazabicycloundec-7-ene (DBU).
  • DIPEA N,N'-diisopropylethylamine
  • DBU 1,8-diazabicycloundec-7-ene
  • the base may be piperidine and DIPEA, preferably piperidine.
  • a peptide represented by Formula VII may be synthesized using a solution-phase synthesis method as in Step (5).
  • the peptide represented by Formula VII may be synthesized by binding between Intermediate I obtained according to Step (2) and Intermediate II obtained according to Step (6) via coupling reaction:
  • the coupling may be carried out at -5 to 45 °C, in the presence of a coupling agent and an organic solvent.
  • the coupling may be additionally carried out in the presence of a base.
  • TDM-621 may be synthesized by deprotecting the peptide obtained according to Step (7) under a reaction condition which is commonly used in the art.
  • the deprotection may be carried out in the presence of a mixture including an acid and a stabilizer.
  • the acid may be a commonly used organic acid or inorganic acid, without specific limitation. Examples of the acid include various acetic acid (such as dichloroacetic acid, aminooxyacetic acid, and trifluoroacetic acid, etc.), hydrochloric acid, nitric acid, and sulfuric acid, and the like.
  • the stabilizer may be a commonly used stabilizer, without specific limitation. Examples of the stabilizer include water, thioanisole, triisopropylene, phenol, ethanedithiol, or a mixture of two or more thereof, and the like.
  • the deprotection may be carried out in the presence of a mixture of trifluoroacetic acid, water, phenol, thioanisole, and ethanedithiol; a mixture of trifluoroacetic acid, triisopropylsilane, and water; or a mixture of trifluoroacetic acid, triisopropylsilane, water, and ethanedithiol.
  • the deprotection may be carried out in the presence of a mixture of trifluoroacetic acid, triisopropylsilane, and water.
  • the present invention provides a method including obtaining a peptide represented by Formula VII by coupling reaction of a peptide represented by Formula II below with a peptide represented by Formula VI below via solution-phase synthesis and deprotecting the obtained peptide:
  • R 1 is hydrogen or a protective group for an amine
  • R 2 is hydrogen or a protective group for a guanidine
  • R 3 is hydrogen or a protective group for a hydroxyl group
  • R 4 is hydrogen or a protective group for a hydroxyl group
  • R 5 is hydrogen or a protective group for an amine.
  • a peptide represented by Formula II may be obtained by preparing a peptide, to which a resin is attached, represented by Formula I below, via a solid-phase synthesis method, and removing the resin:
  • R 1 is hydrogen or a protective group for an amine
  • R 2 is hydrogen or a protective group for a guanidine
  • R 3 is hydrogen or a protective group for a hydroxyl group.
  • deprotection may be carried out, for example, in the presence of a mixture including an acid and a stabilizer.
  • the acid may be a commonly used organic acid, inorganic acid, etc., without specific limitation.
  • Examples of the acid include various acids, such as acetic acid, dichloroacetic acid, aminooxyacetic acid, trifluoroacetic acid, hydrochloric acid, nitric acid, sulfuric acid, and the like.
  • the stabilizer may a commonly used stabilizer, without specific limitation. Examples of the stabilizer include water, thioanisole, triisopropylene, phenol, ethanedithiol, a mixture of two or more thereof, and the like.
  • the deprotection may carried out in the presence of a mixture of trifluoroacetic acid, water, phenol, thioanisole, and ethanedithiol; a mixture of trifluoroacetic acid, triisopropylsilane, and water; or a mixture of trifluoroacetic acid, triisopropylsilane, water, and ethanedithiol.
  • the deprotection may be carried out in the presence of a mixture of trifluoroacetic acid, triisopropylsilane, and water.
  • the peptide represented by Formula VI may be obtained by a method comprising:
  • R 1 is hydrogen or a protective group for an amine
  • R 2 is hydrogen or a protective group for a guanidine
  • R 3 is hydrogen or a protective group for a hydroxyl group
  • R 4 is hydrogen or a protective group for a hydroxyl group
  • R 5 is hydrogen or a protective group for an amine.
  • deprotection may be carried out in the presence of a base.
  • the base may be a common base, particularly an organic base.
  • the organic base may be, without being limited to, one or more selected from the group consisting of piperidine, N,N'-diisopropylethylamine (DIPEA), and 1,8-diazabicycloundec-7-ene (DBU).
