CN113527295B - Preparation method and application of chiral 3, 6-diazabicyclo [3.2.1] octane derivative - Google Patents

Preparation method and application of chiral 3, 6-diazabicyclo [3.2.1] octane derivative Download PDF

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CN113527295B
CN113527295B CN202110383686.7A CN202110383686A CN113527295B CN 113527295 B CN113527295 B CN 113527295B CN 202110383686 A CN202110383686 A CN 202110383686A CN 113527295 B CN113527295 B CN 113527295B
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diazabicyclo
octane derivative
amide
silver
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王海飞
邓启福
张凯强
陈知刚
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Hunan Jiuwei Biopharmaceutical Co.,Ltd.
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Hunan University of Technology
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Abstract

The invention discloses a preparation method of a chiral 3, 6-diazabicyclo [3.2.1] octane derivative, wherein the chiral 3, 6-diazabicyclo [3.2.1] octane derivative is used for synergistically catalyzing 1, 3-dipolar cycloaddition reaction between azomethine ylide and alpha-substituted terminal olefin amide of different series through combination of monovalent silver salt and different chiral phosphine-amide ligands, and the chiral 3, 6-diazabicyclo [3.2.1] octane derivative is directly obtained through intramolecular cyclization under strong alkali treatment. The preparation method has the advantages of simple steps, cheap and easily-obtained raw materials, low corrosion degree, low toxicity and simple and easily-realized reaction conditions. The 3, 6-diazabicyclo [3.2.1] octane derivative obtained by the preparation method of the chiral 3, 6-diazabicyclo [3.2.1] octane derivative can be applied to a drug inhibitor or a drug intermediate.

Description

Preparation method and application of chiral 3, 6-diazabicyclo [3.2.1] octane derivative
Technical Field
The invention relates to the technical field of octane derivative synthesis, and more particularly relates to a preparation method and application of a chiral 3, 6-diazabicyclo [3.2.1] octane derivative.
Background
The 3, 6-diazabicyclo [3.2.1] octane derivative not only has important medical research value (for example, in the aspects of inhibiting thrombin activity and being used as a fragment inhibitor of a serine protease structure and the like), but also is a key intermediate for synthesizing quinolone antibacterial drugs, blood pressure reducing drugs, blood sugar reducing drugs and antitumor drugs.
The literature reports that in 1988 Kleinman group used cyclopentadiene and imine as raw materials to synthesize 3, 6-diazabicyclo [3.2.1] octane derivatives in 4 steps through Diels-Alder reaction, ozone ring opening, Mannich reaction and sodium cyanoborohydride reduction (ref: J.Org.Chem.,1988,53(4), 896-one 899). In 2010 and 2014, Kudryavtsev group reported that the synthesis of 3, 6-diazabicyclo [3.2.1] octane derivatives was achieved by the steps of 1, 3-dipolar cycloaddition, deesterification, amide condensation and cuprous cyanide catalyzed cyclization (refer to Russian Journal of Organic Chemistry,2010,46(3), 372-789; Tetrahedron,2014,70(43), 7854-7864). The method has the advantages of longer steps, higher corrosivity and toxicity of raw materials, and harsh reaction conditions such as low temperature of minus 78 ℃. In addition, the 3, 6-diazabicyclo [3.2.1] octane derivatives synthesized by the above method are mainly obtained as racemic compounds, and chiral synthesis thereof has not been reported. In terms of pharmaceutical activity, chiral compounds with different enantiomers often have obvious difference, so that the synthesis of chiral 3, 6-diazabicyclo [3.2.1] octane derivatives is of great significance.
Disclosure of Invention
The invention aims to solve the technical problems that 3, 6-diazabicyclo [3.2.1] octane derivatives prepared in the prior art are mainly synthesized by racemates, and have the defects of longer reaction steps, higher corrosivity and toxicity of raw materials, harsh reaction conditions and the like, and provides a one-pot preparation method of chiral 3, 6-diazabicyclo [3.2.1] octane derivatives.
The invention also aims to provide an application of the chiral 3, 6-diazabicyclo [3.2.1] octane derivative.
The purpose of the invention is realized by the following technical scheme:
a preparation method of chiral 3, 6-diazabicyclo [3.2.1] octane derivatives comprises the following preparation steps:
s1, stirring a silver catalyst and a chiral phosphine-amide ligand at room temperature for 1-2 hours, then adding azomethine ylide and alpha-substituted terminal olefin amide, and stirring to react at-5-0 ℃ for 2-24;
s2, adding alkali into the step S1, stirring for 1-12 h at room temperature until the reaction is complete;
s3, adding a sodium chloride solution into the solution completely reacted in the step S2, and adding an extracting agent for extraction to obtain an organic phase;
and S4, drying the organic phase obtained in the step S3, filtering, concentrating under reduced pressure, eluting and passing through a column to obtain a product.
