CN105859719A - Preparation method of anti-tumor active compound - Google Patents
Preparation method of anti-tumor active compound Download PDFInfo
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- CN105859719A CN105859719A CN201610365791.7A CN201610365791A CN105859719A CN 105859719 A CN105859719 A CN 105859719A CN 201610365791 A CN201610365791 A CN 201610365791A CN 105859719 A CN105859719 A CN 105859719A
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings
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Abstract
The invention relates to a preparation method of a compound Demethoxyfumitremorgin C having anti-tumor activity. The preparation method includes the steps that L-tryptophan is used as a starting raw material and performs esterification reaction with isopropyl alcohol to obtain L-tryptophan isopropyl ester, then the L-tryptophan isopropyl ester is connection with senecioic acid to obtain amide, a dihydro beta-carboline intermediate is obtained through Bischler-Napieralski reaction, then a cis-tetrahydro beta-carboline intermediate is obtained by using sodium borohydride to reduce imine in a high selectivity mode, a protecting group is removed after connection with protected praline, intramolecular cyclization occurs to obtain the target compound Demethoxyfumitremorgin C (I). The raw material of the preparation method is cheap, the stereoselectivity and yield are high, and the preparation method is suitable for industrial production.
Description
Technical field
The invention belongs to organic chemical synthesis field, relate to the preparation method of a kind of compound Demethoxyfumitremorgin C with anti-tumor activity.
Background technology
Demethoxyfumitremorgin C chemical name is (5aS, 12S, 14aS)-12-(2-methyl-1-propylene base)-1,2,3,5a, 6,14a-hexahydro pyrrolo-[1'', 2'':4', 5'] pyrazine also [1', 2':1,6] pyrido [3,4-b] indole-5,14 (11H, 12H)-diketone, have the potentiality for the treatment of tumor.This compound in 1996 by the Osada group of Japan Chemical institute first from sea, seabed sediment sampleAspergillus fumigatusIsolated in the fermentation liquid of BM939.Activity research shows that it has good inhibitory activity for the cell cycle progression M phase of the tsFT210 cell of mouse, and MIC value is 0.45 μM.The Gu modest group of mean people group of Chinese Marine University in 2006 isolates fungus A-f-11, and isolated Demethoxyfumitremorgin C from its fermented product from Qingdao Area sea mud sample.Anti-tumor activity result shows that it has preferable cytotoxicity, and suppression ratio is 11.5 μMs/mL.The Ren Hong group of Beijing Technology and Business University in 2011 screens anti-tumor activity bacterial strain aspergillus sydowi from Shandong Jiaozhou Bay sea mudAspergillus sydowi, and isolated Demethoxyfumitremorgin C from its fermentation liquid.
At present the preparation method of the Demethoxyfumitremorgin C of report is mainly with the derivant of L-Trp as raw material; Pictet-Spengler is occurred to react with isoamyl olefine aldehydr; obtain the tetrahydro-b-carboline intermediate closed along back mixing; column chromatography for separation is connected with the proline of protection after going out cis intermediate, occurs molecule inner ring condensation to obtain target product after deprotection base.Bailey et al., in " Tetrahedron Letters " phase calendar year 2001 the 42nd, delivers " A concise, efficient route for the 113-115 page
To fumitremorgins ", this article the most successfully uses α, beta-unsaturated aldehyde directly occurs Pictet-Spengler reaction to prepare the tetrahydro-b-carboline intermediate of key.By reducing temperature, dynamics Controlling reaction result.Demethoxyfumitremorgin C has been obtained with the total recovery of 4 steps 21%.But Pictet-Spengler reaction yield is relatively low, and stereo selectivity is the most bad.The emerging group of Jia Yan of Peking University, in " Tetrahedron " the 68th phase in 2012, delivers " Mg (ClO for the 4225-4232 page4)2-catalyzed
Intramolecular allylic amination:application to the total synthesis of demethoxyfumitremorgin C "; this article this route first issues raw intramolecular allyl amino by magnesium perchlorate catalysis and builds 1; 2; 3,4-tetrahydro-b-carboline skeletons.Being the most unique route not using Pictet-Spengler to react, novelty is the strongest.But synthesizing in route oversize, use the disagreeableness heavy metal Hg of environment, stereo selectivity is the most undesirable, so not being a preferable production line.It has been reported that method to there is intermediate stereo selectivity the highest, severe reaction conditions, the shortcomings such as yield is relatively low.
