WO2024093091A1

WO2024093091A1 - Preparation method for intermediate of ecteinascidin compound

Info

Publication number: WO2024093091A1
Application number: PCT/CN2023/082268
Authority: WO
Inventors: 黄金昆; 冯超阳; 王寿平; 李鸿展; 吴成龙
Original assignee: 成都科岭源医药技术有限公司
Priority date: 2022-11-02
Filing date: 2023-03-17
Publication date: 2024-05-10
Also published as: CN115677728A

Abstract

The present invention provides a preparation method for preparing an intermediate of an ecteinascidin compound by taking an electrically neutral organic oxidant as a unique auxiliary agent, comprising the steps of dissolving compound A in an organic solvent, adding an electrically neutral organic oxidant, and performing a reaction at 50-70℃ for 1-25 h. The method of the present invention is simple to operate with the reagent used cheap and easy to obtain, and does not need to use other auxiliary agents such as a catalyst to assist the reaction. The method of the present invention can allow for a reaction in a water-containing system, with mild and unharsh reaction conditions, low amount of the solvent used, high yield, and small pollution to the environment, and thus is suitable for industrial production of a key intermediate of an ecteinascidin compound.

Description

A method for preparing an intermediate of an ectocystin compound

Technical Field

The invention belongs to the field of compound synthesis, and specifically relates to a method for preparing an ecteinascidin compound intermediate.

Background technique

Trabectedin (ET-743) is an alkylating agent isolated and extracted from the Caribbean tunicate Ecteinascidia turbinata. It is the first new marine-derived anti-soft tissue tumor drug with the following structure:

However, as a natural product isolated from animals, trabectedin has limited sources and very low yields. Therefore, the artificial synthesis of trabectedin has become a research hotspot in recent years.

In many of the reported synthetic routes of trabectedin, compound B is a key intermediate, and its structure is as follows:

For example, Cuevas et al., Ma Dawei et al. all disclosed the following route for preparing trabectedin by reacting compound B with 5-(2-aminoethyl)-2-methoxyphenol (Organic Letters, Volume 2, Issue 16, Pages 2545-2548; CN109912629B):

In addition, He et al. also disclosed the synthesis of another ectocystin compound using intermediate compound B. Compound: Method for the preparation of rubicin (Angewandte Chemie, International Edition, 58(12), 3972-3975; 2019).

It can be seen that compound B plays an important role in the synthesis of ecteinascidin compounds. However, to date, the synthesis routes of compound B have defects such as harsh conditions, cumbersome operations, and high costs.

E.J.Corey et al. first synthesized trabectedin in 1996. However, the process of synthesizing the intermediate reported by them used very expensive 4-formyl-1-methylpyridin-1-ium iodide, and it was necessary to add an extremely excessive amount of it to the reaction system (20 equivalents were added), which not only had a high cost, but also had a complicated preparation process, difficult purification, and a low yield. (J.Am.Chem.Soc.1996,118,9202-9203).

Since this method was first reported, although many researchers have used various methods to synthesize trabectedin in subsequent research, when it comes to the synthesis of compound B, they still refer to the method disclosed by E.J.Corey et al. in 1996, that is, 4-formyl-1-methylpyridin-1-ium iodide is used as an oxidant to synthesize intermediate compound B. For example: Fukuyama et al. also used 4-formyl-1-methylpyridin-1-ium iodide as an oxidant to synthesize intermediate compound B in 2002, and finally completed the synthesis of trabectedin. (J.Am.Chem.Soc.2002,124,6552-6554); Jieping Zhu et al. also used 4-formyl-1-methylpyridin-1-ium iodide as an oxidant to complete the synthesis of intermediate compound B in 2006. (J.Am.Chem.Soc.2006,128,87-89); Ma Dawei et al. completed the total synthesis of trabectedin in 2019. The intermediate compound B used was still obtained by oxidation of 4-formyl-1-methylpyridin-1-ium iodide, and the synthesis conditions and yield of the intermediate compound B were still not improved; (Angewandte Chemie, International Edition (2019), 58(12), 3972-3975). The synthesis method of compound B recorded in patents including announcement number CN1096463C is also the same as the method of E.J.Corey et al.