Further, the substituent group of the alpha-substituted terminal olefin amide is one or more of alkyl, aryl and heteroaryl.
Further, the silver oxide (Ag)2O), silver carbonate (Ag)2CO3) One or more monovalent silver salts of silver acetate (AgOAc), silver trifluoroacetate (AgOTf), silver benzoate (PhCOOAg), silver fluoride (AgF).
Further, the base substance is 1,5, 7-triazabicyclo [4.4.0]Dec-5-ene (TBD), 7-methyl-1, 5, 7-triazabicyclo [4.4.0]Dec-5-ene (MTBD), triethylamine (Et)3N), 4-Dimethylaminopyridine (DMAP), 1, 8-diazabicyclo [5.4.0]Undec-7-ene (DBU), cesium carbonate (Cs)2CO3) Potassium carbonate (K)2CO3) Potassium tert-butoxide (f)tBuOK), sodium tert-butoxide (tBuONa) one or more of them.
Further, the phosphorus ligand is a chiral phosphine-amide ligand derived from alkaloid and amino acid.
Further, the molar ratio of azomethine ylide to alpha-substituted terminal olefin amide is 1-2: 1.
Further, the amount of the silver catalyst added is 2 to 4% by mole of the α -substituted terminal olefin amide.
Furthermore, the addition amount of the chiral phosphine-amide ligand is 2-4% of the molar amount of the alpha-substituted terminal olefin amide.
Further, the temperature in the step S1 is-10 to 25 ℃. Preferably, the temperature in step S1 is-5 to 0 ℃.
Further, the amount of the base added is 10 to 20% by mole of the α -substituted terminal olefin amide.
Further, in step S3, the sodium chloride solution is a saturated sodium chloride solution, and the extracting agent is CH2Cl2(ii) a Anhydrous Na for drying organic phase in step S32SO4Drying; the elution column adopts ethyl acetate and petroleum ether.
The 3, 6-diazabicyclo [3.2.1] octane derivative obtained by the preparation method of the 3, 6-diazabicyclo [3.2.1] octane derivative is applied to a drug inhibitor or a drug intermediate.
Compared with the prior art, the beneficial effects are:
the invention creatively utilizes univalent silver salt to be combined with different chiral phosphine-amide ligands to synergistically catalyze 1, 3-dipolar cycloaddition reaction between azomethine ylides of different series and alpha-substituted terminal olefin amide, then directly adds organic strong base or inorganic strong base into a reaction system without separation for post treatment, and directly obtains the chiral 3, 6-diazabicyclo [3.2.1] octane derivative through intramolecular cyclization. The preparation method has the advantages of simple steps, cheap and easily-obtained raw materials, low corrosion degree, low toxicity and simple and easily-realized reaction conditions. The 3, 6-diazabicyclo [3.2.1] octane derivative obtained by the preparation method of the 3, 6-diazabicyclo [3.2.1] octane derivative is applied to a drug inhibitor or a drug intermediate.
Drawings
FIG. 1 is a high performance liquid chromatogram of Compound 3 a; FIG. 2 is a high performance liquid chromatogram of Compound 3 b; FIG. 3 is a high performance liquid chromatogram of Compound 3 c; FIG. 4 is a high performance liquid chromatogram of Compound 3 d; FIG. 5 is a high performance liquid chromatogram of Compound 3 e; FIG. 6 is a high performance liquid chromatogram of Compound 3 f; FIG. 7 is a high performance liquid chromatogram of compound 3 g; FIG. 8 is a high performance liquid chromatogram of Compound 3 h; FIG. 9 is a high performance liquid chromatogram of Compound 3 i; FIG. 10 is a high performance liquid chromatogram of Compound 3 j; FIG. 11 is a high performance liquid chromatogram of Compound 3 k; FIG. 12 is a high performance liquid chromatogram of Compound 3 l; FIG. 13 is a high performance liquid chromatogram of Compound 3 m; FIG. 14 is a high performance liquid chromatogram of Compound 3 n; FIG. 15 is a high performance liquid chromatogram of Compound 3 o; FIG. 16 is a high performance liquid chromatogram of Compound 3 p.
Detailed Description
The following examples are further explained and illustrated, but the present invention is not limited in any way by the specific examples. Unless otherwise indicated, the methods and equipment used in the examples are conventional in the art and all materials used are conventional commercially available materials.
