WO2020134727A1 - 一种四肽化合物及制备方法和用途 - Google Patents

一种四肽化合物及制备方法和用途 Download PDF

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WO2020134727A1
WO2020134727A1 PCT/CN2019/119628 CN2019119628W WO2020134727A1 WO 2020134727 A1 WO2020134727 A1 WO 2020134727A1 CN 2019119628 W CN2019119628 W CN 2019119628W WO 2020134727 A1 WO2020134727 A1 WO 2020134727A1
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alkyl
product
formula
substituted
reaction
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PCT/CN2019/119628
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English (en)
French (fr)
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达朝山
杜智宏
秦文娟
陶宝秀
白彦兵
林行
张连春
殷杭华
余建新
刘学愚
姜伟林
金文究
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兰州大学
杭州鑫富科技有限公司
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Priority to EP19905086.5A priority Critical patent/EP3904367A4/en
Publication of WO2020134727A1 publication Critical patent/WO2020134727A1/zh

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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
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
    • C07K5/101—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
    • 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
    • C07K5/08—Tripeptides
    • C07K5/0821—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp
    • 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
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1016—Tetrapeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/10—Nitrogen as only ring hetero atom
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention relates to a tetrapeptide compound and its preparation method and use.
  • the present invention is a tetrapeptide compound and its preparation method and use, especially a compound and its preparation method and use which can be applied to catalyze the asymmetric conjugate addition reaction of fatty aldehyde and maleimide.
  • Optically active compounds are a common phenomenon in nature and play an irreplaceable role in the life activities of cells and organisms. Many drugs have optical activity, and chirality is an important element of drugs. Catalytic asymmetric reactions with chiral catalysts are the most economical and green method to synthesize chiral compounds. Mismatch catalysis contains three areas, namely chiral ligand-metal complex catalysts, organic small molecule catalysts and biological enzyme catalyzed reactions. Due to its green color and good economic performance, bioenzymatic catalysis has always been a hot research area for asymmetric catalysis, but the complexity, susceptibility to deactivation, and specificity of enzyme protein structures have limited its rapid application.
  • Peptide is a new type of organic catalyst designed and synthesized according to the mechanism of enzyme catalysis. It has many advantages such as simple structure, easy synthesis, wide substrate range, adaptability to many types of reactions, mild reaction conditions, stable structure, etc. It is an excellent simulant of natural enzymes , Is the key direction of chemical biology research.
  • the chiral 3-substituted succinimide synthesized by the asymmetric conjugate addition reaction of nucleophile and N-substituted maleimide can be easily converted into a series of chiral pyrrole after reduction Compound.
  • Chiral pyrrole compounds are the core skeleton of many biologically active compounds. The asymmetric synthesis of chiral pyrrole compounds has always been a core topic in the research of organic chemistry and medicinal chemistry.
  • the chiral 3-substituted succinimide can also be easily converted to chiral succinic acid through hydrolysis, which is an important physiologically active compound and chiral synthetic building block.
  • aldehyde As an asymmetric conjugate addition product of nucleophile and maleimide, aldehyde additionally has an effective group that can be easily derivatized into other functional groups, making the reaction of important application value. Therefore, the continuous development of efficient chiral catalysts to catalyze the asymmetric conjugated addition reaction of fatty aldehyde and maleimide is a goal pursued by many research institutions.
  • the catalysts successfully applied in this reaction are basically chiral organic catalysts, most of which are primary amine thiourea or squaramide catalysts derived from chiral cyclohexanediamine as raw materials, and have achieved ideal results.
  • the present invention provides a tetrapeptide compound and its preparation method and use.
  • the tetrapeptide compound provided by the present invention can overcome the deficiencies of the prior art and can catalyze the conjugate addition of fatty aldehyde and maleimide with high efficiency and asymmetric Reacted compounds.
  • TP tetrapeptide compound of the present invention
  • R 1 and R 2 are any straight chain alkyl group C 1 ⁇ C 6, branched alkyl, cycloalkyl, hydroxy-substituted alkyl, substituted alkyl mercapto, methylthio substituted alkyl, amino-substituted alkyl Radical, guanidino substituted for any of alkyl, aryl, arylmethyl or heteroatom aryl.
  • R 1 and R 2 are any one of any linear alkyl group, branched alkyl group, cyclohexyl group, phenyl group, and benzyl group of C 1 to C 4 , respectively.
  • the product 10 and the catalyst Pd/C are added to the solvent S-7, and hydrogen is passed through at a pressure of 1-30 Mpa for reaction to obtain the final product tetrapeptide TP, in which:
  • R 3 is arylmethyl
  • R 4 , R 5 and R 6 are any one of Boc (tert-butoxyformyl), Cbz (benzyloxyformyl) or Fmoc (fluorenyl methoxyformyl);
  • Condensation reagents C-1, C-2 and C-3 are any of carbodiimide or alkoxyformyl chloride (R 7 OCOCl), R 7 is any linear alkyl group of C 1 to C 4 or Branched chain alkyl;
  • Additives A-1, A-2 and A-3 refer to R 8 R 9 R 10 N or NMM (N-methylmorpholine) or TMEDA (4-dimethylaminopyridine) or HOBt (1-hydroxybenzotriazine) Azole), R 8 , R 9 and R 10 are any linear or branched alkyl groups of C 1 to C 4 ;
  • Solvents S-1, S-2, S-3, S-4, S-5, S-6 are toluene, benzene, methylene chloride, dichloroethane, ether, tetrahydrofuran, ethylene glycol dimethyl ether, methyl alcohol Tert-butyl ether, hexamethylene oxide, ethyl acetate, methyl acetate, acetonitrile or propionitrile any one or a combination of any of several, the solvent S-7 is methanol, ethanol, propanol or butanol Any one or any combination of several;
  • Deprotection agents D-1, D-2 and D-3 are methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, trichloroacetic acid, hydrochloric acid, sulfuric acid, piperidine, Any one of morpholine, tetrahydropyrrole, dihydropyrrole, pyrrole, diethylamine, dipropylamine, dibutylamine, diisopropylamine, or diisobutylamine.
  • the compound preparation method of the present invention is:
  • R 3 is benzyl
  • R 4 , R 5 and R 6 refer to Boc or Cbz
  • Condensation reagents C-1, C-2 and C-3 are DCC (N,N'-dicyclohexylcarbodiimide) or DIC (N,N'-diisopropylcarbodiimide), or alkoxy Formyl chloride R 7 OCOCl, R 7 is Et or i-Pr or i-Bu;
  • Additives A-1, A-2 and A-3 are any of TEA (triethylamine), DIPEA (diisopropylethylamine), NMM or HOBt;
  • Solvents S-1, S-2, S-3, S-4, S-5 and S-6 are methylene chloride or tetrahydrofuran, and solvent S-7 is methanol or ethanol;
  • the deprotecting agents D-1, D-2 and D-3 are methanesulfonic acid or trifluoromethanesulfonic acid or trifluoroacetic acid.
  • the compound preparation method of the present invention is:
  • R 3 is benzyl
  • R 4 , R 5 and R 6 are Boc
  • Condensation reagents C-1, C-2 and C-3 are DCC or DIC or alkoxyformyl chloride R 7 OCOCl, R 7 is Et or i-Pr or i-Bu;
  • the additives A-1, A-2 and A-3 refer to any one of TEA, DIPEA, NMM or HOBt;
  • Solvents S-1, S-2, S-3, S-4, S-5, S-6 refer to methylene chloride or tetrahydrofuran, and solvent S-7 refers to methanol;
  • Deprotection agents D-1, D-2 and D-3 refer to trifluoroacetic acid
  • the hydrogen pressure is 8Mpa.
  • the compound of the present invention can be used for Aldol reaction of ketone and aromatic aldehyde, or for catalyzing the asymmetric conjugate addition reaction of fatty aldehyde and maleimide as shown in Formula 6. That is, the fatty aldehyde 11, maleimide 12, and tetrapeptide TP represented by Formula 6 are added to the reaction vessel containing the solvent S-8 and stirred to obtain the product of the conjugated addition reaction, 3-substituted succinimide ( R)-P,
  • R 11 is hydrogen or any C straight chain alkyl group or branched alkyl group of 1 ⁇ C 6 or benzyl or phenyl
  • R 12 is a C straight chain alkyl or any branched alkyl group of 1 ⁇ C 6 Or phenyl or benzyl, or -R 11 -R 12 -is cyclohexyl or cyclopentyl
  • R 13 is hydrogen or phenyl or substituted phenyl or linear alkyl or cycloalkyl or arylmethyl;
  • Tetrapeptide TP is a tetrapeptide containing two terminal D-type- ⁇ -primary amino acids as shown in Formula 1;
  • the solvent S-8 refers to methylene chloride, chloroform, dichloroethane, ethyl acetate, methyl acetate, toluene, benzene, xylene, diethyl ether, tetrahydrofuran, ethylene glycol dimethyl ether, methyl Any one or more of tert-butyl ether, acetonitrile, propionitrile, ethanol, methanol, propanol, butanol.
  • R 11 is hydrogen or methyl or ethyl
  • R 12 is methyl or ethyl or isopropyl or n-butyl, or -R 11 -R 12 -is cyclohexyl or cyclopentyl
  • R 13 is hydrogen or methyl Group or cyclohexyl or benzyl or phenyl or substituted phenyl, substituted phenyl refers to p-methylphenyl or p-chlorophenyl or p-bromophenyl or p-fluorophenyl or p-nitrophenyl or p-methyl Oxyphenyl;
  • Tetrapeptide TP is any one of the aforementioned TP-1 ⁇ TP-6;
  • the solvent S-8 is any one of methylene chloride, acetonitrile, ethanol, tetrahydrofuran, dimethyl sulfoxide, and toluene.
  • the tetrapeptide TP is TP-3; the solvent S-8 is acetonitrile.
  • the intermediate compounds used in the present invention for preparing the compound TP of Formula 1 are: as shown in Formula 3, as shown in Formula 6, as shown in Formula 3, as shown in Formula 7, or as shown in Formula 4, as shown in Formula 9, or as shown in Formula 4 as shown in Figure 10.
  • the compound of the present invention can catalyze the conjugate addition reaction of fatty aldehyde and maleimide with high yield and high enantioselectivity during asymmetrically catalyzed conjugation reaction of fatty aldehyde and maleimide.
  • the tetrapeptide compound of the present invention can catalyze the conjugate addition reaction of fatty aldehyde and maleimide with high efficiency and asymmetricity.
  • the reaction yield reaches 98%, and the highest enantioselectivity reaches 99%. ,
  • the application prospect is good.
  • the present invention provides a tetrapeptide compound TP as shown in Formula 1,
  • R 1 and R 2 are independently selected from any of C 1 to C 6 linear alkyl, branched alkyl, cycloalkyl, hydroxy substituted alkyl, mercapto substituted alkyl, methylthio substituted alkyl, amino Substituted alkyl, guanidino substituted for any of alkyl, aryl, arylmethyl or heteroatom aryl.
  • the R 1 is selected from any linear alkyl group of C 1 to C 6 , branched alkyl group of C 3 to C 15 , cycloalkyl group of C 3 to C 8 , C 1 to C substituted with hydroxyl group 6 alkyl, substituted C 1-6 alkyl mercapto group, a methylthio group 1 ⁇ C 6 substituted with C 1 ⁇ C 6 alkyl, amino-substituted alkyl group of C, 1 ⁇ C 6 guanidino substituted with C 1 ⁇ C 6 alkyl, C 6 -C 30 aryl, C 6 -C 30 arylmethyl or C 5 -C 15 heteroatom aryl; preferably methyl, ethyl, n-propyl, isopropyl Group, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, cyclopropyl
  • the R 2 is selected from any linear alkyl groups of C 1 to C 6 , branched alkyl groups of C 3 to C 15 , cycloalkyl groups of C 3 to C 8 , and C 1 to C 6 alkyl groups substituted with hydroxyl groups , mercapto-substituted C 1-6 alkyl, methylthio-substituted 1 ⁇ C 6 to C 1 ⁇ C 6 alkyl group, C-alkyl substituted amino, guanidino 1 ⁇ C 6 alkyl substituted with C 1 ⁇ C 6 to Group, C 6 -C 30 aryl group, C 6 -C 30 arylmethyl group or C 5 -C 15 heteroatom aryl group, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl Group, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, cyclo
  • R 1 is i-Bu
  • R 2 is i-Pr, that is, the amino acid sequence of the tetrapeptide compound TP is H 2 ND-Val-Pro-Gly-D-Leu-OH, named TP-1;
  • R 1 is i-Bu
  • R 2 is t-Bu, that is, the amino acid sequence of the tetrapeptide compound TP is H 2 ND-Tle-Pro-Gly-D-Leu-OH, named TP-2;
  • R 1 is i-Bu
  • R 2 is Ph, that is, the amino acid sequence of the tetrapeptide compound TP is H 2 ND-Phg-Pro-Gly-D-Leu-OH, named TP-3;
  • R 1 is i-Bu
  • R 2 is c-hex, that is, the amino acid sequence of the tetrapeptide compound TP is H 2 ND-Chg-Pro-Gly-D-Leu-OH, named TP-4;
  • R 1 is i-Bu
  • R 2 is Bn, that is, the amino acid sequence of the tetrapeptide compound TP is H 2 ND-Phe-Pro-Gly-D-Leu-OH, named TP-5;
  • R 1 is Bn
  • R 2 is Bn, that is, the amino acid sequence of the tetrapeptide compound TP is H 2 ND-Phe-Pro-Gly-D-Phe-OH, which is named TP-6.
  • the present invention also provides a method for preparing the tetrapeptide compound TP represented by Formula 1 of the present invention, which includes:
  • R 1 and R 2 are independently selected from any of C 1 to C 6 linear alkyl, branched alkyl, cycloalkyl, hydroxy substituted alkyl, mercapto substituted alkyl, methylthio substituted alkyl, amino Substituted alkyl, guanidino substituted any of alkyl, aryl, arylmethyl or heteroatom aryl;
  • R 3 is arylmethyl
  • R 6 is selected from tert-butoxyformyl, benzyloxyformyl or fluorenylmethoxyformyl;
  • the product 7 and the amino acid 8 are mixed and reacted to obtain the product 9;
  • the condensation reagent of the condensation reaction is carbodiimide or alkoxyformyl chloride (R 7 OCOCl), wherein R 7 is Any linear or branched alkyl group from C 1 to C 4 ; additives for the reaction are R 8 R 9 R 10 N, NMM (N-methylmorpholine), TMEDA (4-dimethylaminopyridine) Or HOBt (1-hydroxybenzotriazole), wherein R 8 , R 9 , and R 10 are independently selected from any linear or branched alkyl groups of C 1 to C 4 ;
  • the solvent for the reaction is preferably Toluene, benzene, methylene chloride, dichloroethane, ether, tetrahydrofuran, ethylene glycol dimethyl ether, methyl tert-butyl ether, hexamethylene oxide, ethyl acetate, methyl a
  • the present invention has no special requirements for the source of the product 7, and it is preferably prepared according to the following method:
  • the condensation reagent of the reaction is carbodiimide or alkoxyformyl chloride (R 7 OCOCl), wherein R 7 is C 1 ⁇ C 4 any linear or branched alkyl group;
  • the additive for the reaction is R 8 R 9 R 10 N, NMM (N-methylmorpholine), TMEDA (4-dimethylaminopyridine) or HOBt (1-hydroxybenzotriazole), wherein R 8 , R 9 , and R 10 are independently selected from any linear or branched alkyl groups of C 1 to C 4 ;
  • the solvent for the reaction is preferably toluene , Benzene, dichloromethane, dichloroethane, diethyl ether, tetrahydrofuran, ethylene glycol dimethyl ether, methyl tert-butyl ether, hexamethylene oxide, ethyl acetate, methyl acetate,
  • R 1 is selected from any of linear C 1 ⁇ C 6 alkyl, branched alkyl, cycloalkyl, hydroxy-substituted alkyl, substituted alkyl mercapto, methylthio substituted alkyl, amino-substituted alkyl groups, guanidine Any one of alkyl, aryl, arylmethyl or heteroatom aryl;
  • R 3 is arylmethyl
  • R 5 is selected from tert-butoxyformyl, benzyloxyformyl or fluorenylmethoxyformyl;
  • the deprotecting agent of the conversion reaction is preferably methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, trichloromethane Acetic acid, hydrochloric acid, sulfuric acid, piperidine, morpholine, tetrahydropyrrole, dihydropyrrole, pyrrole, diethylamine, dipropylamine, dibutylamine, diisopropylamine or diisobutylamine; the anti-solvent is preferably toluene, One of benzene, methylene chloride, dichloroethane, diethyl ether, tetrahydrofuran, ethylene glycol dimethyl ether, methyl tert-butyl ether, hexamethylene oxide, ethyl acetate, methyl a
  • the product 4 is prepared according to the following method:
  • the condensation reagent of the reaction is carbodiimide or alkoxyformyl chloride R 7 OCOCl, wherein R 7 is C 1 ⁇ C 4 Any linear or branched alkyl group;
  • the additives for the reaction are R 8 R 9 R 10 N, NMM (N-methylmorpholine), TMEDA (4-dimethylaminopyridine) or HOBt (1- Hydroxybenzotriazole), wherein R 8 , R 9 , and R 10 are independently selected from any linear or branched alkyl groups of C 1 to C 4 ;
  • the solvent for the reaction is preferably toluene, benzene, One or more of dichloromethane, dichloroethane, diethyl ether, tetrahydrofuran, ethylene glycol dimethyl ether, methyl tert-butyl ether, hexamethylene oxide, ethyl acetate,
  • R 1 is selected from any of linear C 1 ⁇ C 6 alkyl, branched alkyl, cycloalkyl, hydroxy-substituted alkyl, substituted alkyl mercapto, methylthio substituted alkyl, amino-substituted alkyl groups, guanidine Any one of alkyl, aryl, arylmethyl or heteroatom aryl;
  • R 3 is arylmethyl
  • R 4 and R 5 are independently selected from tert-butoxyformyl, benzyloxyformyl or fluorenylmethoxyformyl;
  • the deprotecting agent of the conversion reaction is preferably methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, trichloromethane Acetic acid, hydrochloric acid, sulfuric acid, piperidine, morpholine, tetrahydropyrrole, dihydropyrrole, pyrrole, diethylamine, dipropylamine, dibutylamine, diisopropylamine or diisobutylamine; the anti-solvent is preferably toluene, One of benzene, methylene chloride, dichloroethane, diethyl ether, tetrahydrofuran, ethylene glycol dimethyl ether, methyl tert-butyl ether, hexamethylene oxide, ethyl acetate, methyl a
  • the step 2) is specifically:
  • the product 9 is deprotected to obtain the product 10; wherein the deprotection agent for deprotection is preferably methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, trichloromethane Acetic acid, hydrochloric acid, sulfuric acid, piperidine, morpholine, tetrahydropyrrole, dihydropyrrole, pyrrole, diethylamine, dipropylamine, dibutylamine, diisopropylamine or diisobutylamine; the anti-solvent is preferably toluene, One of benzene, methylene chloride, dichloroethane, diethyl ether, tetrahydrofuran, ethylene glycol dimethyl ether, methyl tert-butyl ether, hexamethylene oxide, ethyl a
  • R 1 and R 2 are independently selected from any of C 1 to C 6 linear alkyl, branched alkyl, cycloalkyl, hydroxy substituted alkyl, mercapto substituted alkyl, methylthio substituted alkyl, amino Substituted alkyl, guanidino substituted any of alkyl, aryl, arylmethyl or heteroatom aryl;
  • R 3 is arylmethyl
  • R 6 is selected from tert-butoxyformyl, benzyloxyformyl or fluorenylmethoxyformyl;
  • the product 10 is subjected to a catalytic hydrogenation reaction to obtain the tetrapeptide compound TP represented by Formula 1.
