Process for the preparation of the pharmaceutical intermediate (r)-7-ethyl camptothecin

Abstract

The application discloses a preparation method of a medical intermediate (R)-7-ethyl camptothecin, and relates to the field of chemical medicine synthesis. The application comprises the following contents: (R)-4-ethyl-4-hydroxy-7,8-dihydro-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione (formula A) and 1-(2-aminophenyl)propan-1-one (formula B) are used as main raw materials, a target compound (R)-7-ethyl camptothecin is obtained through reaction in an organic solvent under the action of a catalyst. The application provides a novel preparation method of the medical intermediate (R)-7-ethyl camptothecin, and the preparation method is simple, stable, high in yield, and suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the technical field of chemical drug synthesis, specifically to a method for preparing the pharmaceutical intermediate (R)-7-ethylcamptothecin. Background Technology

[0002] (R)-7-ethylcamptothecin is a structural analog of camptothecin. This compound not only exhibits potential antitumor activity and holds promise for the development of antitumor therapeutics, but it is also an important multifunctional pharmaceutical chemical. It can serve as a key intermediate in the synthesis of other camptothecin-derived drugs, and as an analytical control in the field of pharmaceutical analysis for quality control and standardization studies of 7-ethylcamptothecin (especially its specific isomers or mixtures).

[0003] Its epimer (S)-7-ethylcamptothecin can be prepared from naturally derived (S)-camptothecin, but currently, no efficient and practical method for the scalable synthesis of (R)-7-ethylcamptothecin has been reported in the published literature and technical data. Summary of the Invention

[0004] The purpose of this invention is to provide a method for preparing the pharmaceutical intermediate (R)-7-ethylcamptothecin. Using (R)-4-ethyl-4-hydroxy-7,8-dihydro-1H-pyrano[3,4-f]-indene-3,6,10(4H)-trione (compound I) and 1-(2-aminophenyl)prop-1-one (compound II) as main raw materials, the target compound (R)-7-ethylcamptothecin is obtained by reacting in an organic solvent under the action of a catalyst. This invention is the first to clearly report the synthetic route of (R)-7-ethylcamptothecin, filling a technological gap.

[0005] The present invention adopts the following technical solution:

[0006] A method for preparing the pharmaceutical intermediate (R)-7-ethylcamptothecin, comprising the following:

[0007] Using compounds I and II as raw materials, the target compound, as shown in formula C, was obtained by reacting in an organic solvent under the action of a catalyst. The general reaction formula is as follows:

[0008] .

[0009] This invention uses (R)-4-ethyl-4-hydroxy-7,8-dihydro-1H-pyrano[3,4-f] indene-3,6,10(4H)-trione (compound I) and 1-(2-aminophenyl)prop-1-one (compound II) as raw materials, and reacts them in an organic solvent under the action of a catalyst to obtain the target compound (R)-7-ethylcamptothecin (the target compound shown in formula C). This invention directly and efficiently constructs a complete pentacyclic skeleton of camptothecin containing an E ring by linking the tetracyclic system of compound I with the o-aminoacetophenone fragment of compound II via a C-C bond and then closing the ring.

[0010] This invention pre-constructs the (R)-configuration and uses an intermediate with a tetracyclic A / B / C / D skeleton of camptothecin as compound I as the core raw material, avoiding complex chiral resolution or asymmetric synthesis steps in later stages. It shifts chiral control forward and utilizes a stable intermediate to maintain the configuration. Simultaneously, the entire reaction process (condensation, ring closure, dehydration, aromatization) is carried out under mild acid catalysis, preventing racemization or configuration inversion of the chiral center, ensuring that the final product retains the desired (R)-configuration. Furthermore, the readily available 1-(2-aminophenyl)prop-1-one (compound II) is used as the module for constructing the E ring; the synergistic effect of its ortho-amino and ketone groups makes it a highly efficient and specific ring-closing reagent. This route provides a reliable and scalable synthetic method for obtaining the difficult-to-obtain (R)-7-ethylcamptothecin.

[0011] Furthermore, the molar ratio of compound I to compound II is 1:0.8~5.0.

[0012] Furthermore, the molar ratio of compound I to the catalyst is 1:0.05~0.5.

[0013] Furthermore, the catalyst comprises p-toluenesulfonic acid monohydrate.

[0014] Further, the preparation method according to claim 1 specifically includes the following steps:

[0015] Step 1. Dissolve compound I, compound II, and the catalyst in solvent A, reflux the reaction, and concentrate to obtain the concentrate;

[0016] Step 2. Dissolve the concentrate in solvent B, heat and react to obtain the pre-product reaction solution;

[0017] Step 3. Post-process the preproduct reaction to obtain the crude target compound shown in Formula C.

[0018] In step 1, solvent A is concentrated and removed, and the reaction solvent is replaced with solvent B to increase the reaction temperature and ensure complete reaction of the raw materials; in step 2, the reaction temperature is increased to ensure complete reaction of the raw materials. The reflux reaction time in step 1 is 4~4.5h.

[0019] Furthermore, solvent A includes toluene.

[0020] Furthermore, solvent B includes N-methylpyrrolidone.

[0021] Solvent B is preferably N-methylpyrrolidone. The addition of N-methylpyrrolidone increases the reaction temperature, making the reaction of the raw materials more complete, thereby improving the reaction conversion rate. Post-processing avoids column purification, making it easier to industrialize.

[0022] Furthermore, in step 2, the temperature of the heating reaction is 140~145℃, and the reaction time is 2~2.5h.

[0023] Further, in step 3, the post-processing includes the following: adding the pre-product reaction solution to water to precipitate crystals; adding the crystals to methanol, filtering, and obtaining the target compound shown in formula C.

