WO2015033781A1 - 二置換アミノ酸残基を含むジペプチド誘導体の製造方法 - Google Patents
二置換アミノ酸残基を含むジペプチド誘導体の製造方法 Download PDFInfo
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- 0 C[C@](C[C@](C(O)=O)N*)** Chemical compound C[C@](C[C@](C(O)=O)N*)** 0.000 description 4
- AERCCJGORROTKW-QMMMGPOBSA-N C[C@](CCCC=C)(C(O)=O)N Chemical compound C[C@](CCCC=C)(C(O)=O)N AERCCJGORROTKW-QMMMGPOBSA-N 0.000 description 1
- MXECDVKIKUSSNC-JTQLQIEISA-N C[C@](Cc(cccc1)c1F)(C(O)=O)N Chemical compound C[C@](Cc(cccc1)c1F)(C(O)=O)N MXECDVKIKUSSNC-JTQLQIEISA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B51/00—Introduction of protecting groups or activating groups, not provided for in the preceding groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/02—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length in solution
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
- C07K5/06043—Leu-amino acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/0606—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing heteroatoms not provided for by C07K5/06086 - C07K5/06139, e.g. Ser, Met, Cys, Thr
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06086—Dipeptides with the first amino acid being basic
- C07K5/06095—Arg-amino acid
Definitions
- the present invention relates to a method for producing a dipeptide derivative containing a disubstituted amino acid residue.
- Peptide is a compound formed by condensation of amino acids and expresses a wide variety of functions in vivo, and is expected to be used as a medicine. Peptide drugs are expected to exhibit various new and superior functions by examining new amino acid sequences or introducing unnatural amino acids, but they are rapidly degraded by various enzymes in the body. It has the problem that it is done. On the other hand, it has been found that by introducing a disubstituted amino acid in which the ⁇ -carbon atom is substituted with two substituents into a peptide, stability to peptidase in vivo can be enhanced.
- a peptide is bonded to a carboxyl group of an amino acid whose amino group is protected, and then the amino group is deprotected and the amino group is protected.
- the obtained peptide is obtained by repeating the binding of the next amino acid, and the obtained peptide is finally cut out from the resin.
- dipeptide derivatives in which the N-terminal amino group is protected are exclusively used in the presence of a condensing agent between an amino acid whose amino group is protected and an amino acid whose carboxyl group is ester-protected. And then deesterifying the ester protecting group of the carboxyl group (see, for example, Patent Documents 1 and 2 above).
- the above synthesis method is reliable but has a large number of steps, and when a side chain of each constituent amino acid has a protecting group, deesterification of the ester protecting group may be difficult depending on the type of the protecting group. there is a possibility.
- the present invention has been made in view of the circumstances as described above, and has a smaller number of steps than conventional dipeptide production methods, and the desired dipeptide derivative regardless of the type of protecting group on the side chain of each constituent amino acid. It is an object of the present invention to provide a method for producing a dipeptide derivative that can be obtained with good yield.
- the present inventors have surprisingly been concerned about the use of unprotected amino acids in which the carboxyl group is not ester-protected as a raw material, as long as they are disubstituted amino acids.
- the present inventors have found that the desired dipeptide derivative can be obtained with good yield in one step without causing the random peptide binding reaction, and the present invention has been completed.
- the present invention relates to a method for producing a dipeptide having a protected N-terminus represented by the following formula (1) or a salt thereof,
- X represents an amino-protecting group
- R 1 represents a side chain of an ⁇ -monosubstituted amino acid or a hydrogen atom, and the side chain may be protected
- R 2 represents a group that combines with R 1 to form the side chain, or a hydrogen atom
- Ra 2 and Rb 2 each independently represents an alkyl group which may have a substituent, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent or a substituent.
- An aralkyl group which may be present.
- the number of steps is smaller than that of the conventional method for producing a dipeptide, and the desired dipeptide derivative is obtained in a yield regardless of the type of protecting group on the side chain of each constituent amino acid. It becomes possible to obtain well.
- an N-terminal protected ⁇ -monosubstituted amino acid or glycine represented by the formula (2) or a salt thereof and a disubstituted amino acid represented by the formula (3) or a salt thereof are combined in a stoichiometric amount.
- the condensation is preferably carried out in the presence of a stoichiometric amount or more of a condensing agent. By allowing the condensing agent to exist in a stoichiometric amount or more, the condensation reaction can proceed more efficiently.
- the N-terminus was protected when the reaction rate of the ⁇ -monosubstituted amino acid or glycine protected at the N-terminus represented by formula (2) reached 70-80%. It is preferable to terminate the reaction of ⁇ -monosubstituted amino acid or glycine or a salt thereof with a disubstituted amino acid or a salt thereof. As a result, it is possible to prevent further condensation of amino acids with the carboxyl group of the target dipeptide derivative, so that the desired dipeptide derivative can be obtained with higher yield.
- a dipeptide derivative capable of obtaining a desired dipeptide derivative in good yield can be obtained regardless of the type of side chain protecting group of each constituent amino acid, as compared with the conventional dipeptide production method.
- a manufacturing method can be provided.
- amino acid may be represented by three letters or one letter. That is, for example, alanine is Ala or A, arginine is Arg or R, asparagine is Asn or N, aspartic acid is Asp or D, cysteine is Cys or C, glutamic acid is Glu or E, glutamine is Gln or Q, glycine is Gly Or G, histidine is His or H, isoleucine is Ile or I, leucine is Leu or L, lysine is Lys or K, methionine is Met or M, phenylalanine is Phe or F, proline is Pro or P, serine is Ser or S Threonine may be expressed as Thr or T, tryptophan as Trp or W, tyrosine as Tyr or Y, and valine as Val or V.