  • the preparation method of the tetrapeptide compound TP shown in Formula 1 is as follows: the reaction process is shown in Formula 2, Formula 3, Formula 4 and Formula 5, namely:
  • the product 10 and the catalyst Pd/C are added to the solvent S-7, and hydrogen is passed through at a pressure of 1-30 Mpa for reaction to obtain the final product tetrapeptide TP, in which:
  • R 3 is arylmethyl
  • R 4 , R 5 and R 6 are any one of Boc (tert-butoxyformyl), Cbz (benzyloxyformyl) or Fmoc (fluorenyl methoxyformyl);
  • Condensation reagents C-1, C-2 and C-3 are any of carbodiimide or alkoxyformyl chloride (R 7 OCOCl), R 7 is any linear alkyl group of C 1 to C 4 or Branched chain alkyl;
  • Additives A-1, A-2 and A-3 refer to R 8 R 9 R 10 N or NMM (N-methylmorpholine) or TMEDA (4-dimethylaminopyridine) or HOBt (1-hydroxybenzotriazine) Azole), R 8 , R 9 and R 10 are any linear or branched alkyl groups of C 1 to C 4 ;
  • Solvents S-1, S-2, S-3, S-4, S-5, S-6 are toluene, benzene, methylene chloride, dichloroethane, ether, tetrahydrofuran, ethylene glycol dimethyl ether, methyl alcohol Tert-butyl ether, hexamethylene oxide, ethyl acetate, methyl acetate, acetonitrile or propionitrile any one or a combination of any of several, the solvent S-7 is methanol, ethanol, propanol or butanol Any one or any combination of several;
  • Deprotection agents D-1, D-2 and D-3 are methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, trichloroacetic acid, hydrochloric acid, sulfuric acid, piperidine, Any one of morpholine, tetrahydropyrrole, dihydropyrrole, pyrrole, diethylamine, dipropylamine, dibutylamine, diisopropylamine, or diisobutylamine.
  • the R 3 is benzyl
  • R 4 , R 5 and R 6 are independently selected from Boc or Cbz;
  • the condensation reagents C-1, C-2 and C-3 are independently selected from DCC (N,N'-dicyclohexylcarbodiimide) or DIC (N,N'-diisopropylcarbodiimide) or Alkoxyformyl chloride R 7 OCOCl,
  • R 7 is Et or i-Pr or i-Bu
  • Additives A-1, A-2 and A-3 are independently selected from any one of TEA (triethylamine), DIPEA (diisopropylethylamine), NMM or HOBt;
  • the solvents S-1, S-2, S-3, S-4, S-5 and S-6 are independently selected from dichloromethane or tetrahydrofuran, and the solvent S-7 is selected from methanol or ethanol;
  • the deprotecting agents D-1, D-2 and D-3 are independently selected from methanesulfonic acid or trifluoromethanesulfonic acid or trifluoroacetic acid.
  • the R 3 is benzyl
  • R 4 , R 5 and R 6 are independently selected from Boc
  • the condensation reagents C-1, C-2 and C-3 are independently selected from DCC, DIC or alkoxyformyl chloride R 7 OCOCl, wherein R 7 is selected from Et or i-Pr or i-Bu;
  • Additives A-1, A-2 and A-3 are independently selected from any one of TEA, DIPEA, NMM or HOBt;
  • the solvents S-1, S-2, S-3, S-4, S-5, and S-6 are independently selected from dichloromethane or tetrahydrofuran, and the solvent S-7 is methanol;
  • the deprotecting agents D-1, D-2 and D-3 are independently selected from trifluoroacetic acid;
  • the hydrogen pressure is 8Mpa.
  • the present invention also provides a catalyst for catalyzing the asymmetric conjugate addition reaction of fatty aldehyde and maleimide, wherein the catalyst is the tetrapeptide compound TP of Formula 1 shown in the present invention,
  • the structure of the fatty aldehyde is shown in 11, and the structure of the maleimide is shown in 12.
  • the product of the asymmetric conjugate addition has the structure shown in (R)-P; the conjugate addition reaction
  • the solvents are dichloromethane, chloroform, dichloroethane, ethyl acetate, methyl acetate, toluene, benzene, xylene, ether, tetrahydrofuran, ethylene glycol dimethyl ether, methyl tert-butyl ether, acetonitrile, propylene Nitrile, ethanol, methanol, propanol or butanol.
  • R 11 is hydrogen, any linear alkyl group, branched chain alkyl group, C 1 to C 6 alkyl group, phenyl group or benzyl group, more preferably hydrogen, methyl or ethyl group;
  • R 12 is any one of C 1 to C 6 Linear alkyl, branched alkyl, phenyl or benzyl, preferably methyl, ethyl, isopropyl or n-butyl; or -R 11 -R 12 -is cyclohexyl or cyclopentyl
  • R 13 is hydrogen, phenyl, substituted phenyl, linear alkyl, cycloalkyl or arylmethyl, preferably hydrogen, methyl, cyclohexyl, benzyl, phenyl or substituted phenyl, substituted phenyl means P-methylphenyl, p-chlorophenyl, p-bromophenyl, p-fluoropheny
  • the present invention also provides an intermediate compound for preparing the compound TP shown in Formula 1, whose structure is shown in Formula 3 shown in 6.
  • the present invention also provides an intermediate compound for preparing the compound TP shown in Formula 1, whose structure is shown in Formula 3 as 7.
  • the present invention also provides an intermediate compound for preparing the compound TP shown in Formula 1, whose structure is shown in Formula 4 shown in 9.
  • the present invention also provides an intermediate compound for preparing the compound TP shown in Formula 1, whose structure is shown in Formula 4 shown in 10.
  • the compound TP of the present invention can catalyze the conjugate addition reaction of fatty aldehyde and maleimide with high yield and high enantioselectivity during asymmetrically catalyzed conjugation reaction of fatty aldehyde and maleimide.
  • the tetrapeptide compound of the present invention can catalyze the conjugate addition reaction of fatty aldehyde and maleimide with high efficiency and asymmetricity.
  • the reaction yield reaches 98%, and the highest enantioselectivity reaches 99%. ,
  • the application prospect is good.
  • the reaction process of the preparation of the tetrapeptide compound TP according to Formula 1 of the present invention can be referred to the aforementioned Formula 2 to Formula 5, and the preparation method can be referred to the content of the invention.
  • the preparation process is as follows in more detail:
  • Boc-Gly-OH 1 (8.75g, 50mmol) to 100mL of anhydrous THF and stir for 5min in an ice-salt bath under the protection of argon to reduce the temperature of the reaction solution to –15°C.
  • NMM 6.2 mL, 55 mmol
  • ethyl chloroformate 5.3 mL, 55 mmol
  • Boc-Gly-OH 1 (8.75g, 50mmol) to 100mL of anhydrous THF, and stir for 5min in an ice-salt bath under the protection of argon to reduce the temperature of the reaction solution to –15°C, NMM (6.2 mL, 55 mmol) was added, and then isopropyl chloroformate (6.3 mL, 55 mmol) was slowly added dropwise to the reaction solution.
  • the ethyl acetate phase was washed with 1M NaOH solution, water, 1M hydrochloric acid solution, and a small amount of saturated saline solution, and dried over anhydrous sodium sulfate. After that, it was concentrated under reduced pressure to obtain 17.67 g of Boc-Gly-D-Leu-OBn (3a) as a pale yellow oily liquid with a yield of 93%.
  • Boc-Gly-OH (8.75g, 50mmol) to 100mL of anhydrous THF, and stir for 5min in an ice-salt bath under the protection of argon to reduce the temperature of the reaction solution to –15°C
  • TEA Triethylamine, 7.6 mL, 55 mmol
  • isobutyl chloroformate (7 mL, 55 mmol) was slowly added dropwise to the reaction solution.
  • the ethyl acetate phase was washed with 1M NaOH solution, water, 1M hydrochloric acid solution, and a small amount of saturated saline solution, and dried over anhydrous sodium sulfate. After that, it was concentrated under reduced pressure to obtain 16.48 g of Boc-Gly-D-Leu-OBn (3a) as a pale yellow oily liquid with a yield of 87%.
  • Boc-Gly-OH 1 (8.75g, 50mmol) to 100mL of anhydrous THF and stir for 5min in an ice-salt bath under the protection of argon to reduce the temperature of the reaction solution to –15°C.
  • DIPEA diisopropylethylamine, 9.6 mL, 55 mmol
  • isobutyl chloroformate (7 mL, 55 mmol) into the reaction solution.
  • the ethyl acetate phase was washed with 1M NaOH solution, water, 1M hydrochloric acid solution, and a small amount of saturated saline solution, and dried over anhydrous sodium sulfate. After that, it was concentrated under reduced pressure to obtain 15.47 g of Boc-Gly-D-Leu-OBn(3a) as a pale yellow oily liquid with a yield of 81%.
  • Boc-Gly-OH 1 (8.75g, 50mmol) was added to 100mL of anhydrous THF, stirred under an argon atmosphere in an ice salt bath for 5min, the temperature of the reaction solution was reduced to -15 °C, NMM (6.2mL) was added , 55mmol), followed by slowly dropping isobutyl chloroformate (7mL, 55mmol) into the reaction solution.
  • the ethyl acetate phase was washed with 1M NaOH solution, water, 1M hydrochloric acid solution, and a small amount of saturated brine in this order, and dried over anhydrous sodium sulfate. Afterwards, it was concentrated under reduced pressure to obtain Boc-Gly-D-Phe-OBn (3b) as a light yellow oil, which was purified by column chromatography with petroleum ether and ethyl acetate to obtain 19.16g of white solid with a yield of 93%.
  • the dipeptide Boc-Gly-D-Leu-OBn 3a (19g) obtained in the above reaction was dissolved in 50mL of dichloromethane, the reaction solution was cooled to 0°C, and TFA (trifluoroacetic acid, 50mL) was slowly added dropwise to it. After the reaction solution was restored to room temperature and stirred for 5 hours, the reaction solution was concentrated under reduced pressure to remove TFA. The residue was dissolved in dichloromethane, and the pH was adjusted to about 9.0 with 1.0 M NaOH aqueous solution at 0°C. The organic phase was separated and the aqueous phase was separated by two Chloromethane (20mL ⁇ 3) extraction.
  • the dipeptide Boc-Gly-D-Leu-OBn 3a (19g) obtained in the above reaction is dissolved in 50mL of dichloromethane, the reaction solution is cooled to 0°C, and methanesulfonic acid (50mL) is slowly added dropwise thereto ), after naturally recovering the reaction solution to room temperature and stirring for 5 h, adjust the pH to about 9.0 with 1.0 M NaOH aqueous solution at 0°C, separate the organic phase, and extract the aqueous phase with dichloromethane (20 mL ⁇ 3).
  • the dipeptide Boc-Gly-D-Leu-OBn 3a (19g) obtained in the above reaction is dissolved in 50 mL of dichloromethane, the reaction solution is cooled to 0°C, and trifluoromethanesulfonic acid ( 50mL), after naturally recovering the reaction solution to room temperature and stirring for 5h, the pH was adjusted to about 9.0 with 1.0M NaOH aqueous solution at 0°C, the organic phase was separated, and the aqueous phase was extracted with dichloromethane (20mL ⁇ 3).
  • the dipeptide Boc-Gly-D-Phe-OBn 3b (18.2g, 44mmol) obtained in the above reaction was dissolved in 44mL of dichloromethane, the reaction solution was cooled to 0°C, and TFA (44mL) was slowly added dropwise to it, naturally recovering After the reaction solution was stirred at room temperature for 5 hours, the reaction solution was concentrated under reduced pressure to remove TFA. The residue was dissolved in dichloromethane, and the pH was adjusted to about 9.0 with 1M NaOH aqueous solution at 0°C. The organic phase was separated, and the aqueous phase was dichloromethane (20mL ⁇ 3) extraction.
  • Boc-Pro-OH 5 (9.68 g, 45 mmol) was added to 100 mL of anhydrous THF, and the temperature of the reaction solution was lowered to –15°C by stirring in an ice salt bath for 5 min under the protection of argon, and NMM (5.6 mL, 50mmol), slowly add isobutyl chloroformate (6.4mL, 50mmol) dropwise to the reaction solution, after stirring for 5min, add the dipeptide NH 2 -Gly-D-Leu-OBn 4a (12.56) dissolved in anhydrous THF in advance g, 45 mmol) and NMM (5.6 mL).
  • Boc-Pro-OH 5 (7.53g, 35mmol) was added to 100mL of anhydrous THF, stirred under an argon atmosphere in an ice-salt bath for 5min to reduce the temperature of the reaction liquid to -15°C, and NMM (4.3mL, 38.5 mmol), isobutyl chloroformate (4.9 mL, 38.5 mmol) was slowly added dropwise to the reaction solution, and after stirring for 5 min, the dipeptide NH 2 -Gly-D-Phe-OBn 4b previously dissolved in anhydrous THF was added (10.92 g, 35 mmol) and NMM (4.3 mL) solution.
  • the synthetic tripeptide Boc-Pro-Gly-D-Leu-OBn 6a (19g, 40mmol) was completely dissolved in CH 2 Cl 2 (40mL), and TFA (40mL) was slowly added dropwise at 0°C to recover the reaction solution At room temperature, stir for 5h.
  • the reaction solution was concentrated under reduced pressure to remove TFA as much as possible.
  • the organic phase was separated and the aqueous phase was extracted with CH 2 Cl 2 (20 mL ⁇ 3).
  • the synthetic tripeptide Boc-Pro-Gly-D-Phe-OBn 6b (16.5g, 32mmol) was completely dissolved in CH 2 Cl 2 (32mL), and TFA (32mL) was slowly added dropwise at 0°C to recover the reaction solution At room temperature, stir for 5h.
  • the reaction solution was concentrated under reduced pressure to remove TFA as much as possible.
  • the organic phase was separated and the aqueous phase was extracted with CH 2 Cl 2 (20 mL ⁇ 3).
  • Synthetic tetrapeptide TP-1 NH 2 -D-Val-Pro-Gly-D-Leu-OH
  • TP-1 to TP-6 tetrapeptide catalysts of the present invention catalyze the evaluation of the asymmetric conjugated addition reaction of isobutyraldehyde and N-phenylmaleimide.
  • Table 1 The results are shown in Table 1 below. It can be seen from the results that TP-3 and TP-5 have the highest asymmetric catalytic efficiency.
  • Tetrapeptide catalyst catalyzes the asymmetric conjugated addition reaction of isobutyraldehyde and N-phenylmaleimide.
