CN100558729C - The synthetic method of a kind of 7-ethyl-N-oxidation camptothecine - Google Patents

Abstract

The present invention relates to the synthetic method of a kind of 7-ethyl-N-oxidation camptothecine: get catalyzer according to 0.1%～3% of 7-ethyl-camptothecin weight; Catalyzer is added in the Glacial acetic acid solvent, add 30% hydrogen peroxide again, stir; Add intermediate 7-ethyl-camptothecin reaction again, be evaporated to driedly, excess is with chloroform-methanol mixed solvent recrystallization, product.The invention solves that the synthetic difficulty of existing synthetic method is big, synthesis condition is difficult to control, easily produce a large amount of by products, by product is difficult to isolating technical problem.The present invention makes the reaction synthesis temperature reduce to 50 ℃, has saved a large amount of energy, has reduced environmental pollution; Make the reaction times reduce to 1.5h, no coupling product produces, and has improved quality product; Yield can reach 85%.

Description

The synthetic method of a kind of 7-ethyl-N-oxidation camptothecine

Technical field

The present invention relates to the synthetic method of a kind of 7-ethyl-N-oxidation camptothecine.

Background technology

Irinotecan is a kind of PTS, is mainly used in the treatment digestive system tumor clinically as cancer of the stomach, colorectal carcinoma, the rectum cancer etc., and curative effect is preferably arranged, and also can be used for treating leukemia, bladder cancer, liver cancer etc.The crucial actives of irinotecan is exactly intermediate 7-ethyl-N-oxidation camptothecine.Because of it is a kind of active alkaloid, synthetic middle meeting produces a large amount of by products, and synthetic difficulty is very big.If condition control is bad, reaction is incomplete, and its unreacted raw material is mixed in the product, is difficult to separate, but also can produces a large amount of by products, also is difficult to separate.

Present technology is earlier glacial acetic acid and hydrogen peroxide to be mixed; Be warming up to 80 ℃, add the 7-ethyl-camptothecin, oxidizing reaction 3h concentrates, and filters, and gets crude product.Particularly in the oxidizing reaction, must strict control reaction conditions, time, temperature is key factor, however the reaction times has lacked or temperature is low, all can make raw material reaction incomplete, and when the raw material unreacted is complete, just begin to produce by product.So be not enough only with period and temperature.

At present, a large amount of patent documentations both at home and abroad all are adjusting processes on time, temperature, proportioning raw materials, can not solve root problem.

Summary of the invention

The present invention proposes the synthetic method of a kind of 7-ethyl-N-oxidation camptothecine, it has solved, and the synthetic difficulty of existing synthetic method is big, synthesis condition is difficult to control, easily produce a large amount of by products, by product is difficult to isolating technical problem.

Technical solution of the present invention is:

The synthetic method of a kind of 7-ethyl-N-oxidation camptothecine may further comprise the steps:

1] adopt ordinary method to prepare intermediate 7-ethyl-camptothecin;

2] get catalyzer Vanadium Pentoxide in FLAKES or ammonium molybdate; The weight of described Vanadium Pentoxide in FLAKES is the 0.2%-2% of 7-ethyl-camptothecin weight; The weight of described ammonium molybdate is the 0.2%-2% of 7-ethyl-camptothecin weight;

3] catalyzer is added in the Glacial acetic acid solvent, slowly add 30% hydrogen peroxide down in normal temperature again, stir 0.5h;

4] add intermediate 7-ethyl-camptothecin, temperature of reaction is no more than 60 ℃, and reaction times 1-2h is evaporated to driedly, and excess is with chloroform-methanol mixed solvent recrystallization, 7-ethyl-N-oxidation camptothecine.

Above-mentioned reaction times the best is 1h, and temperature of reaction the best is 40--58 ℃.

The advantage of the inventive method is:

1, make synthesis temperature reduce to 50 ℃ by original 80 ℃.Synthetic method in the background technology is under the situation that does not add catalyzer, if synthesis temperature is lower than 60 ℃, then reaction is very slow, if synthesis temperature is higher than 60 ℃, can produce a large amount of by products again.The inventive method is added effective catalyst, solved fully low-temp reaction speed slowly and high temperature produce the problem of a large amount of by products, saved a large amount of energy, reduced environmental pollution.

2, make the reaction times reduce to 1.5h by original 3h.Synthetic method in the background technology is under the situation that does not add catalyzer, if when generated time is lower than 2h, then reactivity is very low; When if generated time is higher than 2h, has by product again and produce thereupon.The inventive method has been added effective catalyst, and raw material reaction not exclusively in short-term, long reaction time produces the problem of a large amount of by products again to have solved the reaction times fully.Both save the energy, improved quality product again.

