CN105859716A - Method for synthesizing 5-6 parallel-ring structure in camptothecin compounds - Google Patents

Abstract

The invention discloses a method for synthesizing the 5-6 asymmetric ring structure in camptothecin compounds, the method is to make the conjugated enynyl ester with the structure of formula II undergo intramolecular series cyclization reaction in a solvent, thereby The 5-6 parallel ring structure shown in formula I is obtained, and the specific reaction formula is: In the formula: R ₁ and R ₂ are independently selected from hydrogen, alkyl, cycloalkyl, aryl or heterocyclic group; or, R ₁ and R ₂ together form a saturated or unsaturated carbocyclic or heterocyclic ring; R ₃ and R ₄ are independently selected from hydrogen, alkyl, cycloalkyl, aryl or heterocyclyl; or, R ₃ and R ₄ together form a saturated or unsaturated carbocyclic or heterocyclic ring; R is selected from C ₁ to C ₄ alkyl; P is an amino protecting group. The method of the invention has the advantages of simple operation, safety and environmental protection, low production cost, high yield, suitable for large-scale production, etc., and has great value in promoting the wide application of this type of compound in the field of medicine.

Description

A method for synthesizing 5-6 ring structure in camptothecin compounds

technical field

The invention relates to a method for synthesizing a 5-6 asymmetric ring structure in camptothecin compounds, belonging to the technical field of organic synthesis.

Background technique

The 5-6 ring structure of dihydropyrrole-2-carbonylpyridine in camptothecin compounds This kind of compound has good anticancer activity, for example: camptothecin (Camptothecin) is a kind of alkaloid that American scientist Wall and Wani equal to 1966 and obtain from the bark of Camptotheca isolated, has become the most famous clinically at present. One of the plant anticancer drugs; in addition, people have also isolated a large number of camptothecin natural products from camptothecin, such as: 10-hydroxycamptochecin, 22-hydroxyacuminate, etc.; based on the chemical research of camptothecin natural medicines, At present, many camptothecin derivatives with good anticancer activity have been developed, such as: the compounds Topotecan and Irinotecan have been approved by the U.S. Food and Drug Administration (FDA), and the chemical structural formulas of the above compounds are as follows:

At present, the synthetic method of the 5-6 ring structure of the dihydropyrrole-2-carbonylpyridine contained in the camptothecin compound mainly contains the following types:

1) The Stork group disclosed the synthetic route of racemic Camptothecin in 1971 (Stork G., Schultz A.G.J.Am.Chem.Soc.1971,36,4074.):

This route needs 16 steps in total, and the total yield is about 20%. The reaction steps are lengthy, the operation is cumbersome, and the production cost is high. Therefore, this synthetic route is not suitable for industrial production.

2) The Comins group disclosed the asymmetric total synthesis route of Camptothecin in 1992 (D.L.Comins, M.F.Baevsky, H.Hong, J.Am.Chem.Soc.1992,114,10971.):

This route requires a total of 10 steps, and the total yield is only 12%. It also needs to use equivalent chiral prosthetic groups, and the production cost is high, so this synthetic route is not suitable for industrial production.

3) The Curran group disclosed the synthetic route of Camptothecin and its various derivatives in 1995 (D.P.Curran, S.KO, H.Josien, Angew.Chem.Int.Ed.1995, 34, 2683.):

This route uses free radical reaction, after 12 steps to synthesize the target product, the total yield is only 3%, the production cost is high, and toxic tin reagent is also used, the environmental pollution is large, and the production safety is relatively poor, so this synthetic route is not Suitable for industrial production.

4) Yao Zhujun’s group disclosed the asymmetric total synthesis route of Camptothecin in 2007 (H.Zhou, G.Liu, Z.Yao, Org.Lett.2007,9,2003.):

This route requires a total of 14 steps of reaction, the reaction steps are lengthy, the operation is cumbersome, the total yield is about 15%, and expensive metal reagents are used, and the production cost is high, so this synthetic route is still not suitable for industrial production.

In summary, although camptothecin compounds with a 5-6 ring structure containing dihydropyrrole-2-carbonylpyridine have good biological activity, the synthesis methods of these compounds still have cumbersome routes, complicated operations, and high cost. Higher, lower yields and other defects have hindered the development and application of these compounds in the field of medicine.

Contents of the invention

In view of the above-mentioned problems existing in the prior art, the purpose of the present invention is to provide a method for synthesizing the 5-6 ring structure in camptothecin compounds with simple operation, safety and environmental protection, and higher yield, so as to promote the synthesis of such compounds in Wide application in the field of medicine.