Wherein, the synthesis scheme of the phosphine-amide ligand used in example 1 is shown in the figure:
Figure GDA0003510603650000031
dissolving the synthesized Boc protected D-tertiary leucine intermediate (1.0mmol,231mg) in dichloromethane (8.0mL), adding the dissolved intermediate into a 50mL round-bottom flask, adding O-benzotriazole-tetramethyluronium Hexafluorophosphate (HBTU) (1.2equiv), stirring at 0 ℃ for 10min, adding primary amine (1equiv) and diisopropylethylamine (1.2equiv), reacting for half an hour, raising the temperature to room temperature, stirring, detecting by TLC until the raw material is completely converted, adding saturated sodium carbonate, quenching, separating, extracting the aqueous phase with dichloromethane for 3 times, combining the organic phases, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and separating the Boc protected intermediate by column chromatography. Dissolving the intermediate in dichloromethane (10mL/mmol), slowly adding trifluoroacetic acid (1mL/mmol, TFA) dropwise in ice water bath, stirring at room temperature overnight, detecting by TLC plate that the raw material is completely consumed, adding saturated NaHCO3 solution into the reaction system until no bubbles are formedGeneration of, with CH2Cl2Extraction (10mL) was performed 3 times, the organic phases were combined, dried and spun to give a concentrate which was used directly in the next reaction without column chromatography. Dissolving the concentrated solution obtained in the previous step in dichloromethane (10mL) under the protection of N2, adding the solution into a 50mL round-bottom flask, sequentially adding o-diphenylphosphinobenzoic acid (1.0mmol,306mg), HBTU (1.2mmol,124mg) and diisopropylethylamine (1.0mmol,0.22mL) into a reaction flask at 0 ℃, stirring for 6h at room temperature, detecting by TLC until the raw materials are completely reacted, quenching the reaction with saturated sodium carbonate, and reacting with CH2Cl2(10mL) extraction was performed 3 times, and the organic phases were combined and Na anhydrous2SO4Dried, concentrated under reduced pressure, extracted with EtOAc: MeOH: Et3N15: 1:0.05 as eluent, eluting with a short column of silica gel, and concentrating under reduced pressure to give a white solid L5.
Similarly, phosphine-amide ligands of different structures can be obtained according to the above process.
Example 1
This example provides the synthesis of a 3, 6-diazabicyclo [3.2.1] octane derivative, according to the following steps:
Figure GDA0003510603650000041
s1, stirring a silver catalyst with the molar weight of 2-4 mol% of alpha-substituted terminal olefin amide and a chiral phosphine-amide ligand with the molar weight of 2-4% of alpha-substituted terminal olefin amide at room temperature for 1-2 h, then adding azomethine ylide and alpha-substituted terminal olefin amide, and stirring for reaction at a certain temperature for t1Is 2 to 24;
s2, adding alkali into the step S1, and stirring the mixture at room temperature for reaction time t21-12 h, and completely reacting;
s3, adding saturated saline solution into the solution system completely reacted in the step S2, and using CH2Cl2Extracting for 3 times, and mixing organic phases;
s4, adding anhydrous Na into the organic phase obtained in the step S32SO4Drying, filtering, concentrating under reduced pressure, and mixing with ethyl acetate and petroleum etherEluting the column, and separating to obtain the product.
Example 2
This example prepared 3, 6-diazabicyclo [3.2.1] octane according to the method provided in example 1 and the physical agent parameters set forth in the following table, as shown in table 1 below:
TABLE 1
Figure GDA0003510603650000051
Figure GDA0003510603650000052
Example 3
According to the preparation described in example 1, the following were synthesized:
Figure GDA0003510603650000061
wherein Et is ethyl.
The product yields for each material were calculated as in table 2:
TABLE 2
Serial number Product yield (%) Ee(％) Serial number Product yield (%) Ee(％)
3a 93 95 3i 87 94
3b 87 93 3j 92 96
3c 78 91 3k 95 94
3d 96 95 3l 97 96
3e 86 94 3m 93 95
3f 90 95 3n 81 91
3g 86 96 3o 67 96
3h 97 94 3q 71 95
Chiral 3, 6-diazabicyclo [3.2.1] octane derivatives were prepared in the examples and the products prepared were characterized by hydrogen and carbon spectra.
The product structural formula and characterization data are as follows:
characterization data for Compound 3a
Figure GDA0003510603650000071
1H NMR(400MHz,CDCl3)δ7.45(d,J＝8.4Hz,2H),7.33-7.23(m,4H),7.17-7.14(m,2H),7.08(t,J＝7.6Hz,2H),6.89-6.85(m,4H),4.97(d,J＝13.2Hz,1H),4.81(d,J＝13.6Hz,1H),4.55(s,1H),4.24(d,J＝4.8Hz,1H),3.82(s,3H),2.83-2.73(m,2H),2.35(brs,1H).
