CN115650969A - Synthetic method of alpha-substituted-beta-aminoxy substituted morpholine compound - Google Patents
Synthetic method of alpha-substituted-beta-aminoxy substituted morpholine compound Download PDFInfo
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Abstract
The invention discloses a method for synthesizing an alpha-substituted-beta-aminoxy substituted morpholine compound, belonging to the technical field of organic synthesis. The technical scheme provided by the invention has the key points that:
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a synthesis method of an alpha-substituted-beta-aminoxy substituted morpholine compound.
Background
The alpha-substituted-beta-aminoxy substituted morpholine compounds are not only important reaction intermediates in organic synthesis, but also main structural units of a plurality of natural products and antitumor drugs, and have important research values in the fields of drug synthesis, chemical biology and the like. At present, the synthesis of alpha-substituted-beta-aminoxy substituted morpholine compounds is usually completed by taking pre-functionalized chain amine as a reaction raw material and further condensing the pre-functionalized chain amine at a later stage. Although the method is reliable, the method still has the problems of difficult preparation of raw materials, harsh reaction conditions, narrow application range of substrates and the like. Therefore, the design and development of the one-pot method for directly completing the alpha-substituted-beta-aminoxy substituted morpholine structural unit from easily available simple raw materials are needed, and no related literature report is found at present. In view of this, it is of great significance to further research and develop a new efficient method for synthesizing alpha-substituted-beta-aminoxy substituted morpholine compounds from easily available simple raw materials.
Disclosure of Invention
The invention provides a synthesis method of alpha-substituted-beta-aminoxy substituted morpholine compounds, which promotes the simple and easily obtained N-aryl substituted morpholine compounds and nucleophilic reagent to perform one-pot multi-step series reaction to synthesize the alpha-substituted-beta-aminoxy substituted morpholine compounds through ammonium peroxysulfate, has the advantages of simple and convenient operation, mild conditions, wide substrate application range, high regional and diastereomeric selectivity and the like, and is suitable for industrial production.
The invention adopts the following technical scheme for solving the technical problems, and the synthesis method of the alpha-substituted-beta-aminoxy substituted morpholine compound is characterized by comprising the following specific synthesis processes: dissolving an N-aryl substituted morpholine compound 1 and a nucleophilic reagent 2 in a solvent, adding an oxyammonium salt 3 and an additive into a reaction system, and reacting at 0-50 ℃ in an air atmosphere to obtain a target product alpha-substituted-beta-aminoxy substituted morpholine compound 4, wherein the reaction equation in the synthesis process is as follows:
wherein R is 1 Is phenyl or substituted phenyl, and the substituent on the benzene ring of the substituted phenyl is fluorine, chlorine, bromine, iodine, C 1-4 Alkyl radical, C 1-4 Alkoxy, trifluoromethyl, nitro or phenyl; r 2 Is C 1-4 Alkyl or C 1-4 An alkoxy group; x - Is BF 4 - 、ClO 4 - 、PF 6 - Or OTf - ；Nu - Is acetylacetone, ethyl acetoacetate, benzoylacetone, malonate, allyltrimethylsilane, potassium phenyltrifluoroborate or substituted potassium phenyltrifluoroborate, and the substituent on the benzene ring of the substituted phenyl is C 1-4 Alkyl or C 1-4 An alkoxy group; the additive is sodium carbonate, potassium carbonate, cesium fluoride, potassium fluoride, ferrous chloride or sodium chloride.
Further defined, the solvent is ethyl acetate, tetrahydrofuran, or dichloromethane.
Further limiting, the ratio of the N-aryl substituted morpholine compound 1, the nucleophilic reagent 2, the oxyammonium salt 3 and the additive feeding substance is 1.
Compared with the prior art, the invention has the following advantages: (1) The method promotes the cascade reaction between the N-aryl substituted morpholine compound and different nucleophiles to directly synthesize the alpha-substituted-beta-aminoxy substituted morpholine compound through the oxyammonium salt, the reaction directly realizes the simultaneous selective functionalization of alpha position and beta position of the morpholine by taking the simple and easily obtained morpholine as a raw material, the operation of the whole process is simple and convenient, and no metal catalyst is needed; (2) the reaction conditions of the invention are mild; (3) The application range of the substrate is wide, the prepared target product can be used for further synthesizing a core structural unit of NK-1 receptor antagonist-L-742, 694 with an antiemetic effect, and the problems that the existing method for synthesizing alpha-substituted-beta-aminoxy substituted morpholine compounds is complicated in steps and harsh in reaction conditions are effectively solved. Therefore, the invention provides an economical and practical novel method for synthesizing the alpha-substituted-beta-aminoxy substituted morpholine compounds.
Detailed Description
The present invention is described in further detail below with reference to examples, but it should not be construed that the scope of the above subject matter of the present invention is limited to the following examples, and that all the technologies realized based on the above subject matter of the present invention belong to the scope of the present invention.