  • the products P-1 to P-17 are characterized as follows.

Abstract

本发明公开一种四肽化合物，以及其制备方法及用途。本发明的四肽化合物为如式1示TP，其制备方法是首先制备出中间化合物，再将中间化合物和催化剂Pd/C加入溶剂中，通入压力为1～30Mpa氢气进行反应，得到终产物四肽TP。本发明所述的化合物可用于酮与芳香醛的Aldol反应，或者用于催化脂肪醛与马来酰亚胺的不对称共轭加成反应。本发明的四肽化合物可以高效率、不对称地催化脂肪醛与马来酰亚胺的共轭加成反应，反应的产率达到98％，对映选择性最高达到了99％。

Description

一种四肽化合物及制备方法和用途
本申请要求于2018年12月27日提交中国专利局、申请号为201811616048X、发明名称为“一种四肽化合物及制备方法和用途”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明涉及一种四肽化合物及制备方法和用途。确切讲本发明是一种四肽化合物及制备方法与用途，特别是一种可应用于催化脂肪醛与马来酰亚胺的不对称共轭加成反应的化合物及制备方法与用途。
背景技术
光学活性化合物是自然界的普遍现象，在细胞和生物体的生命活动过程中发挥着无可替代的作用。许多药物都有光学活性，手征性是药物的一个重要要素。用手性催化剂催化不对称反应是合成手性化合物最为经济、绿色的方法。不对成催化包含了三个领域，即手性配体-金属复合物催化剂、有机小分子催化剂和生物酶催化反应。由于绿色和良好的经济性能，生物酶催化一直是不对称催化的热点研究领域，但是由于酶蛋白结构的复杂性、易失活、专一性等因素限制了其快速应用。多肽是按照酶催化机理设计并合成的一类新型有机催化剂，具有结构简单、易合成、底物范围广泛、适应反应类型多、反应条件温和、结构稳定等诸多优势，是天然酶的优良模拟物，是化学生物学研究的重点方向。
已有报道证明，人工合成的短肽可以较好地替代天然蛋白酶，并模拟酶催化一系列化学反应，被广泛地应用于催化如Aldol、Michael、Stetter、叠氮化、Strecker、Baylis-Hillman、烯丙基取代、氰氢化、环氧化、氢化和酰基化等诸多不对称反应中，合成多种光学活性化合物，有效地克服了蛋白酶催化反应底物专一性和反应类型单一的缺陷，拓展了反应的类型和底物，适合于多种反应条件，并基本保持了生物催化反应绿色、经济的优点[(1)刘爱香，傅尧，刘磊，郭庆祥，有机化学，2007,27,1195-1219.(2)Davie,E.A.C.；Mennen,S.M.；Xu,Y.；Miller,S.J.Chem.Rev.2007,107, 5759-5812.(3)Wennemers,H.Chem.Commun.,2011,47,12036–12041.(4)Lewandowski,B.；Wennemers,H.Curr.Opin.Chem.Biol.2014,22,40–46.(5)Kelly,D.R.；Roberts,S.M.Biopolymers 2006,84,74–89.(6)Akagawa,K.；Kudo,K.Acc.Chem.Res.2017,50,2429-2439.(7)Ball,Z.T.Acc.Chem.Res.2012,46,560-570.]。因而，发现新型高效的短肽催化剂模拟蛋白酶催化有机化学反应，一直是手性化合物合成领域的热点。
在不对称催化条件下，亲核试剂与N-取代马来酰亚胺的不对称共轭加成反应合成的手性3-取代琥珀酰亚胺，经过还原可以方便地转变成一系列手性吡咯化合物。手性吡咯化合物是许多生物活性化合物的核心骨架，不对称合成手性吡咯化合物一直是有机化学与药物化学研究的一个核心课题。此外，手性3-取代的琥珀酰亚胺经过水解反应也可以方便地转换为手性琥珀酸，是很重要的生理活性化合物以及手性合成砌块。醛作为亲核试剂与马来酰亚胺的不对称共轭加成产物，额外具有一个很容易衍生为其它官能团的有效基团，使得该反应具有重要的应用价值。因而持续开发高效的手性催化剂催化脂肪醛与马来酰亚胺的不对称共轭加成反应，是许多研究机构追求的一个目标。总结文献报道，成功应用于这一反应的催化剂基本上都是手性有机催化剂，绝大部分都是手性环己二胺为原料衍生的伯胺类硫脲或方酰胺催化剂，取得了理想的产率和对映选择性[(8)Xue,F.；Liu,L.；Zhang,S.；Duan,W.；Wang,W.Chem.Eur.J.2010,16,7979-7982；(9)Ma,Z.-W.；Liu,Y.-X.；Zhang,W.-J.；Tao,Y.；Zhu,Y.；Tao,J.-C.；Tang,M.-S.Eur.J.Org.Chem.2011,6747-6754.(10)Orlandi,S.；Pozzi,G.；Ghisetti,M.；Benaglia,M.New J.Chem.2013,37,4140-4147.(11)Yu,F.；Jin,Z.；Huang,H.；Ye,T.；Liang,X.；Ye,J.Org.Biomol.Chem.2010,8,4767-4774.(12)Bai,J.-F.；Peng,L.；Wang,L.-L.；Wang,L.-X.；Xu,X.-Y.Tetrahedron 2010,66,8928-8932.(13)Ma,Z.-W.；Liu,Y.-X.；Li,P.-L.；Ren,H.；Zhu,Y.；Tao,J.-C.；Tetrahedron:Asymmetry 2011,22,1740-1748.(14)Ma,Z.-W.；Liu,X.-F.；Liu,J.-T.；Liu,Z.-J.；Tao,J.-C.Tetrahedron Letters 2017,58,4487-4490.]。金鸡纳碱硫脲和2-氯苯基甘氨酸作为一个高效的双催化剂体系，同样取得了理想的产率和对映选择性[(15)Muramulla,S.；Ma,J.-A.； Zhao,J.C.-G.Adv.Synth.Catal.2013,355,1260-1264]。金鸡纳丁衍生的手性伯胺在添加三苯基膦的条件下，其催化产率与对映选择性均非常理想[(16)Yang,W.；Jiang,K.-Z.；Lu,X.；Yang,H.-M.；Li,L.；Lu,Y.；Xu,L.-W.Chem.Asian J.2013,8,1182-1190]。在添加碱金属条件下发现，β-苯丙氨酸、天冬氨酸-α-叔丁酯以及侧链叔丁基保护的苏氨酸、异亮氨酸催化这一反应都取得了很好的不对称催化效果[(17)Kokotos,C.G.Org.Lett.2013,15,2406-2409.(18)Nugent,T.C.；Sadiq,A.；Bibi,A.；Heine,T.；Liu L.；Vankova,N.；Bassil,B.S.Chem.Eur.J.2012,18,4088-4098]。也有一例二肽Ala-Ala催化该丙醛与马来酰亚胺反应的报道，其产物的ee值只有38％[(19)Zhao,G.-L.；Xu,Y.；Sundén,H.；Eriksson,L.；Sayah,M.；Córdova,A.Chem.Commun.2007,734–735.]。因而开发应用于这一反应的高效多肽催化剂，是一个具有挑战性的工作。
发明内容
本发明提供一种四肽化合物及其制备方法和用途，本发明提供的四肽化合物可克服现有技术不足，可以高效率、不对称地催化脂肪醛与马来酰亚胺的共轭加成反应的化合物。
本发明所述的四肽化合物如式1所示TP，
Figure PCTCN2019119628-appb-000001
其中：R 1和R 2分别是C 1～C 6的任意直链烷基、支链烷基、环烷基、羟基取代烷基、巯基取代烷基、甲硫基取代烷基、氨基取代烷基、胍基取代烷基、芳基、芳甲基或杂原子芳基中的任一种。
优选地，本发明的四肽化合物，其R 1和R 2分别是C 1～C 4的任意直链烷基、支链烷基、环己基、苯基、苯甲基中的任一种。
更为具体地，本发明所述的四肽化合物，其R 1＝i-Bu,R 2＝i-Pr，即：其氨基酸序列为H 2N-D-Val-Pro-Gly-D-Leu-OH，命名为TP-1。
或者，本发明所述的四肽化合物，其R 1＝i-Bu,R 2＝t-Bu，即：其氨基酸序列为H 2N-D-Tle-Pro-Gly-D-Leu-OH，命名为TP-2。
或者，本发明所述的四肽化合物，其R 1＝i-Bu,R 2＝Ph，即：其氨基酸序列为H 2N-D-Phg-Pro-Gly-D-Leu-OH，命名为TP-3。
或者，本发明所述的四肽化合物，其R 1＝i-Bu,R 2＝c-hex，即：其氨基酸序列为H 2N-D-Chg-Pro-Gly-D-Leu-OH，命名为TP-4。
或者，本发明所述的四肽化合物，其R 1＝i-Bu,R 2＝Bn，即：其氨基酸序列为H 2N-D-Phe-Pro-Gly-D-Leu-OH，命名为TP-5。
或者，本发明所述的四肽化合物，其R 1＝Bn,R 2＝Bn，即：其氨基酸序列为H 2N-D-Phe-Pro-Gly-D-Phe-OH，命名为TP-6。
本发明的四肽化合物制备方法，其反应历程如式2、式3、式4和式5所示，即：
Figure PCTCN2019119628-appb-000002
将甘氨酸1、氨基酸2、缩合试剂C-1和添加剂A-1加入溶剂S-1搅拌反应，得到产物3，再将产物3和脱保护剂D-1加入溶剂S-2搅拌反应，得到产物4；
将产物4、脯氨酸5、缩合试剂C-2和添加剂A-2加入溶剂S-3中搅拌反应，得到产物6，再将产物6和脱保护剂D-2加入溶剂S-4中搅拌反应，得到产物7；
将产物7、氨基酸8、缩合试剂C-3和添加剂A-3加入溶剂S-5中搅拌反应，得到产物9，再将产物9和脱保护剂D-3加入溶剂S-6中搅拌反应，得到产物10；
将产物10和催化剂Pd/C加入溶剂S-7中，通入压力为1～30Mpa氢气进行反应，得到终产物四肽TP，其中：
R 3是芳基甲基；
R 4、R 5、R 6是Boc(叔丁氧甲酰基)、Cbz(苄氧甲酰基)或Fmoc(芴甲氧甲酰基)中的任一种；
缩合试剂C-1、C-2和C-3是碳二亚胺、或烷氧甲酰氯(R 7OCOCl)中的任一种，R 7是C 1～C 4的任意直链烷基或支链烷基；
添加剂A-1、A-2和A-3是指R 8R 9R 10N或NMM(N-甲基吗啉)或TMEDA(4-二甲氨基吡啶)或HOBt(1-羟基苯并三氮唑)，R 8、R 9、R 10是C 1～C 4的任意直链烷基或支链烷基；
溶剂S-1、S-2、S-3、S-4、S-5、S-6是甲苯、苯、二氯甲烷、二氯乙烷、乙醚、四氢呋喃、乙二醇二甲醚、甲基叔丁基醚、环氧六烷、乙酸乙酯、乙酸甲酯、乙腈或丙腈中的任一种或任数种的组合，溶剂S-7是甲醇、乙醇、丙醇或丁醇中的任一种或任数种的组合；
脱保护剂D-1、D-2和D-3是甲基磺酸、三氟甲磺酸、苯磺酸、对甲苯磺酸、三氟乙酸、三氯乙酸、盐酸、硫酸、哌啶、吗啉、四氢吡咯、二氢吡咯、吡咯、二乙胺、二丙胺、二丁胺、二异丙胺或二异丁胺中的任一种。
优选地，本发明所述的化合物制备方法是其中：
R 3是苄基；
R 4、R 5、R 6是指Boc或Cbz；
缩合试剂C-1、C-2和C-3是DCC(N,N'-二环己基碳二亚胺)或DIC(N,N'-二异丙基碳二亚胺)，或烷氧甲酰氯R 7OCOCl，R 7是Et或i-Pr或i-Bu；
添加剂A-1、A-2和A-3是TEA(三乙胺)、DIPEA(二异丙基乙胺)、NMM或HOBt中的任一种；
溶剂S-1、S-2、S-3、S-4、S-5和S-6是二氯甲烷或四氢呋喃，溶剂S-7是甲醇或乙醇；
脱保护剂D-1、D-2和D-3是甲基磺酸或三氟甲磺酸或三氟乙酸。
优选地，本发明所述的化合物制备方法是其中：
R 3是苄基；
R 4、R 5和R 6是Boc；
缩合试剂C-1、C-2和C-3是DCC或DIC或烷氧甲酰氯R 7OCOCl，R 7是Et或i-Pr或i-Bu；
添加剂A-1、A-2和A-3是指TEA、DIPEA、NMM或HOBt中的任一种；
溶剂S-1、S-2、S-3、S-4、S-5、S-6是指二氯甲烷或四氢呋喃，溶剂S-7是指甲醇；
脱保护剂D-1、D-2和D-3是指三氟乙酸；
氢气压力是8Mpa。
本发明所述的化合物可用于酮与芳香醛的Aldol反应，或者用于如式6所示催化脂肪醛与马来酰亚胺的不对称共轭加成反应。即：将式6所示的脂肪醛11、马来酰亚胺12和四肽TP加入含溶剂S-8的反应容器中搅拌，得到共轭加成反应的产物3-取代琥珀酰亚胺(R)-P，
Figure PCTCN2019119628-appb-000003
其中：R 11是氢或C 1～C 6的任意直链烷基或支链烷基或苯基或苯甲基，R 12是C 1～C 6的任意直链烷基或支链烷基或苯基或苯甲基，或-R 11-R 12-是环己基或环戊基，R 13是氢或苯基或取代苯基或直链烷基或环烷基或芳甲基；
四肽TP是如式1所示含两个末端D-型-α-伯氨基酸的四肽；
在上述反应中，溶剂S-8是指二氯甲烷、氯仿、二氯乙烷、乙酸乙酯、乙酸甲酯、甲苯、苯、二甲苯、乙醚、四氢呋喃、乙二醇二甲醚、甲基叔丁基醚、乙腈、丙腈、乙醇、甲醇、丙醇、丁醇中的任一种或多种。
优选地：
R 11是氢或甲基或乙基，R 12是甲基或乙基或异丙基或正丁基，或-R 11-R 12-是环己基或环戊基，R 13是氢或甲基或环己基或苯甲基或苯基或取代苯基，取代苯基是指对甲基苯基或对氯苯基或对溴苯基或对氟苯基或对硝基苯基或对甲氧基苯基；
四肽TP是前述TP-1～TP-6中的任一种；
溶剂S-8是二氯甲烷、乙腈、乙醇、四氢呋喃、二甲基亚砜、甲苯中的任一种。
更优选地四肽TP是TP-3；溶剂S-8是乙腈。
本发明用于制备式1示化合物TP的中间化合物为：如式3示6或者如式3示7或者如式4示9或者如式4示10。
本发明的化合物在不对称催化的脂肪醛与马来酰亚胺共轭反应过程中可以高产率、高对映选择性地催化脂肪醛与马来酰亚胺的共轭加成反应。根据相关实验，本发明的四肽化合物可以高效率、不对称地催化脂肪醛与马来酰亚胺的共轭加成反应，反应的产率达到98％，对映选择性最高达到了99％，应用前景良好。
具体实施方式
为了使本领域的技术人员更好地理解发明的技术方案，下面结合具体实施方式对本发明作进一步的详细说明。
本发明提供了一种如式1示四肽化合物TP，
Figure PCTCN2019119628-appb-000004
其中，R 1和R 2独立的选自C 1～C 6的任意直链烷基、支链烷基、环烷基、羟基取代烷基、巯基取代烷基、甲硫基取代烷基、氨基取代烷基、胍基取代烷基、芳基、芳甲基或杂原子芳基中的任一种。
