CN109422730B - Non-natural amino acid derivatives containing azetidine skeleton and synthetic method thereof - Google Patents

Non-natural amino acid derivatives containing azetidine skeleton and synthetic method thereof Download PDF

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CN109422730B
CN109422730B CN201710746565.8A CN201710746565A CN109422730B CN 109422730 B CN109422730 B CN 109422730B CN 201710746565 A CN201710746565 A CN 201710746565A CN 109422730 B CN109422730 B CN 109422730B
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amino acid
azetidine
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silver
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CN109422730A (en
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吴滨
赵杰
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South Central Minzu University
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract

The invention belongs to the technical field of chemical synthesis, and particularly discloses a method for synthesizing unnatural amino acid derivatives containing an azetidine skeleton, wherein the structural formula of target products of the unnatural amino acid derivatives is shown as formulas (I), (II), (III), (IV) and (V), and the compounds in the formulas are unnatural amino acid derivatives containing the azetidine skeletonα‑、β-andγ-amino acid derivatives, the nitrogen atom being protected by 2-picolinic acid; carboxyl methyl esterification; formula (I) is a non-natural compound containing an azetidine skeletonα-an amino acid derivative; formula (II) is a non-natural compound containing azetidine bridged ring skeletonα-amino acid derivatives, wherein n =1 or 2; formula (III) is a non-natural compound containing an azetidine fused ring skeletonα-an amino acid derivative; formula (IV) is a non-natural compound containing an azetidine bridged ring skeletonβ-an amino acid derivative; formula (V) is a non-natural compound containing an azetidine fused ring skeletonγ-amino acid derivatives. The experimental results of the invention prove that: these compounds all have potential hypolipidemic activity.

Description

Non-natural amino acid derivatives containing azetidine skeleton and synthetic method thereof
Technical Field
The invention belongs to the field of chemical synthesis, and particularly relates to a non-natural α -, β -and gamma-amino acid derivative containing an azetidine skeleton and shown as formulas (I), (II), (III), (IV) and (V) and a synthetic method thereof.
Background
Amino acids are amphoteric compounds having at least one carboxyl group and one amino group, and the amino acids are classified into α, β, γ, and the like at the positions where the amino groups are linked to carbons, and the amino acids are classified into natural amino acids and unnatural amino acids according to the existence modes.
In an organism, only 20 natural amino acids of proteins perform a series of remarkable functions, and the number of functional groups carried by the only 20 natural amino acids is limited, so that the requirements on the structure and the function of the proteins in chemical and biological science research and application cannot be met. At present, through chemical modification, gene site-directed mutagenesis and computer-aided protein design, although the structural modification of proteins endows the natural proteins with new functions, the methods all rely on 20 natural amino acids per se; the functional groups for modification only comprise limited groups such as sulfydryl, hydroxyl, carboxyl, amino and the like, and the functionalization mode is very limited. In contrast, unnatural amino acids can be designed according to human needs, and have various functional groups, which are prominent in protein modification.
Polypeptide and protein medicines are the most active and most advanced parts in the field of medicine research and development at present. The natural polypeptide medicine is limited to be developed into excellent clinical medicines due to the defects of poor enzymolysis stability, short in-vivo half-life, certain toxic and side effects and the like. The introduction of the non-natural amino acid into the polypeptide medicament can obviously improve the stability of the polypeptide medicament, improve the capability of the polypeptide medicament for penetrating the blood brain barrier and reduce the toxicity of the polypeptide medicament. Therefore, the development of novel multifunctional unnatural amino acids plays an important role in the research and development of polypeptide drugs.
Disclosure of Invention
The invention aims to provide a class of unnatural amino acid derivatives containing azetidine skeletons and a synthesis method thereof, wherein the structural formula of target products of the unnatural amino acid derivatives is shown as formula (I), (II), (III), (IV) or (V):
Figure BDA0001390210090000021
the compounds of formulas (I) - (V) are the same class of unnatural α -, β -and gamma-amino acid derivatives containing an azetidine skeleton, the nitrogen atom of which is protected by 2-picolinic acid, carboxymethylesterified, the formula (I) is an unnatural α -amino acid derivative containing an azetidine skeleton, the formula (II) is an unnatural α -amino acid derivative containing an azetidine bridged ring skeleton, wherein n is 1 or 2, the formula (III) is an unnatural α -amino acid derivative containing an azetidine fused ring skeleton, the formula (IV) is an unnatural β -amino acid derivative containing an azetidine bridged ring skeleton, and the formula (V) is an unnatural gamma-amino acid derivative containing an azetidine fused ring skeleton.
The synthesis method of the compounds of the formulas (I) - (V) is shown in a scheme 2-6, and Pd (II) is used as a catalyst, silver salt is used as an oxidant, and gamma-position sp of amide substrates 1 (a scheme 2), 3 (a scheme 3), 5 (a scheme 4), 7 (a scheme 5) and 9 (a scheme 6) is catalyzed by palladium3The (C-H) bond is activated, and meanwhile intramolecular ammoniation cyclization reaction is carried out, so that the unnatural amino acid derivative containing an azetidine skeleton, even an azetidine bridged ring with higher tension and a cyclic skeleton is successfully constructed.
Route 2
Figure BDA0001390210090000022
Reaction conditions are as follows: pd (OAc)2(10mol％),AgOAc(3equiv),C6F5I(5equiv),BQ(0.5equiv),Na3PO4(1.5equiv),in TCE,microwave,170℃,2h.C6F5I＝Iodoperfluorobenzene,BQ＝Benzoquinone,TCE＝1,1,2,2-Tetrachloroethane.
