Method for preparing and purifying tricyclic intermediate of camptothecin

Abstract

The invention discloses a preparation and purification method of a tricyclic intermediate of camptothecin, which comprises the following steps: S1, catalytic oxidation: carrying out catalytic oxidation reaction in toluene by taking a compound 1 as a substrate under the action of a chiral catalyst CB2, cumyl hydroperoxide and powdered potassium carbonate, and then separating a compound 2 from the reaction system; s2, deprotection: adding the compound 2 into a reaction flask, then adding trifluoroacetic acid and water for reaction, and then adding isopropanol and methyl tert-butyl ether for crystallization treatment to obtain a compound 3 crude product; s3, purification: adding the crude product of the compound 3 into a reaction flask, adding acetone, heating and stirring, cooling and stirring for reaction, filtering, concentrating and heating filtrate, rinsing solids on the reaction flask, cooling, crystallizing, and finally drying to obtain a pure product of the compound 3. The invention also discloses a method. The method has the advantages that the operation is simple, the cost is low, the chiral purity can reach more than 99.9%, and the large-scale industrial production of the (S)-hydroxylactone tricyclic compound is favorably realized.

Description

Technical Field

[0001] The invention belongs to the field of medical technology, and particularly relates to a preparation and purification method of a camptothecin tricyclic intermediate. Background Art

[0002] Camptothecin and its derivatives have become a hot topic in the research of anti-tumor drugs in recent decades due to their unique mechanism of action as DNA topoisomerase inhibitors. Camptothecin anti-tumor drugs are shown below. They are mainly chemically modified on the quinoline ring, while the pyrrole ring, pyridone ring and α-hydroxylactone ring are relatively fixed.

[0003]

[0004] Camptothecins are mainly synthesized by the Friedlander method, which uses the condensation of (S)-hydroxylactone tricyclic compounds with o-aminobenzaldehyde or ketone to construct the pentacyclic structure of camptothecin derivatives in one step. The reaction equation is as follows:

[0005]

[0006] Therefore, (S)-hydroxylactone tricyclic compounds are key intermediates of all camptothecin derivatives, with large market demand and certain commercial value. (S)-hydroxylactone tricyclic compounds contain a chiral center, and the construction of the chiral center is mainly through asymmetric resolution and asymmetric synthesis.

[0007] Asymmetric resolution is mainly divided into chemical resolution and enzymatic resolution. For chemical resolution, the basic principle is to convert the racemic (S)-hydroxylactone tricyclic compound or its precursor compound with another chiral compound (such as (S)-α-methylbenzylamine) into another new compound, and achieve separation and purification through the solubility difference of the other new compound. Enzymatic resolution is to selectively convert the (S)-hydroxylactone tricyclic compound or its precursor compound into a new compound by enzyme. For example, papain can selectively hydrolyze the R-configuration precursor of the acetylated hydroxylactone tricyclic compound and purify it through solubility difference. LipaseAK lipase can selectively hydrolyze the (S)-hydroxylactone tricyclic compound to carboxylic acid, and then achieve chiral separation and purification by adjusting the acid and base. For asymmetric synthesis, there are literature reports that the (S)-hydroxylactone tricyclic compound was prepared by Davis asymmetric hydroxylation, and its chiral purity can reach 86%. There are also literature reports that using chiral catalysts, the chiral purity can reach up to 94% under the oxidation of cumene hydroperoxide.

[0008] However, the tricyclic compound of the target configuration can be obtained by the above chemical splitting or SFC (supercritical fluid chromatography) method, but there is always another half of the configuration that is not needed, resulting in a result of low atomic utilization. Although it is possible to try to convert the other half of the configuration into the desired configuration through chemical reaction, the general problem of relatively cumbersome operation and low total yield is that. For SFC separation, there is still the problem of high cost and unsuitable industrial amplification. Although there are also literature reports that asymmetric oxidation is used to construct a chiral center, the chiral purity of the product after the construction is not high, and can only reach about 90%, which cannot meet the current market requirements for the chiral purity of compounds.

