WO2020088053A1 - 抗生素teixobactin及其类似物的合成路线 - Google Patents

抗生素teixobactin及其类似物的合成路线 Download PDF

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WO2020088053A1
WO2020088053A1 PCT/CN2019/101927 CN2019101927W WO2020088053A1 WO 2020088053 A1 WO2020088053 A1 WO 2020088053A1 CN 2019101927 W CN2019101927 W CN 2019101927W WO 2020088053 A1 WO2020088053 A1 WO 2020088053A1
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formula
group
optionally
compound represented
fmoc
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饶燏
宗昱
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Tsinghua University
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Tsinghua University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/44—Nitrogen atoms not forming part of a nitro radical
    • C07D233/46—Nitrogen atoms not forming part of a nitro radical with only hydrogen atoms attached to said nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/44—Nitrogen atoms not forming part of a nitro radical
    • C07D233/48—Nitrogen atoms not forming part of a nitro radical with acyclic hydrocarbon or substituted acyclic hydrocarbon radicals, attached to said nitrogen atoms

Definitions

  • the present invention relates to the field of medicinal chemistry. Specifically, the present invention relates to a method for preparing new antibiotics for the treatment of drug-resistant Gram-positive bacteria and tuberculosis. More specifically, the present invention relates to the synthetic route of antibiotics teixobactin and its analogs.
  • Gram-positive bacterial infections are common and frequently-occurring diseases that endanger human health.
  • Gram-positive cocci infections have increased day by day, and the detection rate of methicillin-resistant Staphylococcus aureus (MRSA) has increased.
  • MRSA methicillin-resistant Staphylococcus aureus
  • PRSP Penicillin-resistant Streptococcus pneumoniae
  • VRE vancomycin-resistant enterococci
  • multi-drug tuberculosis has increased.
  • research and development of drugs to treat Gram-positive drug-resistant bacterial infections has become a worldwide concern.
  • bacteria can be mutated to obtain drug resistance when they are exposed to antibacterial drugs.
  • the surviving bacteria In the "encounter battle” with antibacterial drugs, the surviving bacteria have accumulated a wealth of "combat experience” and become resistant varieties, and then evolved cross-resistance, multi-resistance, pan-resistance, and full resistance "Super bacteria” such as medicine.
  • MCR-1 the bacteria carrying this gene show strong resistance to polymyxin, and this resistance can also be quickly transferred to other strains, which means a new The "super bacteria” was found.
  • Carbapenem antibiotics are currently recognized as the "ultimate line of defense" for bacteria, and are often used to treat severe infections caused by multi-drug resistant bacteria.
  • carbapenem-resistant bacteria In recent years, the spread of carbapenem-resistant bacteria through plasmids has caused serious bacterial resistance problems, including the recently discovered colistin resistance. Because of their high toxicity, these life-saving drugs are often limited in clinical use. Therefore, there is a need to provide an antibacterial compound with a novel structure.
  • an antibiotic research work published in Nature attracted positive reactions worldwide.
  • Teixobactin is an undecapeptide with a certain complexity. The structure contains a cyclic tetrapeptide formed by a lactone bond between the C-terminal 8 threonine and the 11 isoleucine.
  • the molecule In addition to four D-type amino acids and one N-methylphenylalanine, the molecule also contains an L-allo-Enduracidine (End) unnatural amino acid.
  • End L-allo-Enduracidine
  • teixobactin has a MIC of 0.31 ⁇ 0.125ug / mL against different Mycobacterium tuberculosis, and can effectively inhibit drug-resistant Mycobacterium tuberculosis; and teixobactin will not cause cytotoxicity, hemolysis, hERG inhibition, genotoxicity, etc .; initial in vitro Pharmacokinetic studies have shown that the half-life is more appropriate.
  • siixobactin and its analogues are all simplified, especially the simplification of End's synthetic route.
  • Teixobactin The synthesis difficulties of Teixobactin are mainly the synthesis of the unnatural amino acid L-allo-enduracididine (End) and the construction of a 13-membered ring. Among them, regarding the synthesis of End, there are currently several synthetic routes in the prior art:
  • the inventor has proposed a new synthetic route of L-allo-Enduracidine (End) unnatural amino acid.
  • the operation is simple, the product can be obtained quickly and conveniently, and the yield is high.
  • the inventor also proposed a new total synthesis strategy of teixobactin and its analogues.
  • the synthesis process has fewer by-products, simple separation and purification, high yield, and is suitable for industrial production.
  • the present invention proposes a method for preparing unnatural amino acids.
  • the method includes: subjecting the compound represented by formula (1) to oxidative ring-closure treatment,
  • R 5 is independently Fmoc, Boc, Phth, and Cbz
  • R 6 is independently H, Fmoc, Boc, Phth, and Cbz.
  • the above method may further include at least one of the following additional technical features:
  • the method further includes deprotecting the oxidation ring-closure treatment product to obtain the compound represented by formula (I),
  • the deprotection treatment refers to the removal of R 5 and R 6 substituents.
  • the oxidation ring-closure treatment is performed under the condition of an oxidant.
  • the oxidizing agent includes at least one selected from elemental iodine, NIS, iodophthalic acid, NBS, Dess-Martin oxidizing agent (Dess-Martin high iodine reagent) and trivalent iodine oxidizing agent.
  • the amount of the oxidizing agent is not particularly limited as long as it satisfies the oxidation ring-closure reaction of the compound represented by formula (I).
  • the molar ratio of the compound represented by formula (1) to the oxidant is 1: (1-5).
  • the molar ratio of the compound represented by formula (1) to the oxidant is 1: 3.
  • the deprotection treatment is performed under acidic conditions. Under acidic conditions, it can simultaneously remove R 5 and R 6 groups.
  • the acidic conditions are provided by TFA / H 2 O.
  • the efficiency of removing R 5 and R 6 groups is higher.
  • the present invention provides a method for preparing the compound represented by formula (3).
  • the method includes: 1) performing an esterification reaction between the oxidized ring-closing product of the compound represented by formula (1) and R 7 OH, so as to obtain the compound represented by formula (2), 2) combining (2)
  • the compound shown in the above is subjected to a protective treatment to obtain the compound shown in formula (3),
  • R 7 is methyl, ethyl, or propyl.
  • the esterification reaction is carried out under acidic conditions.
  • the esterification efficiency is high and there are few by-products.
  • the acidic conditions are provided by formic acid or acetic acid.
  • the esterification efficiency is higher and there are fewer by-products.
  • the upper protection treatment is carried out in the presence of a leaving group with an R 6 group.
  • the leaving group bearing the R 6 group is Cbz-OSu or Fmoc-Osu. This makes it possible to more effectively connect only the guanidine group to the protecting group R 6 .
  • R 5 is different from R 6 , and R 5 is easier to remove than R 6 .
  • R 5 is easier to remove than R 6 .
  • the present invention proposes a compound.
  • the compound has the structure represented by formula (3).
  • the compound according to the embodiment of the present invention can be further used in the total synthesis of teixobactin and its analogs, which greatly simplifies the route of total synthesis and improves the yield.
  • the present invention proposes a compound.
  • the compound is obtained by the method described above.
  • the compound according to the embodiment of the present invention can be further used in the total synthesis of teixobactin and its analogs, which greatly simplifies the route of total synthesis and improves the yield.
  • the present invention proposes a method for preparing the compound represented by formula (II) or the salt of the compound represented by formula (II).
  • the method includes: performing condensation treatment on the aforementioned compound with several amino acids, so as to obtain the compound represented by formula (II).
  • the inventors for the first time proposed the synthetic route of the aforementioned L-allo-Enduracidine (End) unnatural amino acid and its derivatives.
  • End L-allo-Enduracidine
  • the R 5 is a Fmoc group
  • the R 6 is a Cbz group, and is connected to the guanidine nitrogen
  • the R 7 is a methyl group
  • the method further includes: 1 ) The above-mentioned compound is subjected to de-Fmoc group treatment; 2) The condensation reaction of the product obtained in step 1) with Alloc-Ala-OH is performed to obtain the compound represented by formula (7); 3) The formula (7) )
  • the compound represented by the formula (8) is hydrolyzed to obtain the compound represented by formula (8); 4)
  • the compound represented by formula (6) and the compound represented by formula (8) are subjected to condensation reaction to obtain the compound represented by formula (9) Compound; 5)
  • R 1 is hydrogen, C 1 ⁇ 15 alkyl group, C 2 ⁇ 15 alkylene group, C 2 ⁇ 15 alkynyl group, C 6-10 aryl group or an acyl group;
  • R 2 is hydrogen, halo, C 1 ⁇ 15 alkyl group, C 2 ⁇ 15 alkylene group, C 2 ⁇ 15 alkynyl group, C 6-10 aryl group or an acyl group, wherein the C 6-10 aryl group may optionally be 1 ⁇ 5 Rx substitutions;
  • Rx is halogen, C 1-6 alkyl, halogenated C 1-6 alkyl
  • R 3 is amino, guanidino, urea or formamide
  • R 4 is C 1 ⁇ 15 alkyl group, C 2 ⁇ 15 alkylene group, C 2 ⁇ 15 alkynyl group, C 6-10 aryl group;
  • X is O, S or NH.
  • the inventor for the first time proposed the above-mentioned new total synthesis strategy of teixobactin and its analogues.
  • the synthesis process has fewer by-products, simple separation and purification, high yield, and is suitable for industrial production.
  • the step 7) further includes: 7-1) subjecting the compound represented by the formula (10) to Boc group removal treatment; 7-2) the removal obtained in step 7-1) The compound except for the Boc group undergoes a condensation reaction with the compound of formula (11); 7-3) The condensation product obtained in step 7-2) is subjected to Cbz group, t-Bu group and Boc group removal treatment in order to obtain The compound represented by formula (II).
  • the removal treatment of the Boc group in the step 7-1) is performed under the condition of an ethyl acetate hydrochloric acid solution for 15 to 20 minutes. Therefore, the removal efficiency of the Boc group is high, and it does not affect other protecting groups, such as t-Bu and Cbz.
  • the concentration of the hydrochloric acid ethyl acetate solution is 2M-3M.
  • the removal efficiency of the Boc group is higher.
  • the condensation reaction in step 7-2) is performed under the conditions of DEPBT / DIEA.
  • the molar ratio of formula (10), DEPBT, and DIEA in step 7-2) is 1: 1: 1.
  • the removal treatment of the Cbz group, t-Bu group and Boc group in step 7-3 is between trifluoroacetic acid, trifluoromethanesulfonic acid, anisole and It is carried out under a mixed solvent of cresol.
  • the removal of the Cbz group, t-Bu group and Boc group can be performed simultaneously, and the removal efficiency is high.
  • the volume ratio of the trifluoroacetic acid, trifluoromethanesulfonic acid, anisole, and m-cresol is (70 ⁇ 5) :( 12 ⁇ 5) :( 10 ⁇ 5) :( 8 ⁇ 5).
  • the removal efficiency is high.
  • the volume ratio of trifluoroacetic acid, trifluoromethanesulfonic acid, anisole, and m-cresol is 70: 12: 10: 8.
  • the removal efficiency is higher.
  • the removal of the Fmoc group in the step 1) is carried out under the condition of diethylamine.
  • the Fmoc group is removed without affecting the removal of other protective groups such as Cbz group and methyl ester group.
  • the condensation reaction in the step 2) is carried out under the condition that the condensation agent is HATU / DIEA or PyAOP, and the solvent is a mixed solvent of dichloromethane and DMF.
  • the molar ratio of the compound shown in claim 5 or 6 in the step 2), Alloc-Ala-OH, HATU, and DIEA is 1: 2: 2: 2.
  • the condensation efficiency is further improved.
  • the hydrolysis reaction in the step 3) is carried out under the condition that the mixed solvent of tetrahydrofuran / water and the base is LiOH.
  • the methyl ester group can be hydrolyzed without affecting other protecting groups such as Cbz group and Alloc group.
  • the molar ratio of the compound represented by formula (7) to LiOH is 1: 1.5.
  • the condensation reaction in the step 4) is carried out under the condition that the condensation agent is DEPBT / DIEA and the solvent is a mixed solvent of THF and DMF.
  • the molar ratio of the compound represented by formula (6), the compound represented by formula (8), DEPBT, and DIEA in step 4) is 1: 0.5: 1: 1.
  • the condensation efficiency is further improved.
  • the removal treatment in step 5) is carried out under acidic conditions provided by tetratriphenylphosphine palladium catalyst and 1,3-dimethylbarbituric acid.
  • the Allyl group and the Alloc group can be removed at the same time, and the removal efficiency is high.
  • the molar ratio of the compound represented by formula (9), tetratriphenylphosphine palladium, and 1,3-dimethylbarbituric acid in step 5) is 0.3: 0.06: 0.6.
  • the removal efficiency is further improved.
  • the condensation reaction in the step 6) is carried out under the condition that the condensation agent is HATU / HOAT / DIEA or PyAop.
  • the molar ratio of the compound represented by formula (9), HATU, HOAT, and DIEA in step 6) is 0.3: 1: 1: 2.
  • the condensation efficiency is high.
  • the salt is hydrochloride, trifluoroacetate, acetate, or sulfonate.
  • R 1 is hydrogen, C 1 ⁇ 10 alkyl group, C 2 ⁇ 10 alkylene group, C 2 ⁇ 10 alkynyl group, C 6-8 acyl group or an aryl group;
  • R 2 is hydrogen, halo, C 1 ⁇ 10 alkyl group, C 2 ⁇ 10 alkylene group, C 2 ⁇ 10 alkynyl group, C 6-8 acyl or aryl group, wherein the C 6-8 aryl group can be optionally 1 ⁇ 5 Rx substitutions;
  • Rx is halogen, C 1-6 alkyl, halogenated C 1-6 alkyl
  • R 4 is C 1 ⁇ 10 alkyl group, C 2 ⁇ 10 alkylene group, C 2 ⁇ 10 alkynyl group, C 6-8 aryl group.
  • R 1 is hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-7 aryl or acyl;
  • R 2 is hydrogen, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-7 aryl or acyl, wherein the C 6-7 aryl or C 5- 6 Heteroaryl groups can be optionally substituted with 1 to 3 Rx;
  • Rx is halogen, C 1-4 alkyl, halogenated C 1-4 alkyl
  • R 4 is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 6-7 aryl.
  • R 1 is hydrogen, methyl, ethyl, n-propyl, isopropyl, butyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, Phenyl, benzyl or acyl;
  • R 2 is hydrogen, halogen, methyl, ethyl, n-propyl, isopropyl, butyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, phenyl, benzyl Or acyl, wherein the phenyl or benzyl can be optionally substituted with 1 to 3 Rx;
  • Rx is halogen, methyl, ethyl, n-propyl, isopropyl, butyl, monofluoromethyl, difluoromethyl, trifluoromethyl;
  • R 4 is methyl, ethyl, n-propyl, isopropyl, butyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, phenyl, benzyl.
  • the compound represented by formula (6) is obtained by the following steps: esterification, aminolysis, and removal of Fmoc group between the compound represented by formula (5) and Fmoc-L-isoleucine Group reaction to obtain the compound represented by formula (6).
  • the esterification reaction is carried out under the condition that the condensing agent is EDCI and the catalyst is DMAP.
  • the molar ratio of the compound represented by formula (5), Fmoc-L-isoleucine, EDCI, and DMAP is 9: 10: 10: 1.