As shown in scheme 2, the synthesis method takes 2-picolinic acid protected amino acid derivative 1 as a raw material and Pd (OAc)2Using AgOAc as an oxidant, adding pentafluoroiodobenzene, benzoquinone and sodium phosphate, using TCE as a solvent, reacting for 2 hours at 170 ℃ in a microwave manner, and selectively reacting on a nitrogen gamma sp3The (C-H) bond is activated and intramolecular ammoniation cyclization is carried out to generate the non-natural α -amino acid derivative 2 containing the azetidine skeleton (namely, the compound of the formula (I)).
Route 3
Figure BDA0001390210090000031
Reaction conditions are as follows: pd (OAc)2(10mol％),AgOAc(3equiv),C6F5I(5-10equiv),BQ(0.5equiv),Na3PO4(1.2-3equiv),in DCE or TCE,microwave,130℃,4h.C6F5I＝Iodoperfluorobenzene,BQ＝Benzoquinone,DCE＝1,2-Dichloroethane,TCE＝1,1,2,2-Tetrachloroethane.
As shown in the scheme 3, the synthesis method takes 2-picolinic acid protected amino acid derivative 3 as a raw material and takes Pd (OAc)2Using AgOAc as an oxidant, adding pentafluoroiodobenzene, benzoquinone and sodium phosphate, using DCE or TCE as a solvent, reacting for 4 hours at 130 ℃ in microwave, and selectively reacting to a nitrogen gamma sp3The (C-H) bond is activated and undergoes intramolecular cyclization by amination to produce the unnatural α -amino acid derivative 4 (i.e., a compound of formula (II)) containing an azetidine bridged ring backbone, where n is 1 or 2.
Route 4
Figure BDA0001390210090000032
Reaction conditions are as follows: pd (OAc)2(10mol％),AgOAc(3equiv),C6F5I(5equiv),BQ(0.5equiv),Na3PO4(1.2equiv),in DCE,microwave,130℃,4h.C6F5I＝Iodoperfluorobenzene,BQ＝Benzoquinone,DCE＝1,2-Dichloroethane.
As shown in the scheme 4, the synthesis method takes 2-picolinic acid protected amino acid derivative 5 as a raw material and takes Pd (OAc)2Using AgOAc as an oxidant, adding pentafluoroiodobenzene, benzoquinone and sodium phosphate, using DCE as a solvent, reacting for 4 hours at 130 ℃ in a microwave manner, and selectively reacting on a nitrogen gamma sp position3The (C-H) bond is activated and intramolecular ammoniation cyclization is carried out to generate the non-natural α -amino acid derivative 6 (namely the compound of the formula (III)) containing the azetidine fused ring skeleton.
Route 5
Figure BDA0001390210090000041
Reaction conditions are as follows: pd (OAc)2(10mol％),AgOAc(3equiv),C6F5I(10equiv),BQ(0.5equiv),Na3PO4(3equiv),in DCE,microwave,130℃,4h.C6F5I＝Iodoperfluorobenzene,BQ＝Benzoquinone,DCE＝1,2-Dichloroethane.
As shown in the scheme 5, the synthesis method takes 2-picolinic acid protected fatty amine derivative 7 as a raw material and takes Pd (OAc)2Using AgOAc as an oxidant, adding pentafluoroiodobenzene, benzoquinone and sodium phosphate, using DCE as a solvent, reacting for 4 hours at 130 ℃ in a microwave manner, and selectively reacting on a nitrogen gamma sp position3The (C-H) bond is activated and undergoes intramolecular ammoniation cyclization to generate the non-natural β -amino acid derivative 8 (i.e. the compound of formula (IV)) containing an azetidine bridged ring skeleton.
Route 6
Figure BDA0001390210090000042
Reaction conditions are as follows: pd (OAc)2(20mol％),AgOAc(3equiv),C6F5I(10equiv),BQ(0.5equiv),Na3PO4(3equiv),in TCE,microwave,160℃,4h.C6F5I＝Iodoperfluorobenzene,BQ＝Benzoquinone,DCE＝1,2-Dichloroethane.
As shown in the scheme 6, the synthesis method takes 2-picolinic acid protected fatty amine derivative 9 as a raw material and takes Pd (OAc)2Using AgOAc as an oxidant, adding pentafluoroiodobenzene, benzoquinone and sodium phosphate, using DCE as a solvent, reacting for 4 hours at 160 ℃ in a microwave manner, and selectively reacting on nitrogen gamma sp3The (C-H) bond is activated and intramolecular ammoniation cyclization is carried out to generate the unnatural gamma-amino acid derivative 10 (namely the compound of the formula (V)) containing the azetidine fused ring skeleton.
Compared with the prior art, the invention has the advantages and beneficial effects that:
the invention provides a novel method for synthesizing unnatural amino acid derivatives, which adopts Pd (II) as a catalyst, silver salt as an oxidant, alkali as an acid-base balancing agent, benzoquinone for stabilizing a metal catalyst, and pentafluoroiodobenzene for oxidation addition to metal central palladium, wherein the intermediate complex is very crowded in space, and due to the electron deficiency property of pentafluorophenyl ester, the intermediate complex is not easy to generate intermolecular reduction elimination and coupling reaction, but generates intramolecular reduction elimination to generate a five-membered aza bridge ring compound, and based on the synthetic method, a series of unnatural α -, β -and gamma-amino acid derivatives are obtained, as shown in formulas (I), (II), (III), (IV) and (V):
Figure BDA0001390210090000051
the synthesis method provided by the invention is sp catalyzed by metal3(C-H) bond activation reaction, and a series of rigid, structurally novel non-natural α -, β -and gamma-amino acid derivatives are constructed in one step.