- alanine is Ala or A
- arginine is Arg or R
- asparagine Asn or N
- aspartic acid Asp or D
- the method for producing the N-terminal protected dipeptide represented by the following formula (1) or a salt thereof [In the formula (1), X represents an amino-protecting group, R 1 represents a side chain of an ⁇ -monosubstituted amino acid or a hydrogen atom, and the side chain may be protected, R 2 represents a group that combines with R 1 to form the side chain, or a hydrogen atom, Ra 2 and Rb 2 each independently represents an alkyl group which may have a substituent, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent or a substituent. An aralkyl group which may be present.
- the condensing agent usually refers to a chemical reagent in chemical synthesis, which takes a molecule of water from a substrate to give a condensate, which is different from a biocatalyst such as an enzyme used in a fermentation method or the like.
- Biocatalysts have a high substrate specificity, and it is necessary to use a catalyst suitable for each target peptide.
- a non-natural amino acid such as a disubstituted amino acid is used as a substrate, it is usually difficult to find a suitable biocatalyst. Have difficulty.
- the condensing agent used in this embodiment can be used without particular limitation as long as it is a condensing agent generally used in chemical synthesis reactions and known to those skilled in the art.
- the condensing agent include HBTU (2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium) hexafluorophosphate, DCC (dicyclohexylcarbodiimide), EDC (1-ethyl). It may be at least one selected from the group consisting of (-3- (3-dimethylaminopropyl) carbodiimide).
- HBTU is particularly preferable.
- the condensing agent is preferably present in a stoichiometric amount or more. That is, in this embodiment, the dehydration condensation of the ⁇ -monosubstituted amino acid or glycine protected at the N-terminus represented by the formula (2) or a salt thereof with the disubstituted amino acid represented by the formula (3) or a salt thereof It is preferable that a condensing agent equivalent to or more than water generated by the reaction is present. As a result, the condensation reaction can proceed more efficiently.
- X represents an amino-protecting group.
- amino-protecting group amino-protecting groups known to those skilled in the art can be employed without any particular limitation.
- Amino protecting groups include, for example, Fmoc (9-fluorenylmethoxycarbonyl), Z (benzyloxycarbonyl), Alloc (allyloxycarbonyl), Troc (2,2,2-trichloroethoxycarbonyl), Boc (t It may be at least one selected from the group consisting of carbamates such as -butyloxycarbonyl) and amides such as Ac (acetyl) and Bz (benzoyl). Among these, Fmoc is particularly preferable.
- R 1 is a side chain of an optionally protected ⁇ -monosubstituted amino acid or a hydrogen atom Represents.
- the ⁇ -monosubstituted amino acid can be adopted regardless of whether it is natural or non-natural, and may be either D-form or L-form.
- Examples of such side chains of ⁇ -monosubstituted amino acids are Me, which is the side chain of Ala, —CH 2 CH 2 CH 2 NHC ( ⁇ NH) NH 2 , which is the side chain of Arg, and Asn.
- —CH (OH) CH 3 which is a side chain of Thr
- —CH 2 CH 2 CH 2 NHC ( ⁇ NH) NH 2 which is a side chain of Arg
- —CH 2 CH (CH) which is a side chain of Leu 3)
- -CH 2 Ph is the side chain of Phe
- -CH 2 CH 2 SH is the side chain of homocysteine
- the side chain of ⁇ -monosubstituted amino acid may be protected.
- the protecting group for protecting the side chain is not particularly limited, and can be appropriately selected from those used as a general side chain protecting group. Examples of the protecting group include Pbf (2,2,4,6,7-pentamethyl-2,2-dihydrobenzofuran-5-sulfonyl) which is a protecting group for guanidyl group, t-butyl which is a protecting group for hydroxyl group, and thiol.
- trityl which is a protective group for groups
- Fmoc, Z, Troc, Ac, Bz and Boc which are protective groups for amino groups
- benzyl which is a protective group for indolyl groups.
- R 2 represents a group that forms a side chain by binding to R 1 or a hydrogen atom.
- R 1 When bonded to R 1 to form a side chain, the carbon atom adjacent to R 1 and the nitrogen atom adjacent to R 2 together form a cyclic group.
- a cyclic group is a nitrogen-containing cyclic group.
- the structure is not particularly limited as long as it has a structure. For example, a 5- to 15-membered monocyclic, bicyclic or tricyclic ring can be formed, and even a saturated ring may be a partially unsaturated ring. There may be. Further, the ring may optionally have a substituent. Examples of the cyclic group as described above include pyrrolidine and piperidine.
- N-terminal protected ⁇ -monosubstituted amino acid or glycine represented by the above formula (2) may optionally be used as a salt.
- N-terminal protected ⁇ -monosubstituted amino acids or salts of glycine include sodium salt, potassium salt, lithium salt, calcium salt, magnesium salt, dicyclohexylamine (DCHA) salt and the like.
- Ra 2 and Rb 2 each independently have an alkyl group which may have a substituent, or a substituent.
- the alkyl group, alkenyl group and alkynyl group can each have a linear or branched structure having, for example, 1 to 14 carbon atoms (preferably 1 to 8 carbon atoms).
- halo nitro
- optionally protected hydroxy optionally protected mercapto
- optionally halo-substituted alkoxy optionally substituted phenyl
- aryl such as carboxy or ester thereof, amino optionally substituted or protected, heteroaryl such as indole optionally substituted or protected, and the like.
- Ra 2 and Rb 2 is more preferably methyl.