For realizing above-mentioned purpose of the invention, the technical scheme that the present invention adopts is as follows:

A method for synthesizing the 5-6 parallel ring structure in camptothecin compounds is to make the conjugated enynyl ester with the structure of formula II undergo an intramolecular series cyclization reaction in a solvent, thereby preparing the compound shown in formula I 5-6 ring structure, the specific reaction formula is as follows:

in:

R ₁ and R ₂ are independently selected from hydrogen, alkyl, cycloalkyl, aryl or heterocyclic group; or, R ₁ and R ₂ together form a saturated or unsaturated carbocycle (including aromatic ring, condensed ring) or Heterocycles (including alkyl heterocycles, aromatic heterocycles, and condensed heterocycles);

R ₃ and R ₄ are independently selected from hydrogen, alkyl, cycloalkyl, aryl or heterocyclic group; or, R ₃ and R ₄ together form a saturated or unsaturated carbocycle (including aromatic ring, condensed ring) or Heterocycles (including alkyl heterocycles, aromatic heterocycles, and condensed heterocycles);

R is selected from C ₁ -C ₄ alkyl groups (for example: methyl, ethyl, propyl, butyl, preferably methyl);

P is an amino protecting group (for example: tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, p-methoxybenzyl, fluorenylmethoxycarbonyl, trityl or acetyl, preferably tert-butoxycarbonyl).

As a preferred version, the compound of formula I has the following structural formula:

in:

Ring A has the structure shown in formula A-1, A-2 or A-3:

Wherein: Ra ₁ , Ra ₄ , Ra ₅ are each independently selected from hydrogen, alkyl, aryl, fluorine or alkoxy; Ra ₂ , Ra ₃ are each independently selected from hydrogen, alkyl, aryl, fluorine or alkane Oxygen; or, Ra ₁ and Ra ₂ , Ra ₂ and Ra ₃ , Ra ₃ and Ra ₄ , Ra ₁ and Ra ₅ together form a carbocyclic or heterocyclic ring;

Ring B has the structure shown in Formula B:

Wherein: Rb ₁ , Rb ₂ , Rx, Rm are each independently selected from hydrogen, alkyl, aryl, fluorine or alkoxy; the dotted line represents an optional double bond, X is C, N, O or S, when 1 When there is a double bond between bit and 2, X can only be C or N; when there is a double bond between 1 and 2 and X is N, Rx does not exist;

m is 0, 1, 2 or 3, and when m is 0, Rm does not exist.

As a further preferred solution, in ring A: Ra ₁ , Ra ₄ , and Ra ₅ are all selected from hydrogen; Ra ₂ and Ra ₃ are all selected from hydrogen, fluorine, alkyl or alkoxy; or, Ra ₂ and Ra ₃ are formed together Oxyheterocycles (e.g. 1,3-dioxolane ); in ring B: Rb ₁ , Rb ₂ , Rx, Rm are each independently selected from hydrogen, alkyl, aryl, fluorine or alkoxy; the dotted line represents an optional double bond, X is C, N or O, When there is a double bond between 1 and 2, X is C or N; when there is a double bond between 1 and 2 and X is N, Rx does not exist; m is 0 or 1, when m is 0 , Rm does not exist.

As a preferred solution, the conjugated enynyl ester having the structure of formula II is dissolved in a solvent, first reacted under acidic conditions at 0±5°C for 1 to 5 hours, then concentrated to remove the acid, and then the obtained product is re-dissolved in the solvent , further reacting under alkaline conditions at 0-60°C to obtain a compound of the formula I structure.

As a further preferred solution, the acid used in the reaction is at least one selected from hydrochloric acid, sulfuric acid, methanesulfonic acid, trifluoroacetic acid, p-toluenesulfonic acid, and camphorsulfonic acid.

As a further preferred version, the base used in the reaction is selected from lithium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilamide, lithium carbonate, carbonic acid Sodium, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium phosphate, sodium tert-butoxide, potassium tert-butoxide, triethylamine, diisopropylethylamine, 1,8-di At least one of azabicycloundec-7-enes.

As a further preferred version, the solvent used in the reaction is selected from toluene, tetrahydrofuran, ethylene glycol dimethyl ether, dichloromethane, 1,4-dioxane, methanol, tert-butanol, N,N-dimethylformaldehyde At least one of amides, dimethyl sulfoxide, and acetonitrile.

As a further preferred solution, the reaction temperature under alkaline conditions is 0-60°C.