Drawings
FIG. 1 is a graph showing the results of experiments on the effect of the compounds prepared in examples 1 to 7 on the survival rate of HL7702 hepatocyte cells.
FIG. 2 is a graph showing the effect of the compounds prepared in examples 1-7 on triglyceride levels in HL7702 hepatocytes. In comparison with the blank set, the results,##P<0.01; in comparison with the set of models,*P<0.05，**P<0.01；n＝3。
Detailed Description
The following specific examples are intended only to illustrate specific embodiments of the present invention in detail, and do not limit the scope of the invention as claimed in the claims.
TCE in the following detailed description means 1,1,2,2-Tetrachloroethane (1,1,2, 2-Tetrachloroethane);
EDCI means 1- (3-methylenepropyl) -3-ethylcarbodiimide Hydrochloride (1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide Hydrochloride);
DMAP refers to 4-dimethylaminopyrdine (4-dimethylaminopyridine).
Synthesis of starting materials
(1) Preparation of compound 1:
Figure BDA0001390210090000061
the operation is as follows: d-norvaline (586mg, 5mmol) and 5mL of methanol were added to a 15mL round-bottom flask and placed under stirring in an ice bathDropwise adding thionyl chloride (1.1mL, 15mmol) into the mixture, gradually returning to room temperature, reacting overnight, after the reaction is finished, evaporating to dryness under reduced pressure, adding a small amount of petroleum ether, filtering, washing the solid with petroleum ether for a plurality of times in a small amount to obtain a white solid, namely D-norvaline ester hydrochloride, adding the obtained D-norvaline ester hydrochloride, picolinic acid (739mg, 6mmol), EDCI (1.44g, 7.5mmol), DMAP (61mg, 0.5mmol) and dichloromethane (7mL) into a 15mL round-bottomed flask, stirring at room temperature for reacting overnight, directly separating by a silica gel chromatographic column (petroleum ether: ethyl acetate: 10: 1) after the reaction is finished to obtain 630mg of a target product 1, wherein the total yield of the two-step reaction is 53% [ α ] of the two-step reaction]25 D-26.2(c 0.68,CHCl3)；1H NMR(400MHz,CDCl3)δ8.64–8.54(m,1H),8.44(d,J＝7.6Hz,1H),8.16(d,J＝7.8Hz,1H),7.83(td,J＝7.7and 1.6Hz,1H),7.46–7.35(m,1H),4.86–4.71(m,1H),3.75(s,3H),1.98–1.85(m,1H),1.85–1.71(m,1H),1.50–1.35(m,2H),0.94(t,J＝7.3Hz,3H)；13C NMR(100MHz,CDCl3)δ172.8,164.0,149.4,148.2,137.3,126.3,122.3,52.3,52.0,34.6,18.7,13.6；HRMS(EI)Calcd for C12H16N2O3[M+]:236.1161,found 236.1154；IR(film)ν(cm-1):2960,1744,1679,1518,1436,1207,752。
(2) Preparation of compound 5:
Figure BDA0001390210090000071
the operation is as follows: cyclohexylglycine (629mg, 4mmol) and 4mL of methanol were added to a 15mL round bottom flask and placed under stirring in an ice bath. Thionyl chloride (0.9mL, 12mmol) was added dropwise thereto, the temperature was gradually returned to room temperature, and the reaction was allowed to proceed overnight. And after the reaction is finished, evaporating to dryness under reduced pressure, adding a small amount of petroleum ether, filtering, and washing the solid with the petroleum ether for a plurality of times in a small amount to obtain a white solid, namely cyclohexyl glycine ester hydrochloride. The resulting cyclohexylglycine ester hydrochloride, picolinic acid (591mg, 4.8mmol), EDCI (1.15g, 6mmol), DMAP (50mg, 0.4mmol) and dichloromethane (5mL) were added to a 15mL round-bottom flask and the reaction was stirred at room temperature overnight. Directly passing through silica gel after the reaction is finishedThe target product 5 (791 mg) was isolated by chromatography (petroleum ether: ethyl acetate: 10: 1) with a total yield of 72% in the two steps [ α ]]25 D+33.8(c 1.22,CHCl3)；1H NMR(400MHz,CDCl3)δ8.57(d,J＝4.4Hz,1H),8.49(d,J＝8.7Hz,1H),8.15(d,J＝7.8Hz,1H),7.82(t,J＝7.6Hz,1H),7.51–7.33(m,1H),4.70(dd,J＝9.1and5.6Hz,1H),3.74(s,3H),1.96–1.86(m,1H),1.80–1.56(m,5H),1.33–1.03(m,5H)；13C NMR(100MHz,CDCl3)δ172.2,164.1,149.4,148.2,137.2,126.3,122.2,57.0,52.1,41.0,29.5,28.3,25.88,25.86；HRMS(EI)Calcd forC15H20N2O3[M+]:276.1474,found 276.1476；IR(film)ν(cm-1):3389,2929,2855,1743,1681,1517。
(3) Preparation of compound 9:
Figure BDA0001390210090000072
the operation is as follows: gabapentin (685mg, 4mmol) and 4mL of methanol were added to a 10mL round bottom flask and stirred in an ice bath. Thionyl chloride (0.9mL, 12mmol) was added dropwise thereto, the temperature was gradually returned to room temperature, and the reaction was allowed to proceed overnight. After the reaction is finished, the mixture is decompressed and evaporated to dryness, a small amount of petroleum ether is added and filtered, and the solid is washed by the petroleum ether for a plurality of times in a small amount to obtain a white solid, namely gabapentin methyl ester hydrochloride. The resulting gabapentin methyl ester hydrochloride, picolinic acid (591mg, 4.8mmol), EDCI (1.15g, 6mmol), DMAP (49mg, 0.4mmol) and dichloromethane (5mL) were added to a 10mL round bottom flask and the reaction was stirred at room temperature overnight. After the reaction, 699mg of the target product 9 was obtained by direct separation through a silica gel column (petroleum ether: ethyl acetate: 10: 1), and the total yield of the two steps was 61%.1H NMR(400MHz,CDCl3)δ8.57(d,J＝4.4Hz,1H),8.49(s,1H),8.19(d,J＝7.8Hz,1H),7.83(td,J＝7.7and 1.4Hz,1H),7.41(dd,J＝6.8and 5.0Hz,1H),3.71(s,3H),3.51(d,J＝6.8Hz,2H),2.39(s,2H),1.66–1.56(m,2H),1.55–1.32(m,8H)；13C NMR(100MHz,CDCl3)δ172.8,164.6,150.0,148.2,137.2,126.0,122.3,51.6,45.8,41.3,38.1,34.1,25.9,21.5；HRMS(EI)Calcd for C16H22N2O3[M+]:290.1630,found 290.1635；IR(KBr)ν(cm-1):3391,2930,2862,1732,1681,1527,1436,1207,752。
(4) Preparation of compound 11:
Figure BDA0001390210090000081
reference is made to the literature: gong Chen; gan he, angelw, chem, int, ed, 2011,50, 5192-.