- a monosubstituted amino acid is substituted with a peptide containing a disubstituted amino acid in which either Ra 2 or Rb 2 is methyl, for example, the effect of improving the stability is obtained while maintaining the action of the peptide as a medicine. Is often particularly easy.
- the disubstituted amino acid represented by the above formula (3) can also be used as a salt.
- salts of disubstituted amino acids include sodium salt, potassium salt, lithium salt, calcium salt, magnesium salt, dicyclohexylamine (DCHA) salt, hydrochloride, sulfate, nitrate, perchlorate, hydrobromide Etc.
- the raw material is charged with an ⁇ -monosubstituted amino acid or glycine protected at the N-terminus represented by formula (2) or a salt thereof and a disubstituted amino acid represented by formula (3) or a salt thereof.
- the ratio is not particularly limited, and can be appropriately experimentally changed by those skilled in the art in consideration of the physical properties of each raw material compound to be used and the ease of removal when the excess is removed after completion of the condensation reaction. It is.
- di-substituted amino acid represented by the formula (3) when used in excess of the theoretical equivalent with respect to the ⁇ -monosubstituted amino acid or glycine protected at the N-terminus represented by the formula (2), as a surplus after completion of the reaction, Existing disubstituted amino acids of formula (3) can be removed using techniques common to those skilled in the art.
- the time for condensing the raw material ⁇ -monosubstituted amino acid or glycine protected at the N-terminus represented by formula (2) with the disubstituted amino acid represented by formula (3) is It is preferable to control the amount of each of the formulas (1), (2), and (3) that change with the progress of the condensation reaction while monitoring.
- the condensation reaction time varies depending on the type of raw materials used, various reaction conditions, and the like. However, if the condensation time is short, the dipeptide represented by formula (1) is not sufficiently produced and the yield decreases. The carboxyl group in the dipeptide represented by (1) further reacts, resulting in a decrease in the yield of the desired dipeptide represented by formula (1). From this point of view, in this embodiment, when the reaction rate of the ⁇ -monosubstituted amino acid or glycine having a protected N-terminus represented by formula (2) or a salt thereof reaches 70 to 80%. It is preferable to terminate the reaction.
- the reaction rate indicates the consumption amount of the raw material due to the progress of the reaction as a ratio to the charged amount.
- the solvent used for the condensation reaction is not particularly limited, and a known solvent generally used in the condensation reaction in peptide synthesis can be appropriately selected. Suitable examples of such solvents include THF, DMF, NMP and the like.
- the temperature in the condensation reaction is not particularly limited, and can be appropriately set within a temperature range generally used by those skilled in the art during peptide synthesis. In view of ease of operation, it is preferable to react at room temperature.
- the dipeptide protected at the N-terminus represented by the formula (1) produced by the production method in the present embodiment can be obtained in a highly pure state. Further, in order to further increase the purity of the obtained N-terminal protected dipeptide represented by the formula (1), it may be isolated and purified with high purity by using various methods known to those skilled in the art. .
- N-terminal protected dipeptide represented by the above formula (1) can be obtained as a salt in some cases.
- the method for producing a dipeptide with the N-terminal protected represented by the formula (1) according to the present embodiment can omit the deprotection step of the carboxyl group compared to the conventional method for producing a dipeptide, and thus shorten the production step.
- the target dipeptide represented by the formula (1) in which the N-terminus is protected can be obtained in good yield.
- the dipeptide represented by the formula (1) produced by the method according to this embodiment the N-terminal amino group is protected. Therefore, the dipeptide is suitable for use as a starting dipeptide in the peptide solid phase synthesis method.
- a peptide containing a disubstituted amino acid residue is synthesized by a method generally employed in the peptide solid phase synthesis method, that is, a method in which one amino acid is sequentially bonded, the asymmetric carbon around the disubstituted amino acid residue. Due to the steric hindrance, the reactivity at the N-terminus may be reduced, leading to a decrease in yield.
- the use of the dipeptide protected at the N-terminus represented by the above formula (1) in the peptide solid phase synthesis method can suppress the effect of such steric hindrance, and bind the dipeptide.
- a peptide solid phase synthesis method known to those skilled in the art is used. Can do.
- the resin carrier for solid phase synthesis to be used is not particularly limited, and examples thereof include Rink Amide MBHA resin (100 to 200 mesh).
- Fmoc 9-fluorenylmethoxycarbonyl
- THF tetrahydrofuran
- HBTU 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate
- TEA triethylamine
- MTBE methyl t-butyl ether
- Hcy homocysteine
- Tr Trityl
- NMP N-methylpiperidone
- HOBt 1-hydroxybenzotriazole
- DIPEA diisopropylethylamine
- TFA trifluoroacetic acid
- Pbf 2,2,4,6,7-pentamethyl-2,2-dimethylbenzofuran-5-sulfonyl.
- reaction rate 70% Not detected (reaction rate 70%), 27: 70: 3.2: 0.17: not detected (reaction rate 73%) at 7.9 hours, 24: 68: 7.6: 23 hours It was 0.45: 0.047 (reaction rate 76%).
- the reaction rate was calculated from the ratio of the area of Fmoc-Gly-OH to the total area of Fmoc-Gly-OH, dipeptide, tripeptide, tetrapeptide and pentapeptide.
- the reaction rate was calculated from the ratio of the area of Fmoc-Thr (Ot-Bu) -OH to the total area of Fmoc-Thr (Ot-Bu) -OH, dipeptide, tripeptide, tetrapeptide and pentapeptide. However, the tetrapeptide and pentapeptide peaks were not detected.
- the ratio of the two major isomers of Fmoc-Thr (Ot-Bu) - ⁇ -Me-o-fluoroPhe-OH was 97.3: 2.7 at 22 hours and 97.4: 2.6 at 31 hours. It was.
