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A method for synthesizing musk extract (2r, 5r)-musclide-a1

A synthetic method and technology for synthesizing musk, applied in the preparation of organic compounds, organic chemical methods, chemical instruments and methods, etc., can solve problems such as limitations, low content, lengthy reaction routes, etc.

Inactive Publication Date: 2020-12-18
CHINA AGRI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] Although (2R,5R)-Musclide-A1 has significant pharmacological effects, its content in musk is extremely low, which limits the clinical application research of (2R,5R)-Musclide-A1
[0007] Although there are two reports on the synthesis of (2R,5R)-Musclide-A1, the existing methods have problems such as long reaction routes and expensive reaction reagents.

Method used

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  • A method for synthesizing musk extract (2r, 5r)-musclide-a1
  • A method for synthesizing musk extract (2r, 5r)-musclide-a1
  • A method for synthesizing musk extract (2r, 5r)-musclide-a1

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Experimental program
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Effect test

Embodiment 1

[0018] Synthesis of (2R,5S)-6-methyl-2-benzyloxy-6-hepten-3-yn-5-ol 3

[0019] Under argon protection, add cyclopropaneaminoalcohol chiral ligand L1 (70.2mg, 0.2mmol, 0.2equiv) into a 10mL Shrek tube, then add toluene (4mL) and (R)-3-benzyloxy-1 - Butyne 2 (480.6mg, 3.0mmol), stir well at room temperature. The mixture was cooled to 0° C., dimethyl zinc (2.5 mL, 1.2M solution in toluene, 1.5 mmol, 3 equiv) was slowly added dropwise, and stirring was continued at this temperature for 2 h. Then the temperature was lowered to -20°C, methacrolein 1 (70.1mg, 1.0mmol) was slowly added dropwise, and the reaction was stirred at -20°C for 48h. After the reaction was completed, the reaction was quenched by adding ice, and the aqueous phase was washed with Et 2 O (3×15 mL) was extracted, and the organic phases were combined. Dry over anhydrous sodium sulfate, concentrate under reduced pressure, and finally purify by silica gel column chromatography (n-hexane / ethyl acetate=5:1) to obtai...

Embodiment 2

[0021] Synthesis of (2R,5R)-6-methyl-2-benzyloxy-5-heptanol sulfate 4

[0022] At 0°C, the Pt 2 O (50.0mg, 0.22mmol) was added to a 25mL Shrek bottle, methanol (2mL) was added under a hydrogen atmosphere, compound 3 (506.0mg, 2.2mmol) was dissolved in methanol (10mL) and added to the reaction system, the reaction temperature rose to room temperature, The reaction was stirred for 8h. After the reaction was completed, it was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product of 6-methyl-2-benzyloxy-5-heptanol.

[0023] The above crude product was dissolved in THF (10 mL), sulfur trioxide pyridine complex (880.0 mg, 5.5 mmol) was added at 0°C, and the reaction was stirred at room temperature for 2 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol=10:1) to obtain (2R,5R...

Embodiment 3

[0025] Synthesis of (2R,5R)-Musclide-A1

[0026] Under hydrogen atmosphere, Pd / C (20.0 mg) and methanol (1 mL) were added to a 25 mL Shrek tube, compound 4 (100.0 mg, 0.31 mmol) was dissolved in methanol (3 mL), the above mixture was added, and the reaction was stirred for 8 h. After the reaction was complete, the reaction mixture was filtered, concentrated under reduced pressure, and finally purified by silica gel column chromatography (dichloromethane / methanol=10:1) to obtain (2R,5R)-Musclide-A1 (57.0mg, yield 81%), It is white powder. [α] D 21 =–8.5 (c 0.5, CHCl 3 ). 1 H NMR (300MHz, CD 3 OD)δ4.19–4.13(m,1H),3.74–3.68(m,1H),2.13–2.01(m,1H),1.77–1.53(m,4H),1.15(d,J=6.2Hz,3H ),0.96(d,J=5.6Hz,3H),0.93(d,J=5.6Hz,3H). 13 C NMR (75MHz, CD 3 OD) δ83.8, 67.1, 34.2, 30.4, 26.1, 21.8, 16.6, 16.3. HRMS (APCI-TOF): calcd for C 8 h 17 o 5 S[M-H] - 225.0791, found 225.0790.

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Abstract

The invention belongs to the technical field of natural product synthesis, and discloses a novel method for synthesizing musk extract (2R, 5R)-Musclide-A1. The method comprises the steps: utilizing cyclopropane-aminoalcohol chiral ligand / zinc to catalyze an addition reaction of methylacrolein 1 and (R)-3-benzyloxy-1-butyne 2 so as to obtain a compound 3, then performing reduction and sulfonation so as to obtain a compound 4, and finally performing deprotection so as to obtain the target compound (2R, 5R)-Musclide-A1. The method has the advantages of a simple synthetic route, mild reaction conditions, environmental friendliness and the like.

Description

technical field [0001] The invention belongs to the technical field of natural product synthesis, and in particular relates to a new method for synthesizing musk extract (2R, 5R)-Musclide-A1. Background technique [0002] Musk is the dry secretion of the male musk deer (Moschus moschiferus L.) sachet. It is not only a precious spice, but also a traditional Chinese medicine (Wang Yuling; Ha Chengyong Chinese Journal of Traditional Chinese Medicine 2018, 43, 3806-3810.). Moschus has multiple pharmacological effects, and can be used as cardiotonic agent, sedative and anti-inflammatory drug etc. .). Musk extract contains muskone, muskpyridine, (2R, 5R)-Musclide-A1, steroids and other active ingredients (Deng Shijun Chinese patent medicine research 1981,28-30.Kadota, S.; Orito, T.; Kikuchi , T.; Uwano, T.; Kimura, I.; Kimura, M. Tetrahedron Lett. 1991, 32, 1733-1736.). Wherein (2R,5R)-Musclide-A1 (formula 1) has cardiotonic pharmacological effect (Kimura, I.; Takamura, Y.; Uwa...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C303/24C07C305/10
CPCC07B2200/07C07C41/30C07C303/24C07C305/10C07C43/1787
Inventor 边庆花马思捷周云钟江春王敏孙效杨森
Owner CHINA AGRI UNIV
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