[0024] The pre-product reaction solution is added to water, causing a solid to precipitate. The solid is then filtered to obtain the crude product. Methanol is added to further wash away impurities from the crystal surface, improving product purity.

[0025] Compared with the prior art, the beneficial effects of the present invention

[0026] This invention utilizes two key raw materials from (R)-4-ethyl-4-hydroxy-7,8-dihydro-1H-pyrano[3,4-f]: indene-3,6,10(4H)-trione (compound I) and 1-(2-aminophenyl)prop-1-one (compound II). Under mild acid catalysis, a one-pot method was employed to construct the core pentacyclic skeleton of camptothecin through a highly efficient cascade reaction involving condensation, cyclization, dehydration, and aromatization, successfully maintaining the desired (R)-configuration. This provides a novel method for preparing the pharmaceutical intermediate (R)-7-ethylcamptothecin, filling a technological gap in the synthesis of (R)-7-ethylcamptothecin. The preparation method is simple, stable, and achieves a yield of up to 77.2%, demonstrating strong feasibility for scale-up. Detailed Implementation

[0027] Example 1

[0028] Add 3.00 g of (R)-4-ethyl-4-hydroxy-7,8-dihydro-1H-pyrano[3,4-f]-indene-3,6,10(4H)-trione, 5.10 g of 1-(2-aminophenyl)prop-1-one, 0.20 g of p-toluenesulfonic acid monohydrate, and 558 mL of toluene to a 1 L reaction flask. Stir and heat, and reflux for 4 h to remove water. Concentrate to remove the solvent. Add 300 mL of N-methylpyrrolidone to the concentrate, stir and heat to 140 °C for 2 h. After cooling to room temperature, add the reaction solution to 1.4 L of water and stir for 0.5 h. Filter. Add the crude product to methanol, stir, filter and dry to obtain the target compound (R)-7-ethylcamptothecin (3.31 g, yield 77.2%).

[0029] 1H (400 MHz, DMSO-d6) δ 8.26 (1 H, dd, J 8.6, 1.4), 8.15 (1 H, dd, J8.6, 1.3), 7.84 (1 H, ddd, J 8.4, 6.8, 1.3), 7.71 (1 H, ddd, J 8.2, 6.7,1.3), 7.32 (1 H, s), 6.52 (1 H, s), 5.44 (2 H, s), 5.29 (2 H, s), 3.21 (2 H,q, J 7.5), 1.96–1.78 (2 H, m, J 7.1), 1.31 (3 H, t, J 7.6), 0.89 (3 H, t, J7.3).

[0030] MS-ESI (m / z) 377.2 [M+H] + .

[0031] Example 2

[0032] Add 3 g of (R)-4-ethyl-4-hydroxy-7,8-dihydro-1H-pyrano[3,4-f]-indene-3,6,10(4H)-trione, 1.36 g of 1-(2-aminophenyl)prop-1-one, 0.11 g of p-toluenesulfonic acid monohydrate, and 558 mL of toluene to a 1 L reaction flask. Stir and heat, and reflux for 4 h with water separation. Concentrate to remove the solvent. Add 300 mL of N-methylpyrrolidone to the concentrate, stir and heat to 142 °C for 2.2 h. After cooling to room temperature, add the reaction solution to 1.4 L of water and stir for 0.5 h. Filter. Add the crude product to methanol and stir, filter and dry to obtain the target compound (R)-7-ethylcamptothecin (3.15 g, yield 73.5%).

[0033] Example 3

[0034] Add 3 g of (R)-4-ethyl-4-hydroxy-7,8-dihydro-1H-pyrano[3,4-f]-indene-3,6,10(4H)-trione, 8.50 g of 1-(2-aminophenyl)prop-1-one, 1.08 g of p-toluenesulfonic acid monohydrate, and 558 mL of toluene to a 1 L reaction flask. Stir and heat, and reflux for 4 h with water separation. Concentrate to remove the solvent. Add 300 mL of N-methylpyrrolidone to the concentrate, stir and heat to 145 °C for 2.5 h. After cooling to room temperature, add the reaction solution to 1.4 L of water and stir for 0.5 h. Filter. Add the crude product to methanol and stir, filter and dry to obtain the target compound (R)-7-ethylcamptothecin (3.26 g, yield 76.0%).

[0035] Finally, it should be noted that the above preferred embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit it. Although the present invention has been described in detail through the above preferred embodiments, those skilled in the art should understand that various changes can be made to it in form and detail without departing from the scope defined by the claims of the present invention.

Claims

1. A method for preparing the pharmaceutical intermediate (R)-7-ethylcamptothecin, characterized in that, Includes the following: Using compounds I and II as raw materials, the target compound, shown in formula C, is obtained by reacting it in an organic solvent under the action of a catalyst. The general reaction formula is as follows: ； Specifically, the following steps are included: Step 1. Dissolve compound I, compound II, and the catalyst in solvent A, reflux the reaction, and concentrate to obtain the concentrate; Step 2. Dissolve the concentrate in solvent B, heat and react to obtain the pre-product reaction solution; Step 3. Post-process the pre-product reaction solution to obtain the target compound shown in formula C; Solvent A is toluene; Solvent B is N-methylpyrrolidone; The catalyst is p-toluenesulfonic acid monohydrate; In step 2, the temperature of the heating reaction is 140~145℃, and the reaction time is 2~2.5h; The post-processing includes the following steps: adding the pre-product reaction solution to water to precipitate crystals; adding the crystals to methanol and filtering.

2. The preparation method according to claim 1, characterized in that, The molar ratio of compound I to compound II is 1:0.8~5.

0.

3. The preparation method according to claim 1, characterized in that, The molar ratio of compound I to the catalyst is 1:0.05~0.5.

Images