Compared with the prior art, the present invention has the following significant beneficial effects:

In the present invention, the 5-6 parallel ring structure in the camptothecin compound is prepared in one step through the tandem cyclization reaction in the molecule of the conjugated enynyl ester (compound represented by formula II), the whole route is simple to operate, and various reagents are simple Easy to get, can be purchased commercially, low cost, and does not involve toxic and harmful reagents, safe and environmentally friendly, while the reaction conditions are mild, no high temperature and high pressure operation is required, the system is stable, the repeatability is good, the production cost is low, and the yield is high (about 90%) ), suitable for large-scale production, thereby promoting the wide application of this type of compound in the field of medicine.

detailed description

The technical solutions of the present invention will be further described in detail and completely below in conjunction with specific embodiments.

Example 1: preparation of

1) Take methyl salicylate 1 (1.7mL, 13.1mmol) in a 100mL round bottom flask, add 60mL (0.2M) of dichloromethane, add 5.5mL triethylamine and 3.3mL trifluoromethane dropwise at 0°C Sulfonic anhydride, then reacted at 0°C for 2 hours, added water, extracted with ethyl acetate, combined the extracts, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, spin-dried the solvent, column chromatography (3% acetic acid ethyl ester/petroleum ether) to obtain a light yellow liquid, namely: compound 2 (3.3 g, yield 89%), Rf=0.56 (20% ethyl acetate-petroleum ether).

2) Weigh commercially available compound 3 (20g, 105mmol) into a 1L round bottom flask, add 500mL (0.2M) tetrahydrofuran, add 4.0g sodium borohydride in batches at 0°C, and then react at 0°C For 1 hour, add acetone to quench the reaction, add water, extract with ethyl acetate, combine the extracts, wash with saturated sodium chloride, dry over anhydrous sodium sulfate, filter, and spin to dry the solvent;

Dissolve the obtained crude product directly in 500 mL (0.2 M) of dry tetrahydrofuran, add dropwise 20 mL of 1,8-diazabicycloundec-7-ene and 26.6 mL of diphenylphosphoryl azide, and react at room temperature for 4 hours , adding 1N hydrochloric acid to quench the reaction, adding water, extracting with ethyl acetate, combining the extracts, washing with saturated sodium bicarbonate and saturated sodium chloride successively, drying with anhydrous sodium sulfate, filtering, and spinning to dry the solvent;

Dissolve the obtained crude product directly in 500mL (0.2M) tetrahydrofuran, add 32.4g triphenylphosphine at 0°C, react at room temperature for 16 hours, add 124mL ammonia water, continue to react at room temperature for 3 hours, add 500mL sodium hydroxide Solution (2.5N), continue to react at room temperature for 2 hours, extract with ethyl acetate, combine the extracts, wash with saturated sodium chloride, dry over anhydrous sodium sulfate, filter, and spin to dry the solvent;

The resulting crude product was directly dissolved in 500 mL (0.2 M) of dichloromethane, 21 mL of triethylamine and 26 mL of di-tert-butyl dicarbonate were added dropwise, and reacted at room temperature for 2 hours, then quenched by adding saturated ammonium chloride, adding water, and using Extracted with ethyl acetate, combined extracts, washed with saturated sodium bicarbonate and saturated sodium chloride successively, dried over anhydrous sodium sulfate, filtered, spin-dried the solvent, column chromatography (3% ethyl acetate/petroleum ether), obtained light Yellow liquid, ie: compound 4 (24.2 g, 79% yield over four steps), Rf=0.27 (20% ethyl acetate-petroleum ether).

3) Weigh compound 4 (1.5g, 5.1mmol) in a 50mL round bottom flask, add 180mg dichlorobistriphenylphosphine palladium, 49mg cuprous iodide, 25mL (0.2M) deoxygenated toluene, under nitrogen protection 2.9 mL of triethylamine and 1.1 mL of trimethylsilylacetylene were added, and reacted at room temperature for 12 hours, filtered through diatomaceous earth, spin-dried the solvent, and column chromatography (5-15% ethyl acetate/petroleum ether) gave light Yellow solid; the resulting product was dissolved in 25mL (0.2M) of methanol, 138mg of potassium carbonate was added at 0°C, reacted at 0°C for 10 minutes, quenched by adding saturated ammonium chloride, added water, extracted with ethyl acetate, The extracts were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, spin-dried, and column chromatography (20-30% ethyl acetate/petroleum ether) to obtain a pale yellow solid, namely: compound 5 (1.3 g, two-step yield 88%), Rf = 0.11 (20% ethyl acetate-petroleum ether).

4) Weigh compound 2 (50mg, 0.18mmol) and compound 5 (50mg, 0.18mmol) in a 50mL round bottom flask, add 10mg tetraphenylphosphine palladium, 196mg tetrabutylammonium iodide, 2mg cuprous iodide , add 2mL (0.1M) deoxygenated triethylamine/acetonitrile (1/4) under nitrogen protection, react at 80°C for 5 hours, filter with diatomaceous earth, spin to dry the solvent, column chromatography (10-15% ethyl acetate/petroleum ether) to give a light yellow solid, that is: the conjugated enynyl ester required for the reaction (52 mg, 70% yield), Rf = 0.41 (30% ethyl acetate-petroleum ether).

