CN116120332A - Synthesis method of racemized camptothecin intermediate tricyclic compound - Google Patents

Abstract

The invention relates to a synthesis method of a racemized camptothecin intermediate tricyclic compound, which belongs to the field of organic chemical synthesis, and aims to overcome the defects that raw materials for synthesizing 4-ethyl-7, 8-dihydro-IH-pyrano [3,4-f ] indene-3, 6, 10 (4H) -trione are expensive and difficult to produce and amplify, and the like. The reaction involved in the invention is mostly conventional reaction, the reaction condition is mild, and compared with the former process, the complexity of the reaction is reduced and the safety is reduced; the used materials are cheaper, the yield of the technological process is improved, and the total cost is reduced; and the synthesis route is short, the yield is high, and the process is easy to purify.

Description

Synthesis method of racemized camptothecin intermediate tricyclic compound

Technical Field

The invention belongs to the field of organic chemical synthesis, and particularly relates to a synthesis method of a racemized camptothecin intermediate tricyclic compound, namely a synthesis method of 4-ethyl-7, 8-dihydro-IH-pyrano [3,4-f ] indene-3, 6, 10 (4H) -trione.

Background

Camptothecins (r1=r2=h, camptothecin, CPT) were one containing quinoline pentacyclic skeleton structure isolated in 1966 from camptothecins of the family daviaceae in the middle of china for the first time by us Wall et al (Wall M E, wani M C, cook C E et al j Am Chem soc.1966,88, 3888-3890). Since it shows remarkable antitumor activity in animal experiments in vivo and in vitro, it becomes one of the key points of the research of antitumor drugs . The development of these compounds has entered a rapid development stage after the discovery of a unique mechanism of action in which camptothecin is a specific inhibitor of topoisomerase I from Hsiang et al (Hsiang Y H, hertzberg R, hertt S et al J Bio chem.1985,260, 14873-14878).

The efficient chemical total synthesis of camptothecins and derivatives thereof has been one of the hot spots in the field of pharmaceutical chemistry research for over twenty years, and various research groups at home and abroad have reported a total synthesis route of over 30 camptothecins and analogues thereof in succession (Du W. Tetrahedron,2003, 59:5120). In a plurality of synthetic strategies, friedlander condensation method is to condense an A ring and a CDE ring to obtain camptothecin, which has unique advantages in structural modification of the camptothecin, the CDE ring of the camptothecin can be obtained by chiral resolution of a racemized CDE ring at present, and the racemized camptothecin and derivatives thereof are also important reference substances for testing the biological activity of the camptothecin.

There are three routes for the racemic CDE ring synthesis of camptothecins, but these routes all have some problems:

1) J.Med. Chem.1980,23,554-560 provides the following synthetic routes:

the route has the following disadvantages: 1. the yields of the first step and the fourth step are low, and the reaction time of the first step is too long; 2. raney nickel used in the reaction process is relatively complex to process; 3. the ethylation reaction needs low-temperature operation, and the reaction time is long; 4. the starting material ethyl 5-cyano-4-methyl-6-oxo-1, 6-dihydropyridine-2-carboxylate is expensive.

2) J.0rg.chem.l993,58,611-617 provides the following synthetic routes:

the disadvantages of this route are as follows: 1. the yield of hydrobromic acid decarboxylation in this process is too low; 2. the oxidation conditions are harsh and the yield is low; 3. waste with higher toxicity can be generated in the reaction process, so that the cost for treating the waste is increased; 4. the cost of the initial raw material alkenyl chloride is high.

3) Current Organic Synthesis 2020,17,5880591 provides the following synthetic route:

the route has the following disadvantages: 1. the price of the initial raw materials used for synthesis is high; 2. the transition metal catalysts are expensive in the reaction process; 3. the toxic gas carbon monoxide is used in the reaction process, which is unfavorable for mass production.

In conclusion, the current synthetic route for synthesizing the key intermediate tricyclic compound of the antitumor drug camptothecin, namely 4-ethyl-7, 8-dihydro-IH-pyrano [3,4-f ] indene-3, 6, 10 (4H) -trione, has larger optimization space and development potential from the aspects of cost and production feasibility.

Disclosure of Invention

Aiming at the problems of low safety, low yield, high raw material cost and the like of the existing synthetic 4-ethyl-7, 8-dihydro-IH-pyrano [3,4-f ] indene-3, 6, 10 (4H) -trione route, the invention provides a novel method for synthesizing 4-ethyl-7, 8-dihydro-IH-pyrano [3,4-f ] indene-3, 6, 10 (4H) -trione.