13C NMR(100MHz,CDCl3)δ174.6,172.2,159.1,137.8,136.4,131.5,128.8,128.5,128.4,127.7,113.8,70.9,60.6,58.9,55.3,42.6,38.9.IR(film)v(cm-1)3366,3043,2946,2347,1732,1680,1611,1511,1450,1295,1247,1145,1031,933.[α]D 25＝+28.5(c 0.37,CH2Cl2).The ee value was 95％,tR(minor)＝13.02min,tR(major)＝21.22min(Chiralcel AD-H,λ＝205nm,iPrOH/hexane＝20:80,flow rate＝1mL/min).
Characterization data for Compound 3b
Figure GDA0003510603650000072
1H NMR(400MHz,CDCl3)δ7.52(dd,J＝6.2,2.6Hz,2H),7.40-7.22(m,8H),7.22-7.13(m,2H),7.08(t,J＝8.0Hz,2H),6.90(d,J＝7.6Hz,2H),5.06(d,J＝13.2Hz,1H),4.88(d,J＝13.6Hz,1H),4.59(s,1H),4.29(d,J＝4.8Hz,1H),2.87-2.85(m,2H),2.08(d,J＝4.8Hz,2H),1.95(brs,1H).
13C NMR(100MHz,CDCl3)δ174.6,172.2,137.8,136.5,136.3,130.0,128.6,128.5,128.5,128.4,128.3,127.8,127.7,70.9,60.6,58.9,43.3,38.9.IR(film)v(cm-1)3361,3042,2948,2360,1733,1680,1497,1450,1344,1204,1143,1073,934.[α]D 25＝+40.1(c 0.32,CH2Cl2).The ee value was 93％,tR(minor)＝9.34min,tR(major)＝15.60min(Chiralcel AD-H,λ＝205nm,iPrOH/hexane＝50:50,flow rate＝1mL/min).
Characterization data for Compound 3c
Figure GDA0003510603650000081
1H NMR(400MHz,CDCl3)δ7.61(s,4H),7.34(d,J＝4.8Hz,3H),7.28(d,J＝5.4Hz,2H),7.21(d,J＝4.6Hz,2H),7.08(t,J＝7.6Hz,2H),6.90(d,J＝7.6Hz,2H),5.07(d,J＝13.6Hz,1H),4.91(d,J＝13.2Hz,1H),4.65(s,1H),4.30(d,J＝4.8Hz,1H),2.87-2.77(m,2H),2.27(brs,1H).
13C NMR(100MHz,CDCl3)δ174.4,172.3,140.3,137.7,136.1,130.3,130.1,129.7,128.6,128.4,128.3,128.1,127.9,127.8,125.4,125.4,125.4,125.3,122.7,70.4,60.6,58.7,42.7,39.2.IR(film)v(cm-1)3361,3050,2946,2344,1737,1689,1620,1497,1425,1321,1133,1065,1021,915.[α]D 25＝+23.4(c 0.60,CH2Cl2).The ee value was 91％,tR(minor)＝13.51min,tR(major)＝17.85min(Chiralcel AD-H,λ＝205nm,iPrOH/hexane＝50:50,flow rate＝0.5mL/min).
Characterization data for Compound 3d
Figure GDA0003510603650000082
1H NMR(400MHz,CDCl3)δ7.42(d,J＝7.6Hz,2H),7.28-7.34(m,4H),7.18(t,J＝6.6Hz,4H),7.10(t,J＝7.6Hz,2H),6.92(d,J＝7.6Hz,2H),5.02(d,J＝13.6Hz,1H),4.86(d,J＝13.2Hz,1H),4.58(s,1H),4.27(d,J＝4.8Hz,1H),2.82(dd,J＝12.0,4.8Hz,1H),2.78(d,J＝12.0Hz,1H),2.40(s,3H),1.73(br.s,1H).
13C NMR(100MHz,CDCl3)δ174.6,172.1,137.8,137.3,136.3,133.5,130.0,129.1,128.5,128.3,127.7,60.6,58.9(d),42.9,38.8,21.1.IR(film):v(cm-1)3428,2939,2352,1734,1720,1680,1447,1344,1226,1126,1042,767,728,585.[α]D 25＝+44.5(c 0.73,CH2Cl2).The ee value was 94％,tR(minor)＝9.12min,tR(major)＝11.88min(Chiralcel AD-H,λ＝205nm,iPrOH/hexanes＝80:20,flow rate＝1ml/min)
Characterization data for Compound 3e
Figure GDA0003510603650000091
1H NMR(400MHz,CDCl3)δ7.51(dd,J＝8.2,5.4Hz 2H),7.28-7.34(m,4H),7.18-7.20(m,2H),7.11(t,J＝7.6Hz 2H),7.03(t,J＝8.6Hz 2H),6.90(d,J＝8Hz 2H),5.00(d,J＝13.6Hz 1H),4.85(d,J＝13.6Hz 1H),4.61(s,1H),4.28(d,J＝4.8Hz 1H),2.84(dd,J＝12,4.8Hz 1H),2.77(d,J＝12Hz 1H),2.15(brs,1H).