5) Weigh the prepared conjugated enynyl ester (100mg, 0.24mmol) into a 10mL reaction tube, add 1.2mL (0.2M) of dichloromethane, dropwise add 0.1mL trifluoroacetic acid at 0°C, then react at 0°C for 12 hours, spin the solvent, and use Vacuum pump to remove excess trifluoroacetic acid; directly dissolve the resulting crude product in 2 mL of methanol, add potassium hydroxide (27 mg, 0.48 mmol), react at 40 ° C for 18 hours, spin to dry the solvent, add water, and extract with dichloromethane , combined the extracts, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, spin-dried the solvent, and column chromatography (40% ethyl acetate/dichloromethane) gave a light yellow solid, namely: (61 mg, 90% yield), Rf = 0.73 (10% methanol/dichloromethane).

Tested: ¹ H NMR (400MHz, CDCl ₃ ): δ8.52(d, J=8.0Hz, 1H), 8.28(s, 1H), 8.19(d, J=8.5Hz, 1H), 7.86(d, J＝8.1Hz,1H),7.80–7.73(m,2H),7.73–7.68(m,1H),7.63(s,1H),7.60–7.51(m,2H),5.33(s,2H);

¹³ C NMR (100MHz, CDCl ₃ ): δ161.0, 153.6, 148.8, 140.0, 137.5, 132.4, 130.7, 130.2, 129.4, 128.8, 128.0(2C), 127.5(2C), 127.3(2C), 126.1, 101.1, 49.4 ppm;

HRMS (m/z): Exact mass calcd for C ₁₉ H ₁₂ N ₂ O [M] ⁺ : 284.0950; found 284.0947.

Example 2: and camptothecin preparation of

1) Take compound 6 (8.5g, 73mmol) in a 500mL round bottom flask, add 140mL (0.5M) of dry tetrahydrofuran, add 65mL lithium diisopropylamide (2.5N) dropwise at -78°C, React at low temperature for 15 minutes, raise the temperature of the system to 20°C and react for 15 minutes, quickly add 23.2mL trimethylchlorosilane, react at 20°C for 15 minutes, add saturated sodium bicarbonate, extract with dichloromethane, combine the extracts, Washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, spin-dried the solvent, and column chromatography (3% ethyl acetate/petroleum ether) gave a light yellow liquid (3.3g, yield 89%), Rf= 0.56 (20% ethyl acetate-petroleum ether);

Take triethyl orthoformate (12.7mL, 77mmol) in a 500mL round bottom flask, add 130mL (0.5M) of dry dichloromethane, add 9mL of tin tetrachloride dropwise at -78°C, and react at -78°C For 15 minutes, add the crude product obtained in the previous step, react at -78°C for 1 hour, add saturated sodium bicarbonate to quench the reaction, filter with diatomaceous earth, extract with dichloromethane, combine the extracts, wash with saturated sodium bicarbonate, no Dried over sodium sulfate, filtered, spin-dried the solvent, and column chromatography (5-20% ethyl acetate/petroleum ether) gave a light yellow liquid, namely: compound 7 (4.9g, two-step yield 39%), Rf =0.38 (10% ethyl acetate-petroleum ether).

2) Take compound 7 (3.6g, 21mmol) in a 250mL round bottom flask, add 100mL (0.5M) of dry tetrahydrofuran, add 10mL lithium diisopropylamide (2.5N) dropwise at -78°C, and React at ℃ for 30 minutes, add 2.3mL ethyl cyanoformate, react at -78℃ for 4 hours, add saturated ammonium chloride to quench the reaction, extract with dichloromethane, combine the extracts, wash with saturated sodium chloride, Dry over anhydrous sodium sulfate, filter, and spin dry the solvent;

Dissolve the obtained crude product directly in 20 mL (1.0 M) of dry tetrahydrofuran, add 26 mL of potassium bistrimethylsilylamide (1.0 N) dropwise at -78 °C, react at -78 °C for 30 minutes, and add 9.2 g of Comins reagent , reacted at room temperature for 3 hours, added saturated ammonium chloride and dichloromethane, extracted 3 times with dichloromethane, washed the organic phase once with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, spin-dried the solvent, and the column layer Analysis (2-4% ethyl acetate/petroleum ether) gave a light yellow liquid, namely: compound 8 (5.8 g, yield 73% in two steps), Rf=0.57 (5% ethyl acetate-petroleum ether).

