Synthesis of tuberculosis resistant compound of arguesterol

A technology for the synthesis of Pugsterol and its synthesis method, which is applied in the direction of steroids, organic chemistry, antibacterial drugs, etc., and can solve the problem that the synthesis of Pugsterol A and Pugsterol B has not been reported, strepsterol is not easy to obtain, and cannot be synthesized in large quantities and other issues, to achieve the effect of easy access, cheap raw materials, and low cost

Inactive Publication Date: 2009-08-19
ARMY MEDICAL UNIV
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AI Technical Summary

Problems solved by technology

In 1956, Idler with △ 2 -3β-acetylcholanic acid chloride as raw material, nucleophilic addition with diisopropyl cadmium reagent to obtain the key intermediate 24-ketocholestane with a yield of 46%, and then with brominated methyltriphenylphosphine The reaction was △ 24(28) -cholestane, finally slough acetyl to synthesize 24-methylene cholesterol with a total yield of 32%, the total yield is low, and diisopropyl cadmium is not only toxic but also pollutes the environment, and cannot be synthesized in large quantities (D.R.Idler, U.H.M. Fagerlund. Marine Sterols. III. The Synthesis of 24-Me-thylene cholesterol and 25-Dehydrocholesterol. J. Am. Chem. Soc. 1956, 79, 1988-1991.)
In 2000, Kozue Nasu reported that the streptosterol (△ 24(25) -cholesterol) as raw material, by BH 3 , alkaline hydrogen peroxide to △ 24(25) -ene addition to give 24-hydroxy compound, PCC oxidation to get 24-keto compound, and then carry out Wittig reaction with methyl triphenylphosphine bromide to get △ 24(28) -compound, remove the TBS protecting group to obtain 24-methylene cholesterol, the whole route starts from 3β-tert-butyldimethylsilyl sterol, and through four steps of reaction, synthesize 24- with a total yield of 37%. Methylene cholesterol, the yield is low, and the chain sterol as raw material is not easy to obtain (Kozue Nasu, Kyoko Takahashi, Masuo Morisaki, Yoshinori Fujimoto. Stereochemical fate of C-26and C-27 during the conversion of isofucosterol to sitosterol and of24-methylenecholesterol to campesterol and dihydrobrassica-sterol in Oryza sativacell cultures. Phytochemistry. 2000, 54, 381-385.)
[0022] So far, the synthesis of Paagsterol A and Paagsterol B has not been reported

Method used

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  • Synthesis of tuberculosis resistant compound of arguesterol
  • Synthesis of tuberculosis resistant compound of arguesterol
  • Synthesis of tuberculosis resistant compound of arguesterol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0067] Preparation Δ 5 Methyl-3β-hydroxycholanate:

[0068]

[0069] Using hyodeoxycholic acid 1 as a raw material, compound Δ was synthesized in 94% yield through three steps of methyl esterification, p-toluenesulfonyl chloride esterification, nucleophilic substitution-trans elimination 5 - Methyl 3β-hydroxycholanate. Melting point: 143.4°C-144.3°C. [α] D 20 -42.3°.

[0070] The product is detected by nuclear magnetic resonance, and the data are as follows: 1 H NMR (400MHz, CDCl 3 )δ ppm : 0.679(s, 3H, 18-H 3 ), 0.925 (d, 3H, J=6.4Hz, 21-H 3 ), 1.006(s, 3H, 19-H 3 ), 3.526(m, 1H, 3α-H), 3.665(s, 3H, COOCH 3 ), 5.359 (d, 1H, J=3.6Hz, 6-H). Detected by mass spectrometry, the data are as follows: EI-MS (m / z): 388 (M), 370 (M-H 2 O). After infrared detection, the data is as follows: IR (cm -1 ): 3489 (OH), 1716 (COOCH 3 ).

