CN1078237A - Steroidal artemisinin - Google Patents

Steroidal artemisinin Download PDF

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CN1078237A
CN1078237A CN 93112358 CN93112358A CN1078237A CN 1078237 A CN1078237 A CN 1078237A CN 93112358 CN93112358 CN 93112358 CN 93112358 A CN93112358 A CN 93112358A CN 1078237 A CN1078237 A CN 1078237A
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artemisinin
steroidal
compound
chch
product
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CN1033274C (en
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戎娅菁
吴毓林
叶斌
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Shanghai Institute of Organic Chemistry of CAS
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Shanghai Institute of Organic Chemistry of CAS
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Abstract

The present invention designs and synthesizes the new analog of artemisinin of a class, and it is with 1,2 of Artemisinin, and 4-three  alkane efficient parts are attached to a class steroidal artemisinin that forms in the steroidal molecule.Because the introducing of steroidal increases the fat-soluble of Artemisinin greatly, thereby can improve the effect of medicine such as antimalarial disease.Steroidal artemisinin also has unique physiologically active, opens the application prospect that has expanded artemisinin-based drug.

Description

Steroidal artemisinin
The invention belongs to the Sauerstoffatom is the heterogeneous ring compound of ring hetero atom, is an analog derivative that belongs to Artemisinin specifically.
Artemisinin is the most effective antimalarial drug now, but yet has some deficiencies, and as fat-soluble not good enough, this just influences the application of Artemisinin as antimalarial agent etc.Fat-soluble in order to improve it, more help entering in the red corpuscle, improve recognition capability, and make it to have unique physiologically active site of action, design and synthesize the popular research topic that the new artemisinin derivative of a class is various countries, world today scientist.
The objective of the invention is fat-soluble steroidal molecule and Artemisinin molecule are combined, design and synthesize a class steroidal artemisinin.
The present invention is the new analog of artemisinin of a class, is with 1,2 of Artemisinin, and 4-trioxane efficient part is attached to a class steroidal artemisinin that forms in the steroidal molecule.Its chemical formulation is as follows:
Figure 931123585_IMG4
In the formula:
X is H 2, O,
Y is CH 2, CHCH 3
The synthetic method of steroidal artemisinin of the present invention is shown in following reaction formula:
Figure 931123585_IMG6
(continuous videing infra)
Figure 931123585_IMG7
Steroidal artemisinin of the present invention synthetic is to be raw material with the cholesterol, by 11 steps react compound 12(X=H 2, Y=CH 2), can get compound 13(X=O, Y=CH by oxidation again with 12 2), continue reduction again with 13 and can get compound 14
Figure 931123585_IMG8
, Y=CH 2).
11 step reactions steps are as follows: cholesterol 1 usefulness monoperphthalic acid magnesium (MMPP) oxidation, Stereoselective gets compound 2,2 with allyl bromide 98 Grignard reagent reacting generating compound 3, then can change into ketone to hydroxyl oxygen and can be oxidized to sour reagent N aIO to terminal olefin again with one 4-RnCl 3One step was oxidized to compound 4 to 3; 4 esterifications quantitatively generate compound 5; generate compound 6 with Catalyzed by p-Toluenesulfonic Acid in the reflux in toluene dehydration again; the α type that is configured as of its 6 side chains; 6 get compound 7 with palladium black as catalyst hydrogenation in pyridine; carbonyl-protection with 7 get up again ester group is reduced compound 8; 8 Yu Geshi reagent reacts generate compound 9; 9 dewater compound 10; 10 through ozonize dewater again compound 11; 11 are dissolved in methylene dichloride; add photosensitizers, logical oxygen shines as light source light with sodium lamp at-78 ℃; add TMSOTf(trifluoromethanesulfonic acid trimethylsilyl group) reset close encircle product steroidal artemisinin compound 12, α configuration 12(α is arranged) and beta comfiguration 12(β).