Summary of the invention
The present invention provides a kind of method preparing Demethoxyfumitremorgin C, the L-Trp that this preparation method uses price relatively low is initiation material, dihydro B-carboline intermediate is obtained through Bischler-Napieralski reaction, the cis tetrahydro-b-carboline intermediate of key is obtained again through sodium borohydride reduction imines height selectivity, avoiding the problem reporting route neutral body poor selectivity, simultaneous reactions yield is higher.
In order to realize the purpose of the present invention, use following technological means.
A kind of preparation method of Demethoxyfumitremorgin C; including: with L-Trp as initiation material; react with senecioic acid after esterification and obtain amide; with sodium borohydride reduction after Bischler-Napieralski reaction cyclization; access deprotection base after proline fragment, occur molecule inner ring condensation to obtain target product subsequently.
The course of reaction of preparation method of the present invention is as follows:
。
Specifically, the preparation method of the present invention, comprise the following steps:
A) with L-Trp (II) as initiation material, adding thionyl chloride in isopropanol, reaction obtains L-Trp isopropyl ester hydrochlorate (III)；
B) L-Trp methyl ester hydrochloric acid uses the wet chemical alkalization of 1N, and extracts with dichloromethane, reacts with senecioic acid and prepare amide (IV) in the system of dicyclohexylcarbodiimide and DMAP；
C) compound (IV) is in ethyl acetate, adds dehydrant and refluxes, and cyclization occurs, and prepares dihydro B-carboline intermediate (V)；D) compound (V) is without isolation in methanol, and reaction temperature is-30oAdding sodium borohydride reduction under C, higher selectivity obtains cis tetrahydro-b-carboline intermediate (VI)；
E) the proline acyl chloride reaction that compound (VI) is protected with N-Fmoc; the amide obtained does not separates; add deprotection base after piperidines; there is molecule inner ring condensation subsequently, obtain target compound Demethoxyfumitremorgin C (I) and a small amount of diastereomer (VII).
Wherein, in step a), reaction temperature is backflow；Response time is 20 ~ 28h, preferably 24h.
In step b), the response time is 6 ~ 10h, preferably 9h；L-Trp isopropyl ester, senecioic acid, dicyclohexylcarbodiimide and DMAP mol ratio are 1:1:1:0.1.
In step c), dehydrant is phosphorus oxychloride, phosphorus pentachloride, polyphosphoric acids, phosphorus pentoxide, preferably phosphorus oxychloride, and answering temperature is backflow.
In step d), reaction temperature is-78 ~-10oC, preferably-30oC；Response time is 0.5 ~ 1.5h, preferably 1h；Compound (V) and sodium borohydride mol ratio are 1:2 ~ 3.
In step e), (VI) reacts under sodium bicarbonate is catalyzed with the proline acyl chlorides of N-Fmoc protection；Deprotection base is with dichloromethane as solvent；The middle response time is 3 ~ 6h, preferably 3h.
Detailed description of the invention
Following example are used for illustrating the present invention, but are not limited to the scope of the present invention.
Embodiment 1
10.0g L-Trp (49.0mmol) is dissolved in 100mL anhydrous isopropyl alcohol, 8.7g thionyl chloride (73.4mmol) it is slowly added dropwise under ice bath, in half an hour, dropping is complete, reaction 24h is continued after being warming up to backflow, it is down to room temperature, isopropanol is evaporated off, rinse by 20mL ethyl acetate, obtain white solid L-Trp isopropyl ester hydrochlorate 13.4g (47.5mmol), productivity 97%.