  • the ammonolysis and Fmoc group removal reactions are carried out under the conditions of a diethylamine solution.
  • the concentration of diethylamine is 33%.
  • the compound represented by formula (5) is obtained by the following steps: the compound represented by formula (4) is subjected to a condensation reaction with Boc-Ser (tBu) -OH to obtain the formula Compound.
  • the condensation reaction is carried out in a mixed solvent of dichloromethane and DMF with HCTU / DIEA as the condensing agent;
  • the compound represented by formula (11) is obtained by a solid-phase synthesis method.
  • the synthesis is simple and efficient.
  • the solid phase synthesis method is performed by the following steps:
  • a substitution reaction between 2-Cl resin and Fmoc-L-isoleucine is performed to obtain the compound represented by formula (a), wherein the circle represents the resin;
  • the 2-Cl resin is subjected to an activation treatment in advance, and the activation treatment is performed in dichloromethane and DMF for 20 minutes.
  • a solvent extraction treatment is further included.
  • the coupling reaction in step 1) is carried out under the condition that DIEA is a condensing agent and DMF is a solvent.
  • the raw materials to be condensed need to be de-Fmoc treated in advance, and the de-Fmoc treatment is performed in a piperidine solution.
  • the condensation reaction in step 2) is carried out under the condition that the condensation agent is HATU / DIEA and room temperature.
  • the deprotection and upper protection reaction (orthogonal protection strategy) strategies are used to successfully realize the introduction of different reactive protective groups at different reaction sites, and then use the protection of different reactive activities
  • the removal order of the groups introduces different groups at different reaction sites.
  • the method according to the embodiment of the present invention is used to synthesize intermediates having different protecting groups, such as compounds represented by formulas (7), (8), etc.
  • the operation is simple, the product can be conveniently and quickly obtained, and the yield is high, and the above
  • the compound is applied to the total synthesis of teixobactin and its analogues.
  • the synthesis process has few by-products, simple separation and purification, high yield, and is suitable for industrial production.
  • condensation reaction of the present invention can select a conventional condensing agent to perform the condensation reaction.
  • the yield may vary with different condensing agents, but as long as the condensation reaction can be completed, they are all protected by the present invention Within range.
  • any step in the overall synthesis route of the present invention can be commercially purchased raw materials, the commercially purchased raw materials can be used for the reaction, or the method proposed in the present invention can be used to synthesize the raw materials for the reaction.
  • the raw materials of the present invention obtained by other methods can be used for the reaction.
  • serial number of the present application does not limit the actual synthesis sequence, and those skilled in the art can adjust it according to their needs in order to obtain the desired target product.
  • the articles “a”, “an” and “said” as used herein are intended to include “at least one” or “one or more”. Therefore, the articles used herein refer to one or more than one (ie, at least one) object articles.
  • a component refers to one or more components, that is, there may be more than one component that is considered to be employed or used in the implementation of the embodiment.
  • the compounds of the present invention may be optionally substituted with one or more substituents, such as the compounds of the general formula above, or like the specific examples, subclasses, and inclusions of the present invention in the examples.
  • substituents such as the compounds of the general formula above, or like the specific examples, subclasses, and inclusions of the present invention in the examples.
  • substituents such as the compounds of the general formula above, or like the specific examples, subclasses, and inclusions of the present invention in the examples.
  • substituents such as the compounds of the general formula above, or like the specific examples, subclasses, and inclusions of the present invention in the examples.
  • substituents such as the compounds of the general formula above, or like the specific examples, subclasses, and inclusions of the present invention in the examples.
  • substituents such as the compounds of the general formula above, or like the specific examples, subclasses, and inclusions of the present invention in the examples
  • C 1 - 6 alkyl refers particularly to the disclosure independently methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl.
  • linking substituents are described.
  • the Markush variables listed for the group should be understood as the linking group.
  • the Markush group definition for the variable lists “alkyl” or “aryl”, it should be understood that the “alkyl” or “aryl” represents the linked group, respectively An alkylene group or an arylene group.
  • alkyl or "alkyl group” used in the present invention means a saturated linear or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may be optionally Are replaced by one or more substituents described in this invention. Unless otherwise specified, alkyl groups contain 1-20 carbon atoms. In one embodiment, the alkyl group contains 1-15 carbon atoms; in another embodiment, the alkyl group contains 1-6 carbon atoms; in yet another embodiment, the alkyl group contains 1 -4 carbon atoms; in still another embodiment, the alkyl group contains 1-3 carbon atoms.
  • alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), Isopropyl (i-Pr, -CH (CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH (CH 3 ) 2 ), sec-butyl (s-Bu, -CH (CH 3 ) CH 2 CH 3 ), tert-butyl (t-Bu, -C (CH 3 ) 3 ), n-pentyl (-CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH (CH 3 ) CH 2 CH 2 CH 3 ), 3-pentyl (-CH (CH 2 CH 3 ) 2 ), 2-methyl -2-butyl (-C (CH 3 ) 2
  • alkylene means a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms from a saturated linear or branched hydrocarbon group. Unless otherwise specified, the alkylene group contains 1-12 carbon atoms. In one embodiment, the alkylene group contains 1-6 carbon atoms; in another embodiment, the alkylene group contains 1-4 carbon atoms; in yet another embodiment, the alkylene group The group contains 1-3 carbon atoms; also in one embodiment, the alkylene group contains 1-2 carbon atoms. Such examples include methylene (-CH 2- ), ethylene (-CH 2 CH 2- ), isopropylidene (-CH (CH 3 ) CH 2- ) and the like.
  • alkenyl refers to a straight-chain or branched monovalent hydrocarbon group containing 2-15 carbon atoms, in which there is at least one site of unsaturation, that is, there is a carbon-carbon sp 2 double bond, wherein the alkenyl group
  • the group may be optionally substituted with one or more substituents described in the present invention, which includes the positioning of "cis” and “tans", or the positioning of "E” and "Z”.
  • the alkenyl group contains 2-8 carbon atoms; in another embodiment, the alkenyl group contains 2-6 carbon atoms; in yet another embodiment, the alkenyl group contains 2 -4 carbon atoms.
  • alkynyl refers to a straight-chain or branched monovalent hydrocarbon group containing 2-15 carbon atoms, in which there is at least one unsaturated site, that is, there is a carbon-carbon sp triple bond, wherein, the alkynyl group It may be optionally substituted with one or more substituents described in the present invention.
  • the alkynyl group contains 2-8 carbon atoms; in another embodiment, the alkynyl group contains 2-6 carbon atoms; in yet another embodiment, the alkynyl group contains 2 -4 carbon atoms.
  • alkynyl groups include, but are not limited to, ethynyl (-C ⁇ CH), propargyl (-CH 2 C ⁇ CH), 1-propynyl (-C ⁇ C-CH 3 ), etc. .
  • aryl refers to monocyclic, bicyclic and tricyclic carbocyclic systems containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring system is aromatic Family, where each ring system contains a ring of 3-7 atoms, and one or more attachment points are connected to the rest of the molecule.
  • aryl may be used interchangeably with the term “aromatic ring”. Examples of aryl groups may include phenyl, naphthyl, and anthracene. The aryl group may be independently optionally substituted with one or more substituents described in the present invention.
  • salts formed by pharmaceutically acceptable non-toxic acids include, but are not limited to, inorganic acid salts formed by reaction with amino groups include hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, And organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or other methods described in the literature such as ion exchange These salts.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphoric acid Salt, camphorsulfonate, cyclopentylpropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate Salt, gluconate, hemisulfate, enanthate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, Malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, paraben, pectate, persulfate, 3 -Phen
  • Salts obtained by suitable bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • the present invention also contemplates the quaternary ammonium salt formed by any compound containing N groups. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization.
  • the alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations formed by counter-ions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, C 1 -8 sulfonate and aromatic sulfonate.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids, such as acetate, aspartate, benzoate, benzenesulfonate, bromide / hydrobromide, bicarbonate / Carbonate, bisulfate / sulfate, camphorsulfonate, chloride / hydrochloride, chlorotheophylline, citrate, ethanedisulfonate, fumarate, glucoheptonate, glucose Urate, glucuronate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, male Salt, malonate, mandelate, mesylate, methyl sulfate, naphthoate, naphthalenesulfonate, nicotinate, nitrate, octadecate, oleate, oxalate Salt, palmitate, parath
  • Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid , Ethanesulfonic acid, p-toluenesulfonic acid, sulfosalicylic acid, etc.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
  • Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from Groups I to XII of the periodic table.
  • the salt is derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium, and magnesium salts.
  • Organic bases from which salts can be derived include primary, secondary, and tertiary amines, and substituted amines include naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like.
  • Certain organic amines include, for example, isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine .
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, basic or acidic moieties using conventional chemical methods.
  • such salts can be prepared by reacting the free acid form of these compounds with a stoichiometric amount of a suitable base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, etc.), or by These compounds are prepared by reacting the free base forms of these compounds with a stoichiometric amount of a suitable acid. This type of reaction is usually carried out in water or an organic solvent or a mixture of both.
  • a suitable base such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, etc.
  • non-aqueous media such as diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile need to be used.
  • non-aqueous media such as diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile need to be used.
  • Stahl and Wermuth Wiley-VCH, Weinheim, Germany, 2002
  • the compounds disclosed in the present invention can also be obtained in the form of their hydrates or in the form of solvents containing them (eg, ethanol, DMSO, etc.) for their crystallization.
  • solvents containing them eg, ethanol, DMSO, etc.
  • the compounds disclosed in the present invention can form solvates inherently or by design with pharmaceutically acceptable solvents (including water); therefore, the present invention is intended to include both solvated and unsolvated forms.
  • any structural formula given by the present invention is also intended to represent the forms in which these compounds are not isotopically enriched and in isotopically enriched forms.
  • Isotope-enriched compounds have the structure depicted by the general formula given in this invention, except that one or more atoms are replaced with atoms having a selected atomic weight or mass number.
  • Exemplary isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O , 18 O, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I.
  • the compounds described in the present invention include isotopically enriched compounds as defined in the present invention, for example, those in which radioactive isotopes such as 3 H, 14 C, and 18 F are present, or in which non-radioactive isotopes are present, such as 2 H and 13 C.
  • isotopically enriched compounds can be used in metabolic studies (using 14 C), reaction kinetic studies (using eg 2 H or 3 H), detection or imaging techniques such as positron emission tomography (PET) or including drugs or Single-photon emission computed tomography (SPECT) for the determination of the distribution of substrate tissues may be used in patient radiotherapy.
  • 18 F enriched compounds are particularly ideal for PET or SPECT studies.
  • Isotope-enriched compounds represented by formula (I) can be prepared by conventional techniques familiar to those skilled in the art or as described in the examples and preparation procedures of the present invention by using appropriate isotope-labeled reagents instead of the unlabeled reagents originally used.
  • isotopes especially deuterium (ie, 2 H or D)
  • deuterium in the present invention is regarded as a substituent of the compound of formula (I).
  • Isotope enrichment factors can be used to define the concentration of this type of heavier isotope, especially deuterium.
  • isotopic enrichment factor refers to the ratio between the isotopic abundance and the natural abundance of the specified isotope.
  • the compound has at least 3500 for each designated deuterium atom (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), At least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% of Deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation) or at least 6633.3 (99.5% deuterium incorporation) isotope enrichment factor.
  • the pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent may be isotopically substituted, such as D 2 O, acetone-d 6 , DMSO-d 6 .
  • HCTU 6-chlorobenzotriazole-1,1,3,3-tetramethylurea hexafluorophosphate
  • the compound represented by Formula 2 (2 mmol) was added to the round bottom flask, 10 ml of dichloromethane was added, CbzOSu (6 mmol) was added and stirred at room temperature, and N, N-diisopropylethylamine (6 mmol) was slowly added, 30 After stirring at °C for 5 hours, the solvent was spin-dried and separated through a normal phase silica gel column (dichloromethane: methanol / 20: 1) to obtain the target product with a yield of 80%.
  • the compound (0.1 mmol) represented by Formula 10 was placed in a round bottom flask, 5 ml of 2M hydrochloric acid ethyl acetate solution was added, stirred at room temperature for 20 min, diluted with 10 ml of ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, and the organic phase was dried After drying over sodium sulfate, the ethyl acetate solvent was distilled off under reduced pressure to obtain a crude intermediate.
  • the mixed solvent trifluoroacetic acid: trifluoromethanesulfonic acid: anisole: m-cresol / 70: 12: 10: 8
  • the solvent was blown dry with nitrogen, precipitated by adding ice ether, and centrifuged to obtain a crude product, which was separated by reverse-phase HPLC and freeze-dried.