Compound 13(α) and 13(β) can be by with corresponding 12(α) and 12(β) use NaIO 4Oxidation obtains, with 13(β) continue promptly to get compound 14(β with sodium borohydride reduction).
In second step reaction of above-mentioned 11 step reactions steps, to use alkene butyl bromide Grignard reagent instead with the allyl bromide 98 Grignard reagent of compound 2 reactions, other step adopts the method for similar synthetic compound 12,13 and 14 can get compound 15(α) and 15(β) (X=H 2, Y=CHCH 3), 16(α) and 16(β) (X=O, Y=CHCH 3) and 17(β)
Figure 931123585_IMG9
Y=CHCH 3).
Figure 931123585_IMG10
The advantage of steroidal artemisinin of the present invention is first with 1 of Artemisinin, 2,4-trioxane efficient part and steroid backbone combine, because the introducing of steroidal structure, increase the fat-soluble of Artemisinin greatly, more help entering in the red corpuscle, improve recognition capability, thereby might significantly improve the effect of medicine such as antimalarial disease site of action.In addition, steroidal artemisinin has unique physiologically active, opens the application prospect that has expanded artemisinin-based drug.
For better geographical Jie the present invention, with embodiment it is described below.
The preparation of embodiment 1 compound 2
30g cholesterol and 0.8g TEBA(triethyl benzyl ammonia chloride) be dissolved in the 100ml chloroform, splashing into 47g monoperphthalic acid magnesium (MMPP) aqueous solution 240ml, is 4.5-5.5 with 5%NaOH solution control PH simultaneously, 50 ℃ of reaction 2-3h, the thin plate layer folding shows that raw material disappears, (3 * 50ml), wash by the merging organic layer with chloroform extraction for water, anhydrous sodium sulfate drying, concentrate white solid, the acetone-water recrystallization gets needle-like crystal 27g compound 2, productive rate 86%.
m.p.142-143℃ [α] D＝-41°（CHCl 3，c＝0.90）
The preparation of embodiment 2 compounds 3
4.8g magnesium ribbon is suspended in the 50ml anhydrous diethyl ether, slowly splash into the diethyl ether solution (17.3ml is dissolved in the 200ml anhydrous diethyl ether) of allyl bromide 98, keep solution steadily to reflux 2 hours, add 5 then, the 250ml benzole soln of 6-epoxy cholesterol (20g) steams the 200ml ether, reflux then and spend the night, cooling adds the 200ml ether, uses 1M H 2SO 4Organic layer is told in acidifying, with the H of 2 * 100ml 1M 2SO 4Wash the washing of 3 * 100ml saturated common salt, organic layer anhydrous Na 2SO 4Drying concentrates, and drains, and column chromatography gets white solid, 15.9g compound 3, productive rate 72%.
m.p.101-102℃ [α] D＝+6.6°（c＝0.91，CHCl 3）
The preparation of embodiment 3 compounds 4
13.3g compound 3 is dissolved in 240ml acetonitrile-tetracol phenixin, adds 48.2g NaIO 4Be dissolved in the aqueous solution of 240ml distilled water, add 120mgRuCl again 36H 2O makes catalyzer, and 25 ℃ are stirred 24h, and the thin plate chromatography shows that reaction finishes, and adds 400ml water and makes NaIO 3Dissolving is filtered and is obtained crude product, and crude product uses 3 * 30ml methylene dichloride to wash with 3 * 30ml washing again, and drying obtains 11.4g solid chemical compound 4, productive rate 83%.
m.p.203-204℃ [α] D＝-2.6°（c＝0.97，dioxan）
The preparation of embodiment 4 compounds 5
2.14g compound 4 is suspended in the 50ml ether, splashes into CH under 0 ℃ 2N 2Diethyl ether solution, be yellow to solution and do not take off, continue to stir 1h, concentrate and take out ether, obtain 2.20g white solid compound 5, productive rate 100%, ethyl acetate-normal hexane recrystallization gets needle-like crystal.
m.p.153-154℃ [α] D＝-6.9°（c＝1.1，CHCl 3）
IR（KBr，cm -1）：3500（OH），1720（C＝0）
The preparation of embodiment 5 compounds 6
Compound 5(2g 4.2mmol) is dissolved in the 50ml toluene, adds the 50mg tosic acid, backflow 1h, and thin plate chromatography detection reaction is complete, takes out solution, and the resistates column chromatography for separation gets 1.64g oily matter compound 6, productive rate 72%.
[α] D＝+59.7°（c＝0.95，CHCl 3）
IR（cm -1）：1740，1680，1610