Embodiment 2

[0072] Preparation of methyl 5,6-broken-3β-hydroxy-5-keto-6-aldehyde cholanate: (ozonation reaction)

[0073]

[0074] Add 3.635g of Δ to a 250ml three-necked bottle 5 -3β-Hydroxycholic acid methyl ester (9.368mmol), under nitrogen protection, add dichloromethane and anhydrous methanol mixture 150ml (CH 2 Cl 2 :MeOH=4:1), placed in a low-temperature reaction tank at -78°C. Introduce ozone for about 30 minutes, the system appears light blue, stop the infusion of ozone, wash the reaction system with nitrogen for 40 minutes, add dropwise a mixture of 8ml dimethyl sulfide and 10ml dichloromethane. After the dropwise addition was completed, it was allowed to rise to room temperature naturally, and stirred overnight. Concentrate to obtain 5.325 g of crude product. Flash column chromatography (Pet:EtOAc=1.75:1) gave 3.355 g of a colorless oily substance, yield 85%. [α] D 20 : +82.3° (C, 0.53, CHCl 3 ).

[0075] The product is detected by nuclear magnetic resonance, and th...

Embodiment 3

[0077] Preparation of B-carbo-3β, 5β-dihydroxy-6β-formaldehyde methyl cholanate: (Adol condensation reaction)

[0078]

[0079] Add 191mg of 5,6-broken-3β-hydroxyl-5-ketone-6-formaldehyde cholanoic acid methyl ester (0.453mmol) in 100ml eggplant-shaped bottle, dissolve with 8ml of dry benzene, add 1.923g of neutral alumina (18.85 mmol), stirred overnight at room temperature, filtered, washed with ethyl acetate, and concentrated to give 203 mg of crude product. Flash column chromatography (Pet:EtOAc=2.5;1) gave 177 mg of colorless crystals, yield 92%. Melting point: 93.3-94.4°C (literature mp: 95-96°C); [α] D 20 : +31.5°(C, 0.53, CHCl 3 )(Document[α] D 20 : +34.6° (C, 1.0, CHCl 3 )).

[0080] The product is detected by nuclear magnetic resonance, and the data are as follows: 1 HNMR (400MH Z , CDCl 3)δ ppm : 0.717(s, 3H, 18-H 3 ), 0.925 (d, 3H, J=6.4Hz, 21-H 3 ), 0.93(s, 3H, 19-H 3 ), 3.636(s, 1H, 6-H), 3.660(s, 3H, COOCH 3 ), 4.119 (m, 1H, 3α-H), 9.698 (d, J=3...

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Abstract

The invention relates to a method for synthesizing parguesterol A and parguesterol B. The method comprises the following steps: performing reactions of methyl esterification, p-toluene sulfonic acid esterification, SN2 nucleophilic substitution, E1 elimination reaction by a three-step one-pot process, ozonization, intramolecular aldol condensation, methylal protection, dimethyl tert-butyl silicon-based protection, isopropylation, olefination reaction, deprotection, intramolecular dehydration and the like on hyodeoxycholic acid to synthesize the parguesterol A and the parguesterol B. The method has the advantages of cheap and available raw materials, short synthetic route, high yield, low cost and mild reaction condition, and being suitable for industrialized production. The parguesterol A and the parguesterol B have effect of inhibiting mycobacterium tuberculosis and can be used for treating tuberculosis.

Description

technical field [0001] The invention relates to a method for efficiently synthesizing anti-tubercle bacillus compounds Pagsterol A and Pagsterol B, in particular, a method for efficiently synthesizing Pagsterol A and Pagsterol B from hyodeoxycholic acid. Background technique [0002] Natural products have been an inexhaustible source of structural diversity and highly bioactive compounds. In the process of searching for new anti-Mycobacterium tuberculosis compounds, two Mycobacterium tuberculosis inhibitors with novel structures—paagsterol A and B attracted our attention. In 2007, Xiamei Wei reported that the activity of anti-tuberculosis bacilli was oriented, and it was isolated and purified from the methanol-chloroform extract of Svenzea zeai in La Parguera Bay (Puerto Rico), Puerto Rico (Puerto Rico), Caribbean Sea. Obtain 3.5mg of Parguesterol A (Parguesterol A, 0.007% yield) and 4.5mg of Parguesterol B (Parguesterol B, 0.009% yield), through 2D NMR, IR, UV and MS spect...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J61/00A61P31/06
CPCY02P20/55
Inventor 周向东马婷徐长荣
Owner ARMY MEDICAL UNIV
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