It can be seen that for a long time, the synthesis of compound B has basically followed the method first disclosed by E.J.Corey et al., and therefore has never been able to overcome the difficulties of large amount of oxidant 4-formyl-1-methylpyridin-1-ium iodide, high cost, cumbersome operation, difficult purification, and low yield.

In recent years, there have also been studies that attempt to use other oxidants to replace 4-formyl-1-methylpyridinium-1-ium iodide to achieve the synthesis of compound B. For example, in the Chinese patent with publication number CN107739387B, sodium glyoxylate and sulfate are added to a mixture of sodium acetate-acetic acid buffer solution and an organic solvent, reacted under inert gas protection, and a series of post-treatment operations such as water washing, extraction, and beating are performed to prepare the intermediate compound B. Although this method improves the yield of compound B, the sodium glyoxylate reagent used is still relatively expensive, and the reaction requires inert gas protection, the conditions are relatively harsh, and the post-treatment operation is cumbersome. The preparation method of trabectedin disclosed in the Chinese patent application with publication number CN114805398A uses 3,5-di-tert-butyl-1,2-benzoquinone as an oxidant, and adds catalysts zinc chloride and oxalic acid, and reacts under anhydrous and oxygen-free conditions to obtain the intermediate compound B. However, the reaction operation is also relatively complicated, and post-treatment must be performed by column chromatography to obtain B with high purity.

In general, although the improved method disclosed in the above patent/patent application avoids the use of 4-formyl-1-methylpyridin-1-ium iodide, it still requires relatively stringent reaction conditions, similar to the reaction conditions originally disclosed by EJ Corey et al., and needs to be controlled to be anhydrous and oxygen-free; in addition, the entire reaction system must be involved in a catalyst, resulting in cumbersome post-processing operations, thereby increasing the cost of the entire process. It is very high, which restricts the industrial production of trabectedin.

In summary, the process of producing intermediate compound B using compound A as raw material has always had a technical bias that requires the control of anhydrous and oxygen-free conditions, or requires a catalyst to assist the oxidant to achieve the reaction. In order to further achieve the scale-up and industrial production of intermediate compound B, and thus achieve mass production of ectenescidin compounds, it is of great significance to further provide a preparation method of key intermediate compound B of ectenescidin compounds with simple operation, mild reaction conditions, low cost and high yield.

Summary of the invention

The object of the present invention is to provide a method for preparing a key intermediate compound B of an ectocystin compound with simple operation, mild reaction conditions, low cost and high yield.

The present invention provides the use of an electrically neutral organic oxidant as the sole auxiliary agent in a reaction for preparing an ectocystin intermediate; the reaction for preparing an ectocystin intermediate is a reaction for preparing a compound B using a compound A as a reactant;

The compound A is: or a salt thereof, compound B is:

Wherein, R is hydrogen or a hydroxyl protecting group.

The present invention also provides a method for preparing an ectocystin compound intermediate, comprising the following steps:

(1) Compound A or its salt is dissolved in an organic solvent;

(2) adding an electrically neutral organic oxidant to react to obtain compound B;

The reaction formula is as follows:

Wherein, R is hydrogen or a hydroxyl protecting group.

Furthermore, the hydroxyl protecting group is methoxymethyl ether, methoxymethyl ethyl ether or allyl.

Furthermore, the electrically neutral organic oxidant in step (2) contains at least one carbonyl group in its structure, and preferably contains at least two carbonyl groups.