- a 30 mL reaction vessel is charged with 0.69 g (1.8 mmol) of Fmoc-D-Phe-OH and 0.42 g (2.1 mmol) of (R) - ⁇ - (7-octenyl) Ala-OH. , Suspended in THF (8.4 mL). To this suspension, 0.88 g (2.3 mmol) of HBTU and 0.37 mL (2.7 mmol) of TEA were added, and the mixture was stirred at room temperature for 31 hours.
- reaction rate 29%) 71: 9.5: 12: 7.2 (reaction rate 29%) at 4.1 hours.
- the reaction rate was calculated from the ratio of the area of Fmoc-Gly-OH to the total area of Fmoc-Thr (Ot-Bu) -OH, dipeptide, tripeptide, tetrapeptide and pentapeptide (pentapeptide not detected).
- the ratio of the two main isomers of Fmoc-Thr (Ot-Bu) -o-fluoroPhe-OH was 54:46 at 1.8 hours, 53:47 at 3 hours, and 51:49 at 4.1 hours. It was. Fmoc-Thr (Ot-Bu) -o-fluorPhe-OH; HRMS m / z: 5855.2371 (calculated for C 32 H 35 FN 2 NaO 6 ([M + Na] + )); 5855.2371 (found).
- Example 3 when the condensation reaction was performed using a disubstituted amino acid, the multimer concerned was concerned even though the carboxyl group of the amino acid was not protected. The desired compound could be obtained with good yield. Furthermore, since disubstituted amino acids were used, epimerization did not occur in principle, and the stereoisomer purity of the obtained compound was high.
- H-Leu-Arg- (S) - ⁇ - (4-Pentenyl) Ala-Phe-NH 2 was synthesized.
- the solvent used was NMP
- the condensation conditions were HBTU / HOBt / DIPEA
- de-Fmocation was piperidine
- elimination from the carrier was TFA / water / triisopropylsilane.
- 25% H-Leu- (S) - ⁇ - (4-Pentenyl) Ala-Phe-NH 2 was mixed in the product.
- H-Leu-Leu- (S) - ⁇ - (4-Pentenyl) Ala-Phe-NH 2 was synthesized in the same manner as in Reference Example 1. In addition to the target product, 0.89% of H-Leu- (S) - ⁇ - (4-Pentenyl) Ala-Phe-NH 2 was mixed in the product. H-Leu-Leu- (S) - ⁇ - (4-Pentenyl) Ala-Phe-NH 2 ; HRMS m / z: 530.3701 (calculated value for C 29 H 48 N 5 O 4 ([M + H] + )); 530.3702 (actual value).
- a dipeptide derivative capable of obtaining a desired dipeptide derivative in good yield can be obtained regardless of the type of side chain protecting group of each constituent amino acid, as compared with the conventional dipeptide production method.
- a manufacturing method can be provided.
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Abstract
Description
[式(1)において、Xはアミノ基の保護基を表し、R1は、α-一置換アミノ酸の側鎖、又は水素原子を表し、該側鎖は保護されていてもよく、
R2は、R1と結合して前記側鎖を形成する基、又は水素原子を表し、
Ra2及びRb2は、それぞれ独立に、置換基を有していてもよいアルキル基、置換基を有していてもよいアルケニル基、置換基を有していてもよいアルキニル基又は置換基を有していてもよいアラルキル基を表す。]
下記式(2)で示されるN-末端が保護されたα-一置換アミノ酸若しくはグリシン又はそれらの塩と、
[式(2)において、X、R1及びR2は式(1)におけるX、R1及びR2と同様に定義される。]
下記式(3)で示される二置換アミノ酸又はその塩とを、
[式(3)において、Ra2及びRb2は式(1)におけるRa2及びRb2と同様に定義される。]
縮合剤の存在下で縮合させることを含む、製造方法を提供する。
