阅读说明：本技术 一种伊沙匹隆二聚体的高收率制备方法 (High-yield preparation method of ixabepilone dimer ) 是由 徐有安 付光明 龚美芳 于 2020-11-30 设计创作，主要内容包括：本发明属于化学工业领域,特别涉及一种伊沙匹隆二聚体的高收率制备方法,通过将埃博霉素羧酸铵盐的溶液加入到至少包括EDCI、K_2CO_3和HOBT的缩合体系中,搅拌得到伊沙匹隆二聚体。本技术方案以埃博霉素B为起始原料,经过叠氮化和还原反应得到开环的埃博霉素羧酸铵盐的溶液,在缩合剂存在的条件下,快速将上述埃博霉素羧酸铵盐的溶液加入到缩合剂的体系中,通过慢速搅拌得到高产率的伊沙匹隆二聚体。之后通过硅胶柱层析纯化,能得到高收率且纯度大于98.0％的伊沙匹隆二聚体。(The invention belongs to the field of chemical industry, and particularly relates to a high-yield preparation method of ixabepilone dimer, which comprises the step of adding solution of epothilone carboxylic acid ammonium salt into at least EDCI and K 2 CO 3 And HOBT to obtain ixabepilone dimer. The technical scheme includes that epothilone B is used as a starting material, ring-opened epothilone carboxylic acid ammonium salt solution is obtained through azide and reduction reaction, the epothilone carboxylic acid ammonium salt solution is quickly added into a condensing agent system in the presence of a condensing agent, and a high-yield ixabepilone dimer is obtained through slow stirring. Then, the ixabepilone dimer with high yield and purity more than 98.0 percent can be obtained by silica gel column chromatography purification.)

1. A high-yield preparation method of ixabepilone dimer is characterized by comprising the following steps: adding a solution of an ammonium salt of an epothilone carboxylic acid to a solution comprising at least EDCI, K₂CO₃And HOBT to obtain ixabepilone dimer.

2. The process for the preparation of ixabepilone dimer in high yield according to claim 1 wherein said solution of epothilone carboxylic acid ammonium salt is prepared by:

s1, adding Pd into a first container with epothilone B₂(dba)₃、NH₄Cl、TBAN₃And THF solution, shake and dissolve;

s2, cooling to 0-10 ℃, and adding PMe into a first container of S1₃Stirring, and then heating to 25-35 ℃ for reaction until TLC monitors that the epothilone B point disappears;

s3, filtering and washing the obtained filter residue with a THF solution to obtain the solution of the epothilone carboxylic acid ammonium salt.

3. The method for the high-yield preparation of ixabepilone dimer according to claim 2, wherein: the solution of the epothilone carboxylic acid ammonium salt is prepared and then added into the condensation system within 2 minutes.

4. The method for the high-yield preparation of ixabepilone dimer according to claim 2, wherein: and adding the solution of the epothilone carboxylic acid ammonium salt into a condensation system, and reacting at the temperature of 20-30 ℃.

5. The method for the high-yield preparation of ixabepilone dimer according to claim 2, wherein: and adding the solution of the epothilone carboxylic acid ammonium salt into the condensation system, and stirring at the speed of 0-20 revolutions per minute until TLC monitors that the intermediate state point of the epothilone B disappears.

6. The method for the high-yield preparation of ixabepilone dimer according to claim 5, wherein: and (3) adding EA and water quenching for reaction after TLC monitors that the intermediate state point of the epothilone B disappears, separating the obtained solution into an upper organic phase, extracting a lower aqueous phase with EA for 1-2 times, combining the organic phases, and purifying through a silica gel column to obtain ixabepilone dimer.

7. The method for the high-yield preparation of ixabepilone dimer according to claim 6, wherein: the silica gel column purification is to firstly use a mixed solvent of ethyl acetate, cyclohexane and triethylamine as an initial mobile phase to remove impurity points, and then use a mixed solvent of tetrahydrofuran, ethyl acetate and triethylamine as a subsequent mobile phase to collect a high-purity target product, namely the ixabepilone dimer.

Technical Field

The invention belongs to the field of chemical industry, and particularly relates to a high-yield preparation method of ixabepilone dimer.

Background

The existing method for preparing ixabepilone dimer has low yield, needs high performance liquid chromatography, has complex process, is not beneficial to mass production and is difficult to meet the requirement.

Disclosure of Invention

In order to solve the above problems, the present invention provides a high yield preparation method of ixabepilone dimer, comprising the steps of: adding a solution of an ammonium salt of an epothilone carboxylic acid to a solution comprising at least EDCI, K₂CO₃And HOBT to obtain ixabepilone dimer.