Embodiment 2
13.4gL-tryptophan isopropyl ester hydrochlorate (47.5mmol) is added in 30mL dichloromethane, add 1N K2CO3Aqueous solution 30mL, stirs half an hour, and solid all dissolves, separatory, aqueous phase extracts with 30mL dichloromethane again, after merging organic facies, washs one time with saturated aqueous common salt 40mL, anhydrous sodium sulfate is dried organic facies, filter, concentrated solvent to 40mL, under ice bath, be sequentially added into 4.8g senecioic acid (47.9mmol), 9.8g dicyclohexylcarbodiimide (47.6mmol), 0.58g DMAP (4.7 mmol).Following reaction is warmed to room temperature.Stirring 9h, TLC detection raw material reaction is complete, sucking filtration, and filter cake 20mL dichloromethane washes twice, and regulates pH to 5 with 1N HCl, extracts separatory, organic facies 1N K2CO3Aqueous solution regulation pH to 8, separatory, organic facies anhydrous magnesium sulfate is dried, and filters, is evaporated, and adds petroleum ether: the mixed solvent of ethyl acetate=4:1 washs, and obtains white solid 14.2g VI (43.2mmol), productivity 91%.
Mp 143-144 oC;
[α]D 20
= +77.9 (c 2.0, CHCl3); 1H NMR (400 MHz, CDCl3)
δ 8.32 (s, 1H), 7.56 (d,J
= 7.9 Hz, 1H), 7.34 (d,J = 8.1 Hz, 1H), 7.20 – 7.14 (m, 1H), 7.10 (dd,J 1 = 11.0 Hz,J 2 =
3.9 Hz, 1H), 6.98 (d,J = 1.8 Hz, 1H), 5.92 (d,J = 7.8 Hz, 1H),
5.51 (s, 1H), 5.04 – 4.88 (m, 2H), 3.31 (t,J = 5.6 Hz, 2H), 2.13 (d,J = 0.8
Hz, 3H), 1.80 (d,J = 0.8 Hz, 3H), 1.17 (dd,J 1
= 9.3 Hz,J 2 = 6.3 Hz, 6H). 13C NMR (101 MHz, CDCl3)
δ 171.89, 166.67, 151.86,
136.22, 127.76, 123.04, 121.87, 119.30, 118.61, 118.17, 111.38, 109.76, 69.19,
53.01, 27.77, 27.10, 21.68, 21.62, 19.85。
Embodiment 3
4.0g IV (12.2mmol) is added in 180mL ethyl acetate, add 5.6g and newly steam phosphorus oxychloride (36.5mmol) generation Bischler-Napieralski reaction, be warming up to backflow, react 1.5h, TLC follows the tracks of and finds that raw material reaction is complete, stopped reaction, is cooled to room temperature, solvent evaporated under room temperature, obtain the crude product of dihydro B-carboline intermediate V, the most purified, add 30mL absolute methanol, reacting liquid temperature is down to-30oC, it is dividedly in some parts 0.93g sodium borohydride (24.6mmol), adding in half an hour, continue to stir half an hour, TLC detection raw material reaction is complete, adding 3N aqueous citric acid solution regulation pH is 6, stir ten minutes, add 50mL ethyl acetate, and regulate pH to 8 with 1N sodium bicarbonate aqueous solution, separatory, aqueous phase extracts one time by 20mL ethyl acetate again.Merge organic facies, wash with saturated aqueous common salt 20mL, separatory, organic facies anhydrous magnesium sulfate is dried, filter, solvent evaporated under room temperature, add 4mL ethanol, stand under ice bath, have white crystal gradually to separate out, filter and use a small amount of absolute ethanol washing, obtaining white crystal 2.7g VI (61.4mmol), two step productivity 71%, owing to having detected a small amount of product generation isomerization in Bischler-Napieralski product, so the cis tetrahydro-b-carboline intermediate finally given contains a small amount of racemization, 74% ee.