Example 1
To the reaction tube were added 1a (33mg, 0.2mmol), THF (1 mL), 2a (41. Mu.L, 0.4 mmol), and the oxyammonium salt T in that order + BF 4 - (3a, 97mg,0.4 mmol) and sodium carbonate (11mg, 0.1mmol) were stirred at 25 ℃ under an air atmosphere for 0.5h, then the reaction was quenched by addition of 10mL of saturated sodium chloride solution, extracted with ethyl acetate (10 mL. Times.3), the organic phases were combined and dried over anhydrous sodium sulfate. Filtered, spin-dried, and separated by a silica gel column (petroleum ether/ethyl acetate =3/1,v/v) to obtain a white solid product 4a (67mg, 80%,>20. The characterization data for this compound are as follows: mp 119-120 ℃. 1 H NMR(400MHz,CDCl3):δ7.24-7.20(m,2H),6.95(d,J＝8.0Hz,2H),6.78(t,J＝7.2Hz,1H),4.94(d,J＝10.8Hz,1H),4.69(d,J＝11.2Hz,1H),4.59(s,1H),4.27-4.22(m,1H),3.60-3.53(m,2H),3.35-3.32(m,1H),2.21(s,3H),1.92(s,3H),1.45-1.42(m,5H),1.28-1.14(m,8H),0.95-0.94(m,5H). 13 C{ 1 H}NMR(150MHz,CDCl 3 ):δ201.9,201.3,150.0,129.2,119.1,116.4,101.7,69.3,60.5,59.3,58.2,57.7,41.8,40.8,40.1,33.84,33.77,31.3,27.3,20.6,19.9,17.0.HRMS(ESI)m/z:[M+H] + Calcd for C 24 H 37 N 2 O 4 417.2748；Found 417.2776。
Example 2
1a (33mg, 0.2mmol), THF (1 mL), 2a (41. Mu.L, 0.4 mmol), and the oxyammonium salt T were added to the reaction tube in this order + ClO 4 - (3b, 102mg,0.4 mmol) and sodium carbonate (11mg, 0.1mmol) were stirred at 25 ℃ for 0.5h under an air atmosphere, then quenched by addition of 10mL of saturated sodium chloride solution, extracted with ethyl acetate (10 mL. Times.3), the organic phases combined and dried over anhydrous sodium sulfate. Filtering, spin-drying, and passingSilica gel column separation (petroleum ether/ethyl acetate =3/1,v/v) gave white solid product 4a (63mg, 76%,>20:1dr)。
example 3
1a (33mg, 0.2mmol), THF (1 mL), 2a (41. Mu.L, 0.4 mmol), and the oxyammonium salt T were added to the reaction tube in this order + PF 6 - (3c, 120mg,0.4 mmol) and sodium carbonate (11mg, 0.1mmol) were stirred at 25 ℃ for 0.5h under an air atmosphere, then the reaction was quenched by addition of 10mL of saturated sodium chloride solution, extracted with ethyl acetate (10 mL. Times.3), the organic phases were combined and dried over anhydrous sodium sulfate. Filtered, spin-dried, and separated by a silica gel column (petroleum ether/ethyl acetate =3/1,v/v) to give a white solid product 4a (53mg, 64%,>20:1dr)。
example 4
1a (33mg, 0.2mmol), THF (1 mL), 2a (41. Mu.L, 0.4 mmol), and the oxyammonium salt T were added to the reaction tube in this order + OTf - (3d, 122mg,0.4 mmol) and sodium carbonate (11mg, 0.1mmol) were stirred at 25 ℃ for 0.5h under an air atmosphere, then quenched by the addition of 10mL of saturated sodium chloride solution, extracted with ethyl acetate (10 mL. Times.3), the organic phases combined and dried over anhydrous sodium sulfate. Filtered, spin-dried, and separated by a silica gel column (petroleum ether/ethyl acetate =3/1,v/v) to obtain a white solid product 4a (58mg, 70%,>20:1dr)。
example 5
To the reaction tube were added 1a (33mg, 0.2mmol), THF (1 mL), 2a (41. Mu.L, 0.4 mmol), and the oxyammonium salt T in that order + BF 4 - (3a, 97mg,0.4 mmol) and cesium fluoride (30mg, 0.2mmol) were stirred at 25 ℃ under an air atmosphere for 0.5h, then quenched by the addition of 10mL of saturated sodium chloride solution, extracted with ethyl acetate (10 mL. Times.3), the organic phases combined and dried over anhydrous sodium sulfate. Filtered, spin-dried, and separated by a silica gel column (petroleum ether/ethyl acetate =3/1,v/v) to obtain a white solid product 4a (58mg, 70%,>20:1dr)。
example 6