3) Weigh compound 8 (4.0g, 10.6mmol) and compound 5 (3.2g, 11.2mmol) prepared in Example 1 in a 250mL round bottom flask, add 373mg dichloroditriphenylphosphine palladium, 251mg triphenylphosphine palladium, Phenylphosphine, 101mg cuprous iodide, add 106mL (0.1M) deoxygenated toluene and 9mL triethylamine under the protection of nitrogen, react at 60°C for 2 hours, filter with diatomaceous earth, spin to dry the solvent, column chromatography (10-20% ethyl acetate/petroleum ether), to obtain a light yellow liquid, that is: the conjugated enynyl ester required for the reaction (5.7 g, 75% yield), Rf = 0.46 (20% ethyl acetate-petroleum ether).

4) Weigh the prepared conjugated enynyl ester (58mg, 0.11mmol) into a 10mL reaction tube, add 0.6mL (0.2M) of dichloromethane, dropwise add 0.05mL trifluoroacetic acid at 0°C, react at 0°C for 12 hours, spin dry the solvent, and use Vacuum pump is enough, the obtained crude product is directly dissolved in 1mL methanol, potassium hydroxide (12mg, 0.22mmol) is added, reacted at 40°C for 8 hours, water is added, extracted with dichloromethane, combined extracts, anhydrous sodium sulfate Drying, filtering, spin-drying solvent, column chromatography (1% methanol/dichloromethane), a light yellow solid was obtained, namely (30 mg, 73% yield), Rf = 0.34 (5% methanol/dichloromethane).

the prepared for camptothecin The preparation, the specific synthesis method is as follows:

1) Weigh the product obtained above (126mg, 0.35mmol) in a 25mL round bottom flask, add 7mL (0.05M) of acetonitrile, add 92 microliters of trifluoromethanesulfonic acid in batches, react at room temperature for 0.5 hours, add saturated sodium bicarbonate to quench the reaction, Add water, extract with dichloromethane, combine the extracts, dry over anhydrous sodium sulfate, filter, spin to dry the solvent, and column chromatography (1% methanol/dichloromethane) to obtain a light yellow solid, namely: compound 9 (95 mg, produced The yield was 86%), Rf = 0.33 (5% methanol/dichloromethane).

2) The obtained compound 9 can realize camptothecin by a two-step known synthetic method full synthesis. (SP Chavan, MS Venkatraman, ARKIVOC 2005, 165.).

Tested: ¹ H NMR (500MHz, DMSO): δ8.69(s, 1H), 8.17(d, J=8.4Hz, 1H), 8.13(d, J=8.1Hz, 1H), 7.87(t, J =7.5Hz,1H),7.72(t,J=7.4Hz,1H),7.35(s,1H),6.53(s,1H),5.43(s,2H),5.29(s,2H),1.95–1.76 (m,2H),0.89(t,J=7.3Hz,3H);

¹³ C NMR (125MHz, DMSO): δ172.9, 157.3, 153.1, 150.5, 148.4, 146.0, 132.0, 130.9, 130.3, 129.5, 129.0, 128.4, 128.1, 119.6, 97.2, 72.9, 65.7, 50.7, 320.8mpp;

HRMS (m/z): Exact mass calcd for C ₂₀ H ₁₆ N ₂ O ₄ [M] ⁺ : 348.1110; found 348.1115.

Example 3: preparation of

1) Weigh compound 10 (1.0g, 4.1mmol) in a 250mL round bottom flask, add 20mL acetonitrile, 82mL silver nitrate aqueous solution (0.1N), 20mL 10% sodium hydroxide aqueous solution, react at room temperature for 15 hours, diatoms Filter with soil, add 6N aqueous sodium hydroxide solution to adjust the pH value to less than 5, extract with ethyl acetate, combine the extracts, wash once with 1N aqueous hydrochloric acid solution, dry over anhydrous sodium sulfate, filter, and spin to dry the solvent;

Dissolve the obtained crude product directly in 20 mL (0.2M) N,N-dimethylformamide, add 338 mg potassium carbonate and 0.5 mL dimethyl sulfate, react at room temperature for 2 hours, add methanol to quench the reaction, and use ethyl acetate Extraction, combined extracts, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, spin-dried solvent, column chromatography (15% ethyl acetate/petroleum ether), to obtain a light yellow liquid, namely: compound 11 (1.06 g, two-step yield 99%), Rf = 0.30 (20% ethyl acetate-petroleum ether).