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Abstract

公开了抗生素teixobactin及其类似物的合成路线以及一种制备非天然氨基酸的方法。该方法包括：将式(1)所示化合物进行氧化关环处理，(I) 其中，R 5独立地为Fmoc、Boc、Phth、Cbz，R 6独立地为H、Fmoc、Boc、Phth、Cbz。该方法是首次提出的，利用氧化关环反应，一步就能得到L-allo-Enduracidine(End)非天然氨基酸，该方法收率高、副产物少，分离纯化简单。

Description

抗生素teixobactin及其类似物的合成路线
优先权信息
本申请请求2018年10月31日向中国国家知识产权局提交的、专利申请号为201811290315.9的专利申请的优先权和权益，并且通过参照将其全文并入此处。
技术领域
本发明涉及药物化学领域，具体地，本发明涉及用于耐药革兰氏阳性菌及结核治疗的新型抗生素的制备方法，更具体地，本发明涉及抗生素teixobactin及其类似物的合成路线。
背景技术
革兰氏阳性细菌感染为常见病与多发病，危害人类健康。近年来，革兰氏阳性球菌感染日见增多，耐甲氧西林金黄色葡萄球菌(MRSA)检出率上升，耐青霉素肺炎链球菌(PRSP)在许多国家与地区传播，耐糖肽和其他多种抗生素的耐万古霉素肠球菌(VRE)出现，多重药性结核杆菌有增无减。为了有效地控制此等现有抗生素与抗菌药的耐药菌感染，研究开发治疗革兰氏阳性耐药菌感染的药物已成为举世关注的点。
目前细菌接触抗菌药物可发生变异而获得耐药性，其机制主要有4种：①产生抗生素酶,灭活抗生素；②作用靶位变异，不应答药物；③外膜通透性改变，阻断药物进入；④增强外排，加速泵出进入菌体内的药物。在与抗菌药物一次次的“遭遇战”中，存活下来的细菌都积累了丰富的“战斗经验”，成为耐药品种，尔后又演进出交叉耐药、多重耐药、泛耐药、全耐药等“超级细菌”。不久前，一项由中外研究者联合进行的、成果发表在新一期《柳叶刀·传染病》杂志上的研究引发关注。该研究显示：存在一种特殊基因MCR-1，携带该基因的细菌对多粘菌素表现出强耐药性，且这种耐药性还能快速转移至其他菌株，这意味着一种新的“超级细菌”被发现。
2015年，我国大肠埃希菌对第三代头孢菌素的耐药菌检出率为59％，对喹诺酮类的耐药菌检出率为53.5％。肺炎克雷伯菌对第三代头孢菌素的耐药菌检出率是36.5％，甲氧西林耐药金黄色葡萄球菌检出率为35.8％，这些具有代表性的耐药菌检出率都处于较高水平。需要指出的是，万古霉素耐药屎肠球菌已成为发达国家的一大挑战，美国ICU患者的血流感染屎肠球菌万古霉素耐药率高达80.7％。全球来看，北美洲屎肠球菌万古霉素耐药平均检出率高达66.8％，拉丁美洲为39.4％。一些多重耐药、泛耐药的细菌已将临床逼到了绝境，加速研发新型抗菌药物迫在眉睫。
目前，碳青霉烯类抗生素是公认的细菌“终极防线”，常用于治疗由多重耐药菌引 起严重感染。近几年，碳青霉烯类耐药菌通过质粒间传播造成了严重的细菌耐药问题，包括近期发现的粘菌素耐药。这些救命药因其毒性较大，往往临床使用受限。因此，需要提供一种结构新颖的抗菌化合物。2015年，发表在Nature上的一项抗生素研究工作吸引了世界范围内的积极反响。美国Northeastern University的Kim Lewis教授通过iChip的技术发现了近30年来第一种新型抗生素－teixobactin，其可以杀死MRSA、结核分枝杆菌等多种致命病原体。这份研究不仅呈现了一种新颖的抗生素结构，而且也给未来新型无耐药性抗生素的出现带来了希望，甚至将teixobactin称为超级抗生素。Teixobactin是结构具有一定复杂性的十一肽，结构中含有一个通过C端8位苏氨酸与11位异亮氨酸的内酯键形成的环状四肽。分子中除了含有四个D型氨基酸和一个N-甲基苯丙氨酸外，还含有一个L-allo-Enduracidine(End)非天然氨基酸。体外活性实验表明teixobactin针对不同结核分枝杆菌的MIC在0.31～0.125ug/mL，而且可有效抑制耐药结核杆菌；并且teixobactin不会引起细胞毒、溶血、hERG抑制、遗传毒性等；初期的体外药动学研究表明其半衰期较合适。
因而，构建高效的汇聚式合成路线是研究teixobactin构效关系的重要手段。其中L-allo-Enduracidine(End)非天然氨基酸对于抗菌活性起到重要的作用，但是其结构复杂，目前还没有较为简单的合成策略，进而，teixobactin的全合成更为困难。
因而，teixobactin及其类似物的全合成路线的简化，特别是其中End的合成路线的简化迫在眉睫。
发明内容
Teixobactin的合成难点主要是非天然氨基酸L-allo-enduracididine(End)的合成和十三元环的构建。其中，关于End的合成，现有技术中目前有如下几种合成路线：
1)Rudolph及其同事以起始原料经四步合成得到L-allo-enduracididine(如下所示)。然而L-allo-enduracididine的非对映体L-enduracididine也被合成得到，与L-allo-enduracididine的比例为1:6，进而造成后续分离困难，
Figure PCTCN2019101927-appb-000001
2)Yuan和其同事建立了一个高立体选择性的合成L-allo-enduracididine的方法。该合成路线以反式羟基脯氨酸为起始原料，经过十步反应得到目标产物，产率约31％，并且非对映体比例甚至超过50:1(如下所示)。但是该方法合成路线长、收率低。
Figure PCTCN2019101927-appb-000002
3)Payne和其研究小组完成了双Cbz保护的L-allo-enduracididine的合成(如下所示)。该合成方法以Boc-L-Asp-OtBu为起始原料，经一系列反应得到受Fmoc和双Cbz保护的L-allo-enduracididine。该合成的难点在于羰基的立体选择性还原为醇羟基。该路线用了三仲丁基硼氢化锂作为还原剂，得到了两个产(2S,4R)和(2S,4S)，其比例为5:1。但两个产物为一对非对映体，需要经过Flash柱层析才可以得到单一的产物。
Figure PCTCN2019101927-appb-000003
由上述方法可知，现有技术中相关的非天然氨基酸End的合成路线长，分离提纯困难。进一步地，teixobactin及其类似物的全合成也被制约着发展，同样也面临着合成路线复杂，合成过程中副产物多，分离纯化困难，产率低，不适合工业化生产等问题。
基于上述事实和问题的发现和认识，发明人提出了一种新的L-allo-Enduracidine(End)非天然氨基酸的合成路线，操作简单，能方便快速得到产物，且产率高。同时，基于上述End的合成路线的提出，发明人还提出了一种新的teixobactin及其类似物的全合成策略，合成过程中副产物少、分离纯化简单，产率高，适合工业化生产。
在本发明的第一方面，本发明提出了一种制备非天然氨基酸的方法。根据本发明的实施例，所述方法包括：将式(1)所示化合物进行氧化关环处理，
Figure PCTCN2019101927-appb-000004
其中，R 5独立地为Fmoc、Boc、Phth、Cbz，R 6独立地为H、Fmoc、Boc、Phth、Cbz。发明人首次提出了利用氧化关环反应，一步就能得到L-allo-Enduracidine(End)非天然氨基酸，同时收率高、副产物少，分离纯化简单。
根据本发明的实施例，上述方法还可以进一步包括如下附加技术特征至少之一：
根据本发明的实施例，所述方法进一步包括将氧化关环处理产物进行脱保护处理，以便获得式(I)所示化合物，
Figure PCTCN2019101927-appb-000005
所述脱保护处理是指脱除R 5和R 6取代基。
根据本发明的实施例，所述氧化关环处理是在氧化剂的条件下进行的。
根据本发明的实施例，所述氧化剂包括选自单质碘、NIS、碘苯二乙酸、NBS、戴斯-马丁氧化剂(Dess-Martin高碘试剂)以及三价碘氧化剂的至少之一。
需要说明的是，氧化剂的用量没有特别限制，只要满足能使得式(I)所示化合物发生氧化关环反应即可。根据本发明的实施例，所述式(1)所示化合物与所述氧化剂的摩尔比为1：(1-5)。
根据本发明的实施例，所述式(1)所示化合物与所述氧化剂的摩尔比为1:3。
根据本发明的实施例，所述脱保护处理是在酸性条件下进行的。在酸性条件下能同时脱除R 5和R 6基团。
根据本发明的实施例，所述酸性条件由TFA/H 2O提供。在TFA/H 2O的条件下，脱除R 5和R 6基团的效率更高。
在本发明的第二方面，本发明提出了一种制备式(3)所示化合物的方法。根据本发明的实施例，所述方法包括：1)将式(1)所示化合物的氧化关环产物与R 7OH进行酯化反应，以便获得式(2)所示化合物，2)将式(2)所示化合物进行上保护处理，以便获得式(3)所示化合物，
Figure PCTCN2019101927-appb-000006
其中，R 7为甲基、乙基、丙基。通过保护基团的引入，得到一个待后续合成teixobactin及其类似物的原料。根据本发明实施例的方法获得的化合物能进一步用到teixobactin及其类似物的全合成中，大大简化了全合成的路线，提高了收率。
根据本发明的实施例，所述酯化反应是在酸性条件下进行的。由此，酯化效率高、副产物少。
根据本发明的实施例，所述酸性条件是甲酸或乙酸提供的。由此，酯化效率更高、副产物更少。
根据本发明的实施例，所述上保护处理是在带有R 6基团的离去基团存在的条件下进行的。
根据本发明的实施例，所述带有R 6基团的离去基团为Cbz-OSu或Fmoc-Osu。由此，能更有效地仅在胍基上连上保护基团R 6。
根据本发明的实施例，所述R 5与R 6不相同，且R 5比R 6易脱除。由此，利用保护基团的脱除难易程度来控制后续在相应的位点连接所需要的基团。
在本发明的第三方面，本发明提出了一种化合物。根据本发明的实施例，所述化合物具有式(3)所示结构。根据本发明实施例的化合物能进一步用到teixobactin及其类似物的全合成中，大大简化了全合成的路线，提高了收率。
在本发明的第四方面，本发明提出了一种化合物。根据本发明的实施例，所述化合物是通过前面所述的方法获得的。根据本发明实施例的化合物能进一步用到teixobactin及其类似物的全合成中，大大简化了全合成的路线，提高了收率。
在本发明的第五方面，本发明提出了一种制备式(II)所示化合物或式(II)所示化合物的盐的方法。根据本发明的实施例，所述方法包括：将前面所述的化合物与数个氨基酸进行缩合处理，以便获得式(II)所示化合物。发明人首次提出了上述L-allo-Enduracidine(End)非天然氨基酸及其衍生物的合成路线，操作简单，能方便快速得到产物，且产率高，并将上述化合物应用到teixobactin及其类似物的全合成中，合成过程中副产物少、分离纯化简单，产率高，适合工业化生产。
需要说明的是，根据R 5、R 6、R 7保护基的不同，本领域技术人员可以进行适度调整脱除上述基团的脱除试剂，以便进行根据本发明实施例的相应的操作。根据本发明的具体实施例，所述R 5为Fmoc基团，所述R 6为Cbz基团，且连接在胍基的氮上，所述R 7为甲基，所述方法进一步包括：1)将前面所述的化合物进行脱Fmoc基团处理；2)将步骤1)所得产物与Alloc-Ala-OH进行缩合反应，以便得到式(7)所示化合物；3)将所述式(7)所示化合物进行水解处理，以便获得式(8)所示化合物；4)将式(6)所示化合物与所述式(8)所示化合物进行缩合反应，以便得到式(9)所示化合物；5)将所述式(9)所示化合物进行Allyl基团和Alloc基团脱除处理：6)将步骤5)脱除处理产物进行缩合处理，以便得到式(10)所示化合物；7)将所述式(10)所示化合物与式(11)所示化合物进行缩合处理，得到式(II)所示化合物；
Figure PCTCN2019101927-appb-000007
Figure PCTCN2019101927-appb-000008
其中，R 1为氢、C 1～15烷基、C 2～15烯基、C 2～15炔基、C 6-10芳基或酰基；
R 2为氢、卤素、C 1～15烷基、C 2～15烯基、C 2～15炔基、C 6-10芳基或酰基，其中所述C 6-10芳基可任选被1～5个Rx取代；
Rx为卤素、C 1-6烷基、卤代C 1-6烷基；
R 3为氨基、胍基、脲基或甲酰胺基；
R 4为C 1～15烷基、C 2～15烯基、C 2～15炔基、C 6-10芳基；
X为O、S或NH。发明人首次提出了上述这种新的teixobactin及其类似物的全合成策略，合成过程中副产物少、分离纯化简单，产率高，适合工业化生产。
根据本发明的实施例，所述步骤7)进一步包括：7-1)将所述式(10)所示化合物进行Boc基团脱除处理；7-2)步骤7-1)中得到的脱除Boc基团的化合物与式(11)化合物进行缩合反应；7-3)步骤7-2)中得到的缩合产物进行Cbz基团、t-Bu基团以及Boc基团脱除处理，以便获得式(II)所示化合物。
