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CN-121991087-A - Synthetic method of camptothecin derivative

CN121991087ACN 121991087 ACN121991087 ACN 121991087ACN-121991087-A

Abstract

The invention relates to the technical field of camptothecin derivative preparation, in particular to a method for synthesizing a camptothecin derivative, which takes 2-nitroacetophenone and isopropylamine as raw materials and obtains the camptothecin derivative through Mannich reaction, methanesulfonylation reaction, nitroreduction reaction and ring closure reaction. The method for synthesizing the camptothecine derivative, which is disclosed by the invention, is used for splitting the complex camptothecine derivative into two fragments 1- (2-aminophenyl) -3- (N-isopropyl-N-methylsulfonylamino) propan-1-one and a compound V which are easy to prepare, and finally, a plurality of rings and chemical bonds are simultaneously constructed through one-step efficient ring closing reaction, so that yield attenuation caused by gradual accumulation of yield in the traditional linear synthesis is avoided, and the total yield is improved.

Inventors

  • DING YINPING
  • XU QIANG
  • LUO LIN

Assignees

  • 四川悦合生物医药股份有限公司

Dates

Publication Date
20260508
Application Date
20260128

Claims (10)

  1. 1.A synthetic method of a camptothecin derivative is characterized by comprising the following steps: S1, adding 2-nitroacetophenone, paraformaldehyde, isopropylamine and hydrochloric acid into isopropanol, heating and stirring for reaction, concentrating under reduced pressure after the reaction is finished, extracting to remove water layer impurities, adjusting the pH of the water layer, extracting again, drying an organic phase, filtering and concentrating under reduced pressure to obtain 1- (2-nitrophenyl) -3- (isopropylamino) propan-1-one; S2, adding the 1- (2-nitrophenyl) -3- (isopropylamino) propan-1-one and N, N-diisopropylethylamine obtained in the S1 into dichloromethane, and adding a methanesulfonylation reagent for reaction at room temperature to obtain 1- (2-nitrophenyl) -3- (N-isopropyl-N-methanesulfonylamino) propan-1-one; S3, adding the 1- (2-nitrophenyl) -3- (N-isopropyl-N-methylsulfonylamino) propan-1-one obtained in the S2 into methanol, and stirring for nitroreduction reaction to obtain 1- (2-aminophenyl) -3- (N-isopropyl-N-methylsulfonylamino) propan-1-one; S4, carrying out a ring closure reaction on the 1- (2-aminophenyl) -3- (N-isopropyl-N-methylsulfonylamino) propan-1-one obtained in the S3 and the compound V under an acidic condition to obtain the camptothecin derivative.
  2. 2. The method for synthesizing a camptothecin derivative according to claim 1, wherein in S1, the temperature of the heating and stirring reaction is 80-100 ℃ and the time is 1-24h.
  3. 3. The method for synthesizing a camptothecin derivative according to claim 1, wherein in S2, the methanesulfonylating agent comprises one or more of methanesulfonyl chloride and methanesulfonic anhydride.
  4. 4. The method for synthesizing the camptothecin derivative according to claim 1, wherein in S2, dilute hydrochloric acid is added for separating after the reaction is finished, an organic phase is washed, dried, filtered and concentrated under reduced pressure, and the obtained crude product is dissolved, crystallized, filtered and dried to obtain 1- (2-nitrophenyl) -3- (N-isopropyl-N-methylsulfonylamino) propan-1-one.
  5. 5. The method for synthesizing a camptothecin derivative according to claim 1, wherein: in S3, the nitro reduction reaction includes one of catalytic hydrogenation reaction, metal reduction reaction, transfer hydrogenation reaction, and alkali sulfide reduction reaction.
  6. 6. The method for synthesizing a camptothecin derivative according to claim 5, wherein in S3, hydrogen and a catalyst are added during the catalytic hydrogenation reaction, and the catalyst is one of palladium carbon, platinum carbon and Raney nickel; one or more of iron powder, stannous chloride and zinc powder are added during metal reduction reaction; adding palladium carbon and a hydrogen donor during transfer hydrogenation reaction, wherein the hydrogen donor is one of ammonium formate, cyclohexene and hydrazine hydrate; One or more of sodium sulfide, sodium hydrosulfide, ammonium sulfide, sodium hydrosulfite and sodium thiosulfate are added during the alkali sulfide reduction reaction.
  7. 7. The method for synthesizing the camptothecin derivative according to claim 1, wherein in S3, the nitroreduction reaction temperature is 0-40 ℃, the reaction time is 5-48 hours, the reaction is carried out, the filtration is carried out, hydrochloric acid is added into the filtrate, the filtrate is concentrated under reduced pressure, the obtained crude product is dissolved and crystallized, and the filtration and the drying are carried out to obtain the 1- (2-aminophenyl) -3- (N-isopropyl-N-methylsulfonylamino) propan-1-one.
  8. 8. The method for synthesizing a camptothecin derivative according to claim 1, wherein in S4, the structural formula of the compound V is 。
  9. 9. The method for synthesizing a camptothecin derivative according to claim 1, wherein in S4, the acidic condition is that one of p-toluenesulfonic acid monohydrate and toluene and N-methylpyrrolidone is added, the temperature of the ring closure reaction is 80-150 ℃ and the time is 5-24h.
  10. 10. The method for synthesizing a camptothecin derivative according to claim 1, wherein in S4, the reaction is cooled to room temperature after the completion of the ring closure reaction, the obtained reaction solution is added into water and stirred, the crude product is obtained after filtration, the crude product is added into methanol and stirred, and the camptothecin derivative is obtained after filtration and drying.