[式(1)において、Xはアミノ基の保護基を表し、R1は、α-一置換アミノ酸の側鎖、又は水素原子を表し、該側鎖は保護されていてもよく、
R2は、R1と結合して前記側鎖を形成する基、又は水素原子を表し、
Ra2及びRb2は、それぞれ独立に、置換基を有していてもよいアルキル基、置換基を有していてもよいアルケニル基、置換基を有していてもよいアルキニル基又は置換基を有していてもよいアラルキル基を表す。]
下記式(2)で示されるN-末端が保護されたα-一置換アミノ酸若しくはグリシン又はそれらの塩と、
[式(2)において、X、R1及びR2は式(1)におけるX、R1及びR2と同様に定義される。]
下記式(3)で示される二置換アミノ酸又はその塩とを、
[式(3)において、Ra2及びRb2は式(1)におけるRa2及びRb2と同様に定義される。]
縮合剤の存在下で縮合させることを含む。
Fmoc-Gly-OH
Fmoc-Thr(Ot-Bu)-OH
Fmoc-D-Phe-OH
Fmoc-D-Hcy(Tr)-OH
Fmoc-Hcy(Tr)-OH
Fmoc-Arg(Pbf)-OH
Fmoc-Leu-OH
Fmoc-Phe-OH
Ac-(Allyl)Gly-OH
Boc-(Allyl)Gly-OH・DCHA
(S)-α-(4-Pentenyl)Ala-OH
(R)-α-(4-Pentenyl)Ala-OH
(S)-α-(7-Octenyl)Ala-OH
(R)-α-(7-Octenyl)Ala-OH
(S)-α-(Allyl)Ala-OH・H2O
(R)-α-(Allyl)Ala-OH・H2O
(S)-α-(Propargyl)Ala-OH
(R)-α-(Propargyl)Ala-OH
(S)-α-(Ethyl)Ala-OH・H2O
(R)-α-(Ethyl)Ala-OH・H2O
(S)-α-Me-Asp(Ot-Bu)-OH
(R)-α-Me-Asp(Ot-Bu)-OH
(S)-α-Me-Leu-OH
(R)-α-Me-Leu-OH
(S)-α-Me-Phe-OH・H2O
(R)-α-Me-Phe-OH・H2O
(S)-α-Me-Val-OH
(R)-α-Me-Val-OH
(S)-α-Me-o-fluoroPhe-OH
(R)-α-Me-o-fluoroPhe-OH
(S)-α-Me-m-fluoroPhe-OH
(R)-α-Me-m-fluoroPhe-OH
(S)-α-Me-p-fluoroPhe-OH
(R)-α-Me-p-fluoroPhe-OH
(S)-α-Me-2,6-difluoroPhe-OH
(R)-α-Me-2,6-difluoroPhe-OH
(S)-α-Me-p-CF3O-Phe-OH
(R)-α-Me-p-CF3O-Phe-OH
(S)-α-Me-o-bromoPhe-OH・H2O
(R)-α-Me-o-bromoPhe-OH・H2O
(S)-α-Me-m-bromoPhe-OH・H2O
(R)-α-Me-m-bromoPhe-OH・H2O
(S)-α-Me-p-bromoPhe-OH
(R)-α-Me-p-bromoPhe-OH
(S)-α-Me-m-iodoPhe-OH・H2O
(R)-α-Me-m-iodoPhe-OH・H2O
(S)-α-Me-p-iodoPhe-OH
(R)-α-Me-p-iodoPhe-OH
(S)-α-Me-o-nitroPhe-OH・H2O
(R)-α-Me-o-nitroPhe-OH・H2O
(S)-α-Me-m-nitroPhe-OH・H2O
(R)-α-Me-m-nitroPhe-OH・H2O
(S)-α-Me-p-phenylPhe-OH・H2O
Fmoc:9-フルオレニルメトキシカルボニル;
THF:テトラヒドロフラン;
HBTU:ヘキサフルオロリン酸2-(1H-ベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウム;
TEA:トリエチルアミン;
MTBE:メチルt-ブチルエーテル;
Hcy:ホモシステイン;
Tr:トリチル;
NMP:N-メチルピペリドン;
HOBt:1-ヒドロキシベンゾトリアゾール;
DIPEA:ジイソプロピルエチルアミン;
TFA:トリフルオロ酢酸;
Pbf:2,2,4,6,7-ペンタメチル-2,2-ジメチルベンゾフラン-5-スルホニル。
Fmoc-Gly-OH、
Fmoc-Gly-(R)-α-(4-Pentenyl)Ala-OH(ジペプチド)、
Fmoc-Gly-(R)-α-(4-Pentenyl)Ala-(R)-α-(4-Pentenyl)Ala-OH(トリペプチド)、
Fmoc-Gly-(R)-α-(4-Pentenyl)Ala-(R)-α-(4-Pentenyl)Ala-(R)-α-(4-Pentenyl)Ala-OH(テトラペプチド)、
Fmoc-Gly-(R)-α-(4-Pentenyl)Ala-(R)-α-(4-Pentenyl)Ala-(R)-α-(4-Pentenyl)Ala-(R)-α-(4-Pentenyl)Ala-OH(ペンタペプチド)、
のそれぞれに相当するピークの面積比は、4.5時間では31:68:1.5:0.065:未検出(反応率69%)、5.5時間では30:68:2.0:0.091:未検出(反応率70%)、7.9時間では27:70:3.2:0.17:未検出(反応率73%)、23時間では24:68:7.6:0.45:0.047(反応率76%)であった。反応率は、Fmoc-Gly-OH、ジペプチド、トリペプチド、テトラペプチド及びペンタペプチドの合計面積に対するFmoc-Gly-OHの面積の割合から計算した。
Fmoc-Gly-(R)-α-(4-Pentenyl)Ala-OH;
融点:130~133℃(未校正)。
1HNMR(400MHz、CDCl3)δppm:1.2~1.4(m、2H);1.60(s、3H);1.86(dt、J1=12.8Hz、J2=4.7Hz、1H);1.9~2.1(m、2H);2.16(dt、J1=12.8Hz、J2=3.6Hz、1H);3.8~4.0(m、2H);4.21(t、J=7.2Hz、1H);4.39(d、J=7.2Hz、2H);4.9~5.0(m、2H);5.70(dt、J1=12.0Hz、J2=10.0Hz、1H);5.78(br.s、1H);6.87(br.s、1H);7.30(dt、J1=7.5Hz、J2=0.9Hz、2H);7.39(t、J=7.5Hz、2H);7.58(d、J=7.5Hz、2H);7.75(d、J=7.5Hz、2H)。