1H-NMR（200MHz，CDCl 3）：δ（ppm） 5.61（s，1H），3.65（s，3H）
1.23（s，3H），0.92（d，3H），0.89（d，6H）
0.72（s，CH 3）
The preparation of embodiment 6 compounds 7
(16.7g 37mmol) is dissolved in the 20ml methyl alcohol (or triethylamine) alpha, beta-unsaturated ketone ester (compound 6), adds catalyzer 200mg palladium, 30 ℃, 20atm pressurization hydrogenation 15h, reaction finishes, and boils off pyridine, the normal hexane recrystallization gets needle-like crystal compound 7,13.4g, productive rate 80%.
m.p.127-128℃
[α] D＝+20.8°（c＝1.1，CHCl 3）
CD：△εmax＝-0.07
IR（KBr，cm -1）：1740，1716，1160
1H-NMR（200MHz，CDCl 3）：δ（ppm）3.63（s，3H），1.04（s，CH 3），
0.86（d，3H），0.83（d，6H），0.64（s，3H）
MS（m/z）：459（M ++1），443（M +-CH 3），3.84（M +-1-CH 2CO 2CH 3）
No element analysis: C 30H 50O 3Calculated value: C, 78.55; H, 10.99
Measured value: C, 78.40; H, 10.96
The preparation of embodiment 7 compounds 8
Compound 7(1.15g, 2.5mmol) be dissolved in the 20ml anhydrous methanol, add 0.3ml trimethyl orthoformate and 10mg tosic acid, reflux 10-15min, the thin plate chromatography shows no raw material, cold slightly, add 5mg salt of wormwood, take out methyl alcohol, add 50ml water, ether extraction (3 * 30ml), wash with saturated common salt, uses anhydrous Na by the ether layer 2SO 4Drying concentrates and obtains white solid ketal 1.2g, productive rate 95%.
Above-mentioned ketal crude product (1.2g, 2.4mmol) be dissolved in the 15ml ether, slowly be added drop-wise in the suspension of 1.5g lithium aluminum hydride and 50ml anhydrous diethyl ether, stirring at room 1.5h, backflow is spent the night, the ice-water bath cooling adds 8ml water destruct lithium aluminum hydride down, elimination solid inorganic thing, 3 * 10ml ether is washed, the combined ether layer, the saturated common salt washing, ether layer anhydrous Na 2SO 4Drying concentrates, and gets 0.95g white solid alcohol, productive rate 84%.
Silica gel (100-200 order) 3g is suspended in the 10ml methylene dichloride, adds the sulfuric acid of 0.3ml15%, stir add again behind the 2min above-mentioned alcohol (0.95g 2.0mmol) is dissolved in the solution of 10ml methylene dichloride, stirring at room 4h, thin plate chromatography detection reaction finishes, and adds Na 2CO 3Neutralization is filtered, dry concentrate 0.82g white solid compound 8, productive rate 96%, the normal hexane recrystallization can get needle-like crystal
m.p.105-106℃
[α] D＝+21.7°（c＝0.9，CHCl 3）
IR（KBr，cm -1）：3350，1710，1100-1000（br）
1H-NMR（200MHz，CDCl 3）：δ（ppm） 3.64（t，2H），1.04（s，3H），0.91（d，3H），0.89（d，6H），0.7（s，3H）
MS（m/z）：430（M +），412（M +-H 2O），3.85（M +-CH 2CH 2）
No element analysis: C 29H 50O 2Calculated value: C, 80.87; H, 11.70
Measured value: C, 80.85; H, 12.07
The preparation of embodiment 8 compounds 9
2.6g magnesium is suspended in the 40ml ether, slowly drips the solution of 6.8ml MeI and 50ml anhydrous diethyl ether, after adding, backflow 5min splashes into the diethyl ether solution 50ml of 5.41g compound 8, and backflow is spent the night, saturated NH 4The Cl neutralization, ether/ethyl acetate extraction, saturated common salt washing, organic layer anhydrous Na 2SO 4Drying concentrates and obtains 5.2g white solid compound 9, productive rate 93%.
IR（KBr，cm -1）：3380s
1HNMR（200Hz，CDCl 3）：δ（ppm） 3.63（t，3H）
MS（m/z）：446（M +），428（M +-H 2O），4.13（M +-H 2O-CH 3）
The preparation of embodiment 9 compounds 10
5.2g compound 9 is dissolved in the 120ml toluene, adds 12g CuSO 4/ SiO 2, refluxing and stir 1.5h, raw material disappears, the elimination solid, filtrate concentrates, and column chromatography for separation gets 4.8g white solid compound 10, productive rate 96%, the normal hexane recrystallization gets needle-like crystal, m.p.80-81 ℃
[α] D＝+24.0°（c＝0.8，CHCl 3）
IR（KBr，cm -1）：3300，1050
1HNMR（600Hz，CDCl 3）：δ（ppm）5.19（s，1H），3.68（m，2H）
1.63（s，3H），0.89（s，3H），0.77（d，3H）
0.75（d，6H），0.65（s，3H）
MS（m/z）：429（M +1），413（M +-CH 3），3.83（M +-CH 2CH 2OH）
No element analysis: C 30H 52O calculated value: C, 84.04; H, 12.23
Measured value: C, 83.52; H, 12.18
The preparation of embodiment 10 compounds 11