按照本发明，所述R 1选自C 1～C 6的任意直链烷基、C 3～C 15的支链烷 基、C 3～C 8的环烷基、羟基取代的C 1～C 6的烷基、巯基取代的C 1～C 6的烷基、甲硫基取代的C 1～C 6的烷基、氨基取代的C 1～C 6的烷基、胍基取代的C 1～C 6的烷基、C 6～C 30的芳基、C 6～C 30的芳甲基或C 5～C 15的杂原子芳基；优选为甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、正己基、环丙基、环丁基、环戊基、环己基、环庚基、羟基甲基、2-羟基乙基、1-羟基乙基(MeCH(OH)-)、氨基甲基、2-氨基乙基、3-氨基正丙基、4-氨基正丁基、巯基甲基、2-巯基乙基、甲硫基甲基、2-甲硫基乙基、苯基、萘基、蒽基、菲基、呋喃基、吡啶基、吡喃基、哌啶基、苯基甲基、萘基甲基或蒽基甲基。
所述R 2选自C 1～C 6的任意直链烷基、C 3～C 15的支链烷基、C 3～C 8的环烷基、羟基取代的C 1～C 6的烷基、巯基取代的C 1～C 6的烷基、甲硫基取代的C 1～C 6的烷基、氨基取代的C 1～C 6的烷基、胍基取代的C 1～C 6的烷基、C 6～C 30的芳基、C 6～C 30的芳甲基或C 5～C 15的杂原子芳基，优选为甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、正己基、环丙基、环丁基、环戊基、环己基、环庚基、羟基甲基、2-羟基乙基、1-羟基乙基(MeCH(OH)-)、氨基甲基、2-氨基乙基、3-氨基正丙基、4-氨基正丁基、巯基甲基、2-巯基乙基、甲硫基甲基、2-甲硫基乙基、苯基、萘基、蒽基、菲基、呋喃基、吡啶基、吡喃基、哌啶基、苯基甲基、萘基甲基或蒽基甲基。
更具体的，所述具有式(I)结构的四肽化合物TP中，
所述R 1为i-Bu,R 2为i-Pr，即四肽化合物TP的氨基酸序列为H 2N-D-Val-Pro-Gly-D-Leu-OH，命名为TP-1；
所述R 1为i-Bu,R 2为t-Bu，即四肽化合物TP的氨基酸序列为H 2N-D-Tle-Pro-Gly-D-Leu-OH，命名为TP-2；
所述R 1为i-Bu,R 2为Ph，即四肽化合物TP的氨基酸序列为H 2N-D-Phg-Pro-Gly-D-Leu-OH，命名为TP-3；
所述R 1为i-Bu,R 2为c-hex，即四肽化合物TP的氨基酸序列为H 2N-D-Chg-Pro-Gly-D-Leu-OH，命名为TP-4；
所述R 1为i-Bu,R 2为Bn，即四肽化合物TP的氨基酸序列为 H 2N-D-Phe-Pro-Gly-D-Leu-OH，命名为TP-5；
所述R 1为Bn,R 2为Bn，即：其四肽化合物TP的氨基酸序列为H 2N-D-Phe-Pro-Gly-D-Phe-OH，命名为TP-6。
本发明还提供了一种本发明所述的式1所示四肽化合物TP的制备方法，包括：
1)将产物7和氨基酸8混合反应，得到产物9；
Figure PCTCN2019119628-appb-000005
其中，R 1和R 2独立的选自C 1～C 6的任意直链烷基、支链烷基、环烷基、羟基取代烷基、巯基取代烷基、甲硫基取代烷基、氨基取代烷基、胍基取代烷基、芳基、芳甲基或杂原子芳基中的任一种；
R 3是芳基甲基；
R 6选自叔丁氧甲酰基、苄氧甲酰基或芴甲氧甲酰基；
2)将产物9转化成式1所示四肽化合物TP；
Figure PCTCN2019119628-appb-000006
按照本发明，本发明将产物7和氨基酸8混合反应，得到产物9；其中，所述缩合反应的缩合试剂为碳二亚胺、或烷氧甲酰氯(R 7OCOCl)，其中，R 7是C 1～C 4的任意直链烷基或支链烷基；所述反应的添加剂为R 8R 9R 10N、NMM(N-甲基吗啉)、TMEDA(4-二甲氨基吡啶)或HOBt(1-羟基苯并三氮唑)，其中，R 8、R 9、R 10独立的选自C 1～C 4的任意直链烷基或支链烷基；所述反应的溶剂优选为甲苯、苯、二氯甲烷、二氯乙烷、乙醚、四氢呋喃、乙二醇二甲醚、甲基叔丁基醚、环氧六烷、乙酸乙酯、乙酸甲酯、乙腈和丙腈中的一种或几种。
本发明中，本发明对所述产物7的来源没有特殊要求，优选按照以 下方法制备得到：
A-1)将产物4与脯氨酸5反应，得到产物6；其中，所述反应的缩合试剂为碳二亚胺、或烷氧甲酰氯(R 7OCOCl)，其中，R 7是C 1～C 4的任意直链烷基或支链烷基；所述反应的添加剂为R 8R 9R 10N、NMM(N-甲基吗啉)、TMEDA(4-二甲氨基吡啶)或HOBt(1-羟基苯并三氮唑)，其中，R 8、R 9、R 10独立的选自C 1～C 4的任意直链烷基或支链烷基；所述反应的溶剂优选为甲苯、苯、二氯甲烷、二氯乙烷、乙醚、四氢呋喃、乙二醇二甲醚、甲基叔丁基醚、环氧六烷、乙酸乙酯、乙酸甲酯、乙腈和丙腈中的一种或几种。
Figure PCTCN2019119628-appb-000007
其中，R 1选自C 1～C 6的任意直链烷基、支链烷基、环烷基、羟基取代烷基、巯基取代烷基、甲硫基取代烷基、氨基取代烷基、胍基取代烷基、芳基、芳甲基或杂原子芳基中的任一种；
R 3是芳基甲基；
R 5选自叔丁氧甲酰基、苄氧甲酰基或芴甲氧甲酰基；
A-2)将产物6转化成产物7，其中，所述转化反应的脱保护剂优选为甲基磺酸、三氟甲磺酸、苯磺酸、对甲苯磺酸、三氟乙酸、三氯乙酸、盐酸、硫酸、哌啶、吗啉、四氢吡咯、二氢吡咯、吡咯、二乙胺、二丙胺、二丁胺、二异丙胺或二异丁胺；所述反溶剂优选为甲苯、苯、二氯甲烷、二氯乙烷、乙醚、四氢呋喃、乙二醇二甲醚、甲基叔丁基醚、环氧六烷、乙酸乙酯、乙酸甲酯、乙腈和丙腈中的一种或几种。
本发明中，所述产物4按照以下方法制备得到：
B-1)将甘氨酸1和氨基酸2混合反应，得到产物3；其中，所述反应的缩合试剂为碳二亚胺、或烷氧甲酰氯R 7OCOCl，其中，R 7是C 1～C 4的任意直链烷基或支链烷基；所述反应的添加剂为R 8R 9R 10N、NMM(N-甲基吗啉)、TMEDA(4-二甲氨基吡啶)或HOBt(1-羟基苯并三氮唑)，其中，R 8、R 9、R 10独立的选自C 1～C 4的任意直链烷基或支链烷基；所述 反应的溶剂优选为甲苯、苯、二氯甲烷、二氯乙烷、乙醚、四氢呋喃、乙二醇二甲醚、甲基叔丁基醚、环氧六烷、乙酸乙酯、乙酸甲酯、乙腈和丙腈中的一种或几种。
Figure PCTCN2019119628-appb-000008
其中，R 1选自C 1～C 6的任意直链烷基、支链烷基、环烷基、羟基取代烷基、巯基取代烷基、甲硫基取代烷基、氨基取代烷基、胍基取代烷基、芳基、芳甲基或杂原子芳基中的任一种；
R 3是芳基甲基；
R 4、R 5独立的选自叔丁氧甲酰基、苄氧甲酰基或芴甲氧甲酰基；
B-2)将产物3转化成产物4，其中，所述转化反应的脱保护剂优选为甲基磺酸、三氟甲磺酸、苯磺酸、对甲苯磺酸、三氟乙酸、三氯乙酸、盐酸、硫酸、哌啶、吗啉、四氢吡咯、二氢吡咯、吡咯、二乙胺、二丙胺、二丁胺、二异丙胺或二异丁胺；所述反溶剂优选为甲苯、苯、二氯甲烷、二氯乙烷、乙醚、四氢呋喃、乙二醇二甲醚、甲基叔丁基醚、环氧六烷、乙酸乙酯、乙酸甲酯、乙腈和丙腈中的一种或几种。
按照本发明，所述步骤2)具体为：
将式产物9通过脱保护，得到产物10；其中，所述脱保护用脱保护剂优选为甲基磺酸、三氟甲磺酸、苯磺酸、对甲苯磺酸、三氟乙酸、三氯乙酸、盐酸、硫酸、哌啶、吗啉、四氢吡咯、二氢吡咯、吡咯、二乙胺、二丙胺、二丁胺、二异丙胺或二异丁胺；所述反溶剂优选为甲苯、苯、二氯甲烷、二氯乙烷、乙醚、四氢呋喃、乙二醇二甲醚、甲基叔丁基醚、环氧六烷、乙酸乙酯、乙酸甲酯、乙腈和丙腈中的一种或几种。
Figure PCTCN2019119628-appb-000009
其中，R 1、R 2独立的选自C 1～C 6的任意直链烷基、支链烷基、环烷 基、羟基取代烷基、巯基取代烷基、甲硫基取代烷基、氨基取代烷基、胍基取代烷基、芳基、芳甲基或杂原子芳基中的任一种；
R 3是芳基甲基；
R 6选自叔丁氧甲酰基、苄氧甲酰基或芴甲氧甲酰基；
将产物10进行催化加氢反应，得到式1所示四肽化合物TP。
更具体的，所述式1所示四肽化合物TP的制备方法具体为：反应历程如式2、式3、式4和式5所示，即：
Figure PCTCN2019119628-appb-000010
将甘氨酸1、氨基酸2、缩合试剂C-1和添加剂A-1加入溶剂S-1搅拌反应，得到产物3，再将产物3和脱保护剂D-1加入溶剂S-2搅拌反应，得到产物4；
将产物4、脯氨酸5、缩合试剂C-2和添加剂A-2加入溶剂S-3中搅拌反应，得到产物6，再将产物6和脱保护剂D-2加入溶剂S-4中搅拌反应，得到产物7；
将产物7、氨基酸8、缩合试剂C-3和添加剂A-3加入溶剂S-5中搅拌反应，得到产物9，再将产物9和脱保护剂D-3加入溶剂S-6中搅拌反应，得到产物10；
将产物10和催化剂Pd/C加入溶剂S-7中，通入压力为1～30Mpa氢气进行反应，得到终产物四肽TP，其中：
R 3是芳基甲基；
R 4、R 5、R 6是Boc(叔丁氧甲酰基)、Cbz(苄氧甲酰基)或Fmoc(芴甲氧甲酰基)中的任一种；
缩合试剂C-1、C-2和C-3是碳二亚胺、或烷氧甲酰氯(R 7OCOCl)中的任一种，R 7是C 1～C 4的任意直链烷基或支链烷基；
添加剂A-1、A-2和A-3是指R 8R 9R 10N或NMM(N-甲基吗啉)或TMEDA(4-二甲氨基吡啶)或HOBt(1-羟基苯并三氮唑)，R 8、R 9、R 10是C 1～C 4的任意直链烷基或支链烷基；
溶剂S-1、S-2、S-3、S-4、S-5、S-6是甲苯、苯、二氯甲烷、二氯乙烷、乙醚、四氢呋喃、乙二醇二甲醚、甲基叔丁基醚、环氧六烷、乙酸乙酯、乙酸甲酯、乙腈或丙腈中的任一种或任数种的组合，溶剂S-7是甲醇、乙醇、丙醇或丁醇中的任一种或任数种的组合；
脱保护剂D-1、D-2和D-3是甲基磺酸、三氟甲磺酸、苯磺酸、对甲苯磺酸、三氟乙酸、三氯乙酸、盐酸、硫酸、哌啶、吗啉、四氢吡咯、二氢吡咯、吡咯、二乙胺、二丙胺、二丁胺、二异丙胺或二异丁胺中的任一种。
其中，本发明的一个优选方案中，
所述R 3是苄基；
所述R 4、R 5、R 6是独立的选自Boc或Cbz；
缩合试剂C-1、C-2和C-3独立的选自DCC(N,N'-二环己基碳二亚胺)或DIC(N,N'-二异丙基碳二亚胺)或烷氧甲酰氯R 7OCOCl，
其中，R 7是Et或i-Pr或i-Bu；
添加剂A-1、A-2和A-3独立的选自TEA(三乙胺)、DIPEA(二异丙基乙胺)、NMM或HOBt中的任一种；
溶剂S-1、S-2、S-3、S-4、S-5和S-6独立的选自二氯甲烷或四氢呋喃，溶剂S-7选自甲醇或乙醇；
脱保护剂D-1、D-2和D-3独立的选自甲基磺酸或三氟甲磺酸或三氟乙酸。
本发明的另一个优选方案中，
所述R 3是苄基；
所述R 4、R 5和R 6独立的选自Boc；
缩合试剂C-1、C-2和C-3独立的选自DCC、DIC或烷氧甲酰氯R 7OCOCl，其中，R 7选自Et或i-Pr或i-Bu；
添加剂A-1、A-2和A-3独立的选自TEA、DIPEA、NMM或HOBt中的任一种；
溶剂S-1、S-2、S-3、S-4、S-5、S-6独立的选自二氯甲烷或四氢呋喃，溶剂S-7为甲醇；
脱保护剂D-1、D-2和D-3独立的选自三氟乙酸；
氢气压力是8Mpa。
本发明还提供了一种用于催化脂肪醛与马来酰亚胺的不对称共轭加成反应的催化剂，其中，所述催化剂为本发明所述的式1示四肽化合物TP，所述脂肪醛的结构如11所示，所述马来酰亚胺的结构如12所示；所述不对称共轭加成的产物具有(R)-P所示结构；所述共轭加成反应的溶剂为二氯甲烷、氯仿、二氯乙烷、乙酸乙酯、乙酸甲酯、甲苯、苯、二甲苯、乙醚、四氢呋喃、乙二醇二甲醚、甲基叔丁基醚、乙腈、丙腈、乙醇、甲醇、丙醇或丁醇。
Figure PCTCN2019119628-appb-000011
R 11为氢、C 1～C 6的任意直链烷基、支链烷基、苯基或苯甲基，更优选为氢、甲基或乙基；R 12为C 1～C 6的任意直链烷基、支链烷基、苯基或苯甲基，优选为甲基、乙基、异丙基或正丁基；或-R 11-R 12-为环己基或环戊基，R 13为氢、苯基、取代苯基、直链烷基、环烷基或芳甲基，优选为氢、甲基、环己基、苯甲基、苯基或取代苯基，取代苯基是指对甲基苯基、对氯苯基、对溴苯基、对氟苯基、对硝基苯基或对甲氧基苯基。
本发明还提供了一种用于制备式1示化合物TP的中间化合物，其结构如式3示6。
本发明还提供了一种用于制备式1示化合物TP的中间化合物，其结构如式3示7。
本发明还提供了一种用于制备式1示化合物TP的中间化合物，其结构如式4示9。
本发明还提供了一种用于制备式1示化合物TP的中间化合物，其结构如式4示10。
本发明的化合物TP在不对称催化的脂肪醛与马来酰亚胺共轭反应过程中可以高产率、高对映选择性地催化脂肪醛与马来酰亚胺的共轭加成反应。根据相关实验，本发明的四肽化合物可以高效率、不对称地催化脂肪醛与马来酰亚胺的共轭加成反应，反应的产率达到98％，对映选择性最高达到了99％，应用前景良好。
以上是对发明内容的详细分析，下面结合实施例对本申请作进一步详细描述，有必要在此指出的是，以下具体实施方式只用于对本申请进行进一步的说明，不能理解为对本申请保护范围的限制，该领域的技术人员可以根据上述申请内容对本申请作出一些非本质的改进和调整。
实施例1
一、四肽化合物TP的制备
本发明式1示四肽化合物TP的制备的反应历程参见前述的式2至式5，其制备方法参见发明内容部分，更详细地制备过程如下:
(一)合成二肽
1.1Boc-Gly-D-Leu-OBn(3a)
Figure PCTCN2019119628-appb-000012
参见上式，把Boc-Gly-OH 1(8.75g，50mmol)加入到100mL的无水THF中，氩气保护下在冰盐浴中搅拌5min，使反应液的温度下降到–15℃，加入NMM(6.2mL，55mmol)，接着把氯甲酸异丁酯(7mL，55mmol)缓慢滴加到反应液中。搅拌5min后，加入事先用无水DMF溶解的D-Leu-OBn 2a对甲苯磺酸盐(19.7g，50mmol)和NMM(6.2mL)的溶液，在–15℃下继续搅拌反应0.5h，撤走冰盐浴，自然恢复反应液至室温，反应过夜。待反应结束后，抽滤除去不溶物，滤液减压浓缩，再用乙酸乙酯溶解，乙酸乙酯相依次用1M NaOH溶液、水、1M盐酸溶 液和少量饱和食盐水洗涤，无水硫酸钠干燥后，减压浓缩得到Boc-Gly-D-Leu-OBn(3a)19g，为淡黄色油状液体，产率100％.[α] D 20＝+5.0(c 1.0,CHCl 3)； 1H NMR(200MHz,CDCl 3)δ7.34–7.28(m,5H),6.94–6.90(d,J＝6.8Hz,1H),5.51(m,1H),5.15(s,2H),4.69–4.64(m,1H),3.83–3.81(m,2H),1.62–1.51(m,3H),1.44(s,9H),0.91–0.89(m,6H)； 13C NMR(100MHz,CDC 13)δ172.6,169.4,156.0,135.3,128.5,128.4,128.2,128.0,80.0,66.9,50.7,44.1,41.1,28.1,24.7,22.7,21.7；ESI-MS calcd for[C 20H 30N 2O 5+H +]379.2,found:379.3.