HRMSm/z:437.2071(C25H29N2O5([M+H]+)に対する計算値);437.2078(実測値)。
Fmoc-Gly-(R)-α-(4-Pentenyl)Ala-(R)-α-(4-Pentenyl)Ala-OH;
HRMSm/z:576.3068(C33H42N3O6([M+H]+)に対する計算値);576.3072(実測値)。
Fmoc-Gly-(R)-α-(4-Pentenyl)Ala-(R)-α-(4-Pentenyl)Ala-(R)-α-(4-Pentenyl)Ala-OH;
HRMSm/z:715.4065(C41H55N4O7([M+H]+)に対する計算値);715.4063(実測値)。
Fmoc-Gly-(R)-α-(4-Pentenyl)Ala-(R)-α-(4-Pentenyl)Ala-(R)-α-(4-Pentenyl)Ala-(R)-α-(4-Pentenyl)Ala-OH;
HRMSm/z:854.5062(C49H67N5O8([M+H]+)に対する計算値);854.5061(実測値)。
融点:61~81℃(未校正)。
HRMSm/z:577.2078(C33H37FN2O6([M+H]+)に対する計算値);577.2710(実測値)。
Fmoc-Thr(Ot-Bu)-OH、
Fmoc-Thr(Ot-Bu)-α-Me-o-FluoroPhe-OH(ジペプチド)、
Fmoc-Thr(Ot-Bu)-α-Me-o-fluoroPhe-α-Me-o-fluoroPhe-OH(トリペプチド)
のそれぞれに相当するピークの面積比は、22時間では23:76:1.7(反応率77%)、31時間では20:78:1.9(反応率80%)であった。反応率は、Fmoc-Thr(Ot-Bu)-OH、ジペプチド、トリペプチド、テトラペプチド及びペンタペプチドの合計面積に対するFmoc-Thr(Ot-Bu)-OHの面積の割合から計算した。ただし、テトラペプチド及びペンタペプチドのピークは未検出であった。
HRMSm/z:756.3455(C43H48F2N3O7([M+H]+)に対する計算値);756.3455(実測値)。
Fmoc-D-Hcy(Tr)-(S)-α-Me-o-fluoroPhe-OHの合成
25mLの反応容器に、0.28g(0.45mmol)のFmoc-D-Hcy(Tr)-OHと、0.11g(0.56mmol)の(S)-α-Me-o-fluoroPhe-OHとを仕込み、THF(2mL)に懸濁させた。この懸濁液に、0.52g(1.4mmol)のHBTUと、0.20mL(1.4mmol)のTEAを加え、室温下で5.8時間撹拌を行った。上水(2.5mL)と、酢酸エチル(3.5mL)を加え、室温下で撹拌後、静置し分液した。有機層を飽和重層水(4mL)、0.5mol/Lの塩酸(2mL)、上水(6mL)の順で洗浄後、減圧下で濃縮した。残渣に酢酸エチル(1.9mL)を加え、分散、静置後、吸引ろ過をした。白色粉末を乾燥させ、0.21gのFmoc-D-Hcy(Tr)-(S)-α-Me-o-fluoroPhe-OHを得た(収率59%)。
1HNMR(400MHz、CDCl3)δppm:1.3~1.6(m、1H);1.46(s、3H);1.6~1.8(m、1H);2.1~2.3(m、2H);3.23(d、J=14.0Hz、1H);3.32(d、J=14.0Hz、1H);4.0~4.2(m、2H);4.17(t、J=6.6Hz、1H);4.34(d、J=6.6Hz、2H);5.29(d、J=8.0Hz、1H);6.49(s、1H);6.9~7.0(m、2H);7.07(t、J=7.0Hz、1H);7.1~7.5(m、20H);7.57(d、J=7.0Hz、2H);7.74(d、J=7.0Hz、2H)。
Fmoc-Hcy(Tr)-(S)-α-Me-o-fluoroPhe-OHの合成
25mLの反応容器に、0.23g(0.42mmol)のFmoc-Hcy(Tr)-OHと、0.11g(0.51mmol)の(S)-α-Me-o-fluoroPhe-OH・H2Oとを仕込み、THF(2mL)に懸濁させた。この懸濁液に、0.52g(1.4mmol)のHBTUと、0.20mL(1.4mmol)のTEAを加え、室温下で3.2時間撹拌を行った。上水(2.5mL)と、酢酸エチル(4.3mL)を加え、室温下で撹拌後、静置し分液した。有機層を飽和重層水(4mL)、0.5mol/Lの塩酸(2mL)、上水(6mL)の順で洗浄後、減圧下で濃縮した。残渣をシリカゲルカラムクロマトグラフィーで精製し、0.11gのFmoc-Hcy(Tr)-(S)-α-Me-o-fluoroPhe-OHを無色油状物質として得た(収率32%)。
1HNMR(400MHz、CDCl3)δppm:1.48(s、3H);1.5~1.7(m、1H);1.7~1.9(m、1H);2.1~2.4(m、2H);3.28(s、2H);4.0~4.1(m、1H);4.1~4.2(m、1H);4.2~4.3(m、1H);4.3~4.4(m、1H);5.25(br.s、1H);6.56(br.s、1H);6.9~7.0(m、2H);7.06(t、J=6.8Hz、1H);7.1~7.5(m、20H);7.54(d、J=7.0Hz、2H);7.73(d、J=7.0Hz、2H)。
1HNMR(400MHz、CDCl3)δppm:0.9~1.0(m、1H);1.0~1.2(m、1H);1.70(t、J=13.3Hz、1H);1.96(dd、J1=13.3Hz、J2=7.0Hz、2H);2.09(t、J=11.0Hz、1H);2.9~3.1(m、1H);3.0~3.2(m、1H);4.18(t、J=6.8Hz、1H);4.2~4.4(m、2H);4.56(br.s、1H);4.8~5.0(m、2H);5.63(d、J=8.0Hz、1H);5.6~5.8(m、1H);6.54(br.s、1H);7.2~7.3(m、5H);7.30(t、J=7.5Hz、2H);7.39(t、J=7.5Hz、2H);7.54(dd、J1=7.5Hz、J2=2.2Hz、2H);7.76(d、J=7.5Hz、2H)。
融点:129~132℃(未校正)。