13C NMR(100MHz,CDCl3)δ174.5,172.2,163.5,161.1,137.8,136.2,132.3(d),132.0,131.9,128.6,128.5,128.3,128.2,127.8(d),115.3,115.1,60.6,58.8(d),42.5,39.0.IR(film):v(cm-1)3360,3060,2959,2875,1733,1681,1508,1448,1373,1343,1263.[α]D 25＝+47.0(c 0.68,CH2Cl2).The ee value was 92％,tR(minor)＝10.03min,tR(major)＝15.50min(Chiralcel AD-H,λ＝205nm,iPrOH/hexanes＝80:20,flow rate＝1ml/min)
Characterization data for Compound 3f
Figure GDA0003510603650000092
1H NMR(400MHz,CDCl3)δ7.33-7.31(m,6H),7.23-7.19(m,4H),4.65(s,1H),4.22(d,J＝5.2Hz,1H),3.88-3.76(m,2H),2.83-2.79(m,1H),2.71(d,J＝11.6Hz,1H),2.37(brs,1H),1.18(t,J＝7.2Hz,3H).
13C NMR(100MHz,CDCl3)δ174.4,172.0,138.2,136.4,128.7,128.5,128.4,128.2,127.8,127.7,70.3,60.6,59.0,39.2,35.1,12.9.IR(film)v(cm-1)3550,3054,2975,2360,1732,1680,1497,1450,1352,1314,1231,1120,1081,887.[α]D 25＝+80.9(c 1.50,CH2Cl2).The ee value was 95％,tR(minor)＝7.94min,tR(major)＝12.37min(ChiralcelAS-H,λ＝205nm,iPrOH/hexane＝50:50,flow rate＝1mL/min).
Characterization data for Compound 3g
Figure GDA0003510603650000101
1H NMR(400MHz,CDCl3)δ7.44(d,J＝8.4Hz,2H),7.30(d,J＝4.6Hz,3H),7.21-7.13(m,2H),6.89-6.87(m,4H),6.78(d,J＝7.8Hz,2H),4.96(d,J＝13.2Hz,1H),4.82(d,J＝13.4Hz,1H),4.53(s,1H),4.23(d,J＝4.6Hz,1H),3.83(s,3H),2.79-6.75(m,2H),2.30(s,3H),2.21(s,1H).
13C NMR(100MHz,CDCl3)δ174.6,172.2,159.0,138.3,136.4,134.7,131.4,129.3,128.8,128.3,128.1,127.7,113.7,70.7,60.5,58.9,58.8,55.2,55.1,42.6,38.7,21.1.IR(film)v(cm-1)3356,3028,2941,1733,1680,1611,1512,1447,1247,1144,1107,1301,910.[α]D 25＝+38.3(c 1.40,CH2Cl2).The ee value was 96％,tR(minor)＝7.86min,tR(major)＝15.07min(Chiralcel AD-H,λ＝205nm,iPrOH/hexane＝50:50,flow rate＝1mL/min).
Characterization data for Compound 3h
Figure GDA0003510603650000102
1H NMR(400MHz,CDCl3)δ7.42(d,J＝8.6Hz,2H),7.35-7.29(m,3H),7.18-7.14(m,2H),6.99(d,J＝8.4Hz,2H),6.86(d,J＝8.6Hz,2H),6.78(d,J＝8.4Hz,2H),4.95(d,J＝13.2Hz,1H),4.75(d,J＝13.4Hz,1H),4.55(s,1H),4.24(d,J＝3.2Hz,1H),3.84(s,3H),2.84-2.67(m,2H),2.37(s,1H).
13C NMR(100MHz,CDCl3)δ174.3,171.9,159.1,136.4,136.0,134.1,131.6,129.6,128.6,128.5,128.3,127.9,127.8,113.7,69.7,60.5,58.7,55.3,42.6,39.3.IR(film)v(cm-1)3365,2942,2346,1735,1680,1610,1511,1247,1143,1093,1032,940.[α]D 25＝+21.8(c 1.27,CH2Cl2).The ee value was 94％,tR(minor)＝15.29min,tR(major)＝25.28min(Chiralcel AS-H,λ＝205nm,iPrOH/hexane＝20:80,flow rate＝1mL/min).