2) Weigh compound 11 (107mg, 0.39mmol) and compound 5 (100mg, 0.35mmol) prepared in Example 1 in a 25mL round bottom flask, add 14mg dichlorodibenzonitrile palladium, 20mg tri-tert-butyl tetrafluoroborate Phosphine, 3mg cuprous iodide, 392mg tetrabutylammonium iodide, add 3.5mL (0.1M) deoxygenated triethylamine/acetonitrile (1/4) under nitrogen protection, react at 80°C for 2 hours, silicon Filter through algal earth, spin to dry the solvent, and column chromatography (10-20% ethyl acetate/petroleum ether) to obtain a light yellow solid, namely: the conjugated enynyl ester required for the reaction (65 mg, 38% yield), Rf = 0.30 (40% ethyl acetate-petroleum ether).

3) Weigh the prepared conjugated enynyl ester (47mg, 0.1mmol) into a 5mL reaction flask, add 0.6mL (0.2M) of dichloromethane, dropwise add 0.05mL trifluoroacetic acid at 0°C, react at 0°C for 12 hours, spin dry the solvent, and use Vacuum pump is enough, the resulting crude product is directly dissolved in 1mL of methanol, cesium carbonate (65mg, 0.2mmol) is added, reacted at 40°C for 12 hours, added water, extracted with dichloromethane, combined extracts, dried over anhydrous sodium sulfate , filtered, spin-dried the solvent, and column chromatography (5-10% methanol/dichloromethane) gave a light yellow solid, namely (19.2 mg, 56% yield over two steps), Rf = 0.51 (5% methanol-dichloromethane).

Tested: ¹ H NMR (500MHz, CDCl ₃ ): δ8.23(s, 1H), 8.17(d, J=8.5Hz, 1H), 7.89–7.81(m, 2H), 7.79–7.74(m, 1H ),7.61–7.55(m,1H),7.54(s,1H),7.06(s,1H),5.31(s,2H),4.04(s,3H),4.03(s,3H);

¹³ C NMR (125MHz, CDCl ₃ ): δ160.3, 153.8, 153.4, 149.8, 148.7, 138.7, 132.9, 130.5, 130.1, 129.3, 128.8, 128.0, 127.8, 127.1, 120.3, 107.2, 107.565.2, 100.3, 8 49.5ppm;

HRMS (m/z): Exact mass calcd for C ₂₁ H ₁₆ N ₂ O ₃ [M]+: 344.1161; found 344.1163.

Example 4: preparation of

1) Dissolve compound 12 (1.0 g, 7.0 mmol) in 35 mL (0.2 M) of dry tetrahydrofuran, add 9.1 mL of bis(trimethylsilyl) potassium amide at -78°C, react for 30 minutes, add 3.0 g of N -Phenyl bis(imine trifluoromethanesulfonate), react overnight at room temperature, add saturated ammonium chloride to quench the reaction, add water, extract with ethyl acetate, combine the extracts, wash with saturated sodium chloride, anhydrous Sodium sulfate was dried, filtered, the solvent was spin-dried, and column chromatography (5% ethyl acetate/petroleum ether) gave a light yellow solid, namely: compound 13 (1.93 g, yield 100%), Rf=0.66 (20% ethyl acetate-petroleum ether).

2) Weigh compound 13 (97mg, 0.35mmol) and compound 5 (100mg, 0.35mmol) prepared in Example 1 in a 25mL round bottom flask, add 20mg tetraphenylphosphine palladium, 392mg tetrabutylammonium iodide, Add 3.4mg of cuprous iodide to 3.5mL (0.1M) deoxygenated triethylamine/acetonitrile (1/4) under nitrogen protection, react at 80°C for 4 hours, filter with diatomaceous earth, spin dry the solvent, and Chromatography (10-20% ethyl acetate/petroleum ether) yielded a pale yellow solid, namely: the conjugated enynyl ester required for the reaction (106 mg, 94% yield), Rf = 0.44 (30% ethyl acetate-petroleum ether).

3) Weigh the prepared conjugated enynyl ester (50mg, 0.12mmol) into a 5mL reaction flask, add 0.6mL (0.2M) of dichloromethane, dropwise add 0.05mL trifluoroacetic acid at 0°C, react at 0°C for 12 hours, spin dry the solvent, and use Vacuum pump to dry, the resulting crude product was directly dissolved in 1mL of methanol, potassium tert-butoxide (27mg, 0.24mmol) was added, reacted at room temperature for 5 hours, added water, extracted with dichloromethane, combined extracts, anhydrous sodium sulfate Drying, filtering, spin-drying solvent, column chromatography (50-80% ethyl acetate/dichloromethane), to obtain a light yellow solid, which is (32 mg, 95% yield over two steps), Rf = 0.43 (5% methanol-dichloromethane).