Figure PCTCN2019119628-appb-000013
或者如上式，把Boc-Gly-OH 1(8.75g，50mmol)加入到100mL的无水THF中，氩气保护下在冰盐浴中搅拌5min，使反应液的温度下降到–15℃，加入NMM(6.2mL，55mmol)，接着把氯甲酸乙酯(5.3mL，55mmol)缓慢滴加到反应液中。搅拌5min后，加入事先用无水DMF溶解的D-Leu-OBn 2a对甲苯磺酸盐(19.7g，50mmol)和NMM(6.2mL)的溶液，在–15℃下继续搅拌反应半小时，撤走冰盐浴，自然恢复反应液至室温，反应过夜。待反应结束后，抽滤除去不溶物，滤液减压浓缩，再用乙酸乙酯溶解，乙酸乙酯相依次用1M NaOH溶液、水、1M盐酸溶液和少量饱和食盐水洗涤，无水硫酸钠干燥后，减压浓缩得到Boc-Gly-D-Leu-OBn(3a)17.30g，为淡黄色油状液体，产率91％。
Figure PCTCN2019119628-appb-000014
或者参见上式，把Boc-Gly-OH 1(8.75g，50mmol)加入到100mL的无水THF中，氩气保护下在冰盐浴中搅拌5min，使反应液的温度下降到–15℃，加入NMM(6.2mL，55mmol)，接着把氯甲酸异丙酯(6.3mL，55mmol)缓慢滴加到反应液中。搅拌5min后，加入事先用无水DMF溶解的D-Leu-OBn 2a对甲苯磺酸盐(19.7g，50mmol)和NMM(6.2mL)的溶液，在–15℃下继续搅拌反应0.5h，撤走冰盐浴，自然恢复反应液至室温，反应过夜。待反应结束后，抽滤除去不溶物，滤液减压浓缩，再 用乙酸乙酯溶解，乙酸乙酯相依次用1M NaOH溶液、水、1M盐酸溶液和少量饱和食盐水洗涤，无水硫酸钠干燥后，减压浓缩得到Boc-Gly-D-Leu-OBn(3a)17.67g，为淡黄色油状液体，产率93％。
Figure PCTCN2019119628-appb-000015
或者如上式，把Boc-Gly-OH(8.75g，50mmol)加入到100mL的无水THF中，氩气保护下在冰盐浴中搅拌5min，使反应液的温度下降到–15℃，加入TEA(三乙胺，7.6mL，55mmol)，接着把氯甲酸异丁酯(7mL，55mmol)缓慢滴加到反应液中。搅拌5min后，加入事先用无水DMF溶解的D-Leu-OBn对甲苯磺酸盐(19.7g，50mmol)和TEA(7.6mL)的溶液，在–15℃下继续搅拌反应0.5h，撤走冰盐浴，自然恢复反应液至室温，反应过夜。待反应结束后，抽滤除去不溶物，滤液减压浓缩，再用乙酸乙酯溶解，乙酸乙酯相依次用1M NaOH溶液、水、1M盐酸溶液和少量饱和食盐水洗涤，无水硫酸钠干燥后，减压浓缩得到Boc-Gly-D-Leu-OBn(3a)16.48g，为淡黄色油状液体，产率87％。
Figure PCTCN2019119628-appb-000016
或者如上式，把Boc-Gly-OH 1(8.75g，50mmol)加入到100mL的无水THF中，氩气保护下在冰盐浴中搅拌5min，使反应液的温度下降到–15℃，加入DIPEA(二异丙基乙胺，9.6mL，55mmol)，接着把氯甲酸异丁酯(7mL，55mmol)缓慢滴加到反应液中。搅拌5min后，加入事先用无水DMF溶解的D-Leu-OBn 2a对甲苯磺酸盐(19.7g，50mmol)和DIPEA(9.6mL)的溶液，在–15℃下继续搅拌反应0.5h，撤走冰盐浴，自然恢复反应液至室温，反应过夜。待反应结束后，抽滤除去不溶物，滤液减压浓缩，再用乙酸乙酯溶解，乙酸乙酯相依次用1M NaOH溶液、水、1M盐酸溶液和少量饱和食盐水洗涤，无水硫酸钠干燥后，减压浓缩得到Boc-Gly-D-Leu-OBn(3a)15.47g，为淡黄色油状液体，产率81％。
1.2 合成Boc-Gly-D-Phe-OBn(3b)
Figure PCTCN2019119628-appb-000017
把Boc-Gly-OH 1(8.75g，50mmol)加入到100mL的无水THF中，氩气保护下在冰盐浴中搅拌5min，使反应液的温度下降到-15℃，加入NMM(6.2mL，55mmol)，接着把氯甲酸异丁酯(7mL，55mmol)缓慢滴加到反应液中。搅拌5min后，加入事先用无水DMF溶解的D-Phe-OBn 2b的对甲苯磺酸盐(21.35g，50mmol)和NMM(6.2mL)的溶液，在-15℃下继续搅拌反应0.5h，撤走冰盐浴，自然恢复反应液至室温反应过夜。待反应结束后，抽滤除去不溶物，滤液减压浓缩，再用乙酸乙酯溶解，乙酸乙酯相依次用1M NaOH溶液、水、1M盐酸溶液和少量饱和食盐水洗涤，无水硫酸钠干燥后，减压浓缩得到淡黄色油状物的Boc-Gly-D-Phe-OBn(3b)，石油醚和乙酸乙酯柱层析纯化得到白色固体19.16g，产率93％。White solid,Mp 73.5-75℃；[α] D 25＝-11.6(c 0.5,CHCl 3)； 1H NMR(600MHz,CDCl 3)δ7.35(m,3H),7.30–7.27(m,1H),7.23–7.18(m,2H),7.13–6.86(m,2H),6.63(d,J＝5.7Hz,1H),5.16-5.08(m,2H),4.92(dd,J＝6,12Hz,1H),3.86–3.71(m,2H),3.15–3.05(m,2H),1.44(d,J＝8.5Hz,9H). 13C NMR(150MHz,CDCl 3)δ171.1,169.1,135.5,135.0,129.3,128.6,128.6,128.5,128.5,128.4,128.2,127.1,77.2,77.0,76.8,67.3,53.1,41.4,37.9,28.3(s),24.8,22.8,21.8；ESI-MS calcd for[C 23H 28N 2O 5+H +]413.2,found 413.2.。
(二)合成化合物4
2.1 合成NH 2-Gly-D-Leu-OBn(4a)
Figure PCTCN2019119628-appb-000018
把上面反应得到的二肽Boc-Gly-D-Leu-OBn 3a(19g)溶于50mL二氯甲烷中，反应液冷却至0℃，向其中缓慢滴加TFA(三氟乙酸，50mL)，自然恢复反应溶液至室温下搅拌5h后，把反应液减压浓缩除去TFA，残留物用二氯甲烷溶解，用1.0M NaOH水溶液在0℃条件下调pH＝9.0左右，分离有机相，水相用二氯甲烷(20mL×3)萃取。合并有机相， 依次用少量饱和食盐水洗涤有机相、无水硫酸钠干燥后，减压浓缩，得到产物NH 2-Gly-D-Leu-OBn(4a)为无色油状液体，产率13.25g(95％)。无需纯化，直接用于下一步反应。
Figure PCTCN2019119628-appb-000019
或者如上式，把上面反应得到的二肽Boc-Gly-D-Leu-OBn 3a(19g)溶于50mL二氯甲烷中，反应液冷却至0℃，向其中缓慢滴加甲基磺酸(50mL)，自然恢复反应溶液至室温下搅拌5h后，用1.0M NaOH水溶液在0℃条件下调pH＝9.0左右，分离有机相，水相用二氯甲烷(20mL×3)萃取。合并有机相，依次用少量饱和食盐水洗涤有机相、无水硫酸钠干燥后，减压浓缩，得到产物NH 2-Gly-D-Leu-OBn(4a)为无色油状液体，产率12.83g(92％)。无需纯化，直接用于下一步反应。
Figure PCTCN2019119628-appb-000020
或者如上式，把上面反应得到的二肽Boc-Gly-D-Leu-OBn 3a(19g)溶于50mL二氯甲烷中，反应液冷却至0℃，向其中缓慢滴加三氟甲磺酸(50mL)，自然恢复反应溶液至室温下搅拌5h后，用1.0M NaOH水溶液在0℃条件下调pH＝9.0左右，分离有机相，水相用二氯甲烷(20mL×3)萃取。合并有机相，依次用少量饱和食盐水洗涤有机相、无水硫酸钠干燥后，减压浓缩，得到产物NH 2-Gly-D-Leu-OBn(4a)为无色油状液体，产率12.7g(91％)。无需纯化，直接用于下一步反应。
2.2 合成H 2N-Gly-D-Phe-OBn(4b)
Figure PCTCN2019119628-appb-000021
把上面反应得到的二肽Boc-Gly-D-Phe-OBn 3b(18.2g,44mmol)溶于44mL二氯甲烷中，反应液冷却至0℃，向其中缓慢滴加TFA(44mL)，自然恢复反应溶液至室温下搅拌5h后，把反应液减压浓缩除去TFA，残留物用二氯甲烷溶解，用1M NaOH水溶液在0℃条件下调pH＝9.0左 右，分离有机相，水相用二氯甲烷(20mL×3)萃取。合并有机相，依次用少量饱和食盐水洗涤有机相、无水硫酸钠干燥后，减压浓缩，得到产物NH 2-Gly-D-Leu-OBn(4b)为无色油状液体，产率12.5g(91％)。无需纯化，直接用于下一步反应。
(三)中间化合物6的合成
3.1 合成Boc-Pro-Gly-D-Leu-OBn(6a)
Figure PCTCN2019119628-appb-000022
将Boc-Pro-OH 5(9.68g，45mmol)加入到100mL的无水THF中，氩气保护下在冰盐浴中搅拌5min使反应液的温度下降到–15℃，加入NMM(5.6mL，50mmol)，把氯甲酸异丁酯(6.4mL，50mmol)缓慢滴加到反应液中，搅拌5min后，加入预先用无水THF溶解的二肽NH 2-Gly-D-Leu-OBn 4a(12.56g，45mmol)和NMM(5.6mL)的溶液。冰盐浴下继续搅拌30min，撤走冰盐浴，使反应自然恢复至室温，反应搅拌过夜至反应结束，抽滤出去不溶物，滤液减压浓缩，残余油状物用乙酸乙酯溶解，然后依次用1.0M NaOH溶液、水、1.0M盐酸溶液和饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩，得到淡黄色油状液体的Boc-Pro-Gly-D-Leu-OBn(6a)，用石油醚和乙酸乙酯柱层析纯化得到20.33g产物，产率95％。White solid,Mp:104–105℃；[α] D 20＝-27(c 1.0,CHCl 3)； 1H NMR(400MHz,CDCl 3)δ7.38–7.32(m,5H),7.22(br,1H),7.03(br,1H),5.08–5.07(dd,J＝12.8Hz,J＝21.6Hz,2H),4.57–4.55(m,1H),4.25–4.11(m,2H),3.86–3.81(dd,J＝4.8Hz,J＝17.2Hz,1H),3.50–3.40(m,2H),2.15–2.11(m,2H),1.92–1.89(m,2H),1.60–1.73(m,3H),1.44(s,9H),0.92–0.89(m,6H)； 13C NMR(100MHz,CDCl 3)δ172.5,169.3,155.8,128.5,128.1,128.0,109.7,80.8,66.7,60.9,51.0,47.4,42.8,40.1,29.5,28.3,24.7,24.6,22.8,21.5；ESI-MS calcd for[C 25H 37N 3O 6+H +]476.3,found:476.3.。
3.2 合成Boc-Pro-Gly-D-Phe-OBn(6b)
Figure PCTCN2019119628-appb-000023
将Boc-Pro-OH 5(7.53g，35mmol)加入到100mL的无水THF中，氩气保护下在冰盐浴中搅拌5min使反应液的温度下降到-15℃，加入NMM(4.3mL，38.5mmol)，把氯甲酸异丁酯(4.9mL，38.5mmol)缓慢滴加到反应液中，搅拌5min后，加入预先用无水THF溶解的二肽NH 2-Gly-D-Phe-OBn 4b(10.92g，35mmol)和NMM(4.3mL)的溶液。冰盐浴下继续搅拌30min，撤走冰盐浴，使反应自然恢复至室温，反应搅拌过夜至反应结束，抽滤出去不溶物，滤液减压浓缩，残余油状物用乙酸乙酯溶解，然后依次用1M NaOH溶液、水、1M盐酸溶液和饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩用石油醚和乙酸乙酯柱层析纯化得到Boc-Pro-Gly-D-Phe-OBn(6b)产物，17.1g，产率96％。White solid,Mp100-102℃；[α] D 25＝-66.0(c 0.5,CHCl 3)； 1H NMR(600MHz,CDCl 3)δ7.34(d,J＝6.5Hz,2H),7.27(s,1H),7.21(t,J＝7.3Hz,2H),7.13–6.89(m,3H),6.54(m,1H),5.12(t,J＝14.8Hz,2H),4.84(s,1H),4.22(s,1H),3.92(d,J＝33.6Hz,2H),3.51–3.33(m,2H),3.17-3.05(m,2H),2.23–2.00(m,2H),1.86(s,2H),1.45(s,9H). 13C NMR(150MHz,CDCl 3)δ172.5,171.1,168.8,136.1,135.3,129.3,129.2,128.6,128.5,128.4,127.0,80.7,77.3,77.0,76.8,67.1,60.6,53.6,47.32,43.0,37.6,28.4,24.6；ESI-MS calcd for[C 28H 35N 3O 6+H +]510.2,found 510.2.。
(四)中间化合物7的合成
4.1 合成NH 2-Pro-Gly-D-Leu-OBn(7a)
Figure PCTCN2019119628-appb-000024
将合成的的三肽Boc-Pro-Gly-D-Leu-OBn 6a(19g，40mmol)完全溶于CH 2Cl 2(40mL)中，在0℃下缓慢滴加TFA(40mL)，恢复反应液至室温下，搅拌5h。将反应液减压浓缩尽量除去TFA，残留物用CH 2Cl 2溶解，再用1M NaOH溶液在0℃下中和至约pH＝9.0左右。分离出有机相，水相用CH 2Cl 2(20mL×3)萃取。合并有机相，饱和食盐水洗一 次，无水硫酸钠干燥，减压浓缩，得到13.54g无色油状液体的NH 2-Pro-Gly-D-Leu-OBn(7a)，产率为90％，无需纯化，直接用于下一步反应。
4.2 合成Pro-Gly-D-Phe-OBn(7b)
Figure PCTCN2019119628-appb-000025
将合成的三肽Boc-Pro-Gly-D-Phe-OBn 6b(16.5g,32mmol)完全溶于CH 2Cl 2(32mL)中，在0℃下缓慢滴加TFA(32mL)，恢复反应液至室温下，搅拌5h。将反应液减压浓缩尽量除去TFA，残留物用CH 2Cl 2溶解，再用1M NaOH溶液在0℃下中和至约pH＝9.0左右。分离出有机相，水相用CH 2Cl 2(20mL×3)萃取。合并有机相，饱和食盐水洗一次，无水硫酸钠干燥，减压浓缩，得到11.8g无色油状液体的Pro-Gly-D-Phe-OBn(7b)，产率为90％。无需纯化，直接用于下一步反应。
(五)中间化合物9的合成
5.1 合成Boc-D-Val-Pro-Gly-D-Leu-OBn(9a)
Figure PCTCN2019119628-appb-000026
把HOBt(4.45g,33mmol)，Boc-D-Val-OH 8a(6.45g，30mmol)加入到150mL的圆底烧瓶中，氩气保护，加入60mL干燥的THF，0℃下搅拌，待瓶内温度降至0℃时，缓慢滴加DIC(N,N'-二异丙基碳二亚胺，5.1mL，33mmol)，0.5h之后加入事先用THF溶解好的三肽Pro-Gly-D-Leu-OBn 7a(11.28g,30mmol)。室温搅拌48h后滤去不溶物，滤液减压浓缩干。残留物用乙酸乙酯溶解，然后依次用1M NaOH溶液、水、1M盐酸溶液和饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩后用石油醚和乙酸乙酯柱层析纯化，得到14.84g白色固体四肽Boc-D-Val-Pro-Gly-D-Leu-OBn(9a)，产率86％。White solid，Mp:123.5–125.5℃；[α] D 20＝+15(c 0.7,CHCl 3)； 1H NMR(400MHz,CDCl 3)δ7.36–7.30(m,5H),7.24–7.23(m,1H),5.34–5.32(d,J＝6.8Hz,1H),5.20–5.13(dd,J＝ 12.4Hz,J＝14.8Hz,2H),4.64–4.59(m,1H),4.50–4.50(t,J＝6.0Hz,l H),4.20–4.14(dd,J＝7.2Hz,J＝16.8Hz,1H),4.07(m,1H),3.98–3.94(m,1H),3.65–3.56(m,2H),2.21–2.16(m,2H),2.09–1.99(m,2H),1.95–1.90(m,1H),1.76–1.61(m,3H),1.40(s,9H),1.01–1.00(d,J＝6.8Hz,3H),0.97–0.95(d,J＝6.8Hz,3H),0.92–0.88(m,6H)； 13C NMR(100MHz,CDCl 3)δ172.6,171.7,169.0,156.9,135.7,128.4,128.0,127.8,80.3,66.4,61.0,58.2,50.7,47.6,43.1,40.7,30.1,29.2,28.1,24.6,23.4,22.8,21.7,19.1,18.8；ESI-MS calcd for[C 30H 46N 4O 7+H +]575.3,found 575.3.