Characterization data for Compound 3i
Figure GDA0003510603650000111
1H NMR(400MHz,CDCl3)δ7.38(d,J＝8.2Hz,2H),7.32(d,J＝3.3Hz,3H),7.25-7.14(m,3H),7.06(s,1H),6.94(t,J＝7.8Hz,1H),6.83(d,J＝8.4Hz,2H),6.73(d,J＝7.6Hz,1H),4.91(d,J＝13.4Hz,1H),4.80(d,J＝13.2Hz,1H),4.55(s,1H),4.23(d,J＝4.2Hz,1H),3.80(s,3H),2.80-2.69(m,2H),2.51(s,1H).
13C NMR(100MHz,CDCl3)δ174.2,171.9,159.0,140.2,136.0,134.1,131.1,129.7,129.0,128.7,128.6,128.2,127.9,127.8,125.9,113.7,69.7,60.6,58.7,58.6,55.3,55.2,42.6,39.4.IR(film)v(cm-1)3352,3040,2935,1735,1680,1609,1510,1430,1247,1142,1031,924.[α]D 25＝+18.7(c 1.13,CH2Cl2).The ee value was 94％,tR(minor)＝7.20min,tR(major)＝11.18min(Chiralcel AD-H,λ＝205nm,iPrOH/hexane＝50:50,flow rate＝1mL/min).
Characterization data for Compound 3j
Figure GDA0003510603650000112
1H NMR(400MHz,CDCl3)δ7.42(d,J＝8.4Hz,2H),7.31(d,J＝4.2Hz,3H),7.17-7.13(m,4H),6.86(d,J＝8.4Hz,2H),6.73(d,J＝8.2Hz,2H),4.95(d,J＝13.4Hz,1H),4.75(d,J＝13.4Hz,1H),4.55(s,1H),4.24(d,J＝3.0Hz,1H),3.84(s,3H),2.87-2.67(m,2H),2.15(s,1H).
13C NMR(100MHz,CDCl3)δ174.2,171.9,159.2,137.0,136.0,131.6,131.5,130.0,128.6,128.3,127.9,127.9,122.4,113.8,69.8,60.5,58.8,58.7,55.3,55.2,42.6,39.4.IR(film)v(cm-1)3353,2939,1734,1678,1610,1510,1251,1174,1141,1102,1028,809.[α]D 25＝+18.0(c 0.63,CH2Cl2).The ee value was 96％,tR(minor)＝8.24min,tR(major)＝16.08min(Chiralcel AD-H,λ＝205nm,iPrOH/hexane＝50:50,flow rate＝1mL/min).
Characterization data for Compound 3k
Figure GDA0003510603650000121
1H NMR(400MHz,CDCl3)δ7.82(d,J＝8.2Hz,1H),7.73(d,J＝8.2Hz,1H),7.62(d,J＝8.6Hz,1H),7.46-7.42(m,3H),7.31-7.19(m,3H),7.11(t,J＝7.6Hz,2H),7.04(t,J＝7.8Hz,3H),6.95(t,J＝7.6Hz,1H),6.87(d,J＝8.4Hz,2H),5.53(s,1H),5.03(d,J＝13.4Hz,1H),4.83(d,J＝13.4Hz,1H),4.30(d,J＝4.8Hz,1H),3.84(s,3H),2.99-2.95(m,1H),2.86(d,J＝11.8Hz,1H),2.03(s,1H).
13C NMR(100MHz,CDCl3)δ174.5,172.9,159.1,135.9,134.0,133.7,132.4,131.5,128.8,128.7,128.6,127.8,127.7,125.9,125.6,125.4,124.5,123.5,113.8,64.8,64.7,60.5,58.8,58.7,55.3,55.2,42.7,39.1.IR(film)v(cm-1)3387,2940,1733,1678,1612,1511,1323,1246,1143,1033,785.[α]D 25＝+17.9(c 0.62,CH2Cl2).The ee value was 94％,tR(minor)＝19.29min,tR(major)＝20.38min(Chiralcel AD-H,λ＝205nm,iPrOH/hexane＝50:50,flow rate＝0.5mL/min).
Characterization data for Compound 3l
Figure GDA0003510603650000122
1H NMR(400MHz,CDCl3)δ7.78(d,J＝7.8Hz,1H),7.55-7.40(m,7H),7.35-7.23(m,4H),7.18(d,J＝7.4Hz,2H),6.95(d,J＝8.4Hz,1H),6.84(d,J＝8.6Hz,2H),4.98(d,J＝13.4Hz,1H),4.84(d,J＝13.6Hz,1H),4.74(s,1H),4.30(d,J＝4.8Hz,1H),3.84(s,3H),2.87-2.83(m,1H),2.77(d,J＝11.8Hz,1H),2.48(s,1H).