(5) Preparation of compound 13:
Figure BDA0001390210090000082
the operation is as follows: 1-aminocycloheptanoic acid (560mg, 3.56mmol) and 4mL of methanol were added to a 15mL round bottom flask and placed under stirring in an ice bath. Thionyl chloride (0.8mL, 11mmol) was added dropwise thereto, the temperature was gradually returned to room temperature, and the reaction was allowed to proceed overnight. After the reaction is finished, the mixture is decompressed and evaporated to dryness, a small amount of petroleum ether is added and filtered, and the solid is washed by the petroleum ether for a plurality of times in a small amount to obtain white solid, namely the aminocycloheptanoate hydrochloride. The resulting aminocycloheptanoate hydrochloride, picolinic acid (529mg, 4.3mmol), EDCI (1.04g, 5.4mmol), DMAP (50mg, 0.4mmol) and dichloromethane (5mL) were added to a 15mL round bottom flask and the reaction was stirred at room temperature overnight. After the reaction, 742mg of the target product 13 was isolated by silica gel chromatography (petroleum ether: ethyl acetate: 10: 1) directly, and the total yield of the two steps was 75%.1H NMR(400MHz,CDCl3)δ8.55(d,J＝4.2Hz,1H),8.29(s,1H),8.14(d,J＝7.8Hz,1H),7.82(t,J＝7.4Hz,1H),7.49–7.35(m,1H),3.72(s,3H),2.32–2.13(m,4H),1.61(s,8H)；13C NMR(100MHz,CDCl3)δ174.9,163.4,149.7,148.0,137.3,126.2,122.1,62.2,52.4,36.3,29.3,22.7；HRMS(EI)Calcd for C15H20N2O3[M+]:276.1474,found 276.1460；IR(KBr)ν(cm-1):3380,2930,1730,1670,1512,1042,750,586。
(6) Preparation of compound 15:
Figure BDA0001390210090000091
the operation is as follows: trans-4-aminocyclohexylcarboxylic acid hydrochloride (898mg, 5mmol) and 5mL of methanol were added to a 15mL round-bottom flask and placed under stirring in an ice bath. Thionyl chloride (1.1mL, 15mmol) was added dropwise thereto, the temperature was gradually returned to room temperature, and the reaction was allowed to proceed overnight. After the reaction is finished, the mixture is decompressed and evaporated to dryness, a small amount of petroleum ether is added and filtered, and the solid is washed by the petroleum ether for a plurality of times in a small amount to obtain white solid, namely trans-4-aminocyclohexyl formate hydrochloride. The resulting trans-4-aminocyclohexyl formate hydrochloride, picolinic acid (739mg, 6mmol), EDCI (1.44g, 7.5mmol), DMAP (61mg, 0.5mmol) and dichloromethane (7mL) were charged into a 15mL round-bottomed flask and the reaction was stirred at room temperature overnight. After the reaction, 558mg of the target product 15 was isolated directly by silica gel chromatography (petroleum ether: ethyl acetate: 10: 1), giving a total yield of 43% in the two steps.1H NMR(400MHz,CDCl3)δ8.52(d,J＝4.2Hz,1H),8.18(d,J＝7.8Hz,1H),7.90(d,J＝7.7Hz,1H),7.83(td,J＝7.7and1.7Hz,1H),7.41(ddd,J＝7.6,4.8and 1.1Hz,1H),4.02–3.86(m,1H),3.68(s,3H),2.30(tt,J＝12.1and 3.6Hz,1H),2.21–2.11(m,2H),2.11–1.98(m,2H),1.62(qd,J＝13.3and3.3Hz,2H),1.33(qd,J＝12.8and 3.4Hz,2H)；13C NMR(100MHz,CDCl3)δ175.7,163.4,149.9,147.9,137.3,126.0,122.1,51.6,47.6,42.3,32.0,27.7；HRMS(EI)Calcd forC14H18N2O3[M+]:262.1317,found 262.1310；IR(KBr)ν(cm-1):3378,2927,1720,1667,1519,1203,754,599。
(7) Preparation of compound 17:
Figure BDA0001390210090000101
the operation is as follows: cis-4-aminocyclohexylcarboxylic acid (286mg, 2mmol) and 2mL of methanol were added to a 10mL round-bottom flask and placed under stirring in an ice bath. Thionyl chloride (0.5mL, 6mmol) was added dropwise thereto, the temperature was gradually returned to room temperature, and the reaction was allowed to proceed overnight. After the reaction is finished, the mixture is decompressed and evaporated to dryness, and a small amount of the mixture is addedPetroleum ether is filtered, and the solid is washed by the petroleum ether for a plurality of times in a small amount to obtain white solid, namely