Figure PCTCN2019119628-appb-000027
或者如上式示，把HOBt(4.45g,33mmol)，Boc-D-Val-OH 8a(6.51g，30mmol)加入到150mL的圆底烧瓶中，氩气保护，加入60mL干燥的THF，0℃下搅拌，待瓶内温度降至0℃时，缓慢滴加用DMF溶解的DCC(N,N'-二环己基碳二亚胺，6.8g，33mmol)，0.5h之后加入事先用THF溶解好的三肽Pro-Gly-D-Leu-OBn 7a(11.28g,30mmol)。室温搅拌48h后滤去不溶物，滤液减压浓缩干。残留物用乙酸乙酯溶解，然后依次用1M NaOH溶液、水、1M盐酸溶液和饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩后用石油醚和乙酸乙酯柱层析纯化，得到12.42g白色固体四肽Boc-D-Val-Pro-Gly-D-Leu-OBn(9a)，产率72％。
5.2 合成Boc-D-Tle-Pro-Gly-D-Leu-OBn(9b)
Figure PCTCN2019119628-appb-000028
把HOBt(4.45g,33mmol)，Boc-D-Tle-OH 8b(6.93g，30mmol)加入到150mL的圆底烧瓶中，氩气保护，加入60mL干燥的THF，0℃下搅拌，待瓶内温度降至0℃时，缓慢滴加DIC(5.1mL，33mmol)，0.5h之后加入事先用THF溶解好的三肽Pro-Gly-D-Leu-OBn 7a(11.28g,30mmol)。室温搅拌48h后滤去不溶物，滤液减压浓缩干。残留物用乙酸乙酯溶解，然后依次用1M NaOH溶液、水、1M盐酸溶液和饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩后用石油醚和乙酸乙酯柱层析纯化， 得到15.02g白色固体的四肽Boc-D-Tle-Pro-Gly-D-Leu-OBn(9b)，产率85％。White solid,Mp 168–169.4℃；[α] D 25＝+9.0(c 0.5,CHCl 3)； 1H NMR(600MHz,CDCl 3)δ7.47(d,J＝7.7Hz,1H),7.35(d,J＝4.4Hz,3H),7.33–7.28(m,1H),7.08–7.03(m,1H),5.48(d,J＝7.1Hz,1H),5.19–5.12(m,2H),4.62-4.55(m,1H),4.46(dd,J＝7.5,4.9Hz,1H),4.22(dd,J＝17.2,7.9Hz,1H),4.15–4.10(m,1H),4.07(d,J＝7.1Hz,1H),3.65–3.59(m,1H),3.56(dd,J＝17.1,5.1Hz,1H),2.20–2.15(m,2H),2.09–2.03(m,1H),2.00(dd,J＝11.3,5.3Hz,1H),1.77–1.56(m,4H),1.40(s,9H),1.04(s,9H),0.88(dd,J＝12.8,6.4Hz,6H). 13C NMR(150MHz,CDCl 3)δ172.7,172.2,171.7,169.1,135.91,128.5,128.1,128.0,77.24,77.0,76.8,66.4,61.3,59.7,50.9,48.3,43.2,40.7,33.9,29.4,28.2,26.5,24.8,24.7,22.8,21.8；ESI-MS calcd for[C 31H 48N 4O 7+H +]588.7,found 588.7.
5.3 合成Boc-D-Phg-Pro-Gly-D-Leu-OBn(9c)
Figure PCTCN2019119628-appb-000029
把HOBt(4.45g,33mmol)，Boc-D-Phg-OH 8c(7.53g，30mmol)加入到150mL的圆底烧瓶中，氩气保护，加入60mL干燥的THF，0℃下搅拌，待瓶内温度降至0℃时，缓慢滴加DIC(5.1mL，33mmol)，0.5h之后加入事先用THF溶解好的三肽Pro-Gly-D-Leu-OBn 7a(11.28g,30mmol)。室温搅拌48h后滤去不溶物，滤液减压浓缩干。残留物用乙酸乙酯溶解，然后依次用1M NaOH溶液、水、1M盐酸溶液和饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩，得到15.52g四肽Boc-D-Phg-Pro-Gly-D-Leu-OBn(9c)，产率85％。White solid,Mp 142–144℃；[α] D 25＝-2.0(c 0.5,CHCl 3)； 1H NMR(600MHz,CDCl 3)δ7.45–7.39(m,2H),7.38–7.32(m,6H),7.27(s,1H),7.22(d,J＝7.0Hz,1H),5.72(d,J＝5.2Hz,2H),5.38-5.30(m,1H),5.17(d,J＝3.3Hz,2H),4.66–4.61(m,1H),4.47–4.39(m,1H),4.04(dd,J＝16.8,6.6Hz,1H),3.98–3.94(m,1H),3.83(dd,J＝12.7,6.3Hz,1H),3.38–3.29(m,1H),2.21–2.16(m,1H),2.09–1.99(m,2H),1.75–1.70(m,2H),1.39(d,J＝4.9Hz,9H),1.13(d,J＝ 6.5Hz,4H),0.96–0.90(m,6H). 13C NMR(150MHz,CDCl 3)δ172.5,171.5,169.0,135.7,129.2,129.1,128.5,128.4,128.1(dd,J＝12.3,9.2Hz),80.5,77.2,77.0,76.8,66.8,61.2,51.0,47.3,43.4,42.1,41.1,28.2,24.6,23.4,22.8,21.8；ESI-MS calcd for[C 33H 44N 4O 7+H +]609.3,found 609.3。
5.4 合成四肽Boc-D-Chg-Phe-Pro-Gly-D-Leu-OBn(9d)
Figure PCTCN2019119628-appb-000030
把HOBt(4.45g,33mmol)，Boc-D-Chg-OH 8d(7.71g，30mmol)加入到150mL的圆底烧瓶中，氩气保护，加入60mL干燥的THF，0℃下搅拌，待瓶内温度降至0℃时，缓慢滴加DIC(5.1mL，33mmol)，0.5h之后加入事先用THF溶解好的三肽Pro-Gly-D-Leu-OBn 7a(11.28g,30mmol)。室温搅拌48h后滤去不溶物，滤液减压浓缩干。残留物用乙酸乙酯溶解，然后依次用1M NaOH溶液、水、1M盐酸溶液和饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩，石油醚和乙酸乙酯柱层析纯化得到四肽Boc-D-Chg-Phe-Pro-Gly-D-Leu-OBn(9d)15.5g，产率84％。White solid,Mp:160–161℃；[α] D 20＝-10(c 0.62,CHCl 3)； 1H NMR(400MHz,CDCl 3)δ7.37–7.30(m,5H),5.28–5.26(d,J＝6.4Hz,1H),5.21–5.13(m,2H),4.66–4.60(m,1H),4.50–4.47(m,1H),4.20–4.07(m,2H),4.00–3.96(m,1H),3.64–3.56(m,2H),2.21–2.16(m,2H),2.10–1.98(m,2H),1.87–1.84(m,1H),1.79–1.56(m,8H),1.39(s,9H),1.28–1.17(m,4H),1.31–1.11(d,J＝6.8Hz,2H),1.06–0.99(m,2H),0.92–0.89(m,6H)； 13C NMR(100MHz,CDCl 3)δ172.5,171.7,169.0,157.0,135.7,128.4,128.0,127.8,80.3,66.3,60.9,57.6,50.7,47.6,43.1,41.8,40.8,39.5,29.4,29.2,28.1,26.0,25.7,25.6,24.6,23.4,22.8,21.7；ESI-MS calcd for[C 33H 50N 4O 7+H +]614.4,found:614.4.。
5.5 合成Boc-D-Phe-Pro-Gly-D-Leu-OBn(9e)
Figure PCTCN2019119628-appb-000031
把HOBt(4.45g,33mmol)，Boc-D-Phe-OH 8e(7.95g，30mmol)加 入到150mL的圆底烧瓶中，氩气保护，加入60mL干燥的THF，0℃下搅拌，待瓶内温度降至0℃时，缓慢滴加DIC(5.1mL，33mmol)，0.5h之后加入事先用THF溶解好的三肽Pro-Gly-D-Leu-OBn 7a(11.28g,30mmol)。室温搅拌48h后滤去不溶物，滤液减压浓缩干。残留物用乙酸乙酯溶解，然后依次用1M NaOH溶液、水、1M盐酸溶液和饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩，石油醚和乙酸乙酯柱层析纯化得到四肽Boc-D-Phe-Pro-Gly-D-Leu-OBn(9e)，16.07g,产率86％。White solid,Mp：160-161℃；[α] D 20＝-10(c 0.62,CHCl 3)； 1H NMR(400MHz,CDCl 3)δ7.40-7.19(m,10H),5.50(br,1H),5.18(s,1H),4.65-4.64(m,1H),4.41-4.38(m,1H),4.32-4.30(m,1H),4.16-4.10(m,1H),3.69-3.61(m,2H),2.68-2.65(m,1H),2.05-2.02(m,1H),1.91-1.56(m,8H),1.39(s,9H),1.14-1.12(m,2H),0.96-0.91(m,6H)； 13C NMR(100MHz,CDCl 3)δ172.6,172.0,171.5,169.0 156.3,135.9,135.7,129.2,128.6,128.5,128.1，127.9,127.2,80.5,66.5,60.9,54.4,50.7,47.1,43.1,42.0,40.9,3 8.1,28.8,28.1,24.6,24.4,23.4,22.9,21.7；ESI-MS calcd for[C 34H 46N 4O 7+H +]623.3,found 623.3.。
5.6 合成Boc-D-Phe-Pro-Gly-D-Phe-OBn(9f)
Figure PCTCN2019119628-appb-000032
把HOBt(3.71g,27.5mmol)，Boc-D-Phe-OH 8e(6.63，25mmol)加入到150mL的圆底烧瓶中，氩气保护，加入50mL干燥的THF，0℃下搅拌，待瓶内温度降至0℃时，缓慢滴加DIC(4.25mL，27.5mmol)，0.5h之后加入事先用THF溶解好的三肽Pro-Gly-D-Phe-OBn 7b(10.23g,25mmol)。室温搅拌48h后滤去不溶物，滤液减压浓缩干。残留物用乙酸乙酯溶解，然后依次用1M NaOH溶液、水、1M盐酸溶液和饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩后用石油醚和乙酸乙酯柱层析纯化得到四肽Boc-D-Phe-Pro-Gly-D-Phe-OBn(9f)，13.45g，产率82％。White solid,Mp 138-139.6℃；[α] D 25＝-49.0(c 0.5,CHCl 3)； 1H NMR(600MHz,CDCl 3)δ7.33–7.28(m,4H),7.25–7.18(m,8H),7.16–7.13(m,3H),5.45 (d,J＝6.5Hz,1H),5.13–5.08(m,2H),4.88(dd,J＝14.4,6.6Hz,1H),4.46–4.41(m,1H),4.33(dd,J＝7.8,3.7Hz,1H),3.98(dd,J＝17.0,6.9Hz,1H),3.73(dd,J＝17.0,5.7Hz,1H),3.66–3.585(b,1H),3.15(dd,J＝6.7,2.6Hz,2H),2.95(t,J＝7.7Hz,2H),2.67(dd,J＝16.8,7.6Hz,1H),2.08–2.02(m,1H),1.84–1.75(b,3H),1.57–1.51(b,1H),1.39(s,9H). 13C NMR(150MHz,CDCl 3)δ171.9,171.5,171.4,168.8,136.2,135.4,129.4,129.3,128.6,128.5,128.4,128.3,128.2,127.2,126.8,80.5,77.2,77.0,76.8,66.9,60.8,53.6,47.1,43.2,38.2,28.7,28.3,24.4；ESI-MS calcd for[C 37H 44N 4O 7+H +]657.3,found 657.3.。
(六)中间化合物10的合成
6.1 合成H 2N-D-Val-Pro-Gly-D-Leu-OBn(10a)
Figure PCTCN2019119628-appb-000033
把前面合成的四肽Boc-D-Val-Pro-Gly-D-Leu-OBn 9a(12.65g,22mmol)溶于CH 2Cl 2(20mL)中，然后在0℃下缓慢滴加TFA(20mL)，室温下搅拌5h。将反应液减压浓缩尽量除去TFA，残留物用CH 2Cl 2溶解，再用1M NaOH溶液在0℃下中和至约pH＝9.0左右。分离有机相，水相用CH 2Cl 2(20mL×3)萃取。合并有机相，饱和食盐水洗一次，无水硫酸钠干燥，减压浓缩，得到10.03g无色油状液体的H 2N-D-Val-Pro-Gly-D-Leu-OBn(10a)，产率为96％。无需纯化，直接用于下一步反应。
6.2 合成H 2N-D-Tle-Pro-Gly-D-Leu-OBn(10b)
Figure PCTCN2019119628-appb-000034
把前面合成的四肽Boc-D-Tle-Pro-Gly-D-Leu-OBn 9b(12.96g,22mmol)溶于CH 2Cl 2(25mL)中，然后在0℃下缓慢滴加TFA(25mL)，室温下搅拌5h。将反应液减压浓缩尽量除去TFA，残留物用CH 2Cl 2溶解，再用1M NaOH溶液在0℃下中和至约pH＝9.0左右。分离有机相，水相用CH 2Cl 2(20mL×3)萃取。合并有机相，饱和食盐水洗一次，无水 硫酸钠干燥，减压浓缩，得到10.22g无色油状液体的H 2N-D-Tle-Pro-Gly-D-Leu-OBn(10b)，产率为95％。无需纯化，直接用于下一步反应。
6.3 合成H 2N-D-Phg-Pro-Gly-D-Leu-OBn(10c)
Figure PCTCN2019119628-appb-000035
把前面合成的四肽Boc-D-Phg-Pro-Gly-D-Leu-OBn 9c(13.4g,22mmol)溶于CH 2Cl 2(25mL)中，然后在0℃下缓慢滴加TFA(25mL)，室温下搅拌5h。将反应液减压浓缩尽量除去TFA，残留物用CH 2Cl 2溶解，再用1M NaOH溶液在0℃下中和至约pH＝9.0左右。分离有机相，水相用CH 2Cl 2(20mL×3)萃取。合并有机相，饱和食盐水洗一次，无水硫酸钠干燥，减压浓缩，得到10.3g无色油状液体的H 2N-D-Phg-Pro-Gly-D-Leu-OBn(10c)，产率为92％。无需纯化，直接用于下一步反应。
6.4 合成四肽H 2N-D-Chg-Pro-Gly-D-Leu-OBn(10d)
Figure PCTCN2019119628-appb-000036
把前面合成的四肽Boc-D-Chg-Pro-Gly-D-Leu-OBn 9d(13.53g,22mmol)溶于CH 2Cl 2(25mL)中，然后在0℃下缓慢滴加TFA(25mL)，室温下搅拌5h。将反应液减压浓缩尽量除去TFA，残留物用CH 2Cl 2溶解，再用1M NaOH溶液在0℃下中和至约pH＝11.0左右。分离有机相，水相用CH 2Cl 2(20mL×3)萃取。合并有机相，依次用饱和食盐水洗涤、无水硫酸钠干燥，减压浓缩，得到无色油状液体的H 2N-D-Chg-Pro-Gly-D-Leu-OBn(10d)10.6g，产率为94％。无需纯化，直接用于下一步反应。
6.5 合成H 2N-D-Phe-Pro-Gly-D-Leu-OBn(10e)
Figure PCTCN2019119628-appb-000037
把前面合成的四肽Boc-D-Phe-Pro-Gly-D-Leu-OBn 9e(13.7g,22mmol)溶于CH 2Cl 2(25mL)中，然后在0℃下缓慢滴加TFA(25mL)，室温下搅拌5h。将反应液减压浓缩尽量除去TFA，残留物用CH 2Cl 2溶解，再用1M NaOH溶液在0℃下中和至约pH＝9.0左右。分离有机相，水相用CH 2Cl 2(20mL×3)萃取。合并有机相，依次用饱和食盐水洗涤、无水硫酸钠干燥，减压浓缩，得到无色油状液体的H 2N-D-Phe-Pro-Gly-D-Leu-OBn(10e)，10.5g,产率为91％。无需纯化，直接用于下一步反应。
6.6 合成H 2N-D-Phe-Pro-Gly-D-Phe-OBn(10f)
Figure PCTCN2019119628-appb-000038
把前面合成的四肽Boc-D-Phe-Pro-Gly-D-Phe-OBn 9f(13.12g,20mmol)溶于CH 2Cl 2(25mL)中，然后在0℃下缓慢滴加TFA(25mL)，室温下搅拌5h。将反应液减压浓缩尽量除去TFA，残留物用CH 2Cl 2溶解，再用1M NaOH溶液在0℃下中和至约pH＝11.0左右。分离有机相，水相用CH 2Cl 2(20mL×3)萃取。合并有机相，饱和食盐水洗一次，无水硫酸钠干燥，减压浓缩，得到10.62g无色油状液体的H 2N-D-Phe-Pro-Gly-D-Phe-OBn(10f)，产率为94％。无需纯化，直接用于下一步反应。
实施例2
以下是本发明的TP-1至TP-6具体化合物的制备方法。
合成四肽TP-1：NH 2-D-Val-Pro-Gly-D-Leu-OH
Figure PCTCN2019119628-appb-000039
把前面合成的NH 2-D-Val-Pro-Gly-D-Leu-OBn 10a(10.0g,21mmol)溶于甲醇(20mL)，转移到100mL的高压反应釜中，然后加入500mg Pd/C(5％)。室温下通入氢气至8Mpa，搅拌6小时。过滤除去Pd/C，滤液减压浓缩，得到产物四肽NH 2-D-Val-Pro-Gly-D-Leu-OH(TP-1)，8.0g，产 率100％。White solid，Mp:152–154℃；[α] D 20＝–58.0(c 0.85,H 2O)； 1H NMR(600MHz,D 2O)δ4.55–4.50(m,1H),4.31–4.25(m,1H),4.04(d,J＝17.1Hz,1H),3.90(d,J＝17.1Hz,1H),3.87-3.83(m,1H),3.77-3.73(m,1H),2.41–2.33(m,2H),2.11-2.04(m,3H),1.74–1.60(m,4H),1.13(d,J＝7.2Hz,3H),1.05(d,J＝12Hz,3H),0.95(d,J＝6Hz 3H),0.91(d,J＝6Hz,3H). 13C NMR(150MHz,D 2O)δ179.7,174.3,170.4,168.9,61.1,57.1,53.5,48.1,42.4,40.5,29.2,28.7,24.5,24.3,22.4,20.5,17.9,15.9；HRMS calcd for[C 18H 32N 4O 5+H +]385.2445,found 385.2438.