1a (33mg, 0.2mmol), THF (1 mL), 2a (41. Mu.L, 0.4 mmol), and the oxyammonium salt T were added to the reaction tube in this order + BF 4 - (3a, 97mg,0.4 mmol) and potassium fluoride (12mg, 0.2mmol) were reacted under air at 25 ℃ with stirring for 0.5h, then 10mL of saturated sodium chloride was addedThe reaction was quenched with ethyl acetate (10 mL. Times.3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel column (petroleum ether/ethyl acetate =3/1,v/v) gave the product 4a as a white solid (47mg, 56%,>20:1dr)。
example 7
1a (33mg, 0.2mmol), THF (1 mL), 2a (41. Mu.L, 0.4 mmol), and the oxyammonium salt T were added to the reaction tube in this order + BF 4 - (3a, 97mg,0.4 mmol) and ferrous chloride (13mg, 0.1mmol) were stirred at 25 ℃ under an air atmosphere for 0.5h, then quenched by the addition of 10mL of saturated sodium chloride solution, extracted with ethyl acetate (10 mL. Times.3), the organic phases combined and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel column (petroleum ether/ethyl acetate =3/1,v/v) gave the product 4a as a white solid (43mg, 52%,>20:1dr)。
example 8
1a (33mg, 0.2mmol), THF (1 mL), 2a (41. Mu.L, 0.4 mmol), and the oxyammonium salt T were added to the reaction tube in this order + BF 4 - (3a, 97mg,0.4 mmol) and sodium chloride (12mg, 0.2mmol) were reacted under air at 25 ℃ with stirring for 0.5h, then quenched by addition of 10mL of saturated sodium chloride solution, extracted with ethyl acetate (10 mL. Times.3), the organic phases combined and dried over anhydrous sodium sulfate. Filtered, spun-dried, and separated by a silica gel column (petroleum ether/ethyl acetate =3/1,v/v) to obtain a white solid product 4a (42mg, 50%,>20:1dr)。
example 9
1a (33mg, 0.2mmol), THF (1 mL), 2a (41. Mu.L, 0.4 mmol), and the oxyammonium salt T were added to the reaction tube in this order + BF 4 - (3a, 146mg,0.6 mmol) and sodium carbonate (11mg, 0.1mmol) were stirred at 25 ℃ for 0.5h under an air atmosphere, then the reaction was quenched by addition of 10mL of saturated sodium chloride solution, extracted with ethyl acetate (10 mL. Times.3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtered, spin-dried, and separated by a silica gel column (petroleum ether/ethyl acetate =3/1,v/v) to give the product 4a (50mg, 60%,>20:1dr)。
example 10
To the reaction tube were added 1a (33mg, 0.2mmol), THF (1 mL), 2a (41. Mu.L, 0.4 mmol), and the oxyammonium salt T in that order + BF 4 - (3a, 97mg,0.4 mmol) and sodium carbonate (44mg, 0.4 mmol), the reaction is stirred at 25 ℃ for 0.5h under an air atmosphere, then quenched by addition of 10mL of saturated sodium chloride solution, extracted with ethyl acetate (10 mL. Times.3), the organic phases are combined and dried over anhydrous sodium sulfate. Filtration, spin-drying, and separation on silica gel column (petroleum ether/ethyl acetate =3/1,v/v) gave the product 4a as a white solid (60mg, 72%,>20:1dr)。
example 11
To the reaction tube were added 1a (33mg, 0.2mmol), ethyl acetate (1 mL), 2a (41. Mu.L, 0.4 mmol), and an oxyammonium salt T in this order + BF 4 - (3a, 97mg,0.4 mmol) and sodium carbonate (11mg, 0.1mmol) were stirred at 25 ℃ under an air atmosphere for 0.5h, then the reaction was quenched by addition of 10mL of saturated sodium chloride solution, extracted with ethyl acetate (10 mL. Times.3), the organic phases were combined and dried over anhydrous sodium sulfate. Filtered, spin-dried, and separated by a silica gel column (petroleum ether/ethyl acetate =3/1,v/v) to give the product 4a (65mg, 78%,>20:1dr)。
example 12