cis-4-aminocyclohexyl formate hydrochloride. The resulting cis-4-aminocyclohexyl formate hydrochloride, picolinic acid (296mg, 2.4mmol), EDCI (575mg, 3mmol), DMAP (25mg, 0.2mmol) and dichloromethane (3mL) were charged into a 10mL round-bottomed flask and the reaction was stirred at room temperature overnight. After the reaction, 234mg of the target product 17 was isolated by silica gel chromatography (petroleum ether: ethyl acetate: 10: 1) directly, and the total yield of the two steps was 45%.1H NMR(400MHz,CDCl3)δ8.52(d,J＝4.5Hz,1H),8.35–7.95(m,2H),7.82(t,J＝7.7Hz,1H),7.40(dd,J＝6.8and 5.4Hz,1H),4.25–4.00(m,1H),3.68(s,3H),2.64–2.39(m,1H),2.10–1.88(m,3H),1.83–1.68(m,5H)；13C NMR(100MHz,CDCl3)δ175.5,163.4,149.9,148.0,137.3,126.0,122.0,51.6,45.7,40.2,29.4,25.0；HRMS(EI)Calcd for C14H18N2O3[M+]:262.1317,found 262.1313；IR(film)ν(cm-1):3384,2945,1731,1675,1521,1204,753。
Example 1 preparation of compound 2 (compound of formula (I)):
Figure BDA0001390210090000102
the operation is as follows: at room temperature, the 2-picolinic acid-protected amino acid derivative 1(35.5mg,0.15mmol), Pd (OAc)2(3.4mg,0.015mmol)、AgOAc(75mg,0.45mmol)、C6F5I(220mg,0.75mmol)、BQ(8.1mg,0.075mmol)、Na3PO4(37mg,0.225mmol) and TCE (1mL) were added to a 10mL microwave reaction tube at 20W and 170 ℃ for 2 hours. After the reaction is finished, the mixture is naturally cooled to room temperature, filtered by diatomite and dried by spinning. The method comprises the following steps of (1) mixing petroleum ether: ethyl acetate 4: 1 as developing agent, was isolated by preparative plate to give 25.3mg of title compound 2 in 72% yield.1H NMR(400MHz,CDCl3)δ8.61–8.34(m,1H),8.19–7.99(m,1H),7.85–7.70(m,1H),7.38–7.27(m,1H),5.59–5.11(m,1H),4.97–4.54(m,1H),3.83–3.49(m,3H),2.60–2.35(m,1H),2.35–2.09(m,1H),1.66–1.34(m,3H)；13C NMR(100MHz,CDCl3)δ172.3,172.1,171.6,164.9,164.3,151.6,151.4,151.3,148.2,147.4,147.3,136.9,136.7,125.6,125.4,125.3,124.1,123.5,123.4,63.3,63.1,61.2,57.1,56.8,56.7,52.3,52.0,51.9,29.9,29.6,28.5,22.5,20.7,20.4；HRMS(EI)Calcd for C12H14N2O3[M+]:234.1004,found 234.1005；IR(KBr)ν(cm-1):2966,1748,1643,1413,1205,750,696。
Example 2 preparation of compound 6 (compound of formula (III)):
Figure BDA0001390210090000111
the operation is as follows: at room temperature, the 2-picolinic acid-protected amino acid derivative 5(41.4mg,0.15mmol), Pd (OAc)2(3.4mg,0.015mmol)、AgOAc(75mg,0.45mmol)、C6F5I(220mg,0.75mmol)、BQ(8.1mg,0.075mmol)、Na3PO4(29.5mg,0.18mmol) and DCE (1mL) were added to a 10mL microwave reaction tube at 20W for 4 hours at 130 ℃. After the reaction is finished, the mixture is naturally cooled to room temperature, filtered by diatomite and dried by spinning. The method comprises the following steps of (1) mixing petroleum ether: ethyl acetate 4: 1 as developing agent, was isolated by preparative plate to give 25.6mg of title compound 6 in 62% yield.1H NMR(400MHz,CDCl3)δ8.57(d,J＝4.4Hz,0.25H),8.42(d,J＝4.3Hz,1H),8.11(d,J＝7.9Hz,1H),8.06(d,J＝7.9Hz,0.25H),7.83–7.71(m,1.25H),7.39–7.27(m,1.25H),5.28(d,J＝4.6Hz,1H),5.20(dd,J＝14.1,6.2Hz,0.25H),4.83–4.70(m,1.25H),3.77(s,0.75H),3.57(s,3H),2.91–2.81(m,0.25H),2.74–2.61(m,1.25H),2.30–2.15(m,1H),1.94–1.82(m,3H),1.80–1.64(m,4H),1.58–1.42(m,3H)；13C NMR(100MHz,CDCl3)δ171.9,171.3,165.9,165.2,151.7,148.3,147.4,136.8,136.6,125.5,125.3,124.0,123.4,69.8,62.8,62.5,58.5,52.2,51.9,34.1,33.4,27.4,24.3,24.0,22.8,18.7,18.6,18.0,17.6；HRMS(EI)Calcd for C15H18N2O3[M+]:274.1317,found 274.1322；IR(KBr)ν(cm-1):2948,1747,1642,1450,1414,1204,751。
Example 3 preparation of compound 10 (compound of formula (V)):
Figure BDA0001390210090000121