The specific technical scheme is as follows:

1) Adding a chloro reagent (1.1-1.2 mol) and methylene dichloride into a reaction kettle, cooling to 0-5 ℃ under the protection of nitrogen, keeping the temperature, dropwise adding a compound (1.0 mol) of the formula 1 in the following reaction line, continuously dropwise adding triethylamine (15-18 mol) under the stirring of 0-5 ℃ after the dropwise adding, and stirring at 25-30 ℃ for reacting for 1.5h; adding dichloromethane for extraction, and concentrating the organic phase after merging; concentrating, filtering the concentrate with a silica gel-filled sand core funnel, eluting with petroleum ether and ethyl acetate mixture (PE/EA=5/1), and concentrating the filtrate to obtain the compound of formula 3.

2) Adding a compound (1.0 mol) of formula 2 into a reaction kettle, adding toluene, adding dimethyl sulfate (1.0-1.1 mol), stirring at 80-90 ℃ for reaction for 12 hours, and adding amine (1.1-1.2 mol) and a compound (1.0 mol) with active methylene; distilling to remove toluene, adding methanol, adding sodium methoxide, refluxing and stirring to react for 2h, distilling to remove methanol, cooling to room temperature, adding ice water into a bottle, and regulating pH to 5-6 with hydrochloric acid solution; extracting the organic phase with dichloromethane, drying with anhydrous sodium sulfate, concentrating, and recrystallizing with petroleum ether to obtain compound of formula 4;

3) Adding a compound (1.0 mol) of formula 3, a compound (0.75-0.80 mol) of formula 4, amine (5.0-6.0 mol) and ethanol into a reaction kettle, and reacting for 12 hours at 25-30 ℃; filtering the reaction solution, and washing a filter cake with petroleum ether to obtain a compound of formula 5;

4) Adding a compound (1.0 mol) of formula 5 and ethylene glycol dimethyl ether into a reaction kettle, cooling to 0-5 ℃, adding potassium tert-butoxide (1.0-1.1 mol), reacting for 30min, adding an ethylation reagent (1.8-2.0 mol), and reacting for 6h at 25-30 ℃; the reaction is extracted by methylene dichloride, the organic phase is dried by anhydrous sodium sulfate and concentrated to obtain the compound of formula 6;

5) Adding a compound (1.0 mol), 1, 4-dioxane, paraformaldehyde (2.0-2.5 mol), acid (0.02-0.025 volume ratio) and water (0.2-0.25 volume ratio) in an autoclave, and reacting for 24 hours at 105-107 ℃; the reaction is extracted by methylene dichloride, the organic phase is dried by anhydrous sodium sulfate and concentrated to obtain the compound of formula 7;

6) Adding a compound (1.0 mol) of formula 7, benzaldehyde (1.0-1.1 mol), a mixed solvent of a catalyst, DMF and THF into a reaction kettle, cooling at-40 ℃ to-50 ℃ and stirring for 10 minutes, adding lithium bis (trimethylsilyl) amide (1.1-1.2 mol), reacting at room temperature for 24 hours, adding a hydrochloric acid solution, stirring for 2 hours, adjusting the pH value to 5-6, and extracting with the mixed solvent of dichloromethane and methanol. The organic phase is dried with anhydrous sodium sulfate, filtered and concentrated; adding the concentrated dry matter into an acid solution, and reacting for 3 hours at 90+/-2 ℃; adding sodium carbonate for neutralization, extracting dichloromethane in the reaction liquid, drying an organic phase by using anhydrous sodium sulfate, and concentrating to obtain a compound shown in a formula 8;

7) Adding a compound (1.0 mol) of formula 8, dichloromethane and methanol solution into a reaction kettle, cooling to-70 ℃ to-75 ℃ and introducing peroxide for 10-30min; introducing oxygen for 10min, adding dimethyl sulfide (1.0 mol), and reacting at 25-30deg.C for 2h; the reaction is extracted by methylene dichloride, the organic phase is dried by anhydrous sodium sulfate and concentrated to obtain the compound of formula 9;

8) Adding a mixed solvent of a compound (1.0 mol) of formula 9, ethylene glycol (2.5-3.0 mol), DCE and DMF into a reaction kettle, dropwise adding acid (1.0-1.1 mol) under stirring at 0-5 ℃, stirring at 80-85 ℃ after the dropwise adding is finished for reaction for 5 hours, adding a 10% sodium carbonate solution into the reaction solution for washing, extracting with dichloromethane, drying an organic phase with anhydrous sodium sulfate, and concentrating to obtain the compound of formula 10.