3, the inventive method yield height.The yield of the synthetic method in the background technology is about 70%, and the inventive method adopts effective catalyst in oxidizing process, and yield can reach 85%.

4, no coupling product of the present invention produces.The by product that is produced in the synthetic method in the background technology does not have utility value, and is difficult to separate.The present invention adopts brand-new synthetic method, has utilized catalyzer, and no coupling product produces.

Embodiment

The invention provides the effective catalyst method of multiple synthetic 7-ethyl-N-oxidation camptothecine:

Embodiment 1:

0.05～0.2g heteropolyacid catalyst is added in the 1800mL Glacial acetic acid, slowly add 200mL30% hydrogen peroxide (oxygenizement) down in normal temperature again, stir 0.5h, add 10g intermediate 7-ethyl-camptothecin, be warming up to 40～58 ℃ of reaction 1h, be evaporated to dried, excess filters, in 60 ℃ of dry 4h with chloroform-methanol mixed solvent recrystallization, get yellow needle crystal, be 7-ethyl-N-oxidation camptothecine 9.1g, productive rate 85%mp255 ℃ (decomposition).NMR (DMSO-d6): 0.87 (3H, t, J=7Hz), 1.28 (3H, t, j=7Hz), 1.84 (2H, G, J=7Hz), 3.10 (3H, G, J=7Hz), 5.26 (2H, s), 5.36 (2H, s), 6.24 (1H, s, D ₂D-is commutative), 7.80 (3H, m), 8.10 (1H, s), 8.35 (1H, m).MS:m/E[M ⁺] (C ₂₂H ₂ON ₂O ₅=392) .NMR and MS have confirmed that all product structure HPLC normalization method confirms that purity is 96%.Get product.

Embodiment 2:

The phospho-molybdic acid catalyzer of 0.01～0.15g is added in the 1800mL Glacial acetic acid, slowly add the 200mL30% hydrogen peroxide down in normal temperature again, stir 0.5h, add 10g intermediate 7-ethyl-camptothecin, be warming up to 40～58 ℃ of reaction 1h, be evaporated to dried, excess filters, in 60 ℃ of dry 4h with chloroform-methanol mixed solvent recrystallization, get yellow needle crystal, be 7-ethyl-N-oxidation camptothecine 9.19g, productive rate 86%.Mp255 ℃ (decomposition).NMR (DMSO-d6): 0.87 (3H, t, J=7HZ), 1.28 (3H, t, J=7HZ), 1.84 (2H, G, J=7HZ), 3.10 (3H, G, J=7HZ), 5.26 (2H, s),, 5.36 (2H, s), 6.24 (1H, s, D ₂D-is commutative), 7.80 (3H, m), 8.10 (1H, s), 8.35 (1H, m) .MS:m/E[M ⁺] (C ₂₂H ₂ON ₂O ₅=392) .NMR and MS have confirmed that all product structure HPLC normalization method confirms that purity is 96%.Get product.

Embodiment 3:

The phosphotungstic acid catalyst of 0.05～0.3g is added in the 1800mL Glacial acetic acid, slowly add the 200mL30% hydrogen peroxide down in normal temperature again, stir 0.5h, add 10g intermediate 7-ethyl-camptothecin, be warming up to 40～58 ℃ of reaction 1h, be evaporated to dried, excess filters, in 60 ℃ of dry 4h with chloroform-methanol mixed solvent recrystallization, get yellow needle crystal, be 7-ethyl-N-oxidation camptothecine 9.1g, productive rate 85%mp255 ℃ (decomposition).NMR (DMSO-d6): 0.87 (3H, t, J=7HZ), 1.28 (3H, t, J=7HZ), 1.84 (2H, G, J=7Hz), 3.10 (3H, G, J=7HZ), 5.26 (2H, s), 5.36 (2H, s), 6.24 (1H, s, D ₂D-is commutative), 7.80 (3H, m), 8.10 (1H, s), 8.35 (1H, m) .MS:m/E[M ⁺] (C ₂₂H ₂ON ₂O ₅=392) .NMR and MS have confirmed that all product structure HPLC normalization method confirms that purity is 96%.Get product.