Furthermore, the structure of the electrically neutral organic oxidant is shown in Formula I:

Wherein, R ₁ and R ₂ are independently selected from: hydrogen, hydroxyl, C _1-5 alkyl, C _1-5 alkoxy, phenyl, or R ₁ and R ₂ are connected to form a 3-7 membered substituted or unsubstituted saturated or unsaturated ring; the substituted substituent is hydroxyl, carbonyl, amino, halogen, cyano or mercapto; n is an integer of 0-6;

G is selected from CO, NH or CR _a R _b , wherein _Ra and R _b in each repeating unit are independently selected from hydrogen, hydroxyl, amino, halogen, cyano or thiol.

Furthermore, the above R ₁ and R ₂ are independently selected from: hydrogen, hydroxyl, methyl, ethoxy, phenyl, or R ₁ and R ₂ are connected to form a 5-6 membered substituted or unsubstituted saturated or unsaturated ring; the substituted substituent is hydroxyl or carbonyl, and n is an integer of 0-4.

Furthermore, the electrically neutral organic oxidant is shown in Formula IA:

Wherein, n1 is 1 or 2, and R ₁ and R ₂ are independently selected from the group consisting of hydrogen, hydroxyl, C _1-5 alkyl, C _1-5 alkoxy, and phenyl;

Preferably, R ₁ and R ₂ are independently selected from the group consisting of hydrogen, hydroxy, methyl, ethoxy and phenyl.

Furthermore, the electrically neutral organic oxidant is represented by Formula IB:

Where n is 1 or 2;

_G1 is nothing, CO, NH or CR _c R _d , _G2 is nothing, CO, NH or CR _e R _f , _G3 is nothing, CO, NH or CR _g R _h ; wherein R _c , R _d , _Re , R _f , R _g , and R _h are independently selected from hydrogen, hydroxyl, amino, thiol or cyano, or R _c and _Re are connected to form a chemical bond, or _Re and R _g are connected to form a chemical bond.

Furthermore, the above R _c , R _d , _Re , R _f , R _g , and R _h are independently selected from hydrogen and hydroxyl groups, or R _c and _Re are connected to form a chemical bond, or _Re and R _g are connected to form a chemical bond.

Furthermore, the electrically neutral organic oxidant is selected from any one of the following compounds or their hydrates:

Furthermore, the electrically neutral organic oxidant is alloxan.

Furthermore, the organic solvent in step (1) is selected from N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, 1,4-dioxane, tetrahydrofuran or N-methylpyrrolidone; preferably N,N-dimethylformamide.

Furthermore, the molar ratio of the compound A to the electrically neutral organic oxidant is: 1:(1-5); preferably: 1:2.

Furthermore, the reaction conditions are 50-70° C. for 1-24 hours; preferably 60° C. for 2-24 hours.

Furthermore, the electrically neutral organic oxidant is glyoxylic acid, glyoxylic acid ester, glyoxal, methylglyoxal, diethyl ketomalonate or phenylglyoxal, and the reaction time is 10 to 14 hours, preferably 12 hours;

Or, the electrically neutral organic oxidant is cyclohexanehexanone or cyclohexane acid, and the reaction time is 20 to 24 hours, preferably 24 hours;

Alternatively, the electrically neutral organic oxidant is alloxan, and the reaction time is 1 to 3 hours, preferably 2 hours.

Furthermore, the above preparation method also includes the following post-processing steps:

(a) pouring the reaction solution obtained after the reaction in step (2) into an aqueous solution of an inorganic base or an organic base at 0 to 4°C;

(b) The solid was precipitated by standing, and the solid was obtained by filtration, which was compound B.

Furthermore, step (a) is: the reaction solution obtained after the reaction in step (2) is poured into a saturated sodium bicarbonate aqueous solution, sodium carbonate aqueous solution or triethylamine aqueous solution at 0°C.