[0009] Therefore, there is a need in the art to develop a new method for preparing and purifying a camptothecin tricyclic intermediate, which is simple to operate, low in cost, and high in chiral purity, and is conducive to the large-scale industrial production of (S)-hydroxylactone tricyclic compounds. Summary of the invention

[0010] In order to solve the above technical problems, the present invention provides a method for preparing and purifying a tricyclic intermediate of camptothecin, comprising the following steps:

[0011] S1. Catalytic oxidation: In toluene, compound 1 is used as a substrate, and a catalytic oxidation reaction is carried out in the presence of a chiral catalyst CB2 (CAS: 1586782-00-4), cumene hydroperoxide and powdered potassium carbonate. The reaction temperature is 15-25° C. The reaction is stirred for at least 48 hours, and then the reaction is quenched to separate compound 2 from the reaction system;

[0012] S2, deprotection: Compound 2 is added to a reaction flask, and trifluoroacetic acid and water are added to react at a temperature of 15-25°C for 2-3 hours, and then isopropanol and methyl tert-butyl ether are added for crystallization to obtain a crude compound 3;

[0013] S3, purification: add the crude compound 3 to a reaction bottle, add a pulping solvent, heat to 50-60°C, stir to react, cool to 5-15°C, stir to react, filter to obtain a racemate and a filtrate, concentrate the filtrate and heat to 50-60°C, rinse the solid on the reaction bottle with a crystallization solvent, cool to 20-30°C, drop methyl tert-butyl ether for crystallization, and finally dry to obtain a pure compound 3 with a chiral purity of 100%;

[0014] Among them, the structural formulas of compound 1, compound 2 and compound 3 are:

[0015]

[0016] Specifically, in S1, the molar ratio of compound 1 to chiral catalyst CB2 is 1:(0.01-0.1), preferably 1:0.02, the molar ratio of compound 1 to cumene hydroperoxide is 1:(1-2), preferably 1:1.5, and the molar ratio of compound 1 to potassium carbonate is 1:(0.8-1.5), preferably 1:1.0

[0017] Specifically, in S2, the mass ratio of compound 2 to trifluoroacetic acid is 1: (2-4), preferably 1: 3.1, and the molar ratio of compound 2 to water is 1: (3-7), preferably 1: 4. Specifically, in S3, the pulping solvent is acetone, and the mass ratio of compound 3 to the pulping solvent is 1: (12-17), preferably 1: 15.8. In S3, the crystallization solvent is acetone, and the volume ratio of compound 3 to the crystallization solvent is 1: (5-6), preferably 1: 5.5, and the volume ratio of the crystallization solvent to methyl tert-butyl ether is 1: (1.4-1.8), preferably 1: 1.6. Specifically, in S1, the reagent used for the quenching reaction is a sodium sulfite solution.

[0018] Specifically, in step 1, in S1, the step of separating compound 2 from the reaction system comprises:

[0019] Adjust the pH to 1-2 with trifluoroacetic acid, separate the layers, and extract the aqueous phase twice with dichloromethane (100 mL*2);

[0020] The organic phases were combined and dried with 0.5X sodium sulfate, rinsed with DCM, and concentrated to 5-6V under reduced pressure. The solid on the inner wall of the reactor was rinsed with 1V dichloromethane, the temperature was adjusted to 20-30°C, and methyl tert-butyl ether and n-heptane were slowly added for crystallization;

[0021] The mixture was stirred at 20-30°C for 10 h, filtered, rinsed with n-heptane, and dried to obtain compound 2.

[0022] Specifically, in S2, the reaction time is 2.5 h.

[0023] Specifically, in S2, the operation process of the crystallization treatment includes:

[0024] Methyl tert-butyl ether was slowly added, and the temperature was then adjusted to -5 to 5°C. The mixture was stirred for 4 hours, filtered, and dried to obtain a crude product of compound 3.

[0025] Specifically, in S3, the stirring reaction time is 0.5-1 h, and the filtrate is concentrated to 5-6 V.

[0026] Specifically, in S3, the operation process of the crystallization treatment includes:

[0027] Methyl tert-butyl ether was added dropwise for crystallization, and the mixture was stirred at 20-30° C. for 0.5 h, filtered, rinsed with methyl tert-butyl ether, and dried to obtain pure compound 3.