Tested: ¹ H NMR (300MHz, CDCl ₃ ): δ8.29(s, 1H), 8.17(d, J=8.5Hz, 1H), 7.88(d, J=8.1Hz, 1H), 7.77(t, J＝7.7Hz, 1H), 7.60(t, J＝7.5Hz, 1H), 7.28(s, 1H), 5.23(s, 2H), 2.98(dd, J＝17.3, 8.1Hz, 4H), 2.36– 2.06(m,2H);

¹³ C NMR (125MHz, CDCl ₃ ): δ159.6, 156.2, 153.2, 148.7, 144.7, 133.5, 130.8, 130.2, 129.4, 129.1, 128.0, 127.8, 127.3, 99.4, 49.5, 34.2, 29.9, 23.9ppm;

HRMS (m/z): Exact mass calcd for C ₁₈ H ₁₄ N ₂ O [M] ⁺ : 274.1106; found 274.1107.

Example 5: preparation of

1) Weigh compound 14 (750mg, 3.5mmol) and compound 5 (500mg, 1.8mmol) prepared in Example 1 in a 50mL round bottom flask, add 100mg tetraphenylphosphine palladium, 2.0g tetrabutylammonium iodide , 17mg cuprous iodide, under the protection of nitrogen, add 18mL (0.1M) deoxygenated triethylamine/acetonitrile (1/4), react at 50°C for 4 hours, filter with diatomaceous earth, spin to dry the solvent, column layer Analysis (30% ethyl acetate/petroleum ether) to give a light yellow solid, namely: the conjugated enynyl ester required for the reaction (628 mg, 97% yield), Rf = 0.52 (50% ethyl acetate-petroleum ether).

2) Weigh the prepared conjugated enynyl ester (200mg, 0.55mmol) into a 10mL reaction flask, add 2.7mL (0.2M) of dichloromethane, dropwise add 0.2mL trifluoroacetic acid at 0°C, react at 0°C for 12 hours, spin dry the solvent, and use The resulting crude product was directly dissolved in 4 mL of methanol, potassium carbonate (150 mg, 1.1 mmol) was added, and reacted at room temperature for 12 hours, water was added, extracted with dichloromethane, the extracts were combined, and dried over anhydrous sodium sulfate. Filtration, spin-dried solvent, column chromatography (2-2% methanol/dichloromethane), to obtain light brown solid, which is (39 mg, 30% yield over two steps), Rf = 0.44 (5% methanol-dichloromethane).

The resulting compound Consistent with known compound data in published literature (T.Kametani, H.Nemoto, H.Takeda, S.Takano, Tetrahedron 1970, 26, 5753; HB Zhou, GS Liu, ZJ Yao, Org. Lett. 2007, 9, 2003.) .

Embodiment 6: preparation of

1) Referring to the method for preparing compound 5 in Example 1, compound 16 was prepared using compound 15 as a raw material.

2) Weigh compound 16 (100mg, 0.36mmol) and known compound 17 (137mg, 0.44mmol) into a 10mL round bottom flask, add 14mg dichlorodibenzonitrile palladium, 20mg tri-tert-butylphosphine tetrafluoroborate, 3mg Cuprous iodide, 400mg tetrabutylammonium iodide, add 3.6mL (0.1M) deoxygenated triethylamine/acetonitrile (1/4) under nitrogen protection, react at 80°C for 12 hours, filter with diatomaceous earth , spin to dry the solvent, column chromatography (12-15% ethyl acetate/petroleum ether), to obtain a light yellow liquid, that is: the conjugated enynyl ester required for the reaction (99 mg, 62% yield), Rf = 0.31 (20% ethyl acetate-petroleum ether).

3) Weigh the prepared conjugated enynyl ester (64mg, 0.15mmol) into a 5mL reaction flask, add 0.7mL (0.2M) of dichloromethane, dropwise add 0.1mL trifluoroacetic acid at 0°C, react at 0°C for 12 hours, spin dry the solvent, and use Vacuum pump to dry, the resulting crude product was directly dissolved in 1.5mL methanol, triethylamine (42μL, 0.3mmol) was added, reacted at room temperature for 8 hours, added water, extracted with dichloromethane, combined extracts, anhydrous sodium sulfate Dry, filter, spin dry the solvent, column chromatography (20-30% ethyl acetate/dichloromethane), obtain light yellow solid, namely (38 mg, 74% yield in two steps), Rf = 0.26 (40% ethyl acetate-petroleum ether).

Tested: ¹ H NMR (500MHz, 5% CD ₃ OD/CDCl ₃ ): δ7.82(d, J=2.6Hz, 1H), 7.53(d, J=8.7Hz, 1H), 7.26(s, 1H ),7.13(s,1H),6.96(s,1H),6.85(s,1H),6.04(s,2H),5.05(s,3H);

¹³ C NMR (125MHz, 5% CD ₃ OD/CDCl ₃ ): δ160.9, 158.1, 149.7, 148.5, 140.3, 132.3, 131.5, 127.8, 127.6, 124.8, 123.1, 106.9, 103.7, 101.9, 100.6, 97.0, 55. 51.9ppm;

HRMS (m/z): Exact mass calcd for C ₁₈ H ₁₃ NO ₄ [M]+: 307.0845; found 307.0848.