Mp 88-90 oC;1H
NMR (400 MHz, CDCl3) δ 7.72 (s, 1H), 7.49 (d,J =
7.5 Hz, 1H), 7.28 (d,J = 7.8 Hz, 1H), 7.14 (dd,
J 1 = 7.5 Hz,J 2 = 6.9 Hz, 1H), 7.09 (dd,J 1 = 7.8 Hz,J 2 =
6.9 Hz, 1H), 5.26 (d,J = 10.5 Hz, 1H), 5.14 (dt,
J 1 = 12.5 Hz,J 2 = 6.3 Hz, 1H), 4.93 (d,J
= 9.1 Hz, 1H), 3.81 (dd,J 1 = 11.1
Hz,J 2 = 4.3 Hz, 1H), 3.11 (dd,J 1
= 15.1 Hz,J 2 = 2.5 Hz, 1H), 2.83 (ddd,
J 1 = 15.1 Hz,J 2 = 11.3 Hz,J 3=
2.1 Hz, 1H), 2.16 (s, 1H), 1.87 (s, 3H), 1.83 (s, 3H), 1.31 (t,J = 5.7
Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 172.65, 137.66, 135.94,
135.10, 127.56, 124.15, 121.66, 119.51, 118.16, 110.90, 107.55, 68.71, 56.68,
51.71, 26.06, 25.66, 21.93, 21.88, 18.54。
Embodiment 4
2.5g VI (8.0mmol) is added 20mL dichloromethane, adds 0.81g sodium bicarbonate (9.6mmol), ice bath, weigh 3.0g R-fluorenylmethyloxycarbonyl-2-chloroformyl pyrrolidine (Fmoc-L-ProCl)
(8.4mmol), it is dissolved in 10mL dichloromethane, it is slowly added dropwise to reactant liquor, 10min dropping is complete, reaction is warming up to room temperature, continue stirring one hour, it is complete that TLC follows the tracks of raw material reaction, amide intermediate is without isolation, reactant liquor is concentrated into 10mL, add 2.5mL piperidines, continue stirring 3 hours, it is complete that TLC follows the tracks of intermediate reaction, extract twice with 30mL dichloromethane and 30mL water, merge organic facies, it is dried with anhydrous magnesium sulfate, filter, it is evaporated solution, use ethyl acetate column chromatography, obtaining 1.9g target product Demethoxyfumitremorgin C is white solid (5.3mmol), productivity 67%.Obtain a small amount of its diastereomer VII 0.30g (0.86mmol), productivity 11% simultaneously.