Compound 10(0.8g 1.9mmol) is dissolved in the methyl alcohol or methylene dichloride of 10ml, under-78 ℃, logical ozone does not take off to the blue look of solution, changes logical nitrogen 30min, add zinc powder 300mg then, add 0.5mlHOAc again, stirring at room 3h filters, add each 50ml of water and ether, tell ether layer, 3 * 30ml washing, anhydrous Na 2SO 4Drying, concentrate crude product.
This crude product is dissolved in 50ml toluene, adds 20mg catalyst P PTS(tosic acid pyridinium salt), the 2h that anhydrates that refluxes is chilled to room temperature, and toluene is taken out in decompression, and resistates is dissolved in ether, saturated NaHCO 3Wash salt washing, organic layer NaSO 4Drying concentrates, and it is 36% that column chromatography gets 11, two step of oily matter 0.30g compound productive rate.
[α] D＝+20.2°（c＝70，CHCl 3）
IR（film，cm -1）：1720，1643，1150-1170
1H-NMR（200MHz，CDCl 3）：δ（ppm）6.11（s，1H），3.70-3.90（m，2H）
2.14（s，3H），1.02（s，3H），0.92（d，3H）
0.85（d，6H），0.68（s，3H）
MS（m/z）：442（M +），427（M +-CH 3），371（M +-CH 3COCH 2CH 3）
HRMS:C 30H 50O 2Calculated value: 442.3811
Measured value: 442.3801
The preparation of embodiment 11 compounds 12
200mg compound 11 is dissolved in the 50ml methylene dichloride, adds photosensitizers methylene blue 5mg, logical O 2,-78 ℃ of illumination treat that raw material disappears substantially, stop logical O 2, use N instead 2Gas shiled adds 10 μ l TMSOTf then, adds 1ml Et3N behind (trifluoromethanesulfonic acid trimethylsilyl group) 0.5h, rises to room temperature, concentrates upper prop, is separated to compound 12(α) 34mg, 12(β) 43mg, productive rate is respectively 16%, 20%.
Compound 12(α) physico-chemical constant:
m.p.59-60℃
[α] D：+54.0°（c＝0.38，CHCl 3）
IR（KBr，cm -1）：1100，1080，880，840
1H-NMR（200MHz，CDCl 3）：δ（ppm）5.023（s，1H），4.130（d，J＝12Hz，1H），3.510（dt，J＝1.5Hz，J＝12Hz，1H），1.424（s，3H），1.024（s，3H），0.883（d，3H），0.855（d，6H），0.655（s，3H）
MS（m/z）：474（M +），459（M +-CH 3）
HRMS:C 30H 50O 4Calculated value: 474.3709
Measured value: 474.3646
Compound 12(β) physico-chemical constant:
m.p.97-98℃
[α] D：-32.3°（c＝0.3，CHCl 3）
IR（KBr，cm -1）：1100，1070，880，830
1H-NMR（600MHz，CDCl 3）：δ（ppm）5.348（s，1H），3.935（dd，J＝4.8Hz，J＝12.6Hz，1H），3.811（t，J＝12.6Hz，1H），1.424（s，3H），0.910（s，3H），0.872（d，6H），0.661（s，3H）
MS（m/z）：475（M ++1），459（M +-CH 3），442（M +-O 2）
HRMS:C 30H 50O 4Calculated value: 474.3709
Measured value: 474.3731
Embodiment 12 compound 13(α or β) preparation
100mg compound 12(α or β) be dissolved in the admixture solvent of 10ml acetonitrile and water, add NaIO 42g, and RuCl 315mg, stirring at room 60h divides water-yielding stratum, water layer ether extraction three times (3 * 30ml), merge organic layer, anhydrous Na 2SO 4Drying concentrates, column chromatography get oily product 13(α or β type be respectively 70 and 75mg) productive rate is 68% and 73%.
Compound 13(α type)
IR（cm -1）：1745，880
1HNMR（δ，CDCl 3）：5.67（1H，s）
MS（m/z）：488（M +）
Compound 13(β type)
IR（cm -1）：1740，890
1HNMR（δ，CDCl 3）：5.76（1H，s）
MS（m/z）：488（M +）
Embodiment 13 compound 14(β types) preparation
50mg compound 13(β type) be dissolved in the 3ml methyl alcohol, be chilled to 0-5 ℃, add the 50mg sodium borohydride under stirring in batches, after 1 hour,, cross post, get oily matter compound 14(β with the Glacial acetic acid neutralization) 46mg, productive rate 92%
IR（cm -1）：3400
1HNMR(δ, CDCl 3): 5.56,5.35(adds up to 1H, s); 5.27, the 4.75(total (1H is d, J=3.5Hz, 9Hz)
MS（m/z）：472（M +-H 2O）
In addition, the allyl bromide 98 among the embodiment 2 replaces with the alkene butyl bromide, and adopts the similar method of above-mentioned many embodiment can make compound 15(α type and β type), 16(α type and β type) and 17(β type).
Compound 15(α type): oily matter
IR（cm -1）：1080，880，830
1H-NMR（90MHz，CDCl 3）：δ（ppm）5.01（s，1H），4.14（d，1H），3.49（dt，1H）
MS（m/z）：488（M +），473（M +-CH 3）
Compound 15(β type): oily matter
IR（cm -1）：1100，880，840
1H-NMR（90MHz，CDCl 3）：δ（ppm）5.35（s，1H），3.94（dd，1H），3.80（t，1H）
MS（m/z）：488（M +），456（M +-O 2）
Compound 16(α type): oily matter
IR（cm -1）：1735，880
1H-NMR（90MHz，CDCl 3）：δ（ppm）5.61（1H，s）
MS（m/z）：502（M +）
Compound 16(β type): oily matter
IR（cm -1）：1740，880
1H-NMR（90MHz，CDCl 3）：δ（ppm）5.77（M +）
MS（m/z）：502（M +）
Compound 17(β type): oily matter
IR（cm -1）：3300
1H-NMR(90MHz, CDCl 3): δ (ppm) 5.33,5.47(adds up to 1H, s), 5.21,5.08(adds up to 1H, is d)
MS（m/z）：486（M +-H 2O）