[0028] The main advantages of the present invention include:

[0029] The preparation and purification method of the camptothecin tricyclic intermediate provided in the present application first obtains the intermediate compound 2 with higher chirality by chiral catalytic oxidation, and then obtains the crude compound 3 with higher chirality after deprotection. Since the racemate and the single S-configuration product have different crystal forms and large solubility differences, the present application dissolves the S-configuration product in the solvent by solvent beating, while the racemate is insoluble, and then separates the racemate by filtration and further improves the chiral purity of the product solution. The method provided in the present application has short reaction steps, mild reaction conditions, simple operation and low cost, and is easy to industrialize and mass produce, which solves the technical problems in the prior art that the chiral purity of the product is not high and the cost is high, and it is not suitable for industrialization and mass production. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 The present invention provides a general route for the preparation and purification of the tricyclic intermediate of camptothecin. DETAILED DESCRIPTION

[0031] The technical solution of the present invention will be described clearly and completely below. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0032] Unless otherwise specified, the experimental materials involved in the present invention are all commercial reagents and can be obtained from commercial channels. The following is an example of the overall synthesis route. Figure 1 As shown:

[0033]

[0034] Example 1: Preparation of Compound 2

[0035] Compound 1 (20 g, 68.7 mmol), chiral catalyst CB2 (888 mg, 1.37 mmol) and cumene hydroperoxide (19.6 g, 103.0 mmol) were added to toluene (600 mL), and powdered potassium carbonate (9.5 g, 68.7 mmol) was added at 15-25°C, and the reaction was stirred at 15-25°C for 48 h. Sodium sulfite solution (100 mL, 68.7 mmol) was added to quench the reaction, and then dichloromethane (200 mL) was added to the reaction solution, and the pH was adjusted to 1-2 with trifluoroacetic acid, and the layers were separated, and the aqueous phase was extracted twice with dichloromethane (100 mL*2). After the organic phases were combined, they were dried over 0.5X sodium sulfate and rinsed with DCM. After concentrating under reduced pressure to 5-6V, rinse the solid on the inner wall of the reactor with 1V of dichloromethane, adjust the temperature to 20-30°C, slowly add methyl tert-butyl ether (200mL) and n-heptane (200mL) for crystallization. Stir at 20-30°C for 10h, filter, rinse with n-heptane, and dry to obtain compound 2 with a yield of 20.2g, a purity of 99.0%, a chiral purity of 89.4%, and a yield of 89.5% (after deducting the net content).

[0036] Example 2: Preparation of crude compound 3

[0037] Compound 2 (10 g, 32.5 mmol) was added to a reaction flask, trifluoroacetic acid (20 mL) and water (2.35 g, 130.2 mmol) were added and reacted at 15-25°C for 2.5 h. Isopropanol (20 mL) was added, and then methyl tert-butyl ether (200 mL) was slowly added for crystallization. The temperature was adjusted to -5 to 5°C, stirred for 4 h, filtered, and dried to obtain a crude compound 3 with a yield of 8.0 g, a purity of 99.6%, a chiral purity of 88.3%, and a yield of 93.3%.

[0038] Example 3: Purification of crude compound 3

[0039] The crude compound 3 (15 g, 57.0 mmol, chiral purity 89.9%) was added to a reaction flask, acetone (300 mL) was added, the temperature was raised to 50-60 ° C and stirred for 0.5 h, and the temperature was lowered to 5-15 ° C and stirred for 1 h. Filtered to obtain 3.35 g of racemate (chiral purity 52.2%) and 239.2 g of filtrate (chiral purity 99.0%). The filtrate was concentrated to 5-6 V, heated to 50-60 ° C, and the solid on the reaction flask was rinsed with acetone (15 mL, 1 V). After cooling to 20-30 ° C, methyl tert-butyl ether (135 mL) was added dropwise for crystallization, stirred at 20-30 ° C for 0.5 h, filtered, rinsed with methyl tert-butyl ether (30 mL), and dried to obtain pure compound 3, with a yield of 9.11 g, a purity of 99.7%, and a chiral purity of 100%.