根据本发明的实施例，所述步骤7-1)中的Boc基团脱除处理是在盐酸乙酸乙酯溶液的条件下进行15～20min。由此，Boc基团脱除效率高，且不会影响其他保护基团，如t-Bu、Cbz。
根据本发明的实施例，所述盐酸乙酸乙酯溶液的浓度为2M～3M。由此，Boc基团脱除 效率更高。
根据本发明的实施例，所述步骤7-2)中的缩合反应是在DEPBT/DIEA的条件下进行的。
根据本发明的实施例，所述步骤7-2)中式(10)、DEPBT、DIEA的摩尔比为1:1:1。
根据本发明的实施例，所述步骤7-3)中的Cbz基团、t-Bu基团以及Boc基团脱除处理是在三氟乙酸、三氟甲烷磺酸、苯甲硫醚以及间甲苯酚的混合溶剂下进行的。由此，能同时进行Cbz基团、t-Bu基团以及Boc基团的脱除，且脱除效率高。
根据本发明的实施例，所述三氟乙酸、三氟甲烷磺酸、苯甲硫醚以及间甲苯酚的体积比为(70±5):(12±5):(10±5):(8±5)。由此，脱除效率高。
根据本发明的实施例，所述三氟乙酸、三氟甲烷磺酸、苯甲硫醚以及间甲苯酚的体积比为70:12:10:8。由此，脱除效率更高。
根据本发明的实施例，所述步骤1)中脱除Fmoc基团是在二乙胺的条件下进行的。由此，仅脱除了Fmoc基团，而不会影响其他保护基团的脱除，如Cbz基团、甲酯基。
根据本发明的实施例，所述步骤2)中的缩合反应是在缩合剂为HATU/DIEA或PyAOP、溶剂为二氯甲烷和DMF的混合溶剂的条件下进行的。
根据本发明的实施例，所述步骤2)中的权利要求5或6所示的化合物、Alloc-Ala-OH、HATU、DIEA的摩尔比为1:2:2:2。由此，缩合效率进一步提高。
根据本发明的实施例，所述步骤3)中的水解反应是在四氢呋喃/水的混合溶剂、碱为LiOH的条件下进行的。由此，能仅仅水解掉甲酯基，而不会影响其他保护基团，如Cbz基团、Alloc基团。
根据本发明的实施例，所述式(7)所示化合物、LiOH的摩尔比为1:1.5。由此，水解效率进一步提高。
根据本发明的实施例，所述步骤4)中的缩合反应是在缩合剂为DEPBT/DIEA、溶剂为THF和DMF的混合溶剂的条件下进行的。
根据本发明的实施例，所述步骤4)中的式(6)所示化合物、式(8)所示化合物、DEPBT、DIEA的摩尔比为1:0.5:1:1。由此，缩合效率进一步提高。
根据本发明的实施例，所述步骤5)中的脱除处理是在催化剂为四三苯基膦钯、在1,3-二甲基巴比妥酸提供的酸性条件下进行的。由此，能同时脱除Allyl基团和Alloc基团，且脱除效率高。
根据本发明的实施例，所述步骤5)中式(9)所示化合物、四三苯基膦钯、1,3-二甲基巴比妥酸的摩尔比为0.3:0.06:0.6。由此，脱除效率进一步提高。
根据本发明的实施例，所述步骤6)中的缩合反应是在缩合剂为HATU/HOAT/DIEA或 PyAop的条件下进行的。
根据本发明的实施例，所述步骤6)中式(9)所示化合物、HATU、HOAT、DIEA的摩尔比为0.3:1:1:2。由此，缩合效率高。
根据本发明的实施例，所述盐为盐酸盐、三氟乙酸盐、醋酸盐、磺酸盐。
根据本发明的实施例，R 1为氢、C 1～10烷基、C 2～10烯基、C 2～10炔基、C 6-8芳基或酰基；
R 2为氢、卤素、C 1～10烷基、C 2～10烯基、C 2～10炔基、C 6-8芳基或酰基，其中所述C 6-8芳基可任选被1～5个Rx取代；
Rx为卤素、C 1-6烷基、卤代C 1-6烷基；
R 4为C 1～10烷基、C 2～10烯基、C 2～10炔基、C 6-8芳基。
根据本发明的实施例，R 1为氢、C 1～6烷基、C 2～6烯基、C 2～6炔基、C 6-7芳基或酰基；
R 2为氢、卤素、C 1～6烷基、C 2～6烯基、C 2～6炔基、C 6-7芳基或酰基，其中所述C 6-7芳基或C 5-6杂芳基可任选被1～3个Rx取代；
Rx为卤素、C 1-4烷基、卤代C 1-4烷基；
R 4为C 1～6烷基、C 2～6烯基、C 2～6炔基、C 6-7芳基。
根据本发明的实施例，R 1为氢、甲基、乙基、正丙基、异丙基、丁基、乙烯基、丙烯基、烯丙基、乙炔基、丙炔基、炔丙基、苯基、苄基或酰基；
R 2为氢、卤素、甲基、乙基、正丙基、异丙基、丁基、乙烯基、丙烯基、烯丙基、乙炔基、丙炔基、炔丙基、苯基、苄基或酰基，其中所述苯基或苄基可任选被1～3个Rx取代；
Rx为卤素、甲基、乙基、正丙基、异丙基、丁基、一氟甲基、二氟甲基、三氟甲基；
R 4为甲基、乙基、正丙基、异丙基、丁基、乙烯基、丙烯基、烯丙基、乙炔基、丙炔基、炔丙基、苯基、苄基。
根据本发明的实施例，所述式(6)所示化合物是通过如下步骤获得的：将式(5)所示化合物与Fmoc-L-异亮氨酸进行酯化、氨解以及脱Fmoc基团反应，以便得到式(6)所示化合物。
根据本发明的实施例，所述酯化反应是在缩合剂为EDCI、催化剂为DMAP的条件下进行的。
根据本发明的实施例，所述式(5)所示化合物、Fmoc-L-异亮氨酸、EDCI、DMAP的摩尔比为9:10:10:1。
根据本发明的实施例，所述氨解以及脱Fmoc基团反应是在二乙胺溶液的条件下进行的。
根据本发明的实施例，所述二乙胺的浓度为33％。
根据本发明的实施例，式(5)所示化合物是通过如下步骤获得的：将式(4)所示化 合物与Boc-Ser(tBu)-OH进行缩合反应，以便得到式(5)所示化合物。
根据本发明的实施例，所述缩合反应是在以二氯甲烷和DMF的混合溶剂中，以HCTU/DIEA为缩合剂的条件下进行的；
Figure PCTCN2019101927-appb-000009
根据本发明的实施例，式(11)所示化合物是通过固相合成方法获得的。由此，合成简便高效。
根据本发明的实施例，所述固相合成方法是通过如下步骤进行的：
A)将2-Cl树脂和Fmoc-L-异亮氨酸发生取代反应，以便得到式(a)所示化合物，其中圆圈表示树脂；
B)将式(a)所示化合物依次与N-Fmoc-N'-三苯甲基-D-谷氨酰胺、Fmoc-L-丝氨酸、Fmoc-L-异亮氨酸、Boc-D-4,4'-二苯基苯丙氨酸以及N-叔丁氧羰基-N-甲基-D-苯丙氨酸中最末端的氨基酸发生缩合反应，以便得到式(b)所示的化合物；
C)将式(b)所示的化合物进行脱树脂反应，以便得到式(11)所示的化合物；
Figure PCTCN2019101927-appb-000010
根据本发明的实施例，所述2-Cl树脂预先经过活化处理，所述活化处理是在二氯甲烷和DMF中进行20min。
根据本发明的实施例，所述活化处理后、偶联反应前进一步包括抽取溶剂处理。
根据本发明的实施例，步骤1)中的偶联反应是在DIEA为缩合剂、DMF为溶剂的条件下进行的。
根据本发明的实施例，步骤2)中的每一次缩合反应进行前需要预先将待缩合原料进行脱Fmoc处理，所述脱Fmoc处理是在哌啶溶液中进行的。
根据本发明的实施例，步骤2)中的缩合反应是在缩合剂为HATU/DIEA、室温的条件下进行的。
根据本发明实施例的方法，利用脱保护和上保护反应(正交保护策略)策略，成功实现了在不同的反应位点引入不同的反应活性的保护基团，进而利用不同的反应活性的保护 基团的脱除顺序，在不同的反应位点上引入不同的基团。进而利用根据本发明实施例的方法合成具有不同保护基团的中间体，如式(7)、(8)等所示化合物，操作简单，能方便快速得到产物，且产率高，并将上述化合物应用到teixobactin及其类似物的全合成中，合成过程中副产物少、分离纯化简单，产率高，适合工业化生产。
具体实施方式
下面详细描述本发明的实施例。下面描述的实施例是示例性的，旨在用于解释本发明，而不能理解为对本发明的限制。
需要说明的是，本发明的缩合反应，可以自行选择常规的缩合剂进行缩合反应，收率可能会随着缩合剂的不同而有所差异，但是只要能完成缩合反应，均在本发明的保护范围内。
需要说明的是，如果本发明的整体合成路线中的任何一步可以进行商业购买到原料，则可以采用商业购买的原料进行反应，也可以采用本发明中提出的方法进行合成原料来进行反应，也可以采用其他方法获得的本发明的原料来进行反应。
需要说明的是，本申请的编号对实际的合成先后顺序不起限定作用，本领域技术人员可以根据其需要来进行调整，以便获得其需要的目标产物。
除非另外说明，本发明所使用的所有科技术语具有与本发明所属领域技术人员的通常理解相同的含义。本发明涉及的所有专利和公开出版物通过引用方式整体并入本发明。
除非另外说明，应当应用本文所使用得下列定义。出于本发明的目的，化学元素与元素周期表CAS版，和《化学和物理手册》，第75版，1994一致。此外，有机化学一般原理可参考"Organic Chemistry",Thomas Sorrell,University Science Books,Sausalito:1999,和"March's Advanced Organic Chemistry”by Michael B.Smith and Jerry March,John Wiley&Sons,New York:2007中的描述，其全部内容通过引用并入本文。
除非另有说明或者上下文中有明显的冲突，本文所使用的冠词“一”、“一个(种)”和“所述”旨在包括“至少一个”或“一个或多个”。因此，本文所使用的这些冠词是指一个或多于一个(即至少一个)宾语的冠词。例如，“一组分”指一个或多个组分，即可能有多于一个的组分被考虑在所述实施方案的实施方式中采用或使用。
像本发明所描述的，本发明的化合物可以任选地被一个或多个取代基所取代，如上面的通式化合物，或者像实施例里面特殊的例子，子类，和本发明所包含的一类化合物。应了解“任选取代的”这个术语与“取代或非取代的”这个术语可以交换使用。一般而言，术语“取代的”表示所给结构中的一个或多个氢原子被具体取代基所取代。除非其他方面表明，一个任选的取代基团可以在基团各个可取代的位置进行取代。当所给出的结构式中不只一个位置能被选自具体基团的一个或多个取代基所取代，那么取代基可以相同或不同 地在各个位置取代。
另外，需要说明的是，除非以其他方式明确指出，在本发明中所采用的描述方式“各…独立地为”与“…各自独立地为”和“…独立地为”可以互换，均应做广义理解，其既可以是指在不同基团中，相同符号之间所表达的具体选项之间互相不影响，也可以表示在相同的基团中，相同符号之间所表达的具体选项之间互相不影响。
在本说明书的各部分，本发明公开化合物的取代基按照基团种类或范围公开。特别指出，本发明包括这些基团种类和范围的各个成员的每一个独立的次级组合。例如，术语“C 1- 6烷基”特别指独立公开的甲基、乙基、C 3烷基、C 4烷基、C 5烷基和C 6烷基。
在本发明的各部分，描述了连接取代基。当该结构清楚地需要连接基团时，针对该基团所列举的马库什变量应理解为连接基团。例如，如果该结构需要连接基团并且针对该变量的马库什基团定义列举了“烷基”或“芳基”，则应该理解，该“烷基”或“芳基”分别代表连接的亚烷基基团或亚芳基基团。
本发明使用的术语“烷基”或“烷基基团”，表示含有1至20个碳原子，饱和的直链或支链一价烃基基团，其中，所述烷基基团可以任选地被一个或多个本发明描述的取代基所取代。除非另外详细说明，烷基基团含有1-20个碳原子。在一实施方案中，烷基基团含有1-15个碳原子；在另一实施方案中，烷基基团含有1-6个碳原子；在又一实施方案中，烷基基团含有1-4个碳原子；还在一实施方案中，烷基基团含有1-3个碳原子。
烷基基团的实例包含，但并不限于，甲基(Me、-CH 3)，乙基(Et、-CH 2CH 3)，正丙基(n-Pr、-CH 2CH 2CH 3)，异丙基(i-Pr、-CH(CH 3) 2)，正丁基(n-Bu、-CH 2CH 2CH 2CH 3)，异丁基(i-Bu、-CH 2CH(CH 3) 2)，仲丁基(s-Bu、-CH(CH 3)CH 2CH 3)，叔丁基(t-Bu、-C(CH 3) 3)，正戊基(-CH 2CH 2CH 2CH 2CH 3)，2-戊基(-CH(CH 3)CH 2CH 2CH 3)，3-戊基(-CH(CH 2CH 3) 2)，2-甲基-2-丁基(-C(CH 3) 2CH 2CH 3)，3-甲基-2-丁基(-CH(CH 3)CH(CH 3) 2)，3-甲基-1-丁基(-CH 2CH 2CH(CH 3) 2)，2-甲基-1-丁基(-CH 2CH(CH 3)CH 2CH 3)，正己基(-CH 2CH 2CH 2CH 2CH 2CH 3)，2-己基(-CH(CH 3)CH 2CH 2CH 2CH 3)，3-己基(-CH(CH 2CH 3)(CH 2CH 2CH 3))，2-甲基-2-戊基(-C(CH 3) 2CH 2CH 2CH 3)，3-甲基-2-戊基(-CH(CH 3)CH(CH 3)CH 2CH 3)，4-甲基-2-戊基(-CH(CH 3)CH 2CH(CH 3) 2)，3-甲基-3-戊基(-C(CH 3)(CH 2CH 3) 2)，2-甲基-3-戊基(-CH(CH 2CH 3)CH(CH 3) 2)，2,3-二甲基-2-丁基(-C(CH 3) 2CH(CH 3) 2)，3,3-二甲基-2-丁基(-CH(CH 3)C(CH 3) 3)，正庚基，正辛基，等等。