1b (36mg, 0.2mmol), THF (1 mL), 2a (41. Mu.L, 0.4 mmol), and the oxyammonium salt T were added to the reaction tube in this order + BF 4 - (3a, 97mg,0.4 mmol) and sodium carbonate (11mg, 0.1mmol) were stirred at 25 ℃ under an air atmosphere for 0.5h, then the reaction was quenched by addition of 10mL of saturated sodium chloride solution, extracted with ethyl acetate (10 mL. Times.3), the organic phases were combined and dried over anhydrous sodium sulfate. Filtered, spin-dried, and separated by a silica gel column (petroleum ether/ethyl acetate =3/1,v/v) to obtain a yellow solid product 4b (71mg, 82%,>20. The characterization data for this compound are as follows: mp 124-125 ℃. 1 H NMR(400MHz,CDCl 3 ):δ6.94-6.90(m,4H),4.80(d,J＝10.8Hz,1H),4.68(d,J＝11.2Hz,1H),4.59(s,1H),4.28-4.22(m,1H),3.62-3.53(m,2H),3.26-3.23(m,1H),2.22(s,3H),1.95(s,3H),1.46-1.43(m,5H),1.26-1.15(m,7H),0.98-0.93(m,6H). 13 C{ 1 H}NMR(150MHz,CDCl 3 ):δ201.8,201.3,156.6(d, 1 J C-F ＝236.3Hz),146.7(d, 4 J C-F ＝2.1Hz),118.0(d, 3 J C-F ＝7.7Hz),115.6(d, 2 J C-F ＝21.9Hz),101.7,69.1,60.5,59.3,59.1,57.5,42.4,40.8,40.1,33.8,33.7,31.3,27.6,20.6,19.9,17.0. 19 F{ 1 H}NMR(376MHz,CDCl 3 ):δ-125.2.HRMS(ESI)m/z:[M+H] + Calcd for C 24 H 36 FN 2 O 4 435.2654；Found 435.2672。
Example 13
1c (48mg, 0.2mmol), THF (1 mL), 2a (41. Mu.L, 0.4 mmol), and the oxyammonium salt T were added to the reaction tube in this order + BF 4 - (3a, 97mg,0.4 mmol) and sodium carbonate (11mg, 0.1mmol) were reacted under air at 25 ℃ for 0.5h with stirring, then quenched by addition of 10mL of saturated sodium chloride solution, extracted with ethyl acetate (10 mL. Times.3), the organic phases combined and dried over anhydrous sodium sulfate. Filtration, spin-drying, and separation on silica gel column (petroleum ether/ethyl acetate =3/1,v/v) gave yellow liquid product 4c (75mg, 76%,>20. The characterization data for this compound are as follows: 1 H NMR(400MHz,CDCl 3 ):δ7.33-7.29(m,2H),6.86-6.82(m,2H),4.86(d,J＝11.2Hz,1H),4.66(d,J＝10.8Hz,1H),4.60(s,1H),4.25-4.18(m,1H),3.59-3.52(m,2H),3.32-3.28(m,1H),2.22(s,3H),1.95(s,3H),1.46-0.96(m,18H). 13 C{ 1 H}NMR(150MHz,CDCl 3 ):δ201.6,201.1,149.1,132.0,117.8,111.0,101.6,69.1,60.5,59.3,58.0,57.6,42.1,40.8,40.1,33.81,33.76,31.2,27.6,20.6,19.9,16.9.HRMS(ESI)m/z:[M+H] + Calcd for C 24 H 36 BrN 2 O 4 495.1853；Found 495.1852。
example 14
1d (46mg, 0.2mmol), THF (1 mL), 2a (41. Mu.L, 0.4 mmol), oxygen were added to the reaction tube in this orderAmmonium salt T + BF 4 - (3a, 97mg,0.4 mmol) and sodium carbonate (11mg, 0.1mmol) were reacted under air at 25 ℃ for 0.5h with stirring, then quenched by addition of 10mL of saturated sodium chloride solution, extracted with ethyl acetate (10 mL. Times.3), the organic phases combined and dried over anhydrous sodium sulfate. Filtration, spin-drying, and separation on silica gel column (petroleum ether/ethyl acetate =3/1,v/v) gave the yellow solid product 4d (77mg, 80%,>20. The characterization data for this compound are as follows: mp 154-155 ℃. 1 H NMR(400MHz,CDCl 3 ):δ7.47(d,J＝8.8Hz,2H),6.99(d,J＝8.8Hz,2H),5.00(d,J＝11.2Hz,1H),4.69(d,J＝10.8Hz,1H),4.63(s,1H),4.26-4.20(m,1H),3.62-3.56(m,2H),3.45-3.41(m,1H),2.24(s,3H),1.98(s,3H),1.45-0.91(m,18H). 13 C{ 1 H}NMR(150MHz,CDCl 3 ):δ201.4,200.9,152.4,126.6(q, 4 J C-F ＝3.3Hz),124.7(q, 1 J C-F ＝269.1Hz),120.4(q, 2 J C-F ＝32.7Hz),115.0,101.6,68.9,60.6,59.4,57.7,41.8,40.8,40.1,33.8,31.2,27.7,20.5,19.7,16.9. 19 F{ 1 H}NMR(376MHz,CDCl 3 ):δ-61.4.HRMS(ESI)m/z:[M+H] + Calcd for C 25 H 36 F 3 N 2 O 4 485.2622；Found 485.2612。
Example 15