The beneficial effects of the present invention are as follows: the present invention uses an electrically neutral organic oxidant as the only auxiliary agent for preparing a key intermediate of an ectocystin compound, and does not require the participation of other auxiliary agents such as a catalyst. The intermediate of an ectocystin compound with a high yield can be obtained through simple and rapid post-treatment under mild and non-harsh conditions, thus overcoming the technical prejudice that in the process of preparing the key intermediate compound B of an ectocystin compound, anhydrous and oxygen-free conditions must be controlled, or the participation of a catalyst is required.

The method of the invention is simple to operate, the reagents used are cheap and easily available, and the reaction can be carried out in an aqueous system. The reaction conditions are mild and not harsh, the solvent usage is low, the yield is high, and the environmental pollution is small. The method is suitable for the industrial production of key intermediates of ecteinascidin compounds.

Terminology Note:

In the present invention, the situation of "R _c and _Re are connected to form a chemical bond" means that a carbon-carbon double bond is formed between G1 and G2, and the other substituent on the carbon atom (R _d , R _f ) is still independently selected from hydrogen, hydroxyl, amino, thiol or cyano. The situation of "or _Re and R _g are connected to form a chemical bond" means that a carbon-carbon double bond is formed between G2 and G3, and the other substituent on the carbon atom (R _f , R _h ) is still independently selected from hydrogen, hydroxyl, amino, thiol or cyano.

“Hydroxy protecting group”: a suitable group for protecting a hydroxy group known in the art, see the hydroxy protecting group in the literature (“Protective Groups in Organic Synthesis”, 5Th Ed. T.W.Greene & P.G.M.Wuts).

"Electrically neutral organic oxidant" refers to a substance that is uncharged, has carbon atoms as the structural skeleton of the compound, and has the ability to acquire electrons.

Obviously, according to the above contents of the present invention, in accordance with common technical knowledge and customary means in the art, without departing from the above basic technical ideas of the present invention, other various forms of modification, replacement or change may be made.

The above contents of the present invention are further described in detail below through specific implementation methods in the form of embodiments. However, this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention.

Detailed ways

The raw materials and equipment used in the present invention are all known products, which are obtained by purchasing commercially available products.

Example 1. Preparation of key intermediates of ecteinascidin compounds

Compound A hydrochloride (1 g, 1.5 mmol) was dissolved in DMF (20 mL), and acetone aldehyde aqueous solution (547 mg, 3.0 mmol, 40 wt% in _H2O ) was added, and stirred at 60°C for 12 hours. After the reaction was completed, the reaction solution was poured into saturated sodium bicarbonate aqueous solution at 0°C, and the solid precipitated. It was filtered to obtain product B (0.9 g, yield 95%).

Example 2

Compound A hydrochloride (1 g, 1.5 mmol) was dissolved in DMF (20 mL), and glyoxylic acid aqueous solution (449 mg, 3.0 mmol, 50 wt% in H ₂ O) was added. The mixture was stirred at 60°C for 12 hours. After the reaction was completed, the reaction solution was poured into saturated sodium bicarbonate aqueous solution at 0°C. Solids precipitated and were filtered to obtain product B (0.86 g, yield 92%).

Example 3

Compound A hydrochloride (1 g, 1.5 mmol) was dissolved in DMF (20 mL), and glyoxylate (306 mg, 3.0 mmol) was added. The mixture was stirred at 60 °C for 12 hours. After the reaction was completed, the reaction solution was poured into a saturated sodium bicarbonate aqueous solution at 0 °C. The solid precipitated and was filtered to obtain product B (0.88 g, yield 94%).

Example 4

Compound A hydrochloride (1 g, 1.5 mmol) was dissolved in DMF (20 mL), and glyoxal aqueous solution (435 mg, 3.0 mmol, 40 wt% in H ₂ O) was added, and stirred at 60°C for 12 hours. After the reaction was completed, the reaction solution was poured into saturated sodium bicarbonate aqueous solution at 0°C, and the solid precipitated. It was filtered to obtain product B (0.86 g, yield 92%).