术语“亚烷基”表示从饱和的直链或支链烃基中去掉两个氢原子所得到的饱和的二价烃基基团。除非另外详细说明，亚烷基基团含有1-12个碳原子。在一实施方案中，亚烷基基团含有1-6个碳原子；在另一实施方案中，亚烷基基团含有1-4个碳原子；在又一实施方案中，亚烷基基团含有1-3个碳原子；还在一实施方案中，亚烷基基团含有1-2个碳原子。 这样的实例包括亚甲基(-CH 2-)，亚乙基(-CH 2CH 2-)，亚异丙基(-CH(CH 3)CH 2-)等等。
术语“烯基”表示含有2-15个碳原子的直链或支链一价烃基，其中至少有一个不饱和位点，即有一个碳-碳sp 2双键，其中，所述烯基基团可以任选地被一个或多个本发明所描述的取代基所取代，其包括“cis”和“tans”的定位，或者“E”和“Z”的定位。在一实施方案中，烯基基团包含2-8个碳原子；在另一实施方案中，烯基基团包含2-6个碳原子；在又一实施方案中，烯基基团包含2-4个碳原子。烯基基团的实例包括，但并不限于，乙烯基(-CH＝CH 2)、烯丙基(-CH 2CH＝CH 2)等等。
术语“炔基”表示含有2-15个碳原子的直链或支链一价烃基，其中至少有一个不饱和位点，即有一个碳-碳sp三键，其中，所述炔基基团可以任选地被一个或多个本发明所描述的取代基所取代。在一实施方案中，炔基基团包含2-8个碳原子；在另一实施方案中，炔基基团包含2-6个碳原子；在又一实施方案中，炔基基团包含2-4个碳原子。炔基基团的实例包括，但并不限于，乙炔基(-C≡CH)、炔丙基(-CH 2C≡CH)、1-丙炔基(-C≡C-CH 3)等等。
术语“芳基”表示含有6-14个环原子，或6-12个环原子，或6-10个环原子的单环、双环和三环的碳环体系，其中，至少一个环体系是芳香族的，其中每一个环体系包含3-7个原子组成的环，且有一个或多个附着点与分子的其余部分相连。术语“芳基”可以和术语“芳香环”交换使用。芳基基团的实例可以包括苯基、萘基和蒽。所述芳基基团可以独立任选地被一个或多个本发明所描述的取代基所取代。
本发明所使用的“药学上可接受的盐”是指本发明的化合物的有机盐和无机盐。药学上可接受的盐在所属领域是为我们所熟知的，如文献：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,1977,66:1-19.所记载的。药学上可接受的无毒的酸形成的盐包括，但并不限于，与氨基基团反应形成的无机酸盐有盐酸盐，氢溴酸盐，磷酸盐，硫酸盐，高氯酸盐，和有机酸盐如乙酸盐，草酸盐，马来酸盐，酒石酸盐，柠檬酸盐，琥珀酸盐，丙二酸盐，或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。其他药学上可接受的盐包括己二酸盐，藻酸盐，抗坏血酸盐，天冬氨酸盐，苯磺酸盐，苯甲酸盐，重硫酸盐，硼酸盐，丁酸盐，樟脑酸盐，樟脑磺酸盐，环戊基丙酸盐，二葡萄糖酸盐，十二烷基硫酸盐，乙磺酸盐，甲酸盐，反丁烯二酸盐，葡庚糖酸盐，甘油磷酸盐，葡萄糖酸盐，半硫酸盐，庚酸盐，己酸盐，氢碘酸盐，2-羟基-乙磺酸盐，乳糖醛酸盐，乳酸盐，月桂酸盐，月桂基硫酸盐，苹果酸盐，丙二酸盐，甲磺酸盐，2-萘磺酸盐，烟酸盐，硝酸盐，油酸盐，棕榈酸盐，扑酸盐，果胶酸盐，过硫酸盐，3-苯基丙酸盐，苦味酸盐，特戊酸盐，丙酸盐，硬脂酸盐，硫氰酸盐，对甲苯磺酸盐，十一酸盐，戊酸盐，等等。通过适当的碱得到的盐包括碱金属，碱土金属，铵和N +(C 1-4烷基) 4的盐。本发明也拟构思了任何所包含N的基团的化合物所形成的季铵盐。水溶性或 油溶性或分散产物可以通过季铵化作用得到。碱金属或碱土金属盐包括钠，锂，钾，钙，镁，等等。药学上可接受的盐进一步包括适当的、无毒的铵，季铵盐和抗平衡离子形成的胺阳离子，如卤化物，氢氧化物，羧化物，硫酸化物，磷酸化物，硝酸化物，C 1-8磺酸化物和芳香磺酸化物。
可药用的酸加成盐可与无机酸和有机酸形成，例如乙酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、溴化物/氢溴酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、樟脑磺酸盐、氯化物/盐酸盐、氯茶碱盐、柠檬酸盐、乙二磺酸盐、富马酸盐、葡庚糖酸盐、葡糖酸盐、葡糖醛酸盐、马尿酸盐、氢碘酸盐/碘化物、羟乙基磺酸盐、乳酸盐、乳糖醛酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、扁桃酸盐、甲磺酸盐、甲基硫酸盐、萘甲酸盐、萘磺酸盐、烟酸盐、硝酸盐、十八酸盐、油酸盐、草酸盐、棕榈酸盐、扑酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、聚半乳糖酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、磺基水杨酸盐、酒石酸盐、甲苯磺酸盐和三氟乙酸盐。
可以由其衍生得到盐的无机酸包括例如盐酸、氢溴酸、硫酸、硝酸、磷酸等。
可以由其衍生得到盐的有机酸包括例如乙酸、丙酸、羟基乙酸、草酸、马来酸、丙二酸、琥珀酸、富马酸、酒石酸、柠檬酸、苯甲酸、扁桃酸、甲磺酸、乙磺酸、对甲苯磺酸、磺基水杨酸等。
可药用碱加成盐可与无机碱和有机碱形成。
可以由其衍生得到盐的无机碱包括，例如铵盐和周期表的I族至XII族的金属。在某些实施方案中，该盐衍生自钠、钾、铵、钙、镁、铁、银、锌和铜；特别适合的盐包括铵、钾、钠、钙和镁盐。
可以由其衍生得到盐的有机碱包括伯胺、仲胺和叔胺，取代的胺包括天然存在的取代的胺、环状胺、碱性离子交换树脂等。某些有机胺包括，例如，异丙胺、苄星青霉素(benzathine)、胆碱盐(cholinate)、二乙醇胺、二乙胺、赖氨酸、葡甲胺(meglumine)、哌嗪和氨丁三醇。
本发明的可药用盐可以用常规化学方法由母体化合物、碱性或酸性部分来合成。一般而言，该类盐可以通过使这些化合物的游离酸形式与化学计量量的适宜碱(如Na、Ca、Mg或K的氢氧化物、碳酸盐、碳酸氢盐等)反应，或者通过使这些化合物的游离碱形式与化学计量量的适宜酸反应来进行制备。该类反应通常在水或有机溶剂或二者的混合物中进行。一般地，在适当的情况中，需要使用非水性介质如乙醚、乙酸乙酯、乙醇、异丙醇或乙腈。在例如“Remington′s Pharmaceutical Sciences”，第20版，Mack Publishing Company，Easton，Pa.，(1985)；和“药用盐手册：性质、选择和应用(Handbook of Pharmaceutical Salts：Properties，Selection，and Use)”，Stahl and Wermuth(Wiley-VCH， Weinheim，Germany，2002)中可找到另外一些适宜盐的列表。
另外，本发明公开的化合物，包括它们的盐，也可以以它们的水合物形式或包含其溶剂(例如乙醇、DMSO，等等)的形式得到，用于它们的结晶。本发明公开化合物可以与药学上可接受的溶剂(包括水)固有地或通过设计形成溶剂化物；因此，本发明旨在包括溶剂化的和未溶剂化的形式。
本发明给出的任何结构式也意欲表示这些化合物未被同位素富集的形式以及同位素富集的形式。同位素富集的化合物具有本发明给出的通式描绘的结构，除了一个或多个原子被具有所选择原子量或质量数的原子替换。可引入本发明化合物中的示例性同位素包括氢、碳、氮、氧、磷、硫、氟和氯的同位素，如 2H， 3H， 11C， 13C， 14C， 15N， 17O， 18O， 18F， 31P， 32P， 35S， 36Cl和 125I。
另一方面，本发明所述化合物包括同位素富集的本发明所定义的化合物，例如，其中存在放射性同位素，如 3H， 14C和 18F的那些化合物，或者其中存在非放射性同位素，如 2H和 13C。该类同位素富集的化合物可用于代谢研究(使用 14C)、反应动力学研究(使用例如 2H或 3H)、检测或成像技术，如正电子发射断层扫描术(PET)或包括药物或底物组织分布测定的单光子发射计算机断层成像术(SPECT)，或可用于患者的放疗中。 18F富集的化合物对PET或SPECT研究而言是特别理想的。同位素富集的式(I)所示化合物可以通过本领域技术人员熟悉的常规技术或本发明中的实施例和制备过程所描述使用合适的同位素标记试剂替代原来使用过的未标记试剂来制备。
此外，较重同位素特别是氘(即， 2H或D)的取代可提供某些治疗优点，这些优点是由代谢稳定性更高带来的。例如，体内半衰期增加或剂量需求降低或治疗指数得到改善带来的。应当理解，本发明中的氘被看做式(I)化合物的取代基。可以用同位素富集因子来定义该类较重同位素特别是氘的浓度。本发明所使用的术语“同位素富集因子”是指所指定同位素的同位素丰度和天然丰度之间的比例。如果本发明化合物的取代基被指定为氘，该化合物对各指定的氘原子而言具有至少3500(各指定氘原子处52.5％的氘掺入)、至少4000(60％的氘掺入)、至少4500(67.5％的氘掺入)，至少5000(75％的氘掺入)，至少5500(82.5％的氘掺入)、至少6000(90％的氘掺入)、至少6333.3(95％的氘掺入)、至少6466.7(97％的氘掺入)、至少6600(99％的氘掺入)或至少6633.3(99.5％的氘掺入)的同位素富集因子。本发明可药用的溶剂化物包括其中结晶溶剂可以是同位素取代的例如D 2O、丙酮-d 6、DMSO-d 6的那些溶剂化物。
本发明中涉及到的缩写如下所示：
HCTU：          6-氯苯并三氮唑-1,1,3,3-四甲基脲六氟磷酸酯
DIEA：          N,N-二异丙基乙胺
EDCI            碳化二亚胺
DMAP            4-二甲氨基吡啶
Fmoc-IIe-OH     Fmoc-L-异亮氨酸
DMF             N,N-二甲基甲酰胺
Et2OH           二乙胺
LiOH            氢氧化锂
DEPBT           3-(二乙氧基磷酰氧基)-1,2,3-苯并三嗪-4-酮
Pd(PPh3)4       四三苯基膦钯
HATU            2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯
HOAT            1-羟基-7-偶氮苯并三氮唑
实施例1：
Figure PCTCN2019101927-appb-000011
Conditions:a)i)3equiv.I 2or NIS,4 equiv.NaHCO 3.0℃,45min；ii)MeOH/AcOH(9:1),30℃,15min,68％for 2steps；b)2.5equiv.CbzOSu,3.5equiv.DIEA,DCM,30℃,4h,80％；c)i)3equiv.LiOH,THF/H 2O；ii)Pd(OH) 2/C,H 2,MeOH.
式2所示化合物的合成：
将式1所示的化合物(10mmol)加入圆底烧瓶中，加入20毫升乙腈，加入碳酸氢钠固体(40mmol)在零度下搅拌，缓慢加入单质碘(30mmol)搅拌一小时后将乙腈旋干；接下来加入乙酸甲醇混合混合溶液(乙酸：甲醇/1：9)室温搅拌15分钟后将甲醇旋掉，碳酸氢钠水溶液洗涤后经过硅胶柱分离(二氯甲烷：甲醇/20：1)得到目标产物，产率71％。1H NMR(400MHz,DMSO)δ(ppm)7.90-7.88(d,J＝7.48Hz,2H),7.82-7.80(d,J＝7.8Hz,1H),7.71-7.69(m,2H),7.43-7.31(m,8H),5.21(s,2H),4.36-4.26(m,3H),4.22-4.21(m,1H),3.97-3.92(t,J＝9.48Hz,1H),3.87-3.80(m,1H),3.62(s,3H),3.51-3.47(m,1H),1.86-1.82(m,2H).13C NMR(400MHz,DMSO)δ172.82,156.07,152.86,151.95,143.74,142.56,140.73,139.41,137.41,135.61,128.92,128.48,128.39,128.24,127.86,127.64,127.28,127.08,125.19,124.90,121.38,120.13,120.02,109.76,67.33,65.64,54.18,52.70,51.96,51.53,50.71,46.64,37.35.
式3所示化合物的合成：