Description

Synthetic method of camptothecin derivative Technical Field The invention relates to the technical field of camptothecin derivative preparation, in particular to a synthetic method of a camptothecin derivative. Background The camptothecine derivative has topoisomerase I inhibiting activity and is cell activity fragment in the antibody molecule of the Kang Shatuo bead for ADC medicine injection. The use of Kang Shatuo beadlets for injection was used in adult patients with unresectable locally advanced or metastatic triple negative breast cancer who had previously received at least 2 systemic treatments, at least 1 of which were directed to advanced or metastatic stages. The synthesis of camptothecin derivatives mainly comprises two methods, namely a total synthesis method and a semi-synthesis method. The total synthesis method is that Sang-sup Jew et al in Korea takes o-nitrotea ethanone as a raw material and obtains the belotecan through five steps of reaction of Mannich reaction, benzyloxycarbonyl protection, sodium hydrosulfite reduction, cyclization reaction and deprotection. The belotecan is subjected to methanesulfonylation reaction to obtain a compound VI, the reaction formula is shown as follows, 。 In the total synthesis method, the total yield is about 1.86%, the yield is too low, the actual production cost is particularly high, and the significance is low. The semisynthesis method is that Soon Kil Ahn et al in Korea takes camptothecin as a raw material, and obtains the belotecan through methylation and Mannich reaction in two steps. The belotecan is subjected to methanesulfonylation reaction to obtain a compound VI, the reaction formula is shown as follows, 。 In the semisynthesis method, the Mannich reaction has a large amount of byproducts, low yield and difficult purification, and influences the application of the route. Thus, there remains a need for a synthetic method for camptothecin derivatives that is simple in process, high in yield, and low in cost. Disclosure of Invention The invention aims to provide a synthetic method of a camptothecin derivative, which has the advantages of simple synthetic process, high yield and low cost. In order to achieve the above object, the present invention provides a method for synthesizing a camptothecin derivative, comprising the steps of: S1, adding 2-nitroacetophenone, paraformaldehyde, isopropylamine and hydrochloric acid into isopropanol, heating and stirring for reaction, concentrating under reduced pressure after the reaction is finished, extracting to remove water layer impurities, adjusting the pH of the water layer, extracting again, drying an organic phase, filtering and concentrating under reduced pressure to obtain 1- (2-nitrophenyl) -3- (isopropylamino) propan-1-one; S2, adding the 1- (2-nitrophenyl) -3- (isopropylamino) propan-1-one and N, N-diisopropylethylamine obtained in the S1 into dichloromethane, and adding a methanesulfonylation reagent for reaction at room temperature to obtain 1- (2-nitrophenyl) -3- (N-isopropyl-N-methanesulfonylamino) propan-1-one; S3, adding the 1- (2-nitrophenyl) -3- (N-isopropyl-N-methylsulfonylamino) propan-1-one obtained in the S2 into methanol, and stirring for nitroreduction reaction to obtain 1- (2-aminophenyl) -3- (N-isopropyl-N-methylsulfonylamino) propan-1-one; S4, carrying out a ring closure reaction on the 1- (2-aminophenyl) -3- (N-isopropyl-N-methylsulfonylamino) propan-1-one obtained in the S3 and the compound V under an acidic condition to obtain the camptothecin derivative. Preferably, in S1, the temperature of the heating and stirring reaction is 80-100 ℃ and the time is 1-24h. Preferably, in S2, the methanesulfonylating agent comprises one or more of methanesulfonyl chloride and methanesulfonic anhydride. Preferably, in S2, dilute hydrochloric acid is added for separating after the reaction is finished, the organic phase is washed, dried and filtered, and the obtained crude product is dissolved, crystallized, filtered and dried to obtain 1- (2-nitrophenyl) -3- (N-isopropyl-N-methylsulfonylamino) propan-1-one. Preferably, in S3, the nitroreduction reaction includes one of catalytic hydrogenation reaction, metal reduction reaction, transfer hydrogenation reaction, and alkali sulfide reduction reaction. Preferably, in S3, hydrogen and a catalyst are added during the catalytic hydrogenation reaction, and the catalyst is one of palladium carbon, platinum carbon and Raney nickel; one or more of iron powder, stannous chloride and zinc powder are added during metal reduction reaction; adding palladium carbon and a hydrogen donor during transfer hydrogenation reaction, wherein the hydrogen donor is one of ammonium formate, cyclohexene and hydrazine hydrate; One or more of sodium sulfide, sodium hydrosulfide, ammonium sulfide, sodium hydrosulfite and sodium thiosulfate are added during the alkali sulfide reduction reaction. Preferably, in S3, the nitroreduction reaction temperature is 0-40 ℃, the reaction t