Claims (2)

1, a class steroidal artemisinin is characterized in that with 1,2 of Artemisinin 4-trioxane efficient part combines with the steroidal molecule, and its chemical formula is:
Figure 931123585_IMG1
X is H in the formula 2,
Figure 931123585_IMG2
Y is CH 2, CHCH 3
2, the synthetic method of steroidal artemisin as claimed in claim 1 is characterized in that:
(I) is that raw material passes through the steroidal artemisinin (X=H that the reaction of 11 steps can get the said structure formula with the cholesterol 2, Y=CH 2, CHCH 3), its reactions steps is:
(1) cholesterol monoperphthalic acid magnesium (MMPP) oxidation
(2) with the reaction of allyl bromide 98 (or alkene butyl bromide) Grignard reagent
(3) can change into the reagent N aIO that ketone can be oxidized to terminal olefin acid again to hydroxyl oxygen with one 4-RuCl 3Carry out oxidation
(4) esterification
(5) use the Catalyzed by p-Toluenesulfonic Acid reflux dewatering
(6) make catalyst hydrogenation with palladium black
(7) carbonyl-protection is got up again ester group is reduced
(8) Yu Geshi reagent react
(9) dehydration
(10) after the ozonize again through the dehydration
(11) add photosensitizers, logical oxygen ,-78 ℃ with sodium lamp as the light source light photograph, add TMSOTf(trifluoromethanesulfonic acid trimethylsilyl group) reset close encircle the product steroidal artemisinin, α configuration and beta comfiguration are arranged;
(II) is with the product NaIO of above-mentioned (I) method gained 4Oxidation gets product steroidal artemisinin (X=O, Y=CH 2, CHCH 3), α configuration and beta comfiguration are arranged;
(III) with the β type product sodium borohydride reduction of above-mentioned (II) method gained, product steroidal artemisinin β type (
Figure 931123585_IMG3
, Y=CH 2, CHCH 3).
CN 93112358 1993-03-05 1993-03-05 Steroidal artemisinin Expired - Fee Related CN1033274C (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101708338B (en) * 2008-12-26 2014-06-04 中国人民解放军军事医学科学院放射与辐射医学研究所 Prodrug containing sterides structures and high dispersion preparation thereof
CN107814717A (en) * 2017-11-14 2018-03-20 中国科学院上海有机化学研究所 A kind of steroidal acetylenic acid compound, its synthetic method and purposes

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101708338B (en) * 2008-12-26 2014-06-04 中国人民解放军军事医学科学院放射与辐射医学研究所 Prodrug containing sterides structures and high dispersion preparation thereof
CN107814717A (en) * 2017-11-14 2018-03-20 中国科学院上海有机化学研究所 A kind of steroidal acetylenic acid compound, its synthetic method and purposes
CN107814717B (en) * 2017-11-14 2019-10-15 中国科学院上海有机化学研究所 A kind of steroidal acetylenic acid compound, its synthetic method and purposes

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