Mp 210-212 oC;
[α]D 20
= +16.6 (c 1.6, CHCl3); NMR (400 MHz, CHCl3) δ 7.96 (s), 7.58 (d,J
= 7.3 Hz, 1H), 7.34 (d,J = 7.5 Hz, 1H), 7.19 (ddd,
J 1 = 7.5 Hz,J 2 = 7.1 Hz,J 3
= 1.3 Hz, 1H), 7.15 (ddd,J 1 = 7.3
Hz,J 2 = 7.1 Hz,J 3 = 1.1 Hz, 1H), 6.04 (d,
J = 9.5 Hz, 1H), 4.93 (d,J = 9.5 Hz, 1H), 4.19 (dd,J 1 = 11.6 Hz,J 2 =
4.8 Hz, 1H), 4.12 (dd,J 1 = 8.2 Hz,
J 2 = 7.8 Hz, 1H), 3.68 – 3.61 (m, 2H), 3.58 (dd,J 1 = 15.9 Hz,J 2 =
5.0 Hz, 1H), 3.13 (dd,J = 15.9, 11.9 Hz, 1H),
2.47 – 2.35 (m, 1H), 2.30-2.18
(m, 1H), 2.12 – 2.03 (m, 1H), 2.01 (d,J
= 1.1 Hz, 3H), 1.99 – 1.89 (m, 1H), 1.65 (d,J = 1.0 Hz, 3H). NMR (101 MHz, CHCl3)
δ 169.53, 165.71, 136.18,
134.32, 133.51, 126.27, 124.00, 122.21, 120.07, 118.35, 111.18, 106.46, 59.25,
56.85, 51.00, 45.43, 28.60, 25.72, 23.08, 21.90, 18.16。
Claims (10)
1. the method preparing the compound Demethoxyfumitremorgin C with anti-tumor activity, it is characterised in that
A) with L-Trp (II) as initiation material, L-Trp isopropyl ester hydrochlorate (III) is obtained through esterification；
B) react with senecioic acid under dehydrant effect after L-Trp methyl ester hydrochloride alkalization extraction, prepare amide (IV)；
C) compound (IV) is in a solvent, heats under catalyst and dehydrant effect, and cyclization occurs, and prepares dihydro B-carboline intermediate (V)；
D) using reducing agent to reduce compound (V) in a solvent, high selectivity obtains cis tetrahydro-b-carboline intermediate (VI)；
E) the proline acyl chloride reaction that compound (VI) is protected with N-Fmoc; obtain amide; without isolation; add deprotection base after piperidines; there is molecule inner ring condensation subsequently, obtain target compound Demethoxyfumitremorgin C (I) and a small amount of diastereomer (VII).
Preparation method the most according to claim 1, it is characterised in that using anhydrous isopropyl alcohol as solvent in step a)；Thionyl chloride is catalyst；Reaction temperature is backflow；Response time is 20 ~ 28h, preferably 24h.
Preparation method the most according to claim 1, it is characterised in that using 1N solution of potassium carbonate and dichloromethane to carry out alkalization extraction in step b), reaction is using dichloromethane as solvent；Temperature is 25oC。
4. according to the preparation method described in claim 1 or 3, it is characterised in that in step b), the response time is 6 ~ 10h, preferably 9h；Dehydrant is dicyclohexylcarbodiimide, and catalyst is DMAP.
5., according to the preparation method described in claim 1 or 4, it is characterised in that L-Trp isopropyl ester, senecioic acid, dicyclohexylcarbodiimide and DMAP mol ratio are 1:1:1:0.1.
Preparation method the most according to claim 1, it is characterised in that in step c), dehydrant is phosphorus oxychloride, phosphorus pentachloride, polyphosphoric acids, phosphorus pentoxide, preferably phosphorus oxychloride.
7., according to the preparation method described in claim 1 or 6, it is characterised in that with toluene in step c), chloroform, ethyl acetate is solvent, ethyl acetate；Reaction temperature is backflow.
Preparation method the most according to claim 1, it is characterised in that in step d), reducing agent is sodium borohydride；Solvent is methanol, ethanol, isopropanol, preferably methanol；Reaction temperature is-78 ~-10oC, preferably-30oC；Response time is 0.5 ~ 1.5h, preferably 1h.
Preparation method the most according to claim 1, it is characterised in that with dichloromethane as reaction dissolvent in step e)；Reaction temperature is room temperature.
10. according to the preparation method described in claim 1 or 9, it is characterised in that step e) deprotection base uses piperidines to be alkali；Solvent is dichloromethane；Response time is 3 ~ 6h, preferably 3h.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2023274203A1 (en) * | 2021-06-28 | 2023-01-05 | 河北科技大学 | Nitrogen-containing polycyclic aromatic compound, preparation method therefor, and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023274203A1 (en) * | 2021-06-28 | 2023-01-05 | 河北科技大学 | Nitrogen-containing polycyclic aromatic compound, preparation method therefor, and application thereof |
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