The preparation method of the solution of the epothilone carboxylic acid ammonium salt comprises the following steps:

s1, adding Pd into a first container with epothilone B₂(dba)₃、NH₄Cl、TBAN₃And THF solution, shake and dissolve;

s2, cooling to 0-10 ℃, and adding PMe into a first container of S1₃Stirring, and then heating to 25-35 ℃ for reaction until TLC monitors that the epothilone B point disappears;

s3, filtering and washing the obtained filter residue with a THF solution to obtain the solution of the epothilone carboxylic acid ammonium salt.

And, the solution of the epothilone carboxylic acid ammonium salt is added to the condensation system within 2 minutes after the preparation.

And adding the solution of the epothilone carboxylic acid ammonium salt into a condensation system and then reacting at the temperature of 20-30 ℃.

And adding the solution of the epothilone carboxylic acid ammonium salt into the condensation system, and stirring at the speed of 0-20 revolutions per minute until TLC monitors that the epothilone B intermediate state point disappears.

And TLC monitors that the intermediate state point of the epothilone B disappears, and then EA and water are added to quench and react, the obtained solution is separated into an upper organic phase, a lower aqueous phase is extracted with EA for 1-2 times, the organic phases are combined, and the ixabepilone dimer is obtained by purifying the organic phases through a silica gel column.

And the silica gel column purification is to firstly use a mixed solvent of ethyl acetate, cyclohexane and triethylamine as an initial mobile phase to remove all impurity points with small polarity, and then use a mixed solvent of tetrahydrofuran, ethyl acetate and triethylamine as a subsequent mobile phase to collect a high-purity target product, namely the ixabepilone dimer.

Compared with the prior art, the technical scheme has the beneficial effects that: the method comprises the steps of taking epothilone B as a starting material, carrying out azide and reduction reactions to obtain a ring-opened epothilone carboxylic acid ammonium salt solution, rapidly adding the epothilone carboxylic acid ammonium salt solution into a condensing agent system in the presence of a condensing agent, and slowly stirring to obtain the ixabepilone dimer with high yield. Then, the ixabepilone dimer with high yield and purity more than 98.0 percent can be obtained by silica gel column chromatography purification.

Drawings

FIG. 1 is a schematic diagram of the reaction mechanism.

Detailed Description

The present invention will be described in detail with reference to examples, but the present invention is not limited to the examples.

Example 1:

(1) in three-necked bottle a: 0.5g of epothilone B (1.0eq) was added, followed by 0.02g of Pd₂(dba)₃[ i.e., tris (dibenzylideneacetone) dipalladium (0) ] 0.022eq and 0.053g NH₄Cl [ i.e. ammonium chloride ] (1.06eq), under argon. Then 2.0ml of THF (tetrahydrofuran) solution was added, followed by stirring, and 2.8ml of TBAN was added₃[ i.e., tetrabutylammonium azide ] solution (preparation method: TBAN)₃-0.42g, water-0.12 ml, DMF-0.67ml, THF-1.9 ml).

(2) Cooling to 0-10 deg.C, and injecting 0.13g (1.8eq) of pure PMe into the bottom of the system₃[ i.e. trimethylphosphine ]. After stirring for 6 minutes, the reaction flask was moved into a magnetically stirred water bath.

(3) Keeping the temperature of 25-35 ℃ for reacting for 1-3 hours, and then monitoring by TLC: the material point disappeared.

(4) Filtration was carried out and the filter residue was washed once with 3.0ml of THF to give a dark cyan clear solution (. about.6 ml) which was stored at 20-30 ℃.

(5) In the three-necked bottle B: sequentially adding 1.5ml of DMF (dimethylformamide) and 1.5ml of THF, stirring in a water bath at 20-30 ℃, and sequentially adding 0.85g of EDCI (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide) (4.5eq) and 0.067g of K₂CO₃[ i.e., potassium carbonate ] (0.4 eq.) and 0.075g of HOBT [ i.e., 1-hydroxybenzotriazole ] (0.56 eq.) were stirred for 0.5 hour.

(6) And (3) quickly adding the filtrate in the step (4) into the mixed system in the step (5) within 1-2 minutes, and stirring at a low speed (0-20 revolutions per minute).

(7) And then keeping the temperature of 20-30 ℃ for reaction for 1.0-2.0 hours, and monitoring by TLC: the intermediate point of the raw material disappears. 6ml of EA [ i.e. ethyl acetate ] and 9ml of water were added to quench the reaction.

(8) The upper organic phase was separated, the lower aqueous phase was extracted 2 times with EA (2.5ml x 2), and the organic phases were combined.