Preferred embodiments of the invention:

the chlorinating reagent required in the step 1) can be selected from 2-chloro-1, 3-dimethyl imidazoline chloride, thionyl chloride, phosphorus oxychloride and the like, and preferably 2-chloro-1, 3-dimethyl imidazoline chloride;

the compound having an active methylene group required in step 2) may be selected from isopropylidene malonate, β -keto ester, preferably isopropylidene malonate; the required amine can be selected from triethylamine, 1, 8-diazo hetero double spiro [5.4.0] undec-7-ene and the like, and is preferably triethylamine;

the amine required in step 3) can be selected from dimethyl ethylenediamine, triethylamine, and the like, preferably triethylamine;

the ethylation reagent required in the step 4) can be selected from ethyl iodide, ethyl bromide and the like, and ethyl iodide is preferred;

the acid required for the hydrolysis in the step 5) can be selected from concentrated sulfuric acid, concentrated hydrochloric acid and the like, and the concentrated sulfuric acid is preferred;

step 6) the catalyst can be tetrabutylammonium bromide, triethylbenzyl ammonium bromide and the like, preferably triethylbenzyl ammonium bromide; the acid for decarboxylation may be hydrobromic acid, hydrochloric acid, sulfuric acid, etc., preferably hydrobromic acid;

the peroxide in the step 7) can be selected from hydrogen peroxide, potassium permanganate, ozone and the like, and ozone is preferred.

The acid required for glycol protection in step 8) can be selected from p-toluenesulfonic acid, trimethylchlorosilane and the like. Trimethylchlorosilane is preferred.

A typical reaction scheme of the invention is as follows:

the invention has the beneficial effects that: the related reactions are mostly conventional reactions, the reaction conditions are mild, and compared with the former process, the complexity and the safety of the reactions are reduced; the used materials are cheaper, the yield of the technological process is improved, and the total cost is reduced; and the synthesis route is short, the yield is high, and the process is easy to purify.

Detailed Description

(1) Synthesis of diene esters

2-chloro-1, 3-dimethylimidazoline chloride (12, 0g,72 mmol) was added to the reaction flask, methylene chloride (600 mL) was added, dimethyl 1, 3-acetonedicarboxylic acid ester (10.0 g,8.6mL,60 mmol) was added under stirring at 0℃and triethylamine (18.1 g,25mL, 178 mmol) was slowly added dropwise under stirring at 0℃and the reaction mixture was stirred at room temperature (25 ℃) for 1.5 hours after the addition. The aqueous phase was extracted with dichloromethane (100 mL), the organic phases combined and concentrated, the concentrate filtered through a sand core funnel with silica gel and rinsed with a mixture of petroleum ether and ethyl acetate (900 mL, pe/ea=5/1). The leacheate was concentrated to give yellow liquid 1 in 75% yield.

(2) Knovenagel condensation

2-pyrrolidone (50.0 g,0.6 mol) was added to the reaction flask, toluene (1L) was added, dimethyl sulfate (75.7 g,0.6 mol) was added, and the mixture was stirred at 90℃for reaction for 12 hours. Triethylamine (68.8 g,95mL,0.68 mol) was slowly added to the reaction system, followed by Mirabilitic acid (86.5 g,0.6 mol) was slowly added thereto, and after stirring and reaction at 90℃for 12 hours, toluene was distilled off. Subsequently methanol (1L) was added, sodium methoxide (64.9 g,1.2 mol) was added, and after stirring under reflux for 2 hours, methanol was distilled off. After the reaction cooled to room temperature, ice water was added to the flask and the pH was adjusted to 5-6 with 2N hydrochloric acid solution. The organic phase was extracted with DCM (500 mL), dried over Na2SO4, concentrated and recrystallized from petroleum ether (100 mL) to give 42.0g of product (2) in 51% yield.

(3) Condensation

A100 mL round bottom flask was charged with yellow liquid 1 (7.0 g,45 mmol), product (2) (5 g,35 mmol), et3N (triethylamine, 0.3mL,2.45 mmol) and EtOH (50 mL), reacted at 25℃for 12h with stirring, TLC detected A07 as no residue, the solid in the system was directly filtered and washed with petroleum ether (50 mL) to give a white solid as 8.2g of product (3) in 89% yield.

(4) Ethylation reaction

To the reaction flask was added the product (3) (16.8 g,63 mmol), ethylene glycol dimethyl ether (250 mL), and potassium tert-butoxide (7.5 g,67 mmol) was added under cooling and stirring at 0℃and the reaction was stirred for 30min. Iodoethane (19.8 g,10mL,127 mmol) was added, the reaction was allowed to return to room temperature (25 ℃ C.) with stirring for 6h, GCMS was complete, extracted with DCM (300 mL), and the organic phase was dried over anhydrous sodium sulfate. Concentration gave (4) as a pale yellow solid (18.0 g) in 100% yield.