  • DIPEA N,N'-diisopropylethylamine
  • DBU 1,8-diazabicycloundec-7-ene
  • the organic base may be piperidine and DIPEA, preferably piperidine.
  • R 1 may be, without being limited to, one or more selected from the group consisting of hydrogen, a carboxybenzyl group, a benzyloxy carbamate group, a t-butyl carbamate group, an acetyl group, a benzyl group, a p-methoxy phenyl group, a benzylamine group, a trifluoroacetamide group, a formamide group and a methyl carbamate group.
  • R 2 may be, without being limited to, one or more selected from the group consisting of a t-butoxycarbonyl group, a benzyloxycarbonyl group, a methoxymethyl group, a benzyloxymethyl group, a triphenylmethyl group, a benzyl group, an allyl group, a t-butyldimethylsilyl group, a triphenylsilyl group, a triisopropylsilyl group, a nitro group, a 2,2,5,7,8-pentamethylchromene-6-sulfonyl group, a 4-methoxy-2,3,6-trimethyl benzene sulfonyl group, a 2,2,4,6,7-pentamethyl-dihydrobenzofuran-5-sulfonyl group, and a toluene sulfonyl group.
  • R 2 may be a t-butoxycarbonyl group, a benzy
  • R 3 to R 5 may each be independently one or more selected from the group consisting of a C 1 to C 8 alkyl group including a t-butyl group, a methyl group, an ethyl group and the like, a trimethylsilyl ether group, a triethylsilyl ether group, a triisopropylsilyl ether group, a t-butyldiphenylsilyl ether group, an acetate group, a benzyl ether group, a benzoate group, a 4-methoxybenzyl ether group, a 2-naphthylmethyl ether group, a methoxymethyl acetal group, a 2-methoxyethoxy methylether group, an ethoxyethyl acetal group, a methoxypropyl acetal group, and a benzyloxymethyl acetal group.
  • a C 1 to C 8 alkyl group including a t-but
  • the resin may be, without being limited to, a trityl chloride resin, a 2-chlorotrityl resin, a 4-methyltrityl resin, or a 4-methoxytrityl resin.
  • the resin may be a trityl chloride resin or 2-chlorotrityl resin, particularly 2-chlorotrityl resin.
  • the resin may be removed under a mild acidic condition.
  • the resin may be removed in the presence of a mixture including an organic solvent and an acid.
  • An organic solvent and an acid used to remove the resin are not specifically limited and may be a commonly used organic acid, inorganic acid, or organic solvent.
  • the acid may be, without being limited to, one or more selected from the group consisting of, for example, various acids, such as acetic acid, dichloroacetic acid, aminooxyacetic acid, and trifluoroacetic acid, hydrochloric acid, nitric acid, sulfuric acid, and the like.
  • the organic solvent may be, without being limited to, one or more selected from the group consisting of dichloromethane, dichloroethane, tetrahydrofuran, ethyl acetate, methanol, ethanol, and the like.
  • the resin may be removed in the presence of the organic solvent including the acid in an amount of 0.1 to 100 % by volume, 0.5 to 80 % by volume, 0.5 to 50 % by volume, 0.5 to 30 % by volume, 0.5 to 20 % by volume, 0.5 to 15 % by volume, or 0.5 to 10 % by volume. Under these conditions, the removal of the resin may be easily carried out while conserving the side-chain protecting groups of the amino acid sequences.
  • the coupling may be carried out in the presence of an organic solvent and a coupling agent. As needed, the coupling may be carried out under a condition in which a base is additionally included.
  • the organic solvent may be one or more selected from the group consisting of dimethylsulfoxide (DMSO), N-methylformamide (NMP), N-methylpyrrolidone, dimethylacetamide, dimethylformamide (DMF), dichloromethane, dichloroethane, and chloroform.
  • DMSO dimethylsulfoxide
  • NMP N-methylformamide
  • DMF dimethylformamide
  • dichloromethane dichloroethane
  • chloroform chloroform
  • the organic solvent may be one or more selected from the group consisting of DMSO, NMP, DMF, and dimethylacetamide (DMAC).
  • the organic solvent may be DMF or DMSO, particularly DMF.
  • the coupling agent may be one or more selected from the group consisting of N,N'-dicyclohexyl carbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP), benzotriazol-1-yl-oxy-tris-(pyrrolidino)-phosphonium hexafluorophosphate (PyBOP), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa
  • the base may be one or more selected from the group consisting of diisopropylethylamine, triethylamine, piperidine, pyrrolidine, pyridine, N-methylmorpholin (NMM), and collidine.