the operation is as follows: at room temperature, the 2-picolinic acid-protected amide derivative 9(28.6mg, 0.1mmol), Pd (OAc)2(4.5mg,0.02mmol)、AgOAc(50mg,0.3mmol)、C6F5I(294mg,1.0mmol)、BQ(5.4mg,0.05mmol)、Na3PO4(49.2mg,0.3mmol) and TCE (1mL) were added to a 10mL microwave reaction tube at 20W for 4 hours at 160 ℃. After the reaction is finished, the mixture is naturally cooled to room temperature, filtered by diatomite and dried by spinning. The method comprises the following steps of (1) mixing petroleum ether: ethyl acetate 4: 1 as developing agent, 15.9mg of the title compound 10 were isolated by preparative plate in 56% yield.1H NMR(400MHz,CDCl3)δ8.56(d,J＝2.7Hz,1H),8.15–7.95(m,1H),7.86–7.70(m,1H),7.40–7.29(m,1H),4.90(t,J＝4.8Hz,0.4H),4.64(d,J＝10.7Hz,0.6H),4.44–4.37(m,0.6+0.6H),4.11(d,J＝10.8Hz,0.4H),3.96(d,J＝10.8Hz,0.4H),3.72–3.60(m,3H),2.74–2.54(m,2H),2.32–2.20(m,0.6H),1.94–1.28(m,7.4H)；13C NMR(100MHz,CDCl3)δ171.7,166.1,165.8,152.33,152.28,148.2,148.0,136.73,136.69,125.21,125.15,123.8,123.7,68.9,65.1,62.7,55.5,51.5,44.0,43.4,35.2,34.9,28.6,27.7,26.3,24.0,18.2,18.0,17.0,16.6；HRMS(EI)Calcd forC16H20N2O3[M+]:288.1474,found288.1482；IR(KBr)ν(cm-1):2946,1736,1633,1450,1417,750,696。
Example 4 preparation of compound 12 (case of compound n ═ 1 of formula (II)):
Figure BDA0001390210090000122
the operation is as follows: at room temperature, the 2-picolinic acid-protected amino acid derivative 11(39.4mg,0.15mmol), Pd (OAc)2(3.4mg,0.015mmol)、AgOAc(75mg,0.45mmol)、C6F5I(220mg,0.75mmol)、BQ(8.1mg,0.075mmol)、Na3PO4(29.5mg,0.18mmol) and DCE (1mL)The mixture was put into a 10mL microwave reaction tube and reacted at 130 ℃ with a power of 20W for 4 hours. After the reaction is finished, the mixture is naturally cooled to room temperature, filtered by diatomite and dried by spinning. The method comprises the following steps of (1) mixing petroleum ether: ethyl acetate 4: 1 as developing agent, isolated by preparative plate to give 33.7mg of title compound 12 in 86% yield.1H NMR(400MHz,CDCl3)δ8.56(d,J＝4.2Hz,0.5H),8.37(d,J＝4.3Hz,0.5H),8.10(dd,J＝13.4and 7.9Hz,1H),7.77(t,J＝7.3Hz,1H),7.39–7.27(m,1H),5.45–5.14(m,0.5H),4.70–4.48(m,0.5H),3.77(s,1.5H),3.53(s,1.5H),2.91–2.77(m,1H),2.69–2.51(m,1H),2.47–2.38(m,0.5H),2.37–2.27(m,0.5H),2.22–2.14(m,0.5H),2.13–2.05(m,0.5H),2.02–1.92(m,1H),1.85–1.73(m,2H),1.73–1.62(m,1H)；13C NMR(100MHz,CDCl3)δ170.69,170.67,165.6,164.3,151.7,151.0,148.3,146.9,136.8,136.7,125.6,125.5,123.7,123.5,74.2,69.0,65.4,58.9,52.3,51.6,35.6,34.3,29.4,28.1,25.8,25.1,15.3,15.1；HRMS(EI)Calcd for C14H16N2O3[M+]:260.1161,found260.1168；IR(KBr)ν(cm-1):2955,1740,1635,1395,1118,750。
Example 5 preparation of compound 14 (case of compound n ═ 2 of formula (II)):
Figure BDA0001390210090000131
the operation is as follows: at room temperature, the 2-picolinic acid-protected amino acid derivative 13(41.0mg,0.15mmol), Pd (OAc)2(3.4mg,0.015mmol)、AgOAc(75mg,0.45mmol)、C6F5I(440mg,1.5mmol)、BQ(8.1mg,0.075mmol)、Na3PO4(74mg,0.45mmol) and TCE (1mL) were added to a 10mL microwave reaction tube at 20W for 4 hours at 130 ℃. After the reaction is finished, the mixture is naturally cooled to room temperature, filtered by diatomite and dried by spinning. The method comprises the following steps of (1) mixing petroleum ether: ethyl acetate 4: 1 as developing agent, was isolated by preparative plate to give 34.2mg of the title compound 14 in 83% yield.1H NMR(400MHz,CDCl3)δ8.55(d,J＝4.1Hz,0.4H),8.36(d,J＝4.1Hz,0.6H),8.19–7.96(m,1H),7.76(t,J＝7.6Hz,1H),7.38–7.25(m,1H),5.34(d,J＝6.8Hz,0.4H),4.82–4.62(m,0.6H),3.75(s,1.2H),3.44(s,1.8H),2.80(t,J＝9.3Hz,1H),2.74–2.55(m,1H),2.35–1.94(m,3H),1.83–1.49(m,5H)；13CNMR(100MHz,CDCl3)δ172.09,172.06,163.8,163.1,151.7,151.0,148.2,146.9,136.8,136.6,125.4,125.3,123.9,123.4,73.7,69.3,63.7,57.8,52.3,51.6,33.1,32.6,31.7,31.2,29.4,28.0,23.7,23.6,23.3,22.9；HRMS(EI)Calcd for C15H18N2O3[M+]:274.1317,found 274.1318；IR(KBr)ν(cm-1):2932,1738,1631,1450,1413,1122,750,694。
Example 6 preparation of compound 16 (one configuration of the compound of formula (IV)):
Figure BDA0001390210090000141
