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Full synthesis method of 4'',5''-dihydroxyl-5-methoxyl-[6'',6''-dimethyl pyran (2'',3'':7,8)] Hirtellanine A

A technology of dimethylpyran and methoxy, applied in the direction of organic chemistry and the like, can solve the problems of difficult separation and low isomer yield, and achieve the effects of simplifying the operation process, improving the synthesis yield and reducing the cost

Inactive Publication Date: 2010-08-04
BASILEA PHARM CHINA LTD
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  • Abstract
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Problems solved by technology

Another literature report (Jain, A.C., et al., Ind.J.Chem.1985, 24B, 250~253; Sittisombut, C., et al., Chem.Pharm.Bull.2006, 54 (8), 1113 ~1118) to the synthesis of its A ring (2,2-dimethyl-2H-pyran ring) by Claisen thermal rearrangement, because the product is a pair of isomers, the separation is relatively difficult, and the required isomer yield and lower

Method used

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  • Full synthesis method of 4'',5''-dihydroxyl-5-methoxyl-[6'',6''-dimethyl pyran (2'',3'':7,8)] Hirtellanine A
  • Full synthesis method of 4'',5''-dihydroxyl-5-methoxyl-[6'',6''-dimethyl pyran (2'',3'':7,8)] Hirtellanine A
  • Full synthesis method of 4'',5''-dihydroxyl-5-methoxyl-[6'',6''-dimethyl pyran (2'',3'':7,8)] Hirtellanine A

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Experimental program
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Embodiment 1

[0034] The preparation of embodiment 1 compound 2

[0035] 5.58 grams of 2,4,6-trihydroxyacetophenone was dissolved in 50 milliliters of DMF, then at room temperature, slowly added 15.2 milliliters of boron trifluoride ether complex (purchased from Sinopharm Group, reconstituted before use) within 50 minutes under stirring. evaporated), followed by the addition of 6.95 mL of methanesulfonyl chloride in 15 mL of DMF. The reaction mixture was stirred at 90° C. for 3 hours, then cooled to room temperature, slowly poured into 120 ml of ice water with vigorous stirring, filtered, and washed with water to obtain 6.8 g of a dark yellow solid crude product. The filtrate was extracted three times with 100 mL of ethyl acetate, and the combined extracts were purified by column chromatography to obtain 4.82 g (90.3%) of compound 2 as a yellow solid. Melting point: 255°C (degradation); 1 H NMR (400MHz, Acetone-d 6 )δppm: 12.76(s, 1H), 8.07(d, J=6.0Hz, 1H), 6.39(s, 1H), 6.26(s, 1H), 6.23...

Embodiment 2

[0036] Example 2 Preparation of Compound 3

[0037] 1.08 grams of intermediate 2 were dissolved in 50 milliliters of acetone, then 2.51 grams of potassium carbonate, 2.52 grams of potassium iodide, 12 milligrams of catalyst cuprous iodide were added, and after argon was introduced, 0.71 milliliters of 3-chloro-3-methyl-1 - Butyne. Then the reaction mixture was refluxed for 3 hours, after cooling, the acetone solvent was eliminated under reduced pressure, and 40 milliliters of water was added to dissolve the solid, extracted three times with ethyl acetate, 50 milliliters each time, and the combined extracts were obtained by column chromatography 1.41 grams (95.2%) of a yellow solid product Compound 3. Melting point: 112~113℃; 1 H NMR (400MHz, CDCl 3 ) ppm: 12.47(s, 1H), 7.75(d, J=6.0Hz, 1H), 6.77(d, J=2.0Hz, 1H), 6.69(d, J=2.0Hz, 1H), 6.22(d, J =5.6Hz, 1H), 2.68(s, 1H), 1.72(s, 6H); ESI-MS m / z 245.2 ([M+1] + , 100%).

Embodiment 3

[0038] Example 3 Preparation of Compound 4

[0039] 508 mg of intermediate 3 was dissolved in 40 ml of o-xylene, and 480 mg of sodium hydride (60% dispersed in solid oil) was added, then the suspension was reacted at 130°C for 20 hours, cooled to room temperature, and dissolved in 30 ml of ice water , separated the organic layer, and the aqueous layer was neutralized with 1N dilute hydrochloric acid to pH = 5, then extracted three times with ethyl acetate, 30 ml each time, combined the extracts, and washed with brine. After dry concentration, the crude product was purified by column chromatography to afford 498 mg (98.0%) of product 4 as a yellow solid. Melting point: 139~141℃; 1 H NMR (400MHz, CDCl 3 ) ppm: 12.86(s, 1H), 7.70(d, J=6.0Hz, 1H), 6.71(d, J=10.0Hz, 1H), 6.31(s, 1H), 6.19(d, J=5.6Hz, 1H ), 5.62(d, J=10.0Hz, 1H), 1.46(s, 6H); 13 C NMR (100MHz, CDCl 3 ) ppm: 155.62, 128.49, 115.58, 111.45, 59.33, 28.55; IR(film)v max : 3441, 3070, 2976, 2926, 1655, 1628, 15...

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Abstract

The invention relates to a chemical full synthesis method of Hirtellanine A 4'',5''-dihydroxyl-5-methoxyl-[6'',6''-dimethyl pyran (2'',3'':7,8)]. the Hirtellanine A with high yield is synthesized from phloroglucinol acetophenone by the following eight steps of selective Claisen rearrangement and cyclization reaction by zones, potful boron esterification and Suzuki coupling, serial cyclization isomerization reaction induced by acid and the like . The invention has the characteristics of easily obtained raw material, simple operation and high yield, provides an effectively approach for greatly synthesizing the Hirtellanine A and is suitable for scale type industrial production.

Description

technical field [0001] The present invention relates to a chemical synthesis method of natural products, in particular to 4′, 5′-dihydroxy-5-methoxyl-[6″, 6″-dimethylpyran (2″, 3″: 7, 8)] Total synthesis of coumarone and chromone (Hirtellanine A). Background technique [0002] Hirtellanine A, chemical name: 4′, 5′-dihydroxy-5-methoxy-[6″, 6″-dimethylpyran (2″, 3″: 7, 8)] coumarone and color Ketones, the chemical structural formula is as follows: [0003] [0004] In 2009, Shou Qingyao et al. (Shou, Q.Y.; et al., Bioorg. Med. Chem. Lett. 2009, 13, 3389) extracted and isolated the stem of the leguminous plant Dahongpao (Campylotropis hirtella) for the first time. Pharmacological experiments have shown that it has a significant inhibitory effect on the proliferation of B lymphocytes and T lymphocytes, and can be used to prepare immunosuppressants or drugs for the treatment of various immune diseases such as rheumatoid arthritis, lupus erythematosus, etc., as well as for th...

Claims

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Application Information

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IPC IPC(8): C07D493/14
Inventor 沈征武郑书岩
Owner BASILEA PHARM CHINA LTD
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