  • the base may be DIPEA or collidine, preferably DIPEA.
  • the coupling may be carried out at -5 to 45°C, or 0 to 25°C.
  • TDM-621 can be easily, economically prepared by combining a solid-phase synthesis method with a solution-phase synthesis method.
  • high-purity TDM-621 can be produced and thus easy isolation and purification thereof are possible. Accordingly, the combined method is suitable for mass production of TDM-621.
  • the present invention provides a method of preparing a peptide represented by Formula II below:
  • R 1 is hydrogen or a protective group for an amine
  • R 2 is hydrogen or a protective group for a guanidine
  • R 3 is hydrogen or a protective group for a hydroxyl group
  • R 4 is hydrogen or a protective group for a hydroxyl group.
  • the present invention also provides a method of preparing a peptide represented by Formula II below, the method comprising: preparing a peptide, to which a resin is attached, which is represented by Formula I below via a solid-phase synthesis method, and removing the resin:
  • R 1 is hydrogen or a protective group for an amine
  • R 2 is hydrogen or a protective group for a guanidine
  • R 3 is hydrogen or a protective group for a hydroxyl group
  • R 4 is hydrogen or a protective group for a hydroxyl group.
  • the present invention also provides a peptide represented by Formula VI below:
  • R 2 is hydrogen or a protective group for a guanidine
  • R 3 is hydrogen or a protective group for a hydroxyl group
  • R 5 is hydrogen or a protective group for an amine.
  • the present invention also provides a method of preparing a peptide represented by Formula VI below, the method comprising:
  • R 1 is hydrogen or a protective group for an amine
  • R 2 is hydrogen or a protective group for a guanidine
  • R 3 is hydrogen or a protective group for a hydroxyl group
  • R 4 is hydrogen or a protective group for a hydroxyl group
  • R 5 is hydrogen or a protective group for an amine.
  • solid/solid refers to (weight/weight) %
  • solid/liquid refers to (weight/volume) %
  • liquid/liquid refers to (volume/volume) %, unless specified otherwise.
  • dichloromethane 100 ml including 9-fluorenyloxycarbonyl-Ala-OH (11.58 g, 37.2 mmol, 3.0 equivalents, GLBiochem Ltd.) was added, and then diisopropylethylamine (12.96 ml, 74.4 mmol, 6.0 equivalents, DAEJUNG CHEMICALS & METALS CO., LTD.) was added thereto, then, the same were allowed to react at room temperature for two hours.
  • N,N-dimethylformamide 100 ml including 9-fluorenyloxycarbonyl-Asp(tBu)-OH (10.2 g, 24.8 mmol, 2 equivalents, GL Biochem Ltd.), 1-hydroxybenzotriazol (3.35 g, 24.8 mmol, 2 equivalents, GL Biochem Ltd.), and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU, 9.41 g, 24.8 mmol, 2 equivalents, GL Biochem Ltd.) was added, and then diisopropylethylamine (8.64 ml, 49.6 mmol, 4 equivalents, DAEJUNG CHEMICALS & METALS CO., LTD.) was added thereto, then, the same were allowed to react at room temperature for one hour.
  • a resultant product was subjected to vacuum filtration to remove a reaction solution, and the resin was washed with 100 ml of N,N-dimethylformamide three times and 100 ml of dichloromethane three times, thereby obtaining a 9-fluorenyloxycarbonyl-Asp(tBu)-Ala-2-chlorotrityl resin.
  • 9-fluorenyloxycarbonyl-Ala-OH (9.65 g, 31.0 mmol, 2.5 equivalents, GL Biochem Ltd.), 1-hydroxybenzotriazol (4.19 g, 31.0 mmol, 2.5 equivalents, GL Biochem Ltd.), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU, 9.41 g, 31.0 mmol, 2.5 equivalents, GL Biochem Ltd.), and diisopropylethylamine (10.8 ml, 62.0 mmol, 5 equivalents, DAEJUNG CHEMICALS & METALS CO., LTD.) were reacted for one hour.
  • a resultant product was subjected to vacuum filtration to remove a reaction solution, and the resin was washed with 100 ml of N,N-dimethylformamide three times and 100 ml of dichloromethane three times, thereby obtaining an Ac-Arg(Pbf)-Ala-Asp(tBu)-Ala-Arg(Pbf)-Ala-Asp(tBu)-Ala-2-chlorotrityl resin.