1e (48mg, 0.2mmol), THF (1 mL), 2a (41. Mu.L, 0.4 mmol), and the oxyammonium salt T were added to the reaction tube in this order + BF 4 - (3a, 97mg,0.4 mmol) and sodium carbonate (11mg, 0.1mmol) were reacted under air at 25 ℃ for 0.5h with stirring, then quenched by addition of 10mL of saturated sodium chloride solution, extracted with ethyl acetate (10 mL. Times.3), the organic phases combined and dried over anhydrous sodium sulfate. Filtered, spin-dried, and separated by a silica gel column (petroleum ether/ethyl acetate =3/1,v/v) to give a yellow liquid product 4e (66mg, 67%,>20. The characterization data for this compound are as follows: 1 H NMR(400MHz,CDCl 3 ):δ7.56-7.47(m,4H),7.39(t,J＝8.0Hz,2H),7.27(t,J＝7.6Hz,1H),7.04-7.01(m,2H),4.98(d,J＝10.8Hz,1H),4.70(d,J＝11.2Hz,1H),4.62(s,1H),4.30-4.24(m,1H),3.64-3.38(m,3H),2.23(s,3H),1.97(s,3H),1.59-0.86(m,18H). 13 C{ 1 H}NMR(150MHz,CDCl 3 ):δ201.9,201.4,149.4,140.8,131.8,128.8,128.7,127.8,126.4,116.5,101.7,69.4,60.6,59.4,58.1,57.8,42.0,40.8,40.2,33.8,31.3,27.4,20.6,19.9,17.0.HRMS(ESI)m/z:[M+H] + Calcd for C 30 H 41 N 2 O 4 493.3061；Found 493.3067。
example 16
1f (44mg, 0.2mmol), THF (1 mL), 2a (41. Mu.L, 0.4 mmol), and the oxyammonium salt T were added to the reaction tube in this order + BF 4 - (3a, 97mg,0.4 mmol) and sodium carbonate (11mg, 0.1mmol) were stirred at 25 ℃ under an air atmosphere for 0.5h, then the reaction was quenched by addition of 10mL of saturated sodium chloride solution, extracted with ethyl acetate (10 mL. Times.3), the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, spin-drying, and separation on silica gel column (petroleum ether/ethyl acetate =3/1,v/v) gave yellow liquid product 4f (68mg, 72%,>20. The characterization data for this compound are as follows: 1 H NMR(400MHz,CDCl 3 ):δ7.24(dd,J 1 ＝6.8Hz,J 2 ＝2.0Hz,2H),6.89(d,J＝8.8Hz,2H),4.88(d,J＝10.8Hz,1H),4.69(d,J＝10.8Hz,1H),4.57(s,1H),4.28-4.27(m,1H),3.58-3.51(m,2H),3.30-3.27(m,1H),2.21(s,3H),1.94(s,3H),1.44-0.88(m,27H). 13 C{ 1 H}NMR(150MHz,CDCl 3 ):δ202.1,201.5,147.9,142.2,125.9,116.5,101.8,69.4,60.5,59.3,59.0,57.6,41.8,40.8,40.1,33.9,33.8,31.4,31.2,27.2,20.6,19.8,17.0.HRMS(ESI)m/z:[M+H] + Calcd for C 28 H 45 N 2 O 4 473.3374；Found 473.3387。
example 16
1g (42mg, 0.2mmol), THF (1 mL), 2a (41. Mu.L, 0.4 mmol), and the oxyammonium salt T were added to the reaction tube in this order + BF 4 - (3a, 97mg,0.4 mmol) and sodium carbonate (11mg, 0.1mmol) were reacted under air at 25 ℃ for 0.5h with stirring, then quenched by addition of 10mL of saturated sodium chloride solution, extracted with ethyl acetate (10 mL. Times.3), the organic phases combined and dried over anhydrous sodium sulfate. Filtration, spin-drying, and separation on a silica gel column (petroleum ether/ethyl acetate =3/1,v/v) to give 4g (55mg, 60%,>20. The characterization data for this compound are as follows: 1 H NMR(400MHz,CDCl 3 ):δ7.76(t,J＝2.4Hz,1H),7.62(dd,J1＝8.0Hz,J2＝1.2Hz,1H),7.38(t,J＝8.0Hz,1H),7.30-7.27(m,1H),4.97(d,J＝11.2Hz,1H),4.71(d,J＝11.2Hz,1H),4.65(s,1H),4.27-4.24(m,1H),3.63-3.60(m,2H),3.49-3.45(m,1H),2.26(s,3H),2.04(s,3H),1.44-0.85(m,18H). 13 C{ 1 H}NMR(150MHz,CDCl 3 ):δ201.1,200.7,150.9,149.3,129.9,121.7,113.6,109.6,101.6,68.7,60.6,59.4,58.2,57.4,42.0,40.7,40.1,33.8,31.2,28.0,20.5,19.6,16.9.HRMS(ESI)m/z:[M+H] + Calcd for C 24 H 36 N 3 O 6 462.2599；Found 462.2602。
example 17