将式2所示化合物(2mmol)加入加入圆底烧瓶中，加入10毫升二氯甲烷，加入CbzOSu(6mmol)在室温下搅拌，缓慢加入N,N-二异丙基乙胺(6mmol)，30℃搅拌5小时后将溶剂旋干，经过正相硅胶柱分离(二氯甲烷：甲醇/20：1)得到目标产物，产率80％。1H NMR (400MHz,DMSO)δ(ppm)7.89-7.87(d,J＝7.52Hz,2H),7.84-7.82(d,J＝7.92Hz,1H),7.71-7.69(d,J＝7.40Hz,2H),7.48-7.46(d,J＝6.56Hz,2H),7.43-7.42(m,2H),7.36-7.29(m,10H),5.15(s,2H),5.05(s,2H),4.36-4.35(m,2H),4.24-4.23(m,2H),4.00-3.95(t,J＝9.56Hz,1H),3.84-3.81(m,1H),3.62(s,3H),2.12-2.08(m,1H),1.88-1.81(m,1H).
式5所示化合物的合成：
Figure PCTCN2019101927-appb-000012
将Boc-Ser(tBu)-OH置于圆底烧瓶中，加入二氯甲烷和N,N-二甲基甲酰胺当混合溶剂50ml，HCTU(6-氯苯并三氮唑-1,1,3,3-四甲基脲六氟磷酸酯)(11mmol)和DIEA(N,N-二异丙基乙胺)(11mmol)加入到反应液中，再加入式4所示化合物(10mmol)，室温搅拌3小时后，加入稀盐酸淬灭反应。加入100ml二氯甲烷稀释反应液，分别用碳酸氢钠，氯化钠饱和水溶液洗涤，减压蒸去二氯甲烷，所得产品采用硅胶柱分离(石油醚：乙酸乙酯2：1)，得式5所示化合物。 1H NMR(400MHz,CDCl 3)δ(ppm)7.23-7.21(d,J＝8.72Hz,1H),5.92-5.85(m,1H),5.44(s,1H),5.34-5.29(dd,J 1＝1.28Hz,J 2＝17.2Hz,1H),5.24-5.21(dd,J 1＝1.04Hz,J 2＝10.36Hz,1H),4.66-4.64(d,J＝7.44Hz,2H),4.61-4.58(m,1H),4.31-4.30(m,1H),4.20(s,1H),3.76-3.75(m,1H),3.45-3.41(m,1H),1.46-1.43(m,9H),1.21-1.15(m,12H). 13C NMR(400MHz,CDCl 3)δ171.22,170.48,155.65,131.58,119.03,118.94,80.19,74.17,68.25,66.16,61.77,57.51,54.91,28.41,27.46,20.02.
式6所示化合物的合成：
Figure PCTCN2019101927-appb-000013
将Fmoc-L-异亮氨酸(10mmol)置于圆底烧瓶中，EDCI(碳化二亚胺)(10mmol)、DMAP(4-二甲氨基吡啶)(1mmol)加入到反应液中搅拌20min，再加入式5所示化合物(9mmol)室温搅拌过夜后，加入稀盐酸淬灭反应。加入100ml二氯甲烷稀释反应液，分别用碳酸氢钠，氯化钠饱和水溶液洗涤，减压蒸去二氯甲烷，再将中间体加入圆底烧瓶中，加入33％二乙胺溶液30毫升，待反应完成后，所得产品采用硅胶柱分离(石油醚：乙酸乙酯2：1)分离得到化合物6，产率71％。 1H NMR(400MHz,CDCl 3)δ(ppm)7.21-7.20(s,1H),5.90-5.82(m,1H),5.50-5.44(m,2H),5.33-5.29(d,J＝17.24Hz,1H),5.26-5.23(d,J＝9.36Hz,1H),4.86-4.83(d,J＝10.36Hz,1H),4.64-4.52(m,2H),4.24(s,1H),3.80(s,1H),3.46-3.42(m, 1H),3.24-3.23(d,J＝4.84Hz,1H),1.68-1.67(s,1H),1.60(s,1H),1.45(s,9H),1.29-1.28(d,J＝6.40Hz,3H),1.20(s,1H),1.19-1.17(m,2H),0.90-0.89(m,6H). 13C NMR(400MHz,CDCl 3)δ174.47,171.36,169.05,155.63,131.35,119.29,80.19,74.21,71.29,66.41,61.72,59.68,55.52,54.82,38.73,28.44,27.53,24.18,17.06,15.80,11.68.
式8所示化合物的制备
Figure PCTCN2019101927-appb-000014
将化合物3(1mmol)置于圆底烧瓶中，加入33％二乙胺10ml，室温搅拌15分钟，将溶剂旋干；将Alloc-Ala-OH(2mmol)和HATU(2mmol)、DIEA(2mmol)加入到圆底烧瓶中，加入二氯甲烷和N,N-二甲基甲酰胺当混合溶剂10mL，室温搅拌3小时，加入稀盐酸淬灭反应。加入100mL二氯甲烷稀释反应液，分别用碳酸氢钠、氯化钠饱和水溶液洗涤，减压蒸去二氯甲烷，所得产品采用硅胶柱分离(石油醚：乙酸乙酯1：1)，得式7所示化合物。 1H NMR(400MHz,CDCl 3)δ(ppm)7.40-7.34(m,10H),5.94-5.87(m,1H),5.73-5.71(d,J＝8Hz,1H),5.31-5.27(m,1H),5.24-5.17(m,5H),4.83-4.82(m,1H),4.57-4.55(d,J＝5.32Hz,2H),4.39-4.36(m,1H),4.13-4.10(m,1H),3.74(s,3H),3.47-3.45(m,1H),2.22-2.20(m,1H),1.87-1.89(m,1H),1.43-1.41(d,J＝7Hz,3H). 13C NMR(400MHz,CDCl 3)δ173.23,171.73,155.87,152.27,135.75,134.88,133.00,128.87-128.43(t,10C),117.56,68.77,68.13,65.70,60.52,53.56,52.84,50.65,50.46,50.33,37.96,19.07,0.13.
将化合物7置于圆底烧瓶中，加入混合溶剂四氢呋喃/水(3：1)，加入氢氧化锂(1.5mmol)，室温搅拌3分钟，加入稀盐酸猝灭反应，加入乙酸乙酯萃取，将溶剂旋干得到化合物8。
式9所示化合物的制备
Figure PCTCN2019101927-appb-000015
将化合物6(1mmol)、化合物8(0.5mmol)置于圆底烧瓶中，加入四氢呋喃和N,N-二甲基甲酰胺混合溶剂5mL，置于零度下搅拌，将DEPBT(1mmol)、DIEA(1mmol)加入到反应液中，室温搅拌过夜，加入稀盐酸淬灭反应。加入100ml二氯甲烷稀释反应液，分别用碳酸氢钠，氯化钠饱和水溶液洗涤，减压蒸去二氯甲烷，所得产品采用硅胶柱分离(二氯甲烷：甲醇/10：1)，得式9所示化合物，产率58％。 1H NMR(400MHz,CDCl 3)δ(ppm)7.41-7.38(m,4H),7.33-7.31(m,6H),6.62-6.61(m,1H),5.92-5.86(m,2H),5.48(s,1H),5.31(s,1H),5.27-5.26(m,1H),5.23-5.22(m,2H),5.20-5.15(m,3H),4.69-4.68(m,1H),4.57(s,2H),4.52(s,2H),4.32(s,1H),4.31-4.30(m,1H),4.27-4.23(m,1H),4.20-4.18(m,1H),4.04-4.03(m,2H),3.68-3.66(m,1H),3.61-3.59(m,2H),2.10(s,1H),1.91-1.89(m,2H),1.44(s,9H),1.37-1.35(m,3H),1.26-1.25(m,3H),1.17(s,9H),0.91-0.90(m,6H). 13C NMR(400MHz,CDCl 3)δ175.92,173.75,173.08,171.28,169.97,158.19,157.38,152.55,138.02,136.85,134.22,132.90,129.56-128.97(m,10C),118.90,117.60,80.74,74.65,72.79,69.22,68.34,67.25,67.18,66.93,66.90,66.87,66.58,63.23,58.81,56.71,56.62,56.36,54.81,52.31,50.81,38.57,37.83,28.71,27.73,25.93,18.07,17.21,16.27,16.02,11.87.
式10所示化合物的制备
Figure PCTCN2019101927-appb-000016
将式9所示化合物(0.3mmol)、四三苯基膦钯(0.06mmol)、1，3-二甲基巴比妥酸置于圆底烧瓶中，加入二氯甲烷5ml，室温搅拌2小时,待反应完成后，加入混合溶剂至100毫升(二氯甲烷：N,N-二甲基甲酰胺/4：1)，HATU(2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯-缩合剂(1mmol)、HOAT(1-羟基-7-偶氮苯并三氮唑)(1mmol)、DIEA(2mmol)加入到反应液中，室温搅拌24小时，洗涤，减压蒸去二氯甲烷，所得产品采用硅胶柱分离(二氯甲烷：甲醇10：1)，得式10所示化合物。 1H NMR(400MHz,CDCl 3)δ(ppm)7.40-7.37(m,4H),7.31-7.29(m,6H),5.59-5.57(m,1H),5.28-5.23(m,2H),5.20-5.12(m,2H),4.63-4.59(m,1H),4.24-4.22(d,J＝8.12Hz,1H),4.14-4.11(m,2H),4.09-4.05(m,2H),3.67-3.61(m,3H),3.31-3.30(m,2H),2.16(m,1H),2.07(m,1H),1.73(s,1H),1.45(s,9H),4.42-1.40(m,3H),1.32-1.30(d,J＝6.52Hz,3H),1.26-1.24(m,1H),1.20(s,9H),0.92-0.86(m,6H).
式11所示化合物的制备
Figure PCTCN2019101927-appb-000017
(a)(i)piperidine,DMF；(ii)Fmoc-AA-OH,HATU,DIEA,DMF；；
(b)TFE:DCM/1:4,3h
按照多肽固相合成的方法，将2-Cl树脂(0.5mmol)置于固相合成管中，加入二氯甲烷和N,N-二甲基甲酰胺，活化20min，抽取溶剂，将Fmoc-L-异亮氨酸(5mmol)，DIEA(5mmol)溶解在DMF中加入反映仪器中，搅拌2h，抽去溶剂，用20％哌啶溶液脱去Fmoc 15min，将Fmoc-D-异亮氨酸(1.5mmol)，HATU(1.5mmol)，DIEA(3mmol)加入反应容器中，室温搅拌50min。接下来按照同样的方式条件，将N-Fmoc-N'-三苯甲基-D-谷氨酰胺、Fmoc-L-丝氨酸、Fmoc-L-异亮氨酸以及Boc-D-4,4'-二苯基苯胺或N-叔丁氧羰基-N-甲基-D-苯丙氨酸最末端的氨基酸接上去。最后将25wt％三氟乙醇(用二氯甲烷稀释)加入反应管中，室温搅拌4h，将溶剂旋干，得到式11所示化合物。
式(II)所示化合物的制备
Figure PCTCN2019101927-appb-000018
Conditions:a)1.0equiv.compound 10,3M HCl in dioxane,15min；b)1.2equiv.compound 11,1.2equiv.DEPBT,1.2equiv.DIEA,THF:DMF/1:1,12h,60％；c)TFA:TfOH:thioanisole:mcresol(70:12:10:8v/v/v/v).
将式10所示化合物(0.1mmol)置于圆底烧瓶中，加入2M盐酸乙酸乙酯溶液5ml，室温搅拌20min，加入乙酸乙酯10ml稀释，加入饱和碳酸氢钠水溶液洗涤，有机相用无水硫酸钠干燥，减压蒸去乙酸乙酯溶剂，得到粗品中间体。再将化合物11(0.13mmol)置于圆底烧瓶中，加四氢呋喃和N,N-二甲基甲酰胺当混合溶剂4ml，置于冰水浴下，加入DEPBT(0.13mmol)，DIEA(0.13mmol)，待反应1小时后，置于室温下搅拌过夜。加入稀盐酸淬灭反应。加入10ml乙酸乙酯稀释反应液，氯化钠饱和水溶液洗涤，减压蒸去乙酸乙酯，所得产品采用硅胶柱分离(二氯甲烷：甲醇10：1)。最后将混合溶剂(三氟乙酸：三氟甲烷磺酸：苯甲硫醚：间甲苯酚/70：12：10：8)加入圆底烧瓶中，将所有保护基脱除得到终产物12，用氮气将溶剂吹干，加入冰乙醚沉淀，离心得到粗品，用反相HPLC分离后冷冻干燥。
最终化合物12的核磁结果如下表1所示。
表1：
Figure PCTCN2019101927-appb-000019
Figure PCTCN2019101927-appb-000020
Figure PCTCN2019101927-appb-000021
其中，左侧为化合物12Teixobactin的核磁数据，右侧为阳性对照(positive control)。 1H-NMR(400MHz,CD 3OD)δ(ppm)由上述数据可知，所制备的化合物结构正确。
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。