  • NMR data and mass data of an obtained peptide were investigated and illustrated in FIG. 1 (NMR data) and FIG. 2 (mass data).
  • dichloromethane 100 ml including 9-fluorenyloxycarbonyl-Asp(tBu)-OH (15.3g, 37.2 mmol, 3.0 equivalents, GLBiochem Ltd.) was added, and then diisopropylethylamine (12.96 ml, 74.4 mmol, 6.0 equivalents, DAEJUNG CHEMICALS & METALS CO., LTD.) was added thereto, then, the same were allowed to react at room temperature for two hours.
  • methanol 10 ml, 10% dichloromethane, DAEJUNG CHEMICALS & METALS CO., LTD.
  • methanol 10 ml, 10% dichloromethane, DAEJUNG CHEMICALS & METALS CO., LTD.
  • a resultant product was subjected to vacuum filtration to remove a reaction solution.
  • the resin was washed with dichloromethane three times and N,N-dimethylformamide three times, thereby obtaining a 9-fluorenyloxycarbonyl-Asp(tBu)-2-chlorotrityl resin.
  • N,N-dimethylformamide 100 ml including 9-fluorenyloxycarbonyl-Ala-OH (9.65 g, 31.0 mmol, 2.5 equivalents, GL Biochem Ltd.), 1-hydroxybenzotriazol (4.19 g, 31.0 mmol, 2.5 equivalents, GL Biochem Ltd.), and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU, 11.76g, 31.0 mmol, 2.5 equivalents, GL Biochem Ltd.) was added, and then diisopropylethylamine (8.64 ml, 62.0 mmol, 5 equivalents, DAEJUNG CHEMICALS & METALS CO., LTD.) was added thereto, then, the same were allowed to react at room temperature for one hour.
  • a resultant product was subjected to vacuum filtration to remove a reaction solution, and the resin was washed with 100 ml of N,N-dimethylformamide three times and 100 ml of dichloromethane three times, thereby obtaining a 9-fluorenyloxycarbonyl-Ala-Asp(tBu)-2-chlorotrityl resin.
  • L-alaninamide hydrochloride (H-Ala-NH 2 ⁇ HCl, 2.78g, 22.34 mmol, 2.0 equivalents, GL Biochem Ltd.) was dissolved in 180 ml of N,N-dimethylformamide and then fed into a reactor.
  • NMR data and mass data of an obtained peptide were investigated and illustrated in FIG. 3 (NMR data) and FIG. 4 (mass data).
  • Example 1-6 The peptide (9.72 g, 6.65 mmol) obtained in Example 1-6 was added to N,N-dimethylformamide (200 ml) and dissolved therein, followed by sequentially adding the peptide (10 g, 6.65 mmol, 1 equivalent) obtained in Example 1-2, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU, 2.78 g, 7.32 mmol, 1.1 equivalents, GL Biochem Ltd.), and 1-hydroxybenzotriazol (0.99 g, 73.2 mmol, 1.1 equivalents) thereto and dissolving therein.
  • HBTU 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate
  • NMR data and mass data of the obtained TDM-621 were investigated and illustrated in FIG. 5 (NMR data) and FIG. 6 (mass data).
  • TDM-621 problems of a conventional solid-phase synthesis method were addressed, and thus, high-purity and high-yield TDM-621 was able to be produced in a relatively simple method. Accordingly, a novel method of preparing TDM-621 according to the present invention is advantageous in commercially, mass producing TDM-621.

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Abstract

L'invention concerne un procédé de préparation de TDM-621. Selon la présente invention, les problèmes classiques d'un procédé de synthèse en phase solide peuvent être résolus et on peut ainsi préparer, au moyen d'un procédé relativement simple, du TDM-621 à haut rendement et de grande pureté. De ce fait, un nouveau procédé de préparation de TDM-621 selon la présente invention est approprié et avantageux pour produire du TDM-621 en très grande quantité et de manière commerciale.
PCT/KR2016/008306 2015-07-30 2016-07-28 Procédé de préparation de tdm-621 Ceased WO2017018835A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023222057A1 (fr) * 2022-05-19 2023-11-23 江苏奥赛康药业有限公司 Procédé de préparation de peptide rada16 à auto-assemblage au moyen d'une synthèse convergente en phase solide

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5602231A (en) * 1991-06-14 1997-02-11 Zeneca Limited Process for making peptides
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