CN117142976A - Preparation method of key intermediate of ADC drug toxin irinotecan - Google Patents

Abstract

The invention provides a method for preparing a key intermediate of ADC drug toxin ixatecan, which includes the following steps: (1) Compound 1 reacts with isoamyl nitrite under the action of potassium tert-butoxide to form compound 2; (2) Compound 2 2 reacts with zinc powder under the action of acetic acid and acetic anhydride to obtain compound 3. This method uses low-priced reducing agent zinc powder to replace expensive metal platinum carbon catalyst, avoids the use of pressurized hydrogenation equipment, greatly reduces costs, and is of great significance for the industrial production of ixatecan.

Description

Preparation method of key intermediate of ADC drug toxin ixatecan

Technical field

The invention belongs to the field of medical technology and relates to a preparation method of an ADC drug toxin ixatecan intermediate.

Background technique

Ixanotecan is a camptothecin derivative developed by Daiichi Sankyo. It was initially used as a separate chemotherapy drug and advanced to Phase III clinical trials. Its main indications are bone cancer, prostate cancer, breast cancer, pancreatic cancer, etc. However, like most camptothecin drugs, high lipid solubility and low water solubility seriously affect its efficacy. In addition, as a topoisomerase inhibitor, it lacks specificity for tumor cells and has severe side effects, which limits its clinical application. Increasing water solubility and improving targeting are major advantages of ADC drugs. The combination of specific antibodies and antigens carries toxins around target cells. By releasing toxins near target cells, it effectively kills tumor cells and reduces toxic side effects. Ishatecan has good application prospects as an ADC drug toxin molecule. Isanotecan is a new topoisomerase I inhibitor camptothecin analogue, which is 10 times more active than irinotecan. The structure of ixatecan is formula I.

The structure of ixatecan contains two chiral centers, and its synthesis and preparation routes are relatively complicated. The synthesis process of ixatecan requires the use of a key intermediate, namely compound 3, whose structure is as follows:

It has been reported in the prior art that after the α-position of the carbonyl group of compound 1 undergoes an oximation reaction, compound 3 is obtained by reduction using a platinum carbon catalyst under pressurized hydrogenation conditions. Since the platinum carbon catalyst is expensive, it increases the cost, and pressurized hydrogenation requires high equipment, which is not conducive to industrial production.

Contents of the invention

In order to solve the above technical problems, the present invention provides a method for preparing the key intermediate of the ADC drug toxin ixatecan, which uses low-priced reducing agent zinc powder to replace the metal platinum carbon catalyst and avoids the use of pressurized hydrogenation equipment. This method has mild reaction conditions, is easy to purify, and is simple to operate. It can be scaled up and produced with stable and acceptable yields, and the purity can also meet the requirements of subsequent steps. The cost is greatly reduced, which is of great significance for the industrial production of ixatecan.

In order to achieve the purpose of the present invention, the inventor finally obtained the following technical solution through a large number of experimental studies:

The invention provides a preparation method of a key intermediate of ixotecan, which is characterized by comprising the following steps:

In step (1), the reaction temperature is -10~0°C, the reaction time is about 2 hours, the molar ratio of compound 1 to isoamyl nitrite is 1:1.3, and the molar ratio of compound 1 to potassium tert-butoxide is 1 :1.15, the reaction solvent is tetrahydrofuran.

In step (2), zinc powder is selected as the reducing agent and does not require pressurized hydrogenation conditions. The reaction temperature is 20-30°C, the reaction time is about 18 hours, the mass ratio of compound 2 to zinc powder is 1:1, and the mass ratio of compound 2 to zinc powder is 1:1. The mass and volume ratio of acetic acid is 1:3, and the volume ratio of acetic acid and acetic anhydride is 1:1.

Detailed ways

The following examples can enable those skilled in the art to understand the present invention more comprehensively, but do not limit the present invention to the scope of the described embodiments.

Example 1

Preparation of compound 2

Add 50.0g compound 1, 27.5g potassium tert-butoxide and 750mL tetrahydrofuran in sequence to the reaction bottle, replace with nitrogen, cool to -10~-5°C, add 32.5g isoamyl nitrite dropwise to the system, complete the addition, and keep the reaction warm. . At the end of the reaction, add 1N HCl dropwise to the system to adjust the pH, evaporate the solvent under reduced pressure, add 350mL methyl tert-butyl ether and 500mL water to the residue to make a slurry, filter with suction, rinse the filter cake with an appropriate amount of water, and then use 250mL methyl tert-butyl ether to slurry the residue. The filter cake was washed with tert-butyl ether and dried to obtain 44.8g of compound 2, with a yield of 83%.

Example 2

Preparation of compound 3

Add 10.0g of compound 2, 30mL of acetic acid and 30mL of acetic anhydride into a single-port reaction bottle in sequence, stir under a nitrogen atmosphere, then add 10.0g of zinc powder to the reaction system, complete the addition, replace with nitrogen, and react at 30°C for 18 hours under a nitrogen atmosphere. . At the end of the reaction, 200 mL acetonitrile and 50 mL water were added to the reaction system, followed by suction filtration. The filtrate was crystallized in an ice bath, suction filtrated, and the filter cake was dried to obtain 8.5 g of compound 3 as a yellow solid with a yield of 65%.

The basic principles and main features of the invention as well as the advantages of the invention have been shown and described above. Those skilled in the industry should understand that the present invention is not limited by the above embodiments. The above embodiments and descriptions only illustrate the principles of the present invention. The present invention will also have other aspects without departing from the spirit and scope of the present invention. Various changes and modifications are possible, which fall within the scope of the claimed invention. The scope of protection of the present invention is defined by the appended claims and their equivalents.

Claims (3)

1. A method for preparing the key intermediate of the ADC drug toxin Ixanotecan, which is characterized by comprising the following steps: (1) Compound 1 reacts with isoamyl nitrite in the presence of potassium tert-butoxide to obtain compound 2: (2) Compound 2 reacts with zinc powder under the action of acetic acid and acetic anhydride to obtain compound 3: 2. The preparation method of a key intermediate of ADC drug toxin ixatecan according to claim 1, characterized in that: in step (1), the reaction temperature is -10~0°C, and the reaction time is about 2h. The molar ratio of compound 1 to isoamyl nitrite is 1:1.3, the molar ratio of compound 1 to potassium tert-butoxide is 1:1.15, and the reaction solvent is tetrahydrofuran. 3. The preparation method of a key intermediate of ADC drug toxin Ixanotecan according to claim 1, characterized in that: in step (2), zinc powder is selected as the reducing agent and does not require pressurized hydrogenation conditions. The reaction temperature The reaction temperature is 20-30°C, the reaction time is about 18 hours, the mass ratio of compound 2 to zinc powder is 1:1, the mass volume ratio of compound 2 to acetic acid is 1:3, and the volume ratio of acetic acid to acetic anhydride is 1:1.