把前面合成的NH 2-D-Val-Pro-Gly-D-Leu-OBn 10a(10.0g)溶于乙醇(20mL)，转移到100mL的高压反应釜中，然后加入500mg Pd/C(5％)。室温下通入氢气至8Mpa，搅拌6小时。过滤除去Pd/C，滤液减压浓缩，得到产物四肽NH 2-D-Val-Pro-Gly-D-Leu-OH(TP-1)，为白色固体，7.45g，产率93％。
实施例2
合成TP-2：H 2N-D-Tle-Pro-Gly-D-Leu-OH
Figure PCTCN2019119628-appb-000040
把前面合成的NH 2-D-Tle-Pro-Gly-D-Leu-OBn 10b(9.76g,20mmol)溶于甲醇(20mL)，转移到100mL的高压反应釜中，然后加入500mg Pd/C(5％)。室温下通入氢气至8Mpa，搅拌6小时。过滤除去Pd/C，滤液减压浓缩，得到产物四肽NH 2-D-Tle-Pro-Gly-D-Leu-OH(TP-2)，7.8g，产率98％。White solid，Mp：204–205℃,[α] D 20＝–28.0(c 1.0,DMF)； 1H NMR(600MHz,D 2O)4.38–4.34(m,1H),4.12–4.02(m,2H),3.81(q,J＝17.1Hz,2H),3.72–3.63(m,2H),3.21(d,J＝0.4Hz,1H),2.24–2.18(m,1H),1.91(s,3H),1.57–1.52(m,1H),1.50–1.42(m,2H),0.97(s,9H),0.76(dd,J＝22.8,5.8Hz,6H)； 13C NMR(150MHz,D 2O)δ179.8,174.3,170.4,168.2,61.0,59.1,53.7,49.0,42.4,40.6,33.9,29.3,25.3,24.5,24.26,22.4,20.5；HRMS calcd for[C 19H 30N 4O 5+H +]399.2602,found 399.2599。
实施例3.
合成TP-3：H 2N-D-Phg-Pro-Gly-D-Leu-OH
Figure PCTCN2019119628-appb-000041
把前面合成的NH 2-D-Phg-Pro-Gly-D-Leu-OBn 10c(10.0g,19.5mmol)溶于甲醇(20mL)，转移到100mL的高压反应釜中，然后加入500mg Pd/C(5％)。室温下通入氢气至8Mpa，搅拌6h。过滤除去Pd/C，滤液减压浓缩，得到产物四肽NH 2-D-Phg-Pro-Gly-D-Leu-OH(TP-3)，7.8g，产率96％。White solid，Mp:150–153℃,[α] D 20＝–94.0(c 1.0,H 2O)； 1H NMR(600MHz,D 2O)δ7.62–7.42(m,5H),5.47(s,1H),4.50(dd,J＝9.0,3.8Hz,1H),4.31(dd,J＝10.6,3.2Hz,1H),4.09(d,J＝17.2Hz,1H),3.89(d,J＝17.2Hz,1H),3.80–3.71(m,1H),3.07–3.00(m,1H),2.25–2.15(m,1H),2.05–1.94(m,2H),1.86–1.72(m,2H),1.69–1.53(m,2H),1.01–0.86(m,6H)； 13C NMR(150MHz,D 2O)δ179.9,174.3,170.3,167.4,130.6,129.8,129.6,128.9,128.5,61.5,56.4,53.6,47.5,42.3,40.6,28.9,24.6,24.2,22.4,20.6；HRMS calcd for[C 21H 30N 4O 5+H +]419.2289,found:419.2285.。
实施例4
合成TP-4：H 2N-D-Chg-Pro-Gly-D-Leu-OH
Figure PCTCN2019119628-appb-000042
把前面合成的NH 2-D-Chg-Pro-Gly-D-Leu-OBn 10d(10.0g,19.4mmol)溶于甲醇(20mL)，转移到100mL的高压反应釜中，然后加入500mg Pd/C(5％)。室温下通入氢气至8Mpa，搅拌6小时。过滤除去Pd/C，滤液减压浓缩，得到产物四肽NH 2-D-Chg-Pro-Gly-D-Leu-OH(TP-4),7.94g，产率97％。White solid，Mp:167–169℃,[α] D 20＝–96.0(c 1.0,H 2O)； 1H NMR(600MHz,D 2O)δ4.55–4.46(m,1H),4.33–4.20(m,2H),4.03(d,J＝17.1Hz,1H),3.93–3.70(m,3H),2.40–2.32.(m,1H),2.13–1.94(m,3H),1.86–1.57(m,7H),1.37–1.07(m,5H),0.98–0.86(m,6H)； 13C NMR(150MHz,D 2O)δ179.6,174.3,170.4,168.8,61.1,56.6,53.9,53.4,48.1,42.4,40.5,38.4,29.3,28.5,27.1,25.1,24.5,24.2,22.4,20.5；HRMS calcd  for[C 21H 36N 4O 5+H +]425.2758,found 425.2748.。
实施例5
合成TP-5：NH 2-D-Phe-Pro-Gly-D-Leu-OH
Figure PCTCN2019119628-appb-000043
把前面合成的NH 2-D-Phe-Pro-Gly-D-Leu-OBn 9e(10.0g,19.1mmol)溶于甲醇(20mL)，转移到100mL的高压反应釜中，然后加入500mg Pd/C(5％)。室温下通入氢气至8Mpa，搅拌6小时。过滤除去Pd/C，滤液减压浓缩，得到产物四肽NH 2-D-Phe-Pro-Gly-D-Leu-OH(TP-5)，为白色固体，7.7g，产率93％。White solid,Mp:198-200℃；[α] D 20＝–98.0(c 1.0,H 2O)； 1H NMR(600MHz,D 2O)7.45-7.39(m,3H),7.35(d,J＝6.9Hz,2H),4.62-4.57(m,1H),4.37(dd,J＝8.8,4.6Hz,1H),4.26(dd,J＝10.5,3.5Hz,1H),4.01(d,J＝17.1Hz,1H),3.88(d,J＝17.2Hz,1H),3.64–3.57(m,1H),3.30-3.18(m,2H),2.86-2.80(m,1H),2.16–2.08(m,1H),1.97-1.85(m,2H),1.73–1.56(m,4H),0.92(dd,J＝28.0,6.0Hz,6H)； 13C NMR(150MHz,D 2O)δ179.8,174.1,170.3,168.5,133.3,129.4,129.1,128.1,61.0,53.6,53.0,47.7,42.4,40.5,36.3,29.1,24.5,24.0,22.4,20.5；HRMS calcd for[C 22H 32N 4O 5+H +]433.2445,found 419.2439.。
实施例6.
合成TP-6：NH 2-D-Phe-Pro-Gly-D-Phe-OH
Figure PCTCN2019119628-appb-000044
把前面合成的NH 2-D-Phe-Pro-Gly-D-Phe-OBn 10f(10.2g,18mmol)溶于甲醇(20mL)，转移到100mL的高压反应釜中，然后加入500mg Pd/C(5％)。室温下通入氢气至8Mpa，搅拌6小时。过滤除去Pd/C，滤液减压浓缩，得到产物四肽NH 2-D-Phe-Pro-Gly-D-Phe-OH(TP-6)，为白色固体，7.8g，产率92％。Mp 182.5–184.4℃,[α] D 20＝–50.0(c 0.5,DMF)； 1H NMR(600MHz,DMSO)δ8.50–8.16(m,2H),7.41–7.03(m,10H),4.38 (m,3H),3.76–3.64(m,1H),3.50–3.32(m,2H),3.20–2.79(m,4H),1.87–1.60(m,3H),1.40–1.26(m,1H),0.98(d,J＝6.5Hz,1H)； 13C NMR(150MHz,DMSO)δ175.0,171.4,170.2,168.3,139.3,136.0,129.9,129.7,128.9,128.3,127.5,126.2,61.2,52.9,47.1,42.1,40.4,40.2,40.1,39.9,39.7,39.6,38.8,29.3,24.4,23.7；HRMS calcd for[C 25H 30N 4O 5+H +]467.2288,found:467.2289.。
二、化合物TP的应用例
实施例7
在洁净的5mL圆底烧瓶中加入准确称量的本发明的四肽催化剂TP(0.025mmol)、N-苯基马来酰亚胺(87mg,0.5mmol)和1.0mL干燥重蒸过的甲苯，在冰水浴和磁力搅拌条件下加入重蒸的异丁醛(92μL,1.0mmol)，恢复反应液至室温下继续搅拌反应，通过TLC检测至反应结束后，加3～4滴饱和氯化铵溶液，用乙酸乙酯萃取(10mL×3)，少量饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩，残余油状物利用石油醚和乙酸乙酯柱层析纯化，获得纯产物。
本发明的TP-1～TP-6 6种四肽催化剂催化异丁醛与N-苯基马来酰亚胺的不对称共轭加成反应的评价，结果如下表1所示。由结果可知，TP-3和TP-5的不对称催化效率最高。
表1.四肽催化剂催化异丁醛与N-苯基马来酰亚胺的不对称共轭加成反应. a
Figure PCTCN2019119628-appb-000045
Figure PCTCN2019119628-appb-000046
Figure PCTCN2019119628-appb-000047
a分离产率，ee由手性HPLC确定。
实施例8.
溶剂对四肽TP-5催化异丁醛与N-苯基马来酰亚胺不对称共轭加成反应的影响。
在洁净的5mL圆底烧瓶中加入准确称量的四肽催化剂TP-5(0.025mmol，10.8mg)、N-苯基马来酰亚胺(87mg,0.5mmol)和1.0mL干燥重蒸过的反应溶剂，在冰水浴下和磁力搅拌条件下加入重蒸的异丁醛(92μL,1.0mmol)，恢复反应液至室温下继续搅拌反应，通过TLC检测至反应结束后，加3～4滴饱和氯化铵溶液，用乙酸乙酯萃取(10mL×3)，少量饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩，残余油状物利用石油醚和乙酸乙酯柱层析纯化，获得纯产物。
各种溶剂对反应的产率和ee值影响，结果见下表2所示。结果显示：与甲苯相比较，乙腈为溶剂时产率和ee值都显著提高。
表2.溶剂对四肽TP-5催化异丁醛与N-苯基马来酰亚胺的不对称共轭加成反应的影响 a
Figure PCTCN2019119628-appb-000048
a分离产率，ee由手性HPLC确定。 b没有检测到反应。
实施例9.
观察催化剂用量对不对称共轭加成反应的催化效率的影响。
在洁净的5mL圆底烧瓶中加入准确称量的四肽催化剂TP-5或TP-3(0.025mmol)、N-苯基马来酰亚胺(87mg,0.5mmol)和1.0mL干燥重蒸过的反应溶剂，在冰水浴下和磁力搅拌条件下加入重蒸的异丁醛(92μL,1.0mmol)，恢复反应液至室温下继续搅拌反应，通过TLC检测至反应结束后，加3～4滴饱和氯化铵溶液，用乙酸乙酯萃取(10mL×3)，少量饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩，残余油状物利用石油醚和乙酸乙酯柱层析纯化，获得纯产物。
反应产率和ee值如下表3所示。结果显示，使用2.5mol％用量的TP-3四肽为催化剂，以乙腈为溶剂，可以获得最优的不对称催化效果。
表3.四肽使用量对不对称共轭加成反应的影响 a.
Figure PCTCN2019119628-appb-000049
a分离产率，ee由手性HPLC确定。
实施例10
观察四肽TP-3催化脂肪醛与马来酰亚胺不对称共轭加成反应的底物适应范围。
在洁净的5mL圆底烧瓶中加入准确称量的四肽催化剂2.5％TP-3(0.0125mmol，5.3mg)、马来酰亚胺(0.5mmol)和1.0mL干燥重蒸过的乙腈，在冰水浴下和磁力搅拌条件下加入重蒸的脂肪醛(1.0mmol)，恢复反应液至室温下继续搅拌反应，通过TLC检测至反应结束后，加3～4滴饱和氯化铵溶液，用乙酸乙酯萃取(10mL×3)，少量饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩，残余油状物利用石油醚和乙酸乙酯柱层析纯 化，获得纯产物。
结果如表4所示。
表4.四肽TP-3催化的脂肪醛与马来酰亚胺的不对称共轭加成反应. a
Figure PCTCN2019119628-appb-000050
a分离产率，ee由手性HPLC确定。
产物P-1～P-17表征如下。
Figure PCTCN2019119628-appb-000051
P-1,[α] D 25＝-6.0(c＝1.0,CHCl 3)； 1H NMR(600MHz,CDCl 3)δ9.51(s,1H),7.48-7.44(m,2H),7.40–7.36(m,1H),7.29-7.25(m,2H),3.14(dd,J＝9.6,5.6Hz,1H),2.96(dd,J＝18.6,9.6Hz,1H),2.61(dd,J＝18.4,5.6Hz,1H),1.32(s,3H),1.28(s,3H).
Figure PCTCN2019119628-appb-000052
P-2,[α] D 25＝+2.0(c＝1.0,CHCl 3)； 1H NMR(600MHz,CDCl 3)δ9.49(s,1H),7.28–7.24(m,2H),7.17-7.12(m,2H),3.11(dd,J＝9.6,5.6Hz,1H),2.97(dd,J＝18.3,9.6Hz,1H),2.61(dd,J＝18.4,5.6Hz,1H),1.35(s,3H),1.28(s,3H).
Figure PCTCN2019119628-appb-000053
P-3,[α] D 25＝+3.0(c＝1.0,CHCl 3)； 1H NMR(600MHz,CDCl 3)δ9.49(s,1H),7.49–7.40(m,2H),7.28–7.22(m,2H),3.11(dd,J＝9.6,5.6Hz,1H),2.97(dd,J＝18.3,9.6Hz,1H),2.62(dd,J＝18.3,5.6Hz,1H),1.36(s,3H),1.29(s,3H).
Figure PCTCN2019119628-appb-000054
P-4,[α] D 25＝+3.0(c＝1.0,CHCl 3)； 1H NMR(600MHz,CDCl 3)δ9.49(s,1H),7.62–7.57(m,1H),7.23–7.15(m,2H),3.11(dd,J＝9.6,5.4Hz,1H), 2.97(dd,J＝18.4,9.6Hz,1H),2.62(dd,J＝18.4,5.6Hz,1H),1.36(s,3H),1.29(s,3H).
Figure PCTCN2019119628-appb-000055
P-4,[α] D 25＝+6.0(c＝1.0,CHCl 3)； 1H NMR(600MHz,CDCl 3)δ9.46(s,1H),8.35–8.29(m,2H),7.61–7.54(m,2H),3.10(dd,J＝9.6,5.4Hz,1H),3.00(dd,J＝18.6,9.6 Hz,1H),2.65(dd,J＝18.6,5.4Hz,1H),1.41(s,3H),1.30(s,3H).
Figure PCTCN2019119628-appb-000056
P-6,[α] D 25＝+5.0(c＝1.0,CHCl 3)； 1H NMR(600MHz,CDCl 3)δ9.52(s,1H),7.21–7.15(m,2H),6.99–6.95(m,2H),3.82(s,3H),3.13(dd,J＝9.6,5.4Hz,1H),2.96(dd,J＝18.4,9.6Hz,1H),2.60(dd,J＝18.6,5.4Hz,1H),1.32(s,3H),1.28(s,3H)。
Figure PCTCN2019119628-appb-000057
P-7,[α] D 25＝+6.0(c＝1.0,CHCl 3)； 1H NMR(600MHz,CDCl 3)δ9.52(s,1H),7.27(d,J＝7.2Hz,2H),7.14(d,J＝8.4Hz,2H),3.14(dd,J＝9.6,5.4Hz,1H),2.97(dd,J＝18.4,9.6Hz,1H),2.61(dd,J＝18.4,5.5Hz,1H),2.37(s,3H),1.32(s,3H),1.28(s,3H).