融点:102~147℃(未校正)。
1HNMR(400MHz、CDCl3)δppm:1.35(br.s、2H);1.42(s、6H);1.51(s、3H);1.6~1.7(m、2H);1.7~1.8(m、1H);1.8~1.9(m、3H);1.9~2.1(m、2H);2.06(s、3H);2.49(s、3H);2.56(s、3H);2.90(s、2H);3.1~3.3(m、2H);4.0~4.2(m、1H);4.2~4.3(m、3H);4.8~5.0(m、2H);5.69(dt、J1=16.8Hz、J2=6.5Hz、1H);6.42、6.70(br.s、3H);7.20(t、J=7.6Hz、2H);7.43(t、J=7.6Hz、2H);7.55(d、J=7.6Hz、2H);7.71(d、J=7.6Hz、2H)。
1HNMR(400MHz、CDCl3)δppm:0.8~1.0(m、6H);1.1~1.3(m、1H);1.2~1.4(m、1H);1.5~1.7(m、3H);1.62(s、3H);1.84(dt、J1=12.8Hz、J2=4.0Hz、1H);1.97(dd、J1=12.8Hz、J2=6.4Hz、2H);2.30(dt、J1=12.8Hz、J2=4.0Hz、1H);4.19(t、J=7.0Hz、2H);4.3~4.5(m、2H);4.48(br.s、1H);4.8~5.0(m、2H);5.5~5.7(m、2H);7.21(br.s、1H);7.30(dt、J1=7.4Hz、J2=0.6Hz、2H);7.39(t、J=7.4Hz、2H);7.57(dd、J1=7.4Hz、J2=2.8Hz、2H);7.75(d、J=7.5Hz、2H)。
1HNMR(400MHz、CDCl3)δppm:0.94(br.s、6H);1.2~1.3(m、1H);1.3~1.4(m、1H);1.5~1.7(m、3H);1.62(s、3H);1.82(dt、J1=13.1Hz、J2=4.4Hz、1H);2.0~2.1(m、2H);2.2~2.4(m、1H);4.20(t、J=7.1Hz、1H);4.3~4.4(m、1H);4.42(dd、J1=10.0Hz、J2=7.1Hz、1H);4.55(br.s、1H);4.9~5.0(m、2H);5.5~5.6(m、1H);5.72(dt、J1=17.0Hz、J2=6.8Hz、1H);7.21(br.s、1H);7.30(t、J=7.5Hz、2H);7.39(t、J=7.5Hz、2H);7.57(d、J=7.5Hz、2H);7.76(d、J=7.5Hz、2H)。
1HNMR(400MHz、CDCl3)δppm:1.0~1.1(m、2H);1.21(br.s、4H);1.32(br.s、2H);1.53(s、3H);1.6~1.8(m、1H);1.9~2.0(m、2H);2.0~2.1(m、1H);3.0~3.1(m、2H);4.15(t、J=7.2Hz、1H);4.2~4.3(m、1H);4.35(dd、J1=10.2Hz、J2=7.2Hz、1H);4.71(br.s、1H);4.8~5.0(m、2H);5.7~5.9(m、2H);6.85(br.s、1H);7.2~7.3(m、5H);7.28(t、J=7.5Hz、2H);7.39(t、J=7.5Hz、2H);7.5~7.6(m、2H);7.75(d、J=7.5Hz、2H)。
Fmoc-Thr(Ot-Bu)-OH、
Fmoc-Thr(Ot-Bu)-o-fluoroPhe-OH(ジペプチド)、
Fmoc-Thr(Ot-Bu)-o-fluoroPhe-o-fluoroPhe-OH(トリペプチド)、
Fmoc-Thr(Ot-Bu)-o-fluoroPhe-o-fluoroPhe-o-fluoroPhe-OH(テトラペプチド)、
のそれぞれに相当するピークの面積比は、1.8時間では72:11:12:5.7(反応率29%)、3時間では72:9.9:13:5.3(反応率28%)、4.1時間では71:9.5:12:7.2(反応率29%)であった。反応率は、Fmoc-Thr(Ot-Bu)-OH、ジペプチド、トリペプチド、テトラペプチド及びペンタペプチドの合計面積に対するFmoc-Gly-OHの面積の割合から計算した(ペンタペプチドは未検出)。
Fmoc-Thr(Ot-Bu)-o-fluoroPhe-OH;
HRMSm/z:585.2371(C32H35FN2NaO6([M+Na]+)に対する計算値);585.2371(実測値)。
Fmoc-Thr(Ot-Bu)-o-fluoroPhe-o-fluoroPhe-OH;
HRMSm/z:728.3142(C41H44F2N3O7([M+H]+)に対する計算値);728.3138(実測値)。
Fmoc-Thr(Ot-Bu)-o-fluoroPhe-o-fluoroPhe-o-fluoroPhe-OH;
HRMSm/z:893.3732(C50H52F3N4O8([M+H]+)に対する計算値);893.3729(実測値)。
H-Leu-Arg-(S)-α-(4-Pentenyl)Ala-Phe-NH2;
HRMSm/z:573.3871(C29H49N8O4([M+H]+)に対する計算値);573.3876(実測値)。
H-Leu-(S)-α-(4-Pentenyl)Ala-Phe-NH2;
HRMSm/z:417.2860(C23H37N4O3([M+H]+)に対する計算値);417.2860(実測値)。
MSデータ
HEMSm/z:573.3871(C29H49N8O4([M+H]+)に対する計算値);573.3874(実測値)。
H-Leu-D-Hcy-(S)-α-Me-o-fluoroPhe-Phe-NH2の合成
参考例1と同様の方法で、H-Leu-D-Hcy-(S)-α-Me-o-fluoroPhe-Phe-NH2を合成した。生成物中には目的物の他に、目的物に対し1.0%のH-Leu-(S)-α-Me-o-fluoroPhe-Phe-NH2及び1.2%のH-(S)-α-Me-o-fluoroPhe-Phe-NH2が混入した。
H-Leu-D-Hcy-(S)-α-Me-o-fluoroPhe-Phe-NH2;
HRMSm/z:574.2858(C29H41FN5O4S([M+H]+)に対する計算値);574.2856(実測値)。
H-Leu-(S)-α-Me-o-fluoroPhe-Phe-NH2;