Embodiment 4:

The vanadium pentoxide catalyst of 0.02～0.2g is added in the 1800mL Glacial acetic acid, slowly add the 200mL30% hydrogen peroxide down in normal temperature again, stir 0.5h, add 10g intermediate 7-ethyl-camptothecin, be warming up to 40～58 ℃ of reaction 1h, be evaporated to dried, excess filters, in 60 ℃ of dry 4h with chloroform-methanol mixed solvent recrystallization, get yellow needle crystal, be 7-ethyl-N-oxidation camptothecine 9.0g, productive rate 84%mp255 ℃ (decomposition).NMR (DMSO-d6): 0.87 (3H, t, J=7HZ), 1.28 (3H, t, J=7HZ), 1.84 (2H, G, J=7HZ), 3.10 (3H, G, J=7HZ), 5.26 (2H, s), 5.36 (2H, s), 6.24 (1H, s, D ₂D-is commutative), 7.80 (3H, m), 8.10 (1H, s), 8.35 (1H, m) .MS:m/E[M ⁺] (C ₂₂H ₂ON ₂O ₅=392) .NMR and MS have confirmed that all product structure HPLC normalization method confirms that purity is 96%.Get product.

Embodiment 5:

The ammonium molybdate catalyzer of 0.02～0.2g is added in the 1800mL Glacial acetic acid, slowly add the 200mL30% hydrogen peroxide down in normal temperature again, stir 0.5h, add 10g intermediate 7-ethyl-camptothecin, be warming up to 40～58 ℃ of reaction 1h, be evaporated to dried, excess filters, in 60 ℃ of dry 4h with chloroform-methanol mixed solvent recrystallization, get yellow needle crystal, be 7-ethyl n-oxidation camptothecine 9.0g, productive rate 84%mp255 ℃ (decomposition).NMR (DMSO-d6): 0.87 (3H, t, J=7HZ), 1.28 (3H, t, J=7HZ), 1.84 (2H, G, J=7HZ), 3.10 (3H, G, J=7HZ), 5.26 (2H, s), 5.36 (2H, s), 6.24 (1H, s, D ₂D-is commutative), 7.80 (3H, m), 8.10 (1H, s), 8.35 (1H, m).MS:m/E[M ⁺] (C ₂₂H ₂ON ₂O ₅=392) .NMR and MS have confirmed that all product structure HPLC normalization method confirms that purity is 96%.Get product.

More than each embodiment through more than 6 times repeatedly the experiment, yield is all very stable.

The principle of the invention: at first utilize propionic aldehyde, ethylation reaction generates intermediate 7-ethyl-camptothecin.7-ethyl-the reaction mechanism of N-oxidation camptothecine is to use the Peracetic Acid oxidizing reaction in solvent acetic acid, but directly unsatisfactory with the Peracetic Acid reaction, and forms a large amount of by products.So the mechanism of this reaction constantly produces Peracetic Acid after can thinking that basically hydrogen peroxide adds in the glacial acetic acid, and simultaneous oxidation 7-ethyl-camptothecin.The 7-ethyl-camptothecin is progressively oxidation in the continuous formation of Peracetic Acid.So the time is less than 1.5h reaction not exclusively, can produce a large amount of by products again after being higher than 2h.For this reason, the present invention is by testing instruments, and high performance liquid phase is followed the tracks of detection.Confirm that temperature of reaction is lower than 60 ℃, reaction times 1.5h is an optimum reaction condition, but this condition must could realize under the condition of adding catalyzer.

The inventive method reaction process is as follows:

Claims (2)

1, the synthetic method of a kind of 7-ethyl-N-oxidation camptothecine is characterized in that: said method comprising the steps of:

1] adopt ordinary method to prepare intermediate 7-ethyl-camptothecin;

2] get catalyzer Vanadium Pentoxide in FLAKES or ammonium molybdate; The weight of described Vanadium Pentoxide in FLAKES is the 0.2%-2% of 7-ethyl-camptothecin weight; The weight of described ammonium molybdate is the 0.2%-2% of 7-ethyl-camptothecin weight;

3] catalyzer is added in the Glacial acetic acid solvent, slowly add 30% hydrogen peroxide down in normal temperature again, stir 0.5h;

4] add intermediate 7-ethyl-camptothecin, temperature of reaction is no more than 60 ℃, and reaction times 1-2h is evaporated to driedly, and excess is with chloroform-methanol mixed solvent recrystallization, 7-ethyl-N-oxidation camptothecine.

2, the synthetic method of 7-ethyl according to claim 1-N-oxidation camptothecine, it is characterized in that: the described reaction times is 1h, temperature of reaction is 40--58 ℃.