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Asymmetric synthesis method for ergot alkaloids

A synthetic method and alkaloid technology, applied in the direction of asymmetric synthesis, organic chemical methods, chemical instruments and methods, etc., can solve the problems of long steps, difficulty in realizing industrial production, and no step-by-step construction of B/C/D rings, etc.

Inactive Publication Date: 2019-01-29
PEKING UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Since Woodward first completed the total synthesis of lysergic acid in 1956 [3] In the past 60 years, people have continuously completed the total synthesis of this type of natural products, but their synthetic methods are either relatively long steps, difficult to achieve industrial production, or only one or two natural products can be synthesized
Moreover, their ring formation strategy is mainly to build a C / D or B / C ring in one step, but there is no report on the construction of a B / C / D ring in one step.

Method used

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  • Asymmetric synthesis method for ergot alkaloids
  • Asymmetric synthesis method for ergot alkaloids
  • Asymmetric synthesis method for ergot alkaloids

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] The preparation of embodiment 1 compound 2

[0063] Compound 1 was dissolved in a mixed solution of ethanol and water (the ratio of absolute ethanol to water was 5:1), potassium cyanide was added, and the molar ratio of compound 1 to potassium cyanide was 1:1.1. Stir at 25°C for 4h , ethanol was evaporated under reduced pressure, the remaining mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness under reduced pressure, and the crude product was subjected to column chromatography (PE-EtOAc, 3:1). Compound 2 was isolated as a yellow solid.

[0064] The yield of this step is 75%, and the relevant analysis data are as follows:

[0065] 1 H NMR (400MHz, CDCl 3 )δ7.79(d, J=7.6Hz, 1H), 7.74(d, J=8.0Hz, 1H), 7.45(t, J=8.0Hz, 1H), 4.66(s, 2H); 13 C NMR (100MHz, CDCl 3 ) δ 133.2, 132.4, 128.7, 124.8, 115.9, 115.3, 25.5.

Embodiment 2

[0066] The preparation of embodiment 2 compound 4

[0067] Compound 2 was dissolved in 0.3M tetrahydrofuran (THF) solution, cooled to -78°C, lithium hexamethyldisilazide was added dropwise, and after stirring for 10 minutes, the THF solution of compound 3 was added dropwise to the reaction solution, dropwise After the addition was complete, the temperature was raised to 25° C., and the reaction was stirred for 4 h, then quenched by adding a saturated NaCl solution, and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The crude product was separated by column chromatography (PE-EtOAc, 6:1) to obtain compound 4 as a pale yellow oil. The molar ratio of compounds 2 and 3 to lithium hexamethyldisilazide is 1:1.1:1.1.

[0068] The yield of this step is 90%, and the relevant analysis data are as follows

[0069] 1 H NMR (400MHz, CDCl 3 )δ7.8...

Embodiment 3

[0070] The preparation of embodiment 3 compound 5

[0071] Compound 4 was dissolved in 0.2M toluene solution, the temperature was lowered to -78°C, and diisobutylaluminum hydride was added dropwise according to the molar ratio of compound 4 and diisobutylaluminum hydride being 1:1.1. React at -78°C for 30 minutes, slowly add saturated sodium bicarbonate solution dropwise at 25°C until the solid precipitates, filter with suction, wash the solid with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, filter, and evaporate to dryness under reduced pressure to obtain The crude product (aldehyde compound) was directly sent to the next step without purification.

[0072] The crude product and (R)-tert-butylsulfinamide were dissolved in 0.36M tetrahydrofuran solution, and tetraethoxytitanium (Ti(OEt) was added 4 ), the molar ratio of the crude product to tert-butylsulfinamide and tetraethoxytitanium is 1:2:2. React at 25°C for 6h, add saturated sodium chlo...

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Abstract

The invention discloses an asymmetric synthesis method for ergot alkaloids, which belongs to the technical field of chemical synthesis. According to the method, after a cheap and easily available compound 1 and compound 2 are subjected to alkylation, a cyano group is subjected to reduction to obtain a compound, then the compound and tert-butyl sulfonamide in R configuration are subjected to condensation, reduction is performed on a nitro group, an amino group is protected by utilizing an acetyl group, an Larock ring closure precursor compound is obtained by controlling chirality of zinc reagent addition by utilizing the tert-butyl sulfonamide, an intermediate compound having a 3,4-bridged ring indole structure is prepared by palladium-catalyzed Larock cyclization reaction, and starting from the intermediate compound, chiral natural products are obtained by a few steps of conversion, wherein the chiral natural products are Festuclavine, Pyroclavine, Costaclavine, epi-Costaclavine, Pibocin A, 9-Deacetoxyfumigaclavine C, Fumigaclavine G and Dihydrosetoclavine. The asymmetric synthesis method adopts a novel synthesis strategy, is high in reaction repeatability, is good in operability,and can meet needs of large-scale industrial production.

Description

technical field [0001] The invention relates to an asymmetric synthesis method of ergot alkaloids, belonging to the technical field of chemical synthesis. Background technique [0002] Ergot alkaloids contain many natural products, which are mainly derived from secondary metabolites produced by fungi of the Ergot family (such as Ergot and Endophytes) and Phytomycetes (including Aspergillus and Penicillium). This type of compound not only has a unique ergoline skeleton, but most of the compounds show good biological and pharmacological activities, and even some compounds have been widely used as clinical drugs for the treatment of Parkinson's disease, migraine, type II diabetes, hypergalactia Hyperglycemia etc. For example, pergolide (pergolide) and cabergoline (cabergolide) have a good therapeutic effect on Parkinson's, and ergonovine is used clinically to treat uterine bleeding, poor uterine involution, and menorrhagia; ergotamine can inhibit cerebral arteries. Abnormal d...

Claims

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Application Information

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IPC IPC(8): C07D457/02C07B53/00
CPCC07B53/00C07B2200/07C07D457/02Y02P20/55
Inventor 贾彦兴刘海超
Owner PEKING UNIV
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