To the reaction tube were added 1a (33mg, 0.2mmol), THF (1 mL), 2b (51. Mu.L, 0.4 mmol), and the oxyammonium salt T in that order + BF 4 - (3a, 97mg,0.4 mmol) and sodium carbonate (11mg, 0.1mmol) were reacted under air at 25 ℃ for 0.5h with stirring, then quenched by addition of 10mL of saturated sodium chloride solution, extracted with ethyl acetate (10 mL. Times.3), the organic phases combined and dried over anhydrous sodium sulfate. Filtration, spin-drying, silica gel column separation (petroleum ether/ethyl acetate =3/1,v/v) afforded the product as a yellow liquid for 4h (71mg, 80%,>20. The characterization data for this compound are as follows: 1 H NMR(400MHz,CDCl 3 ):δ7.21-7.17(m,2H),6.90(d,J＝8.0Hz,2H),6.73(t,J＝7.2Hz,1H),4.85(d,J＝10.8Hz,1H),4.76(s,1H),4.44(d,J＝11.2Hz,1H),4.34-4.27(m,1H),3.91-3.87(m,1H),3.68-3.59(m,3H),3.35-3.32(m,1H),2.21(s,3H),1.45-0.87(m,21H). 13 C{ 1 H}NMR(150MHz,CDCl 3 ):δ200.5,167.1,150.4,128.9,118.6,115.9,102.0,61.6,59.9,58.26,58.23,41.3,40.8,40.2,34.0,33.8,29.9,20.6,19.7,17.0,13.7.HRMS(ESI)m/z:[M+H] + Calcd for C 25 H 39 N 2 O 5 447.2853；Found 447.2846。
example 18
1a (33mg, 0.2mmol), THF (1 mL), 2c (46. Mu.L, 0.4 mmol), and the oxyammonium salt T were added to the reaction tube in this order + BF 4 - (3a, 97mg,0.4 mmol) and sodium carbonate (11mg, 0.1mmol) were reacted under air at 25 ℃ for 0.5h with stirring, then quenched by addition of 10mL of saturated sodium chloride solution, extracted with ethyl acetate (10 mL. Times.3), the organic phases combined and dried over anhydrous sodium sulfate. Filtration, spin-drying, and separation on silica gel column (petroleum ether/ethyl acetate =3/1,v/v) gave yellow liquid product 4i (64mg, 71%,>20. The characterization data for this compound are as follows: 1 H NMR(400MHz,CDCl 3 ):δ7.21(t,J＝8.0Hz,2H),6.80(d,J＝8.8Hz,2H),6.77-6.73(m,1H),4.93(s,1H),4.84(d,J＝10.8Hz,1H),4.33-4.27(m,2H),3.71(s,3H),3.66-3.60(m,2H),3.31-3.26(m,4H),1.47-0.93(m,18H). 13 C{ 1 H}NMR(100MHz,CDCl 3 ):δ167.9,167.3,150.1,129.0,118.8,116.0,101.7,60.5,59.4,58.8,58.3,52.6,52.1,51.4,41.1,40.8,40.2,34.0,33.8,20.6,19.8,17.0.HRMS(ESI)m/z:[M+H] + Calcd for C 24 H 37 N 2 O 6 449.2646；Found 449.2634。
example 19
1h (40mg, 0.2mmol), THF (1 mL), 2d (65mg, 0.4 mmol), and the oxyammonium salt T were added to the reaction tube in this order + BF 4 - (3a, 97mg,0.4 mmol) and sodium carbonate (11mg, 0.1mmol) were reacted under air at 25 ℃ for 0.5h with stirring, then quenched by addition of 10mL of saturated sodium chloride solution, extracted with ethyl acetate (10 mL. Times.3), the organic phases combined and dried over anhydrous sodium sulfate. Filtered, spin-dried, and separated by a silica gel column (petroleum ether/ethyl acetate =3/1,v/v) to obtain a yellow liquid product 4j (60mg, 59%,>20. The characterization data for this compound are as follows: 1 H NMR(400MHz,CDCl 3 ):δ7.92(d,J＝7.6Hz,2H),7.57(t,J＝7.2Hz,1H),7.45(t,J＝7.2Hz,2H),7.05(d,J＝8.8Hz,2H),6.72(d,J＝8.8Hz,2H),5.53(d,J＝10.8Hz,1H),4.99(d,J＝10.4Hz,1H),4.86(s,1H),4.32-4.27(m,1H),3.59-3.55(m,1H),3.40-3.33(m,1H),3.14-3.11(m,1H),2.23(s,3H),1.51-0.76(m,18H). 13 C{ 1 H}NMR(150MHz,CDCl 3 ):δ200.8,193.8,149.4,137.1,133.8,129.1,128.7,128.6,123.7,117.3,102.2,61.6,60.7,60.5,59.4,57.7,41.8,40.8,40.2,33.8,30.4,27.0,20.6,19.5,17.0.HRMS(ESI)m/z:[M+H] + Calcd for C 29 H 38 ClN 2 O 4 513.2515；Found 513.2516。
example 20
1a (33mg, 0.2mmol), THF (1 mL), 2e (86mg, 0.4mmol), and the oxyammonium salt T were added to the reaction tube in this order + BF 4 - (3a, 97mg,0.4 mmol) and sodium carbonate (11mg, 0.1mmol) were reacted under air at 25 ℃ for 0.5h with stirring, then quenched by addition of 10mL of saturated sodium chloride solution, extracted with ethyl acetate (10 mL. Times.3), the organic phases combined and dried over anhydrous sodium sulfate. Filtered, spun-dried, and separated by a silica gel column (petroleum ether/ethyl acetate =5/1,v/v) to give a yellow liquid product 4k (42mg, 50%,>20. The characterization data for this compound are as follows: 1 H NMR(400MHz,CDCl 3 ):δ7.29(d,J＝8.8Hz,2H),7.23-7.17(m,2H),6.80-6.75(m,5H),5.29(d,J＝2.4Hz,1H),4.81(d,J＝2.0Hz,1H),4.20-4.16(m,1H),3.96-3.93(m,1H),3.75(s,3H),3.43-3.40(m,2H),1.51-1.44(m,5H),1.32-1.27(m,4H),1.11(br s,6H),0.99(br s,3H). 13 C{ 1 H}NMR:δ158.7,150.4,131.2,129.1,128.8,118.9,115.9,113.7,105.2,62.7,61.6,60.6,59.4,55.3,44.4,40.5,40.1,34.2,33.8,20.8,20.1,17.2.HRMS(ESI)m/z:[M+H] + Calcd for C 26 H 37 N 2 O 3 425.2799；Found 425.2790。