(5) Closing ring

Compound (4) (18.0 g,63 mmol) was dissolved in 1, 4-dioxane (95 mL) and added to a sealed, thick-walled pressure-resistant bottle. Paraformaldehyde (11.3 g,126 mmol), concentrated sulfuric acid (3.7 mL), and water (3.7 mL) were then added sequentially. The thick-wall pressure-resistant bottle is screwed tightly, and the reaction is stirred for 24 hours at 107 ℃ (the reaction bottle is placed behind the explosion-proof baffle for reaction). TLC and GCMS showed that the reaction was complete as pale yellow solid (4). Extraction with DCM (200 mL) and drying of the organic phase over anhydrous MgSO4, filtration and concentration gave the crude product as a yellow liquid (5) 18.0g in 100% yield.

(6) Alkylation and decarboxylation

In the reaction flask, yellow liquid (5) (15.0 g,52 mmol), benzaldehyde (5.5 g,52 mmol), triethylbenzyl ammonium bromide (283 mg,1.0 mmol), a mixed solvent of DMF and THF (104 ml, DMF/thf=1/1) were added sequentially. Cooled down at-40 ℃ and stirred for 10 minutes, lithium bis (trimethylsilyl) amide (62.4mL,62.4mmol,1M in THF) was added, the reaction was carried out at room temperature for 24 hours, and after the reaction was completed, hydrochloric acid solution (21 ml,6 m) was added and stirring was continued for 2 hours. The pH was adjusted to 5-6, and the mixture was extracted with a mixed solvent of methylene chloride (600 mL) and methanol (60 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude carboxylic acid compound.

The crude carboxylic acid was added to an aqueous solution of hydrobromic acid (50 mL, 40%) and reacted at 90℃for 3h. After completion of the reaction, hydrobromic acid was neutralized with saturated sodium carbonate until no bubbles were formed, and the reaction mixture was extracted with methylene chloride (500 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give 16.0g of crude product (6) in 96% yield.

(7) Debenzylation

In a reaction flask, crude product (6) (3.0 g,9.3 mmol), dichloromethane and 93mL (1:1) of methanol solution were added sequentially. Ozone is introduced at-70 ℃ for 10-30 minutes (until the solid in the system disappears and the system is clear), TLC detection (6) is carried out, and oxygen is introduced for 10 minutes. Dimethyl sulfide (578 mg,9.3 mmol) was added after aeration was complete, and then reacted at room temperature for 2h. After the reaction was completed, TLC detected that the reaction was completely oxidized, extracted with dichloromethane (20 mL), dried over anhydrous sodium sulfate, concentrated and spin-dried column chromatography (eluent=ea) to give the target product as pale yellow (7) 1.7g in 74% yield.

(8) Glycol protection

In a reaction flask, the desired product was added light yellow (7) (124.0 mg,0.5 mmol), ethylene glycol (102.4 mg,1.65 mmol), a mixed solvent of dichloroethane and N, N-dimethylformamide (2 ml, dce: dmf=36:1) in sequence. Trimethylchlorosilane (0.5 mmol,54.3 mg) was added dropwise with stirring at 0deg.C, and the mixture was reacted at 80deg.C for 5 hours. After the reaction, 10% sodium carbonate solution was added for washing, followed by extraction with methylene chloride (50 mL), drying over anhydrous sodium sulfate and concentration to give 146.0mg of 4-ethyl-7, 8-dihydro-IH-pyrano [3,4-f ] indene-3, 6, 10 (4H) -trione in 65% yield.

Claims (9)

1. A method for synthesizing a racemic camptothecin intermediate tricyclic compound, which is characterized by comprising the following steps:

1) Adding a chloro reagent and dichloromethane into a reaction kettle, cooling to 0-5 ℃ under the protection of nitrogen, keeping the temperature, dropwise adding a compound of formula 1, continuously dropwise adding triethylamine under the stirring of 0-5 ℃ after the dropwise adding, stirring and reacting at 25-30 ℃ after the dropwise adding is finished, adding dichloromethane for extraction, and concentrating after the organic phases are combined; concentrating and filtering, leaching the concentrate by using a mixed solution of petroleum ether and ethyl acetate, and concentrating the filtrate to obtain a compound shown in a formula 3;