13C NMR(100MHz,CDCl3)δ174.5,172.2,159.1,136.2,135.1,133.2,132.9,131.4,128.4,128.3,128.2,128.1,127.8,127.7,127.5,126.3,126.1,125.3,113.8,70.9,60.6,58.9,55.2,42.7,39.0.IR(film)v(cm-1)3352,3036,2946,2251,1732,1676,1608,1503,1436,1326,1026,921.[α]D 25＝+21.23(c 1.42,CH2Cl2).The ee value was 96％,tR(minor)＝10.48min,tR(major)＝14.76min(Chiralcel AD-H,λ＝205nm,iPrOH/hexane＝50:50,flow rate＝1mL/min).
Characterization data for Compound 3m
Figure GDA0003510603650000131
1H NMR(400MHz,CDCl3)δ7.44(d,J＝8.4Hz,2H),7.28-7.22(m,2H),7.12-7.06(m,3H),7.01-6.94(m,2H),6.89-6.81(m,4H),4.97(d,J＝13.2Hz,1H),4.80(d,J＝13.6Hz,1H),4.47(s,1H),4.26(d,J＝4.8Hz,1H),3.82(s,3H),2.83-2.78(m,1H),2.72(d,J＝12.0Hz,1H),2.48(brs,1H).
13C NMR(100MHz,CDCl3)δ174.3,172.0,163.4,161.0,159.1,137.3,131.9,131.5,130.2,130.1,128.9,128.6,128.5,128.3,114.6,114.4,113.7,71.4,59.9,58.8,55.3,42.7,38.7.IR(film)v(cm-1)3381,3038,2942,2539,1736,1679,1608,1512,1247,1148,1108,1028,934.[α]D 25＝+33.5(c 0.38,CH2Cl2).The ee value was 95％,tR(minor)＝9.71min,tR(major)＝17.05min(Chiralcel AD-H,λ＝205nm,iPrOH/hexane＝40:60,flow rate＝1mL/min).
Characterization data for Compound 3n
Figure GDA0003510603650000132
1H NMR(400MHz,CDCl3)δ7.44(d,J＝8.4Hz,2H),7.23(d,J＝7.4Hz,1H),7.08(t,J＝7.6Hz,2H),6.88-6.85(m,4H),6.73(d,J＝8.0Hz,1H),6.65(d,J＝8.4Hz,1H),6.58(s,1H),5.97-5.84(m,2H),4.96(d,J＝13.6Hz,1H),4.79(d,J＝13.2Hz,1H),4.48(s,1H),4.20(d,J＝4.4Hz,1H),3.82(s,3H),2.76-2.66(m,2H),2.53(s,1H).
13C NMR(100MHz,CDCl3)δ174.4,172.2,159.1,147.0,146.9,137.8,131.4,130.1,128.7,128.6,128.5,128.3,121.1,113.7,109.8,107.4,101.0,71.3,60.3,58.8,55.2,42.6,39.1.IR(film)v(cm-1)3364,2925,1732,1679,1611,1509,1436,1342,1245,1146,1034,929.[α]D 25＝+50.5(c 2.03,CH2Cl2).The ee value was 91％,tR(minor)＝26.72min,tR(major)＝33.79min(Chiralcel AD-H,λ＝205nm,iPrOH/hexane＝20:80,flow rate＝1mL/min).
Characterization data for Compound 3o
Figure GDA0003510603650000141
1H NMR(400MHz,CDCl3)δ7.35(d,J＝8.4Hz,2H),7.28-7.32(m,6H),7.17(t,J＝7.6Hz,2H),7.05(d,J＝7.6Hz,2H),6.86(d,J＝8.4Hz,2H),4.82(d,J＝13.2Hz,1H),4.71(d,J＝13.2Hz,1H),4.45(s,1H),4.09(d,J＝4.8Hz,1H),3.85(s,3H),3.50(d,J＝13.6Hz,1H),2.82(d,J＝14Hz,1H),2.45(brs,1H),2.18(dd,J＝12,4.2Hz,1H),2.06(d,J＝12Hz,1H).
13C NMR(100MHz,CDCl3)δ174.4,172.7,158.9,137.6,137.2,131.1,130.4,129.1,128.4,128.2,126.7,113.6,69.3,58.9,58.9,55.2,42.0,37.8,36.9.IR(film)v(cm-1)3358,3038,2934,1733,1679,1610,1511,1450,1348,1246,1175,1028,965.[α]D 25＝-99.1(c 0.66,CH2Cl2).The ee value was 96％,tR(major)＝15.44min,tR(minor)＝19.01min(Chiralcel AD-H,λ＝205nm,iPrOH/hexane＝20:80,flow rate＝1mL/min).