HRMSm/z:457.2609(C25H34FN4O3([M+H]+)に対する計算値);457.2611(実測値)。
H-(S)-α-Me-o-fluoroPhe-Phe-NH2;
HRMSm/z:344.1769(C19H23FN3O2([M+H]+)に対する計算値);344.1761(実測値)。
H-Leu-D-Hcy-(S)-α-Me-o-fluoroPhe-Phe-NH2の合成
Fmoc-D-Hcy(Tr)-OH、(S)-Fmoc-α-Me-o-fluoroPhe-OHの代わりに実施例4で調製したFmoc-D-Hcy(Tr)-(S)-α-Me-o-fluoroPhe-OHを用いて、参考例3と同様の方法でH-Leu-D-Hcy-(S)-α-Me-o-fluoroPhe-Phe-NH2を合成した。目的物中に、H-Leu-(S)-α-Me-o-fluoroPhe-Phe-NH2及びH-(S)-α-Me-o-fluoroPhe-Phe-NH2の混入はなかった。
HRMSm/z:574.2858(C29H41FN5O4S([M+H]+)に対する計算値);574.2862(実測値)。
H-Leu-Leu-(S)-α-(4-Pentenyl)Ala-Phe-NH2;
HRMSm/z:530.3701(C29H48N5O4([M+H]+)に対する計算値);530.3702(実測値)。
H-Leu-(S)-α-(4-Pentenyl)Ala-Phe-NH2;
HRMSm/z:417.2860(C23H36N4O3([M+H]+)に対する計算値);417.2856(実測値)。
HRMSm/z:530.3701(C29H48N5O4([M+H]+)に対する計算値);530.3708(実測値)。
Claims (3)
- 下記式(1)で示されるN-末端が保護されたジペプチド又はその塩の製造方法であって、
[式(1)において、Xはアミノ基の保護基を表し、
R1は、α-一置換アミノ酸の側鎖、又は水素原子を表し、該側鎖は保護されていてもよく、
R2は、R1と結合して前記側鎖を形成する基、又は水素原子を表し、
Ra2及びRb2は、それぞれ独立に、置換基を有していてもよいアルキル基、置換基を有していてもよいアルケニル基、置換基を有していてもよいアルキニル基又は置換基を有していてもよいアラルキル基を表す。]
下記式(2)で示されるN-末端が保護されたα-一置換アミノ酸若しくはグリシン又はそれらの塩と、
[式(2)において、X、R1及びR2は式(1)におけるX、R1及びR2と同様に定義される。]
下記式(3)で示される二置換アミノ酸又はその塩とを、
[式(3)において、Ra2及びRb2は式(1)におけるRa2及びRb2と同様に定義される。]
縮合剤の存在下で縮合させることを含む、製造方法。 - 前記式(2)で示されるN-末端が保護されたα-一置換アミノ酸若しくはグリシン又はそれらの塩と、前記式(3)で示される二置換アミノ酸又はその塩とを、化学量論量以上の縮合剤の存在下で縮合させる、請求項1に記載の製造方法。
- 前記式(2)で示されるN-末端が保護されたα-一置換アミノ酸若しくはグリシン又はそれらの塩の反応率が70~80%に達した時点で、前記式(2)で示されるN-末端が保護されたα-一置換アミノ酸若しくはグリシン又はそれらの塩と前記式(3)で示される二置換アミノ酸又はその塩との反応を終了させる、請求項1又は2に記載の製造方法。
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Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5931744A (ja) | 1982-06-17 | 1984-02-20 | シエリング・コ−ポレ−シヨン | 置換ジペプチド類、その製造方法、該ペプチドを含有する医薬組成物および該医薬組成物の製造方法 |
JPH01163197A (ja) | 1980-10-23 | 1989-06-27 | Schering Plough Corp | カルボキシアルキルジペプチド、その製造方法および医薬組成物 |
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2014
- 2014-08-20 JP JP2015535415A patent/JP6275150B2/ja active Active
- 2014-08-20 US US14/914,458 patent/US9605020B2/en active Active
- 2014-08-20 WO PCT/JP2014/071804 patent/WO2015033781A1/ja active Application Filing
- 2014-08-20 EP EP14841691.0A patent/EP3042911A4/en not_active Withdrawn
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH01163197A (ja) | 1980-10-23 | 1989-06-27 | Schering Plough Corp | カルボキシアルキルジペプチド、その製造方法および医薬組成物 |
JPS5931744A (ja) | 1982-06-17 | 1984-02-20 | シエリング・コ−ポレ−シヨン | 置換ジペプチド類、その製造方法、該ペプチドを含有する医薬組成物および該医薬組成物の製造方法 |
Non-Patent Citations (5)
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US20160207958A1 (en) | 2016-07-21 |
EP3042911A1 (en) | 2016-07-13 |
JPWO2015033781A1 (ja) | 2017-03-02 |
JP6275150B2 (ja) | 2018-02-07 |
EP3042911A4 (en) | 2017-04-26 |
US9605020B2 (en) | 2017-03-28 |
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