2) Adding a compound of formula 2 into a reaction kettle, adding toluene, adding dimethyl sulfate, stirring at 80-90 ℃ for reaction, and then adding amine and a compound with active methylene; distilling to remove toluene, adding methanol, adding sodium methoxide, refluxing and stirring to react for 2h, distilling to remove methanol, cooling to room temperature, adding ice water into a bottle, and regulating pH to 5-6 with hydrochloric acid solution; extracting the organic phase with dichloromethane, drying and concentrating with anhydrous sodium sulfate, and recrystallizing with petroleum ether to obtain a compound shown in formula 4;

3) Adding a compound of formula 3, a compound of formula 4, amine and ethanol into a reaction kettle, and reacting at 25-30 ℃; filtering the reaction solution, and washing a filter cake with petroleum ether to obtain a compound of formula 5;

4) Adding a compound shown in the formula 5 and ethylene glycol dimethyl ether into a reaction kettle, cooling to 0-5 ℃, adding potassium tert-butoxide, reacting, adding an ethylation reagent, and continuing to react at 25-30 ℃; the reaction is extracted by methylene dichloride, the organic phase is dried by anhydrous sodium sulfate and concentrated to obtain the compound of formula 6;

5) Adding a compound of formula 6, 1, 4-dioxane, paraformaldehyde, acid and water into an autoclave, and reacting at 105-107 ℃; the reaction is extracted by methylene dichloride, the organic phase is dried by anhydrous sodium sulfate and concentrated to obtain the compound of formula 7;

6) Adding a mixed solvent of a compound of formula 7, benzaldehyde, a catalyst, DMF and THF into a reaction kettle, cooling and stirring at-40 ℃ to-50 ℃, adding lithium bis (trimethylsilyl) amide, reacting at room temperature, adjusting the pH value to 5-6, and extracting with a mixed solvent of dichloromethane and methanol. The organic phase is dried with anhydrous sodium sulfate, filtered and concentrated; adding the concentrated dry matter into an acid solution, and reacting at 90+/-2 ℃; adding sodium carbonate for neutralization after the reaction, extracting methylene dichloride in the reaction liquid, drying an organic phase by using anhydrous sodium sulfate, and concentrating to obtain a compound of formula 8;

7) Adding a compound of formula 8, dichloromethane and methanol solution into a reaction kettle, cooling to-70 ℃ to-75 ℃ and introducing peroxide; introducing oxygen, adding dimethyl sulfide, and reacting at 25-30deg.C; the reaction is extracted by methylene dichloride, the organic phase is dried by anhydrous sodium sulfate and concentrated to obtain the compound of formula 9;

8) Adding a mixed solvent of the compound of formula 9, ethylene glycol, DCE and DMF into a reaction kettle, dropwise adding acid under stirring at 0-5 ℃, stirring at 80-85 ℃ for reaction after the dropwise adding, adding 10% sodium carbonate solution into the reaction solution for washing, extracting with dichloromethane, drying an organic phase with anhydrous sodium sulfate, and concentrating to obtain the compound of formula 10.

2. The method for synthesizing a racemic camptothecin intermediate tricyclic compound according to claim 1, wherein the chlorinating agent required in step 1) is selected from the group consisting of 2-chloro-1, 3-dimethylimidazoline chloride, thionyl chloride and phosphorus oxychloride.

3. The method of synthesizing a racemic camptothecin intermediate tricyclic compound according to claim 1, wherein the compound having an active methylene group required in step 2) is selected from isopropylidene malonate, malonate or β -keto ester.

Or the required amine can be triethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene.

4. The method of synthesizing a racemic camptothecin intermediate tricyclic compound according to claim 1, wherein the amine required in step 3) is selected from the group consisting of dimethylethylenediamine and triethylamine.

5. The method of synthesizing a racemic camptothecin intermediate tricyclic compound according to claim 1, wherein the ethylating reagent required in step 4) is selected from the group consisting of ethyl iodide and ethyl bromide.

6. The method for synthesizing the racemic camptothecin intermediate tricyclic compound according to claim 1, wherein the acid required for the hydrolysis in the step 5) is selected from concentrated sulfuric acid and concentrated hydrochloric acid.

7. The method of synthesizing a racemic camptothecin intermediate tricyclic compound according to claim 1, wherein the catalyst of step 6) is selected from tetrabutylammonium bromide or triethylbenzyl ammonium bromide;

or the acid used for decarboxylation is selected from hydrobromic acid, hydrochloric acid or sulfuric acid.

8. The method of synthesizing a racemic camptothecin intermediate tricyclic compound according to claim 1, wherein step 7) peroxide is selected from hydrogen peroxide, potassium permanganate, or ozone.

9. The method of synthesizing a racemic camptothecin intermediate tricyclic compound according to claim 1, wherein the acid required for ethylene glycol protection in step 8) is selected from p-toluenesulfonic acid or trimethylchlorosilane.