Claims (10)

  1. 一种制备非天然氨基酸的方法，其特征在于，
    将式(1)所示化合物进行氧化关环处理，
    Figure PCTCN2019101927-appb-100001
    其中，R 5独立地为Fmoc、Boc、Phth、Cbz，
    R 6独立地为H、Fmoc、Boc、Phth、Cbz。
  2. 根据权利要求1所述的方法，其特征在于，进一步包括将氧化关环处理产物进行脱保护处理，以便获得式(I)所示化合物，
    Figure PCTCN2019101927-appb-100002
  3. 根据权利要求1或2所述的方法，其特征在于，所述氧化关环处理是在氧化剂的条件下进行的；
    任选地，所述氧化剂包括选自单质碘、NIS、碘苯二乙酸、NBS、戴斯-马丁氧化剂以及三价碘氧化剂的至少之一；
    任选地，所述式(1)所示化合物与所述氧化剂的摩尔比为1：(1-5)，优选为1:3；
    任选地，所述脱保护处理是在酸性条件下进行的；
    任选地，所述酸性条件由TFA/H 2O提供。
  4. 一种制备式(3)所示化合物的方法，其特征在于，
    1)将式(1)所示化合物的氧化关环产物与R 7OH进行酯化反应，以便获得式(2)所示化合物，
    2)将式(2)所示化合物进行上保护处理，以便获得式(3)所示化合物，
    Figure PCTCN2019101927-appb-100003
    其中，R 7为甲基、乙基、丙基；
    任选地，所述酯化反应是在酸性条件下进行的；
    任选地，所述酸性条件是甲酸或乙酸提供的；
    任选地，所述上保护处理是在带有R 6基团的离去基团存在的条件下进行的；
    任选地，所述带有R 6基团的离去基团为Cbz-OSu或Fmoc-Osu；
    任选地，所述R 5与R 6不相同，且R 5比R 6易脱除。
  5. 一种化合物，其特征在于，具有式(3)所示结构。
  6. 一种化合物，其特征在于，是通过权利要求4所述的方法获得的。
  7. 一种制备式(II)所示化合物或式(II)所示化合物的盐的方法，其特征在于，包括：
    将权利要求5或6所述的化合物与数个氨基酸进行缩合处理，以便获得式(II)所示化合物。
  8. 根据权利要求7所述的方法，其特征在于，所述R 5为Fmoc基团，所述R 6为Cbz基团，且连接在胍基的氮上，所述R 7为甲基，所述方法进一步包括：
    1)将权利要求5或6所述的化合物进行脱Fmoc基团处理；
    2)将步骤1)所得产物与Alloc-Ala-OH进行缩合反应，以便得到式(7)所示化合物；
    3)将所述式(7)所示化合物进行水解处理，以便获得式(8)所示化合物；
    4)将式(6)所示化合物与所述式(8)所示化合物进行缩合反应，以便得到式(9)所示化合物；
    5)将所述式(9)所示化合物进行Allyl基团和Alloc基团脱除处理：
    6)将步骤5)脱除处理产物进行缩合处理，以便得到式(10)所示化合物；
    7)将所述式(10)所示化合物与式(11)所示化合物进行缩合处理，得到式(II)所示化合物；
    Figure PCTCN2019101927-appb-100004
    Figure PCTCN2019101927-appb-100005
    其中，R 1为氢、C 1～15烷基、C 2～15烯基、C 2～15炔基、C 6-10芳基或酰基；
    R 2为氢、卤素、C 1～15烷基、C 2～15烯基、C 2～15炔基、C 6-10芳基或酰基，其中所述C 6-10芳基可任选被1～5个Rx取代；
    Rx为卤素、C 1-6烷基、卤代C 1-6烷基；
    R 3为氨基、胍基、脲基或甲酰胺基；
    R 4为C 1～15烷基、C 2～15烯基、C 2～15炔基、C 6-10芳基；
    X为O、S或NH；
    任选地，所述步骤7)进一步包括：
    7-1)将所述式(10)所示化合物进行Boc基团脱除处理；
    7-2)步骤7-1)中得到的脱除Boc基团的化合物与式(11)化合物进行缩合反应；
    7-3)步骤7-2)中得到的缩合产物进行Cbz基团、t-Bu基团以及Boc基团脱除处理，以便获得式(II)所示化合物；
    任选地，所述步骤7-1)中的Boc基团脱除处理是在盐酸乙酸乙酯溶液的条件下进行15～20min；
    任选地，所述盐酸乙酸乙酯溶液的浓度为2M～3M；
    任选地，所述步骤7-2)中的缩合反应是在DEPBT/DIEA的条件下进行的；
    任选地，所述步骤7-2)中式(10)、DEPBT、DIEA的摩尔比为1:1:1；
    任选地，所述步骤7-3)中的Cbz基团、t-Bu基团以及Boc基团脱除处理是在三氟乙酸、三氟甲烷磺酸、苯甲硫醚以及间甲苯酚的混合溶剂下进行的；
    任选地，所述三氟乙酸、三氟甲烷磺酸、苯甲硫醚以及间甲苯酚的体积比为(70±5):(12±5):(10±5):(8±5)；
    优选地，所述三氟乙酸、三氟甲烷磺酸、苯甲硫醚以及间甲苯酚的体积比为70:12:10:8；
    任选地，所述步骤1)中脱除Fmoc基团是在二乙胺的条件下进行的；
    任选地，所述步骤2)中的缩合反应是在缩合剂为HATU/DIEA或PyAOP、溶剂为二氯甲烷和DMF的混合溶剂的条件下进行的；
    任选地，所述步骤2)中的权利要求5或6所示的化合物、Alloc-Ala-OH、HATU、DIEA 的摩尔比为1:2:2:2；
    任选地，所述步骤3)中的水解反应是在四氢呋喃/水的混合溶剂、碱为LiOH的条件下进行的；
    任选地，所述式(7)所示化合物、LiOH的摩尔比为1:1.5；
    任选地，所述步骤4)中的缩合反应是在缩合剂为DEPBT/DIEA、溶剂为THF和DMF的混合溶剂的条件下进行的；
    任选地，所述步骤4)中的式(6)所示化合物、式(8)所示化合物、DEPBT、DIEA的摩尔比为1:0.5:1:1；
    任选地，所述步骤5)中的脱除处理是在催化剂为四三苯基膦钯、在1,3-二甲基巴比妥酸提供的酸性条件下进行的；
    任选地，所述步骤5)中式(9)所示化合物、四三苯基膦钯、1,3-二甲基巴比妥酸的摩尔比为0.3:0.06:0.6；
    任选地，所述步骤6)中的缩合反应是在缩合剂为HATU/HOAT/DIEA或PyAop的条件下进行的；
    任选地，所述步骤6)中式(9)所示化合物、HATU、HOAT、DIEA的摩尔比为0.3:1:1:2；
    任选地，所述盐为盐酸盐、三氟乙酸盐、醋酸盐、磺酸盐；
    任选地，R 1为氢、C 1～10烷基、C 2～10烯基、C 2～10炔基、C 6-8芳基或酰基；
    R 2为氢、卤素、C 1～10烷基、C 2～10烯基、C 2～10炔基、C 6-8芳基或酰基，其中所述C 6-8芳基可任选被1～5个Rx取代；
    Rx为卤素、C 1-6烷基、卤代C 1-6烷基；
    R 4为C 1～10烷基、C 2～10烯基、C 2～10炔基、C 6-8芳基；
    任选地，R 1为氢、C 1～6烷基、C 2～6烯基、C 2～6炔基、C 6-7芳基或酰基；
    R 2为氢、卤素、C 1～6烷基、C 2～6烯基、C 2～6炔基、C 6-7芳基或酰基，其中所述C 6-7芳基或C 5-6杂芳基可任选被1～3个Rx取代；
    Rx为卤素、C 1-4烷基、卤代C 1-4烷基；
    R 4为C 1～6烷基、C 2～6烯基、C 2～6炔基、C 6-7芳基；
    任选地，R 1为氢、甲基、乙基、正丙基、异丙基、丁基、乙烯基、丙烯基、烯丙基、乙炔基、丙炔基、炔丙基、苯基、苄基或酰基；
    R 2为氢、卤素、甲基、乙基、正丙基、异丙基、丁基、乙烯基、丙烯基、烯丙基、乙炔基、丙炔基、炔丙基、苯基、苄基或酰基，其中所述苯基或苄基可任选被1～3个Rx取代；
    Rx为卤素、甲基、乙基、正丙基、异丙基、丁基、一氟甲基、二氟甲基、三氟甲基；
    R 4为甲基、乙基、正丙基、异丙基、丁基、乙烯基、丙烯基、烯丙基、乙炔基、丙炔 基、炔丙基、苯基、苄基；
    任选地，所述式(6)所示化合物是通过如下步骤获得的：
    将式(5)所示化合物与Fmoc-L-异亮氨酸进行酯化、氨解以及脱Fmoc基团反应，以便得到式(6)所示化合物；
    任选地，所述酯化反应是在缩合剂为EDCI、催化剂为DMAP的条件下进行的；
    任选地，所述式(5)所示化合物、Fmoc-L-异亮氨酸、EDCI、DMAP的摩尔比为9:10:10:1；
    任选地，所述氨解以及脱Fmoc基团反应是在二乙胺溶液的条件下进行的；
    任选地，所述二乙胺的浓度为33％；
    任选地，式(5)所示化合物是通过如下步骤获得的：
    将式(4)所示化合物与Boc-Ser(tBu)-OH进行缩合反应，以便得到式(5)所示化合物；
    任选地，所述缩合反应是在以二氯甲烷和DMF的混合溶剂中，以HCTU/DIEA为缩合剂的条件下进行的；
    Figure PCTCN2019101927-appb-100006
  9. 根据权利要求8所述的方法，其特征在于，式(11)所示化合物是通过固相合成方法获得的；
    任选地，所述固相合成方法是通过如下步骤进行的：
    A)将2-Cl树脂和Fmoc-L-异亮氨酸发生取代反应，以便得到式(a)所示化合物，其中圆圈表示树脂；
    B)将式(a)所示化合物依次与N-Fmoc-N'-三苯甲基-D-谷氨酰胺、Fmoc-L-丝氨酸、Fmoc-L-异亮氨酸、Boc-D-4,4'-二苯基苯丙氨酸以及N-叔丁氧羰基-N-甲基-D-苯丙氨酸中最末端的氨基酸发生缩合反应，以便得到式(b)所示的化合物；
    C)将式(b)所示的化合物进行脱树脂反应，以便得到式(11)所示的化合物；
    Figure PCTCN2019101927-appb-100007
  10. 根据权利要求9所述的方法，其特征在于，所述2-Cl树脂预先经过活化处理，所述活化处理是在二氯甲烷和DMF中进行20min；
    任选地，所述活化处理后、偶联反应前进一步包括抽取溶剂处理；
    任选地，步骤1)中的偶联反应是在DIEA为缩合剂、DMF为溶剂的条件下进行的；
    任选地，步骤2)中的每一次缩合反应进行前需要预先将待缩合原料进行脱Fmoc处理，所述脱Fmoc处理是在哌啶溶液中进行的；
    任选地，步骤2)中的缩合反应是在缩合剂为HATU/DIEA、室温的条件下进行的。
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12435108B2 (en) 2019-07-24 2025-10-07 Sunshine Lake Pharma Co., Ltd. Teixobactin analogue and use thereof