Example 5

Compound A hydrochloride (1 g, 1.5 mmol) was dissolved in DMF (20 mL), and diethyl ketomalonate (522 mg, 3.0 mmol) was added. The mixture was stirred at 60 °C for 12 hours. After the reaction was completed, the reaction solution was poured into a saturated sodium bicarbonate aqueous solution at 0 °C. The solid precipitated and was filtered to obtain product B (0.82 g, yield 88%).

Example 6

Compound A hydrochloride (1 g, 1.5 mmol) was dissolved in DMF (20 mL), phenylglyoxal (402 mg, 3.0 mmol) was added, and the mixture was stirred at 60 ° C for 12 hours. After the reaction was completed, the reaction solution was poured into a saturated sodium bicarbonate aqueous solution at 0 ° C. The solid precipitated and was filtered to obtain product B (0.85 g, yield 90%).

Example 7

Compound A hydrochloride (1 g, 1.5 mmol) was dissolved in DMF (20 mL), cyclohexanone (504 mg, 3.0 mmol) was added, and the mixture was stirred at 60 ° C for 24 hours. After the reaction was completed, the reaction solution was poured into a saturated sodium bicarbonate aqueous solution at 0 ° C. The solid precipitated and was filtered to obtain product B (0.86 g, yield 91%).

Example 8

Compound A hydrochloride (1 g, 1.5 mmol) was dissolved in DMF (20 mL), and ketoic acid (426 mg, 3.0 mmol) was added. The mixture was stirred at 60 °C for 24 hours. After the reaction was completed, the reaction solution was poured into a saturated sodium bicarbonate aqueous solution at 0 °C. The solid precipitated and was filtered to obtain product B (0.84 g, yield 89%).

Example 9

Compound A hydrochloride (1 g, 1.5 mmol) was dissolved in DMF (20 mL), and alloxan (480 mg, 3.0 mmol) was added. The mixture was stirred at 60 °C for 2 hours. After the reaction was completed, the reaction solution was poured into a saturated sodium bicarbonate aqueous solution at 0 °C. The solid precipitated and was filtered to obtain product B (0.92 g, yield 96%).

The electrically neutral organic oxidants, reaction conditions and corresponding yields are shown in Table 1:

Among them, glyoxylic acid, glyoxylic acid ester and glyoxal are all added in the form of aqueous solution.

The structures of the electrically neutral organic oxidants are as follows:

In summary, the present invention provides a method for synthesizing key intermediates of ecteinascidin compounds, which is simple to operate, uses cheap and easily available reagents, can react in an aqueous system, has mild and non-harsh reaction conditions, uses low solvents, has high yields, and causes little environmental pollution. The method is suitable for the industrial production of key intermediates of ecteinascidin compounds.

Claims

Use of an electrically neutral organic oxidant as the sole auxiliary agent in a reaction for preparing an ectocystin intermediate; the reaction for preparing an ectocystin intermediate is a reaction for preparing compound B using compound A as a reactant;

The compound A is: or a salt thereof, compound B is:

Wherein, R is hydrogen or a hydroxyl protecting group.
A method for preparing an ectocystin compound intermediate, characterized in that it comprises the following steps:

(1) Compound A or its salt is dissolved in an organic solvent;

(2) adding an electrically neutral organic oxidant to react to obtain compound B;

The reaction formula is as follows:

Wherein, R is hydrogen or a hydroxyl protecting group.
The preparation method according to claim 2, characterized in that the hydroxyl protecting group is methoxymethyl ether, methoxymethyl ethyl ether or allyl.
The preparation method according to claim 2, characterized in that the electrically neutral organic oxidant in step (2) contains at least one carbonyl group in its structure, preferably contains at least two carbonyl groups.
The preparation method according to claim 4, characterized in that the structure of the electrically neutral organic oxidant is as shown in Formula I:

Wherein, R 1 and R 2 are independently selected from: hydrogen, hydroxyl, C 1-5 alkyl, C 1-5 alkoxy, phenyl, or R 1 and R 2 are connected to form a 3-7 membered substituted or unsubstituted saturated or unsaturated ring; the substituted substituent is hydroxyl, carbonyl, amino, halogen, cyano or mercapto; n is an integer of 0-6;

G is selected from CO, NH or CR a R b , wherein Ra and R b in each repeating unit are independently selected from hydrogen, hydroxyl, amino, halogen, cyano or thiol.
The preparation method according to claim 5, characterized in that R 1 and R 2 are independently selected from: hydrogen, hydroxyl, methyl, ethoxy, phenyl, or R 1 and R 2 are connected to form a 5-6 membered substituted or unsubstituted saturated or unsaturated ring; the substituted substituent is hydroxyl or carbonyl, and n is an integer of 0-4.
The preparation method according to claim 6, characterized in that the electrically neutral organic oxidant is as shown in Formula IA:

Wherein, n1 is 1 or 2, and R 1 and R 2 are independently selected from the group consisting of hydrogen, hydroxyl, C 1-5 alkyl, C 1-5 alkoxy, and phenyl;

Preferably, R 1 and R 2 are independently selected from the group consisting of hydrogen, hydroxy, methyl, ethoxy and phenyl.
The preparation method according to claim 6, characterized in that the electrically neutral organic oxidant is as shown in Formula IB:

Where n is 1 or 2;

G1 is nothing, CO, NH or CR c R d , G2 is nothing, CO, NH or CR e R f , G3 is nothing, CO, NH or CR g R h ; wherein R c , R d , Re , R f , R g , and R h are independently selected from hydrogen, hydroxyl, amino, thiol or cyano, or R c and Re are connected to form a chemical bond, or Re and R g are connected to form a chemical bond.
The preparation method according to claim 8, characterized in that the R c , R d , Re , R f , R g , and R h are independently selected from hydrogen and hydroxyl groups, or R c and Re are connected to form a chemical bond, or Re and R g are connected to form a chemical bond.
The preparation method according to any one of claims 4 to 10, characterized in that the electrically neutral organic oxidant is selected from any one of the following compounds or their hydrates:
The preparation method according to claim 10, characterized in that the electrically neutral organic oxidant is alloxan.
The preparation method according to claim 2, characterized in that the organic solvent in step (1) is selected from N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, 1,4-dioxane, tetrahydrofuran or N-methylpyrrolidone; preferably N,N-dimethylformamide.
The preparation method according to claim 2, characterized in that the molar ratio of compound A to the electrically neutral organic oxidant is: 1:(1-5); preferably: 1:2.
The preparation method according to claim 2, characterized in that the reaction conditions are 50-70°C for 1-24 hours; preferably 60°C for 2-24 hours.
The preparation method according to claim 14, characterized in that the electrically neutral organic oxidant is glyoxylic acid, glyoxylic acid ester, glyoxal, methylglyoxal, diethyl ketomalonate or phenylglyoxal, and the reaction time is 10 to 14 hours, preferably 12 hours;

Or, the electrically neutral organic oxidant is cyclohexanehexanone or cyclohexane acid, and the reaction time is 20 to 24 hours, preferably 24 hours;

Alternatively, the electrically neutral organic oxidant is alloxan, and the reaction time is 1 to 3 hours, preferably 2 hours.
The preparation method according to claim 2, characterized in that it also includes the following post-processing steps:

(a) the reaction solution obtained after the reaction in step (2) is poured into an aqueous solution of an inorganic base or an organic base at 0 to 4°C;

(b) The solid was precipitated by standing, and the solid was obtained by filtration, which was compound B.
The preparation method according to claim 16, characterized in that step (a) is: the reaction solution obtained after the reaction in step (2) is poured into a saturated sodium bicarbonate aqueous solution, sodium carbonate aqueous solution or triethylamine aqueous solution at 0°C.