example 21
To the reaction tube were added 1a (33mg, 0.2mmol), THF (1 mL), 2f (64. Mu.L, 0.4 mmol), and the oxyammonium salt T in that order + BF 4 - (3a, 97mg,0.4 mmol) and sodium carbonate (11mg, 0.1mmol) were stirred at 25 ℃ under an air atmosphere for 0.5h, then the reaction was quenched by addition of 10mL of saturated sodium chloride solution, extracted with ethyl acetate (10 mL. Times.3), the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel column (petroleum ether/ethyl acetate =5/1,v/v) gave 4l (39mg, 54%,>20. The characterization data for this compound are as follows: mp 73-74 ℃. 1 H NMR(400MHz,CDCl 3 ):δ7.28-7.23(m,2H),6.85(d,J＝8.0Hz,2H),6.81-6.78(m,1H),5.76-5.66(m,1H),5.10-5.01(m,2H),4.98(s,1H),4.28-4.22(m,1H),4.05-4.01(m,1H),3.74-3.70(m,1H),3.31-3.17(m,2H),2.52-2.44(m,1H),2.24-2.18(m,1H),1.50-1.13(m,18H). 13 C{ 1 H}NMR(150MHz,CDCl 3 ):δ150.0,135.0,129.3,118.6,117.9,115.1,102.0,60.4,59.3,59.2,58.5,41.3,40.6,40.1,34.3,33.9,31.8,20.8,20.2,17.1.HRMS(ESI)m/z:[M+H] + Calcd for C 22 H 35 N 2 O 2 359.2693；Found 359.2689。
Example 22
1a (33mg, 0.2mmol), THF (1 mL), 2a (41. Mu.L, 0.4 mmol), oxoammonium salt 3e (109mg, 0.4 mmol) and sodium carbonate (11mg, 0.1mmol) were added in this order to a reaction tube, and the reaction was stirred at 25 ℃ for 0.5h under an air atmosphere, followed by addition of 10mL of saturatedThe reaction was quenched with sodium chloride solution, extracted with ethyl acetate (10 mL. Times.3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtered, spin-dried, and separated by a silica gel column (petroleum ether/ethyl acetate =3/1,v/v) to obtain a yellow liquid product 4m (75mg, 84%,>20. The characterization data for this compound are as follows: 1 H NMR(400MHz,CDCl 3 ):δ7.22(t,J＝7.6Hz,2H),6.94(d,J＝8.0Hz,2H),6.78(t,J＝7.2Hz,1H),4.93(d,J＝11.2Hz,1H),4.68(d,J＝10.8Hz,1H),4.59(s,1H),4.28-4.21(m,1H),4.61-3.54(m,2H),3.40-3.29(m,5H),2.21(s,3H),1.93(s,3H),1.87-1.84(m,2H),1.38-1.19(m,8H),1.01(s,3H),1.98(s,3H). 13 C{ 1 H}NMR(150MHz,CDCl 3 ):δ201.9,201.3,150.0,129.2,119.2,116.3,101.8,71.4,69.2,60.9,59.6,58.3,57.8,55.8,45.5,44.8,41.7,34.0,33.9,31.2,27.4,21.6,20.9.HRMS(ESI)m/z:[M+H] + Calcd for C 25 H 39 N 2 O 5 447.2853；Found 447.2852。
example 23
1a (33mg, 0.2mmol), THF (1 mL), 2a (41. Mu.L, 0.4 mmol), oxyammonium salt 3f (104mg, 0.4 mmol) and sodium carbonate (11mg, 0.1mmol) were added to the reaction tube in this order, and the reaction was stirred at 25 ℃ for 0.5h under an air atmosphere, followed by quenching with 10mL of saturated sodium chloride solution, extraction with ethyl acetate (10 mL. Times.3), combination of organic phases and drying over anhydrous sodium sulfate. Filtration, spin-drying, and separation on silica gel column (petroleum ether/ethyl acetate =3/1,v/v) gave 4n (67mg, 77%,>20. The characterization data for this compound are as follows: 1 H NMR(400MHz,CDCl 3 ):δ7.22(t,J＝7.6Hz,2H),6.94(d,J＝8.0Hz,2H),6.78(t,J＝7.2Hz,1H),4.93(d,J＝11.2Hz,1H),4.68(d,J＝10.8Hz,1H),4.59(s,1H),4.28-4.22(m,1H),4.14-4.09(m,1H),3.61-3.54(m,2H),3.36-3.33(m,1H),2.22(s,3H),2.03(s,1H),1.94(s,3H),1.88-1.78(m,2H),1.45-1.39(m,2H),1.27(s,3H),1.18(s,3H),1.00(s,3H),0.97(s,3H). 13 C{ 1 H}NMR(150MHz,CDCl 3 ):δ202.0,201.3,149.9,129.2,119.3,116.3,101.8,69.2,62.8,61.0,59.7,58.4,57.7,49.1,48.4,41.7,33.9,33.8,31.2,27.4,21.5,20.8.HRMS(ESI)m/z:[M+H] + Calcd for C 24 H 37 N 2 O 5 433.2697；Found 433.2695。