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109320590B (zh) * 2018-10-31 2021-03-02 清华大学 抗生素teixobactin及其类似物的合成路线

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014089053A1 (en) * 2012-12-03 2014-06-12 Novobiotic Pharmaceuticals, Llc Novel depsipeptide and uses thereof
CN107266531A (zh) * 2017-07-28 2017-10-20 北京大学深圳研究生院 Teixobactin及其制备方法
CN109320590A (zh) * 2018-10-31 2019-02-12 清华大学 抗生素teixobactin及其类似物的合成路线

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1617881C2 (de) * 1965-10-13 1984-07-05 Takeda Chemical Industries, Ltd., Osaka Antibiotikum Enduracidin und seine Herstellung
WO2017181179A1 (en) * 2016-04-15 2017-10-19 The Regents Of The University Of California Antimicrobial compositions
CN107778352B (zh) * 2016-08-29 2020-10-27 清华大学 一种用于耐药革兰氏阳性菌及结核治疗的新型抗生素
CN106632604B (zh) * 2016-12-22 2021-03-19 深圳先进技术研究院 一种Teixobactin类似物及其制备方法和应用

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014089053A1 (en) * 2012-12-03 2014-06-12 Novobiotic Pharmaceuticals, Llc Novel depsipeptide and uses thereof
CN107266531A (zh) * 2017-07-28 2017-10-20 北京大学深圳研究生院 Teixobactin及其制备方法
CN109320590A (zh) * 2018-10-31 2019-02-12 清华大学 抗生素teixobactin及其类似物的合成路线

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ATKINSON, DARCY J. ET AL.: "Enduracididine, a Rare Amino Acid Component of Peptide Antibiotics: Natural Products and Synthesis", BEILSTEIN JOURNAL OF ORGANIC CHEMISTRY, vol. 12, 7 November 2016 (2016-11-07), pages 2325 - 2342, XP055459646, DOI: :10.3762/bjoc.12.226 *
CRAIG, WILLIAM ET AL.: "A Highly Stereoselective and Scalable Synthesis of L-allo-Enduracididine", ORGANIC LETTERS, vol. 17, no. 18, 10 September 2015 (2015-09-10), pages 4620 - 4623, XP055700060, ISSN: 1523-7060, DOI: 10.1021/acs.orglett.5b02362 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12435108B2 (en) 2019-07-24 2025-10-07 Sunshine Lake Pharma Co., Ltd. Teixobactin analogue and use thereof

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