the operation is as follows: at room temperature, the 2-picolinic acid-protected amino acid derivative 15(39.4mg,0.15mmol), Pd (OAc)2(3.4mg,0.015mmol)、AgOAc(75mg,0.45mmol)、C6F5I(440mg,1.5mmol)、BQ(8.1mg,0.075mmol)、Na3PO4(74mg,0.45mmol) and DCE (1mL) were added to a 10mL microwave reaction tube and reacted at 130 ℃ for 4 hours at a power of 20W. After the reaction is finished, the mixture is naturally cooled to room temperature, filtered by diatomite and dried by spinning. The method comprises the following steps of (1) mixing petroleum ether: ethyl acetate 4: 1 as developing agent, was isolated by preparative plate to give 28.0mg of the title compound 16 in 72% yield.1H NMR(400MHz,CDCl3)δ8.56(t,J＝5.0Hz,1H),8.09(dd,J＝7.7and 3.8Hz,1H),7.79(t,J＝7.7Hz,1H),7.35(dd,J＝7.0and 5.2Hz,1H),5.34–5.24(m,0.5H),5.24–5.11(m,0.5H),4.80–4.68(m,0.5H),4.66–4.52(m,0.5H),3.70(s,3H),3.59–3.41(m,1H),2.69–2.55(m,1H),2.46–2.15(m,2H),2.06–1.87(m,2H),1.81–1.77(m,1H)；13C NMR(100MHz,CDCl3)δ174.1,164.3,163.4,152.0,148.34,148.30,136.8,136.7,125.4,125.3,123.7,66.6,66.4,61.0,60.1,51.84,51.82,43.9,40.9,27.6,26.9,26.6,25.0,18.2,18.0；HRMS(EI)Calcd for C14H16N2O3[M+]:260.1161,found 260.1157；IR(KBr)ν(cm-1):2955,1732,1630,1448,1413,750,694。
Example 7 preparation of compound 18 (another configuration of the compound of formula (IV)):
Figure BDA0001390210090000142
the operation is as follows: at room temperature, the 2-picolinic acid-protected amino acid derivative 17(39.4mg,0.15mmol), Pd (OAc)2(3.4mg,0.015mmol)、AgOAc(75mg,0.45mmol)、C6F5I(440mg,1.5mmol)、BQ(8.1mg,0.075mmol)、Na3PO4(74mg,0.45mmol) and DCE (1mL) were added to a 10mL microwave reaction tube and reacted at 130 ℃ for 4 hours at a power of 20W. After the reaction is finished, the mixture is naturally cooled to room temperature, filtered by diatomite and dried by spinning. The method comprises the following steps of (1) mixing petroleum ether: ethyl acetate 4: 1 as developing agent, was isolated by preparative plate to give 16.8mg of title compound 18 in 54% yield.1H NMR(400MHz,CDCl3)δ8.52(d,J＝4.3Hz,0.4H),8.44(d,J＝4.3Hz,0.6H),8.03(d,J＝7.7Hz,1H),7.86–7.63(m,1H),7.38–7.26(m,1H),5.55(s,0.6H),5.13(s,0.4H),4.93(s,0.4H),4.60(d,J＝1.8Hz,0.6H),3.74(s,1.2H),3.20(s,1,8H),2.97–2.81(m,5H),2.81–2.72(m,0.5H),2.62–2.45(m,1H),2.27–2.10(m,1H),2.10–1.91(m,1H),1.91–1.74(m,1H),1.59–1.43(m,1H).；13C NMR(100MHz,CDCl3)δ173.8,173.6,164.7,164.2,152.1,152.0,148.1,147.6,136.7,136.6,125.15,125.10,123.8,123.6,67.6,66.4,62.1,60.2,52.1,51.3,45.3,43.6,33.5,32.3,27.3,24.6,17.9,17.4；HRMS(EI)Calcd for C14H16N2O3[M+]:260.1161,found 260.1165；IR(KBr)ν(cm-1):2955,1735,1629,1449,1414,1205,751,696。
Effect of Compounds prepared in examples 1-7 on triglyceride content in HL7702 hepatocytes
(1) Material
Sample preparation: compounds 2, 6, 10, 12, 14, 16, 18
The instrument comprises the following steps: biosafety cabinets, ESCO (singapore); CO 22Cell incubator: ESCO (singapore); cky31 inverted microscope Olympus (Japan); centrifuge, Termo Fisher Scientific (USA); GF-M3000 enzyme-linked immunosorbent assay (ELISA) instrument, ShandongHigh-density rainbow analysis instruments ltd (china), etc.
Reagent: high-glucose DMEM medium, fetal calf serum, penicillin-streptomycin and trypsin digestion solution are purchased from BI company; oleic acid, bovine serum albumin fifth fraction without free fatty acids and DMSO were purchased from Sigma; cell proliferation detection kit (CellTiter)
Figure BDA0001390210090000151
AQueous One Solution Reagent) available from Promega corporation; BCA assay kit was purchased from Thermo Fisher Scientific; curcumin was purchased from Guangdong-force group pharmaceutical Co., Ltd; the paraformaldehyde and triglyceride test box is purchased from Nanjing to build a biological research institute.
(2) Experimental methods
Preparing a sample solution: all detection samples are dissolved by DMSO, the initial concentration is 100mmol/L, and the final concentration of the samples is 100 mu mol/L. The initial concentration of curcumin is 20mmol/L, and the final concentration is 20 μmol/L.