Characterization data for Compound 3p
Figure GDA0003510603650000142
1H NMR(400MHz,CDCl3)δ7.33(d,J＝8.4Hz,2H),7.18(t,J＝7.2Hz,1H),7.07(t,J＝7.4Hz,2H),6.95(d,J＝7.6Hz,2H),6.82(d,J＝8.4Hz,2H),4.79(s,1H),4.76-4.65(m,2H),4.15(d,J＝5.0Hz,1H),4.04(d,J＝10.8Hz,1H),3.95(d,J＝10.8Hz,1H),3.81(s,3H),2.53(dd,J＝11.8,5.2Hz,1H),2.13(d,J＝11.8Hz,1H),1.19-1.05(m,21H),0.97(d,J＝3.6Hz,1H).
13C NMR(100MHz,CDCl3)δ174.6,172.8,159.0,137.9,131.2,129.1,128.4,127.9,126.5,113.6,63.4,60.5,59.3,58.9,55.2,41.8,36.0,18.0,11.9.IR(film)v(cm-1)3377,2993,2949,2358,1724,1674,1613,1512,1460,1381,1244,1177,1079,1030,932.[α]D 25＝-41.8(c 1.92,CH2Cl2).The ee value was 95％,tR(major)＝5.74min,tR(minor)＝6.21min(Chiralcel AD-H,λ＝205nm,iPrOH/hexane＝20:80,flow rate＝1mL/min).
It should be understood that the above-described embodiments of the present invention are merely examples for clearly illustrating the present invention, and are not intended to limit the embodiments of the present invention. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither required nor exhaustive of all embodiments. Any modification, equivalent replacement, and improvement made within the spirit and principle of the present invention should be included in the protection scope of the claims of the present invention.

Claims (6)

1. A method for preparing chiral 3, 6-diazabicyclo [3.2.1] octane derivatives is characterized by comprising the following steps:
s1, stirring a silver catalyst and a chiral phosphine-amide ligand at room temperature for 1-2 hours, then adding azomethine ylide and alpha-substituted terminal olefin amide, and stirring at a certain temperature to react for 2-24 hours;
s2, adding alkali into the step S1, stirring for 1-12 h at room temperature until the reaction is complete;
s3, adding a saturated sodium chloride solution into the solution completely reacted in the step S2, and adding an extracting agent for extraction to obtain an organic phase;
s4, drying the organic phase obtained in the step S3, filtering, concentrating under reduced pressure, eluting and passing through a column to obtain a product;
the silver catalyst is one or more monovalent silver salts of silver oxide, silver carbonate, silver acetate, silver benzoate and silver fluoride;
the chiral phosphine-amide ligand structure is one of L4 or L5:
Figure FDA0003547861570000011
the alkali is one or more of 1,5, 7-triazabicyclo [4.4.0] dec-5-ene, 7-methyl-1, 5, 7-triazabicyclo [4.4.0] dec-5-ene, triethylamine, 4-dimethylaminopyridine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, cesium carbonate, potassium tert-butoxide and sodium tert-butoxide;
the chiral 3, 6-diazabicyclo [3.2.1] octane derivative has the structure as follows:
Figure FDA0003547861570000021
2. the method for preparing the chiral 3, 6-diazabicyclo [3.2.1] octane derivative of claim 1, wherein the molar ratio of azomethine ylide to the alpha-substituted terminal olefin amide is 1-2: 1.
3. The method for preparing the chiral 3, 6-diazabicyclo [3.2.1] octane derivative according to claim 1, wherein the silver catalyst is added in an amount of 2 to 4% by mole based on the α -substituted terminal olefin amide; the addition amount of the chiral phosphine-amide ligand is 2-4% of the molar amount of the alpha-substituted terminal olefin amide.
4. The method for preparing the chiral 3, 6-diazabicyclo [3.2.1] octane derivative according to claim 1, wherein the temperature in step S1 is-10 to 25 ℃.
5. The method for preparing the chiral 3, 6-diazabicyclo [3.2.1] octane derivative of claim 1, wherein the base is added in an amount of 10 to 20% by mole based on the α -substituted terminal olefin amide.
6. The chiral 3, 6-diazabicyclo [3.2.1] ring of claim 1]The preparation method of the octane derivative is characterized in that the sodium chloride solution in the step S3 is a saturated sodium chloride solution, and the extracting agent is CH2Cl2(ii) a Anhydrous Na for drying organic phase in step S42SO4Drying; the elution column adopts ethyl acetate and petroleum ether.
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CN105435845A (en) * 2015-11-18 2016-03-30 湖南工业大学 Novel multifunctional phosphine/amide ligand catalyst as well as synthesis method and application thereof

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[3+2]环加成反应及ibophyllidine类生物碱的合成研究;张琛;《中国优秀博硕士学位论文全文数据库(硕士)医药卫生科技辑》;20210215(第02期);第E079-106页 *
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