Figure PCTCN2019119628-appb-000058
P-8,[α] D 25＝+20.0(c＝1.0,CHCl 3)； 1H NMR(600MHz,CDCl 3)δ9.63(s,1H),7.48(t,J＝7.8Hz,2H),7.40(t,J＝7.5Hz,1H),7.34–7.28(m,2H),3.31-3.26(m,1H),3.12–3.06(m,1H),2.93(dd,J＝18.0,9.7Hz,1H),2.60(dd,J＝18.0,5.7Hz,1H),1.40(d,J＝7.8Hz,3H)。
Figure PCTCN2019119628-appb-000059
P-9,[α] D 25＝+16.0(c＝1.0,CHCl 3)； 1H NMR(600MHz,CDCl 3)δ9.78(s,1H),7.50–7.45(m,2H),7.41–7.36(m,1H),7.31-7.28(m,2H),3.17(dd,J＝7.2,3.7Hz,1H),3.11–2.99(m,1H),2.87(dd,J＝18.0,9.6Hz,1H),2.73(dd,J＝18.0,6.0Hz,1H),2.36–2.28(m,1H),1.26(d,J＝6.6Hz,3H),1.10(d,J＝6.6Hz,3H).
Figure PCTCN2019119628-appb-000060
P-10,[α] D 25＝+41.0(c＝1.0,CHCl 3)； 1H NMR(600MHz,CDCl 3)δ9.75(s,1H),7.47(t,J＝6Hz,2H),7.41-7.37(m,1H),7.32-7.26(m,2H),3.36-3.32(m,1H),3.03–2.96(m,2H),2.57(dd,J＝18.0,5.4Hz,1H),1.94-1.88(m,1H),1.70-1.62(m,1H),1.51–1.45(m,2H),1.42-1.36(m,2H),0.93(t,J＝6Hz,3H).
Figure PCTCN2019119628-appb-000061
P-11,[α] D 25＝-40.0(c＝1.0,CHCl 3)； 1H NMR(600MHz,CDCl 3)δ9.39(s,1H),7.49-7.46(m,2H),7.40-7.37(m,1H),7.34–7.29(m,2H),3.05-2.94(m,2H),2.58(dd,J＝18,5.4Hz,1H),2.37–2.27(m,1H),2.14–2.03(m,2H),1.88–1.69(m,5H).
Figure PCTCN2019119628-appb-000062
P-12,[α] D 25＝-5.0(c＝1.0,CHCl 3)； 1H NMR(600MHz,CDCl 3)δ9.55(s,1H),7.47(t,J＝7.7Hz,2H),7.40-7.38(m,1H),7.31–7.27(m,2H),3.22(dd,J＝9.0,6.0Hz,1H),2.87(dd,J＝18.0,9.6Hz,1H),2.68(dd,J＝18.2,5.9Hz,1H),1.99–1.85(m,3H),1.67–1.49(m,6H).
Figure PCTCN2019119628-appb-000063
P-13,[α] D 25＝+10.0(c＝1.0,CHCl 3)； 1H NMR(600MHz,CDCl 3)δ9.63(s,1H),7.47(t,J＝7.8Hz,2H),7.39(t,J＝7.5Hz,1H),7.29–7.25(m,2H),3.25(dd,J＝9.6,6.0Hz,1H),2.97(dd,J＝18.4,9.6Hz,1H),2.69(dd,J＝18.4,6.0Hz,1H),2.02–1.83(m,3H),1.74(dq,J＝15.0,7.5Hz,1H),1.03–0.97(m,6H).
Figure PCTCN2019119628-appb-000064
P-14,[α] D 25＝-9.0(c＝1.0,CHCl 3)； 1H NMR(600MHz,CDCl 3)δ9.51(s,1H),3.04(dd,J＝9.6,5.4Hz,1H),2.99(s,3H),2.82(dd,J＝18.3,9.4Hz,1H),2.45(dd,J＝18.3,5.4Hz,1H),1.22(d,J＝6.4Hz,6H).
Figure PCTCN2019119628-appb-000065
P-15,[α] D 25＝-11.0(c＝1.0,CHCl 3)； 1H NMR(600MHz,cdcl 3)δ9.51(s,1H),3.98–3.91(m,1H),2.97(dd,J＝9.5,5.2Hz,1H),2.74(dd,J＝18.3,9.5Hz,1H),2.37(dd,J＝18.3,5.2Hz,1H),2.16-2.08m,2H),1.80(d,J＝13.4Hz,2H),1.66-1.53(m,3H),1.32-1.23(m,2H),1.23–1.12(m,7H).
Figure PCTCN2019119628-appb-000066
P-16,[α] D 25＝-14.0(c＝1.0,CHCl 3)； 1H NMR(600MHz,CDCl 3)δ9.48(s,1H),7.37–7.34(m,2H),7.31-7.28(m,2H),4.65(q,J＝14.4Hz,2H),3.03(dd,J＝9.4,5.4Hz,1H),2.81(dd,J＝18.3,9.4Hz,1H),2.45(dd,J＝18.3,5.4Hz,1H),1.16(d,J＝2.3Hz,6H).
Figure PCTCN2019119628-appb-000067
P-17,[α] D 25＝+5.0(c＝1.0,CHCl 3)； 1H NMR(600MHz,CDCl 3)δ9.46(s,1H),8.81(s,1H),3.07(dd,J＝9.6,5.4Hz,1H),2.83(dd,J＝18.4,9.6Hz,1H),2.48(dd,J＝18.4,5.4Hz,1H),1.21(d,J＝6.9Hz,6H).
以上实施例的说明只是用于帮助理解本发明的方法及其核心思想。应当指出，对于本技术领域技术人员来说，在不脱离本发明原理的前提下，还可以对本发明进行若干改进和修饰，这些改进和修饰也落入本发明权利要求的保护范围内。

Claims (16)

  1. 一种如式1示四肽化合物TP，
    Figure PCTCN2019119628-appb-100001
    其中，R 1和R 2独立的选自C 1～C 6的任意直链烷基、支链烷基、环烷基、羟基取代烷基、巯基取代烷基、甲硫基取代烷基、氨基取代烷基、胍基取代烷基、芳基、芳甲基或杂原子芳基中的任一种。
  2. 根据权利要求1所述的四肽化合物TP，其特征在于，所述R 1选自C 1～C 6的任意直链烷基、C 3～C 15的支链烷基、C 3～C 8的环烷基、羟基取代的C 1～C 6的烷基、巯基取代的C 1～C 6的烷基、甲硫基取代的C 1～C 6的烷基、氨基取代的C 1～C 6的烷基、胍基取代的C 1～C 6的烷基、C 6～C 30的芳基、C 6～C 30的芳甲基或C 5～C 15的杂原子芳基；
    所述R 2选自C 1～C 6的任意直链烷基、C 3～C 15的支链烷基、C 3～C 8的环烷基、羟基取代的C 1～C 6的烷基、巯基取代的C 1～C 6的烷基、甲硫基取代的C 1～C 6的烷基、氨基取代的C 1～C 6的烷基、胍基取代的C 1～C 6的烷基、C 6～C 30的芳基、C 6～C 30的芳甲基或C 5～C 15的杂原子芳基。
  3. 根据权利要求1所述的四肽化合物TP，其特征在于，所述R 1为甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、正己基、环丙基、环丁基、环戊基、环己基、环庚基、羟基甲基、2-羟基乙基、1-羟基乙基(MeCH(OH)-)、氨基甲基、2-氨基乙基、3-氨基正丙基、4-氨基正丁基、巯基甲基、2-巯基乙基、甲硫基甲基、2-甲硫基乙基、苯基、萘基、蒽基、菲基、呋喃基、吡啶基、吡喃基、哌啶基、苯基甲基、萘基甲基或蒽基甲基；
    所述R 2为甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、正己基、环丙基、环丁基、环戊基、环己基、环庚基、羟基甲基、2-羟基乙基、1-羟基乙基(MeCH(OH)-)、氨基甲基、2-氨基 乙基、3-氨基正丙基、4-氨基正丁基、巯基甲基、2-巯基乙基、甲硫基甲基、2-甲硫基乙基、苯基、萘基、蒽基、菲基、呋喃基、吡啶基、吡喃基、哌啶基、苯基甲基、萘基甲基或蒽基甲基。
  4. 根据权利要求1所述的四肽化合物TP，其特征在于，所述具有式(I)结构的四肽化合物TP中，
    所述R 1为i-Bu,R 2为i-Pr，即四肽化合物TP的氨基酸序列为H 2N- D-Val-Pro-Gly- D-Leu-OH，命名为TP-1；
    所述R 1为i-Bu,R 2为t-Bu，即四肽化合物TP的氨基酸序列为H 2N- D-Tle-Pro-Gly- D-Leu-OH，命名为TP-2；
    所述R 1为i-Bu,R 2为Ph，即四肽化合物TP的氨基酸序列为H 2N- D-Phg-Pro-Gly- D-Leu-OH，命名为TP-3；
    所述R 1为i-Bu,R 2为c-hex，即四肽化合物TP的氨基酸序列为H 2N- D-Chg-Pro-Gly- D-Leu-OH，命名为TP-4；
    所述R 1为i-Bu,R 2为Bn，即四肽化合物TP的氨基酸序列为H 2N- D-Phe-Pro-Gly- D-Leu-OH，命名为TP-5；
    所述R 1为Bn,R 2为Bn，即：其四肽化合物TP的氨基酸序列为H 2N- D-Phe-Pro-Gly- D-Phe-OH，命名为TP-6。
  5. 一种权利要求1所述的式1所示四肽化合物TP的制备方法，包括：
    1)将产物7和氨基酸8混合反应，得到产物9；
    Figure PCTCN2019119628-appb-100002
    其中，R 1和R 2独立的选自C 1～C 6的任意直链烷基、支链烷基、环烷基、羟基取代烷基、巯基取代烷基、甲硫基取代烷基、氨基取代烷基、胍基取代烷基、芳基、芳甲基或杂原子芳基中的任一种；
    R 3是芳基甲基；
    R 6选自叔丁氧甲酰基、苄氧甲酰基或芴甲氧甲酰基；
    2)将产物9转化成式1所示四肽化合物TP；
    Figure PCTCN2019119628-appb-100003
  6. 根据权利要求5所述的制备方法，其特征在于，所述产物7按照以下方法制备得到：
    A-1)将产物4与脯氨酸5反应，得到产物6；
    Figure PCTCN2019119628-appb-100004
    其中，R 1选自C 1～C 6的任意直链烷基、支链烷基、环烷基、羟基取代烷基、巯基取代烷基、甲硫基取代烷基、氨基取代烷基、胍基取代烷基、芳基、芳甲基或杂原子芳基中的任一种；
    R 3是芳基甲基；
    R 5选自叔丁氧甲酰基、苄氧甲酰基或芴甲氧甲酰基；
    A-2)将产物6转化成产物7。
  7. 根据权利要求6所述的制备方法，其特征在于，所述产物4按照以下方法制备得到：
    B-1)将甘氨酸1和氨基酸2混合反应，得到产物3；
    Figure PCTCN2019119628-appb-100005
    其中，R 1选自C 1～C 6的任意直链烷基、支链烷基、环烷基、羟基取代烷基、巯基取代烷基、甲硫基取代烷基、氨基取代烷基、胍基取代烷基、芳基、芳甲基或杂原子芳基中的任一种；
    R 3是芳基甲基；
    R 4、R 5独立的选自叔丁氧甲酰基、苄氧甲酰基或芴甲氧甲酰基；
    B-2)将产物3转化成产物4。
  8. 根据权利要求5所述的制备方法，其特征在于，所述步骤2)具 体为：
    将式产物9通过脱保护，得到产物10；
    Figure PCTCN2019119628-appb-100006
    其中，R 1、R 2独立的选自C 1～C 6的任意直链烷基、支链烷基、环烷基、羟基取代烷基、巯基取代烷基、甲硫基取代烷基、氨基取代烷基、胍基取代烷基、芳基、芳甲基或杂原子芳基中的任一种；
    R 3是芳基甲基；
    R 6选自叔丁氧甲酰基、苄氧甲酰基或芴甲氧甲酰基；
    将产物10进行催化加氢反应，得到式1所示四肽化合物TP。
  9. 根据权利要求5所述的制备方法，其特征在于，所述式1所示四肽化合物TP的制备方法具体为：反应历程如式2、式3、式4和式5所示，即：
    Figure PCTCN2019119628-appb-100007
    将甘氨酸1、氨基酸2、缩合试剂C-1和添加剂A-1加入溶剂S-1搅拌反应，得到产物3，再将产物3和脱保护剂D-1加入溶剂S-2搅拌反应，得到产物4；
    将产物4、脯氨酸5、缩合试剂C-2和添加剂A-2加入溶剂S-3中搅 拌反应，得到产物6，再将产物6和脱保护剂D-2加入溶剂S-4中搅拌反应，得到产物7；
    将产物7、氨基酸8、缩合试剂C-3和添加剂A-3加入溶剂S-5中搅拌反应，得到产物9，再将产物9和脱保护剂D-3加入溶剂S-6中搅拌反应，得到产物10；
    将产物10和催化剂Pd/C加入溶剂S-7中，通入压力为1～30Mpa氢气进行反应，得到终产物四肽TP，其中：
    R 3是芳基甲基；
    R 4、R 5、R 6是Boc(叔丁氧甲酰基)、Cbz(苄氧甲酰基)或Fmoc(芴甲氧甲酰基)中的任一种；
    缩合试剂C-1、C-2和C-3是碳二亚胺、或烷氧甲酰氯R 7OCOCl中的任一种，R 7是C 1～C 4的任意直链烷基或支链烷基；
    添加剂A-1、A-2和A-3是指R 8R 9R 10N或NMM(N-甲基吗啉)或TMEDA(4-二甲氨基吡啶)或HOBt(1-羟基苯并三氮唑)，R 8、R 9、R 10是C 1～C 4的任意直链烷基或支链烷基；
    溶剂S-1、S-2、S-3、S-4、S-5、S-6是甲苯、苯、二氯甲烷、二氯乙烷、乙醚、四氢呋喃、乙二醇二甲醚、甲基叔丁基醚、环氧六烷、乙酸乙酯、乙酸甲酯、乙腈或丙腈中的任一种或任数种的组合，溶剂S-7是甲醇、乙醇、丙醇或丁醇中的任一种或任数种的组合；
    脱保护剂D-1、D-2和D-3是甲基磺酸、三氟甲磺酸、苯磺酸、对甲苯磺酸、三氟乙酸、三氯乙酸、盐酸、硫酸、哌啶、吗啉、四氢吡咯、二氢吡咯、吡咯、二乙胺、二丙胺、二丁胺、二异丙胺或二异丁胺中的任一种。
  10. 根据权利要求9所述的制备方法，其特征在于：
    所述R 3是苄基；
    所述R 4、R 5、R 6是独立的选自Boc或Cbz；
    缩合试剂C-1、C-2和C-3独立的选自DCC(N,N'-二环己基碳二亚胺)或DIC(N,N'-二异丙基碳二亚胺)或烷氧甲酰氯R 7OCOCl，
    其中，R 7是Et或i-Pr或i-Bu；
    添加剂A-1、A-2和A-3独立的选自TEA(三乙胺)、DIPEA(二异丙基乙胺)、NMM或HOBt中的任一种；
    溶剂S-1、S-2、S-3、S-4、S-5和S-6独立的选自二氯甲烷或四氢呋喃，溶剂S-7选自甲醇或乙醇；
    脱保护剂D-1、D-2和D-3独立的选自甲基磺酸或三氟甲磺酸或三氟乙酸。
  11. 根据权利要求9所述的制备方法，其特征在于，
    所述R 3是苄基；
    所述R 4、R 5和R 6独立的选自Boc；
    缩合试剂C-1、C-2和C-3独立的选自DCC、DIC或烷氧甲酰氯R 7OCOCl，其中，R 7选自Et或i-Pr或i-Bu；
    添加剂A-1、A-2和A-3独立的选自TEA、DIPEA、NMM或HOBt中的任一种；
    溶剂S-1、S-2、S-3、S-4、S-5、S-6独立的选自二氯甲烷或四氢呋喃，溶剂S-7为甲醇；
    脱保护剂D-1、D-2和D-3独立的选自三氟乙酸；
    氢气压力是8Mpa。
  12. 一种用于催化脂肪醛与马来酰亚胺的不对称共轭加成反应的催化剂，其特征在于，所述催化剂为权利要求1～4任意一项所述的式1示四肽化合物TP。
  13. 用于制备式1示化合物TP的中间化合物，其特征在于如式3示6。
  14. 用于制备式1示化合物TP的中间化合物，其特征在于如式3示7。
  15. 用于制备式1示化合物TP的中间化合物，其特征在于如式4示9。
  16. 用于制备式1示化合物TP的中间化合物，其特征在于如式4示10。
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