Finally, it should be pointed out here that: the above are only some preferred embodiments of the present invention, and should not be interpreted as limiting the protection scope of the present invention. Those skilled in the art can make some non-essential improvements and adjustments based on the above-mentioned contents of the present invention. All belong to the protection scope of the present invention.

Claims (8)

1. one kind synthesizes 5-6 the method for ring structure in camptothecine compounds, it is characterised in that: described method is to make to have There is intramolecular series connection cyclization in the conjugated enynes ester of Formula II structure, thus prepares the 5-6 shown in Formulas I also in a solvent Ring structure, concrete reaction equation is as follows:

Wherein:

R₁And R₂It is respectively and independently selected from hydrogen, alkyl, cycloalkyl, aryl or heterocyclic radical；Or, R₁And R₂Formed full together With or undersaturated carbocyclic ring or heterocycle；

R₃And R₄It is respectively and independently selected from hydrogen, alkyl, cycloalkyl, aryl or heterocyclic radical；Or, R₃And R₄Formed full together With or undersaturated carbocyclic ring or heterocycle；

R is selected from C₁～C₄Alkyl；

P is amino protecting group.

Method the most according to claim 1, it is characterised in that compound of formula I has a following general structure:

Wherein:

Ring A has a structure shown in formula A-1, A-2 or A-3:

Wherein: Ra₁、Ra₄、Ra₅The most independent choosing From hydrogen, alkyl, aryl, fluorine or alkoxyl；Ra₂、Ra₃It is independently selected from hydrogen, alkyl, aryl, fluorine or alkoxyl； Or, Ra₁And Ra₂、Ra₂And Ra₃、Ra₃And Ra₄、Ra₁And Ra₅Form carbocyclic ring or heterocycle together；

Ring B has a structure shown in formula B:

Wherein: Rb₁、Rb₂, Rx, Rm be independently selected from hydrogen, alkyl, aryl, fluorine or alcoxyl Base；Dotted line represents optional double bond, and X is C, N, O or S, and when being double bond between 1 and 2, X is only C Or N；When being N for double bond and X between 1 and 2, Rx does not exists；

M is 0,1,2 or 3, and when m is 0, Rm does not exists.

Method the most according to claim 2, it is characterised in that in ring A: Ra₁、Ra₄、Ra₅It is selected from hydrogen；Ra₂、 Ra₃It is selected from hydrogen, fluorine, alkyl or alkoxyl；Or, Ra₂And Ra₃Form oxa-ring together；In ring B: Rb₁、Rb₂、 Rx, Rm are independently selected from hydrogen, alkyl, aryl, fluorine or alkoxyl；Dotted line represents optional double bond, and X is C, N Or O, when being double bond between 1 and 2, X is C or N；When being N for double bond and X between 1 and 2, Rx does not exists；M is 0 or 1, and when m is 0, Rm does not exists.

Method the most according to claim 1, it is characterised in that: make the conjugated enynes ester with Formula II structure be dissolved in solvent In, first at acid condition, react 1～5 hour at 0 ± 5 DEG C, then concentrate and remove acid, then make the product obtained the most molten In solvent, in alkalescence condition, react further at 0～60 DEG C, prepare the compound of Formulas I structure.

Method the most according to claim 4, it is characterised in that: acid used in reaction is selected from hydrochloric acid, sulfuric acid, first sulphur At least one in acid, trifluoroacetic acid, p-methyl benzenesulfonic acid, camphorsulfonic acid.

Method the most according to claim 4, it is characterised in that: alkali used in reaction selected from lithium diisopropylamine, Lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, lithium carbonate, sodium carbonate, carbon Acid potassium, cesium carbonate, lithium hydroxide, NaOH, potassium hydroxide, potassium phosphate, sodium tert-butoxide, potassium tert-butoxide, triethylamine, At least one in diisopropyl ethyl amine, 1,8-diazabicylo 11 carbon-7-alkene.

Method the most according to claim 4, it is characterised in that: solvent used in reaction selected from toluene, oxolane, Glycol dimethyl ether, dichloromethane, 1,4-dioxane, methyl alcohol, the tert-butyl alcohol, N,N-dimethylformamide, dimethyl sulfoxide, At least one in acetonitrile.

Method the most according to claim 4, it is characterised in that: the reaction temperature under the conditions of alkalescence is 0～60 DEG C.