[0040] According to the above examples, it can be seen that the method provided in the present application can effectively improve the chiral purity of the product solution, and at the same time has the advantages of simple operation, mild conditions, low cost, and suitability for large-scale industrial production.

[0041] In summary, the above embodiments are only preferred embodiments of the present invention and are not intended to limit the protection scope of the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing and purifying a camptothecin tricyclic intermediate, characterized in that: The steps include: S1. Catalytic oxidation: In toluene, compound 1 is used as a substrate, and a catalytic oxidation reaction is carried out in the presence of a chiral catalyst CB2, cumene hydroperoxide and powdered potassium carbonate. The reaction temperature is 15-25°C, and the reaction is stirred for at least 48 hours. After that, the reaction is quenched and compound 2 is separated from the reaction system. S2, deprotection: Compound 2 is added to a reaction flask, and trifluoroacetic acid and water are added to react at a temperature of 15-25°C for 2-3 hours, and then isopropanol and methyl tert-butyl ether are added for crystallization to obtain a crude compound 3; S3, purification: add the crude compound 3 to a reaction bottle, add a pulping solvent, heat to 50-60°C, stir to react, cool to 5-15°C, stir to react, filter to obtain a racemate and a filtrate, concentrate the filtrate and heat to 50-60°C, rinse the solid on the reaction bottle with a crystallization solvent, cool to 20-30°C, drop methyl tert-butyl ether for crystallization, and finally dry to obtain a pure compound 3 with a chiral purity of 100%; Among them, the structural formulas of compound 1, compound 2 and compound 3 are:

2. The method according to claim 1, characterized in that In S1, the molar ratio of compound 1 to chiral catalyst CB2 is 1:(0.01-0.1), the molar ratio of compound 1 to cumene hydroperoxide is 1:(1-2), and the molar ratio of compound 1 to potassium carbonate is 1:(0.8-1.5).

3. The method according to claim 1, characterized in that In S2, the mass ratio of compound 2 to trifluoroacetic acid is 1:(2-4), and the molar ratio of compound 2 to water is 1:(3-7).

4. The method according to claim 1, characterized in that: In S3, the pulping solvent is acetone, and the mass ratio of compound 3 to the pulping solvent is 1:(12-17). In S3, the crystallization solvent is acetone, and the volume ratio of compound 3 to the crystallization solvent is 1:(5-6). The volume ratio of the crystallization solvent to methyl tert-butyl ether is 1:(1.4-1.8).

5. The method according to claim 1, characterized in that: In S1, the reagent used to quench the reaction is a sodium sulfite solution.

6. The method according to claim 1, characterized in that In the step 1, in S1, the step of separating compound 2 from the reaction system comprises: Adjust the pH to 1-2 with trifluoroacetic acid, separate the layers, and extract the aqueous phase twice with dichloromethane (100 mL*2); After the organic phases are combined, they are dried with 0.5X sodium sulfate, rinsed with dichloromethane, and concentrated to 5-6V under reduced pressure. Then, the solid on the inner wall of the reactor is rinsed with 1V dichloromethane, the temperature is adjusted to 20-30°C, and methyl tert-butyl ether and n-heptane are slowly added for crystallization; The mixture was stirred at 20-30°C for 10 h, filtered, rinsed with n-heptane, and dried to obtain compound 2.

7. The method according to claim 1, characterized in that In S2, the reaction time is 2.5 h.

8. The method according to claim 1, characterized in that: In S2, the operation process of the crystallization treatment includes: After adding isopropanol, methyl tert-butyl ether was slowly added, and then the temperature was adjusted to -5 to 5°C. After stirring for 4 hours, the mixture was filtered and dried to obtain a crude product of compound 3.

9. The method according to claim 1, characterized in that: In S3, the stirring reaction time is 0.5-1h, and the filtrate is concentrated to 5-6V.

10. The method according to claim 1, characterized in that In S3, the operation process of the crystallization treatment includes: Methyl tert-butyl ether was added dropwise for crystallization, and the mixture was stirred at 20-30°C for 0.5 h, filtered, rinsed with methyl tert-butyl ether, and dried to obtain pure compound 3.

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