Effect of samples on hepatocyte cell viability: according to the literature[1]The method detects the effect of the sample on the viability of the cells. After incubating human liver HL7702 cells for 48h with the samples, CellTiter was used
Figure BDA0001390210090000161
The AQueous One Solution Reagent Solution was incubated for 1 h. And detecting the OD value at the 490nm wavelength by using a microplate reader, and setting a zero setting hole. The results are expressed as cell viability (%). Cell viability (%) - (measured OD value-zero well OD value)/(blank OD value-zero well OD value) × 100.
Document [1] Xu C; hu Y; hou L et al.J Mol Cell Cardiol,2014,75, 111-.
Establishing a high fat cell model: human liver cell line HL7702 was cultured in DMEM medium containing 10% fetal bovine serum. When the cell density is about 70%, incubating HL7702 cells with oleic acid with the final concentration of 0.2mmol/L for 48h to establish a high fat cell model.
Effect of the sample on the triglyceride content of the hepatocytes: the HL7702 liver cells are inoculated in a 24-pore plate, the samples to be detected are respectively added while the oleic acid is added, and the curcumin is taken as a positive control. After 48h incubation, the content of Triglyceride (TG) was measured with reference to the triglyceride test kit instructions and the protein concentration was determined by BCA method. The TG content in the cells was expressed as the amount of TG per g of cellular protein (mg/g).
(3) Results of the experiment
As shown in fig. 1, 100 μmol/L of compounds 2, 6, 10, 12, 14, 16, 18 and 20 μmol/L of curcumin had no significant toxicity to HL7702 hepatocytes; as shown in fig. 2, compounds 2, 6, 10, 12, 14, 16, 18 and curcumin can significantly reduce the content of oleic acid-induced HL7702 hepatocyte TG.

Claims (9)

1. The structural formula of the unnatural amino acid derivative containing the azetidine skeleton is shown as the formula (I), (II), (III), (IV) or (V):
Figure FDA0002282772270000011
and n is 1 or 2.
2. The azetidine skeleton-containing unnatural amino acid derivative according to claim 1, wherein: the structural formula is
Figure FDA0002282772270000012
3. A method for synthesizing an azetidine skeleton-containing unnatural amino acid derivative according to claim 1 or 2, which comprises:
to be provided with
Figure FDA0002282772270000013
Figure FDA0002282772270000014
Taking Pd (II) as a catalyst and silver salt as an oxidant, adding pentafluoroiodobenzene, benzoquinone and alkali, and reacting in a solvent at 130-170 ℃ for 1-4 hours by using microwaves to obtain a target product;
Figure FDA0002282772270000021
wherein n is 1 or 2.
4. The method of synthesis according to claim 3, characterized in that: the catalyst Pd (II) is palladium acetate Pd (OAc)2Pd trifluoroacetate (OCOCF)3)2PdCl, palladium dichloride2PdI, Pd diiodide2Palladium dichlorodiphenylcyanide PdCl2(PhCN)2Dichloro bis (triphenylphosphino) palladium PdCl2(PPh3)2And/or palladium dichlorodiacetonitrile PdCl2(CH3CN)2The amount of the catalyst is 0.01 to 0.2 equivalent.
5. The method of synthesis according to claim 3, characterized in that: the silver salt of the oxidant is silver acetate, silver carbonate, silver trifluoroacetate, silver tetrafluoroborate, silver hexafluoroantimonate and/or silver hexafluorophosphate, and the using amount of the silver salt is 1-3 equivalents.
6. The method of synthesis according to claim 3, characterized in that: the solvent is 1, 2-dichloroethane or 1,1,2, 2-tetrachloroethane.
7. The method of synthesis according to claim 3, characterized in that: the base is a carbonate, bicarbonate, acetate, phosphate, hydrogenphosphate or dihydrogenphosphate of a 1 or 2 valent metal.
8. The method of synthesis according to claim 7, characterized in that: the alkali is sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, calcium carbonate, potassium bicarbonate, sodium acetate, potassium acetate, sodium phosphate, potassium phosphate, sodium hydrogen phosphate and/or sodium dihydrogen phosphate, and the using amount of the alkali is 1-3 equivalents.
9. Use of the unnatural amino acid derivative with an azetidine skeleton according to any one of claims 1-2 for the preparation of a hypolipidemic agent.
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103214407A (en) * 2013-05-07 2013-07-24 北京大学 Method for preparing pyrrolidine derivative
WO2016119707A1 (en) * 2015-01-29 2016-08-04 Hutchison Medipharma Limited Novel heteroaryl and heterocycle compounds, compositions and methods
CN106103433A (en) * 2014-03-07 2016-11-09 住友化学株式会社 Fused heterocyclic compound and PCO application thereof
WO2017050807A1 (en) * 2015-09-21 2017-03-30 AbbVie Deutschland GmbH & Co. KG Pyridyl or pyrazinyl compounds carrying a methyl-bound alpha-amino acid amide group

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103214407A (en) * 2013-05-07 2013-07-24 北京大学 Method for preparing pyrrolidine derivative
CN106103433A (en) * 2014-03-07 2016-11-09 住友化学株式会社 Fused heterocyclic compound and PCO application thereof
WO2016119707A1 (en) * 2015-01-29 2016-08-04 Hutchison Medipharma Limited Novel heteroaryl and heterocycle compounds, compositions and methods
WO2017050807A1 (en) * 2015-09-21 2017-03-30 AbbVie Deutschland GmbH & Co. KG Pyridyl or pyrazinyl compounds carrying a methyl-bound alpha-amino acid amide group

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