example 24
To the reaction tube were added 4k (64mg, 0.15mmol), THF (2 mL), H in that order 2 O (3 mL), acOH (2 mL), and zinc powder (96mg, 1.5 mmol) were stirred at 25 ℃ for 1h under an air atmosphere, and then zinc powder (96mg, 1.5 mmol) was added to the reaction system and stirred at 70 ℃ for 2h under an air atmosphere. The reaction was then quenched with aqueous sodium hydroxide, extracted with ethyl acetate (10 mL × 3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel column (petroleum ether/ethyl acetate =2/1,v/v) gave product 5 as a yellow liquid (24mg, 56%). The characterization data for this compound are as follows: 1 H NMR(400MHz,CDCl 3 ):δ7.25-7.15(m,4H),6.90-6.87(m,3H),6.76-6.74(m,2H),5.20-5.14(m,1H),4.35-4.34(m,1H),4.20-3.88(m,2H),3.72(s,3H),3.42-3.07(m,3H). 13 C{ 1 H}NMR(100MHz,CDCl 3 ):δ158.9,150.5,130.7,129.8,129.0,121.5,120.1,119.4,113.8,113.5,95.3,65.8,61.7,55.1,47.6.HRMS(ESI)m/z:[M+H] + Calcd for C 17 H 20 NO 3 286.1438；Found 286.1438。
compound 5 can be further synthesized into a core structural unit with antiemetic NK-1 receptor antagonist-L-742,694 via a three-step reaction reported in the following literature (ZHao, G.; canterbury, D.P.; taylor, A.P.; cheng, X.; mikochik, P.; bagley, S.W.; tong, R.Org.Lett.2020,22,458 He, Y. -P.; wu, H.; wang, Q.; zhu J.J.Am.Chem.Soc.2021,143,7320.).
The foregoing embodiments have described the general principles, major features, and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are given by way of illustration of the principles of the present invention, and that various changes and modifications may be made without departing from the scope of the principles of the present invention, and such changes and modifications are within the scope of the present invention.
Claims (3)
1. A synthetic method of alpha-substituted-beta-aminoxy substituted morpholine compounds is characterized by comprising the following specific synthetic processes: dissolving an N-aryl substituted morpholine compound 1 and a nucleophilic reagent 2 in a solvent, adding an oxyammonium salt 3 and an additive into a reaction system, and reacting at 0-50 ℃ in an air atmosphere to obtain a target product alpha-substituted-beta-aminoxy substituted morpholine compound 4, wherein the reaction equation in the synthesis process is as follows:
wherein R is 1 Is phenyl or substituted phenyl, and the substituent on the benzene ring of the substituted phenyl is fluorine, chlorine, bromine, iodine, C 1-4 Alkyl radical, C 1-4 Alkoxy, trifluoromethyl, nitro or phenyl; r is 2 Is C 1-4 Alkyl or C 1-4 An alkoxy group; x - Is BF 4 - 、ClO 4 - 、PF 6 - Or OTf - ；Nu - Is acetylacetone, ethyl acetoacetate, benzoylacetone, malonate, allyltrimethylsilane, potassium phenyltrifluoroborate or substituted potassium phenyltrifluoroborate, and the substituent on the benzene ring of the substituted phenyl is C 1-4 Alkyl or C 1-4 An alkoxy group; the additive is sodium carbonate, potassium carbonate, cesium fluoride, potassium fluoride, ferrous chloride or sodium chloride.
2. The method for synthesizing α -substituted- β -aminoxy substituted morpholines as claimed in claim 1, wherein: the solvent is ethyl acetate, tetrahydrofuran or dichloromethane.
3. The method for synthesizing alpha-substituted-beta-aminoxy substituted morpholine compounds according to claim 1, wherein: the ratio of the N-aryl substituted morpholine compound 1, the nucleophilic reagent 2, the oxyammonium salt 3 and the additive to the feeding materials is (1-3).
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