(9) After sample mixing by silica gel, purifying by using a silica gel (200-300 meshes) column: after removing all small amount of impurities with small polarity (wherein the volume ratio of ethyl acetate to cyclohexane is 1: 1) with eluent of ethyl acetate, cyclohexane and triethylamine with volume fraction of 1%, eluent of tetrahydrofuran, ethyl acetate and triethylamine with volume fraction of 1% was used to obtain the target dimer (wherein the volume ratio of tetrahydrofuran to ethyl acetate is 5: 1), 0.4g of white solid was obtained after concentration, yield 80% and purity 98.5%. Under the same analysis method conditions, the RRT of the obtained white solid is consistent with the RRT time of the dimer impurity in the standard spectrum of the original research company. The reaction mechanism is shown in figure 1.

Example 2:

(1) in three-necked bottle a: 5g of epothilone B (1.0eq) was added, followed by 0.2g of Pd₂(dba)₃(0.022eq) and 0.53g of NH₄Cl (1.06eq), under argon. Then, 20ml of THF was added thereto, followed by stirring, and 28ml of TBAN was added thereto₃Solution (preparation method: TBAN)₃4.2g, water-1.2 ml, DMF-6.7ml, THF-19 ml).

(2) Cooling to 0-10 deg.C, and injecting 1.3g (1.8eq) of pure PMe into the bottom of the system₃. After stirring for 6 minutes, the reaction flask was moved into a magnetically stirred water bath.

(3) Keeping the temperature of 25-35 ℃ for reacting for 1-3 hours, and then monitoring by TLC: the material point disappeared.

(4) Filtration was carried out and the filter residue was washed once with 30ml of THF to give a dark cyan clear solution (. about.60 ml) which was stored at 20-30 ℃.

(5) In the three-necked bottle B: sequentially adding 15ml of DMF and 15ml of THF, stirring in a water bath at 20-30 ℃, and sequentially adding8.5g of EDCI (4.5eq), 0.67g of K₂CO₃(0.4eq) and 0.75g HOBT (0.56eq) were stirred for 0.5 h.

(6) And (3) quickly adding the filtrate in the step (4) into the mixed system in the step (5) within 1-2 minutes, and stirring at a low speed (0-20 revolutions per minute).

(7) And then keeping the temperature of 20-30 ℃ for reaction for 1.0-2.0 hours, and monitoring by TLC: the intermediate point of the raw material disappears. The reaction was quenched by adding 60ml of EA and 90ml of water.

(8) The upper organic phase was separated, the lower aqueous phase was extracted 2 times with EA (25ml 2), and the organic phases were combined.

(9) After sample mixing by silica gel, purifying by using a silica gel (200-300 meshes) column: first, using (volume ratio) ethyl acetate: cyclohexane 1: 1 plus 1% (volume fraction) of triethylamine to remove all small amounts of impurities of small polarity, followed by the use of (volume ratio) tetrahydrofuran: ethyl acetate ═ 5: 1 plus an eluent of 1% (volume fraction) triethylamine gave the target dimer, which after concentration gave 4.3g of a white solid, 86% yield and 98.8% purity.

Example 3:

(1) in three-necked bottle a: 1.0g of epothilone B (1.0eq) was dosed, followed by 0.04g of Pd₂(dba)₃(0.022eq) and 0.1g of NH₄Cl (1.06eq), under argon. 4.0ml of THF was further injected, and after stirring, 5.6ml of TBAN was further injected₃Solution (preparation method: TBAN)₃-0.84g, water-0.24 ml, DMF-1.3ml, THF-4.0 ml).

(2) Cooling to 0-10 deg.C, and injecting 0.26g (1.8eq) of pure PMe into the bottom of the system₃. After stirring for 6 minutes, the reaction flask was moved into a magnetically stirred water bath.

(3) Keeping the temperature of 25-35 ℃ for reacting for 1-3 hours, and then monitoring by TLC: the material point disappeared.

(4) Filtration was carried out and the filter residue was washed once with 6.0ml of THF to give a dark cyan clear solution (. about.12 ml) which was stored at 20-30 ℃.

(5) In the three-necked bottle B: sequentially adding 3ml of DMF and 3ml of THF, stirring in a water bath at 20-30 ℃, and sequentially adding 1.7g of EDCl (4.5eq) and 0.13g of K₂CO₃(0.4eq) and 0.15g HOBT (0.56eq) were stirred for 0.5 hrThen (c) is performed.

(6) And (3) quickly adding the filtrate in the step (4) into the mixed system in the step (5) within 1-2 minutes, and stirring at a low speed (0-20 revolutions per minute).

(7) And then keeping the temperature of 20-30 ℃ for reaction for 1.0-2.0 hours, and monitoring by TLC: the intermediate point of the raw material disappears. The reaction was quenched by the addition of 12ml of EA and 18ml of water.

(8) The upper organic phase was separated, the lower aqueous phase was extracted 2 times with EA (5ml 2), and the organic phases were combined.

(9) After sample mixing by silica gel, purifying by using a silica gel (200-300 meshes) column: first, using (volume ratio) ethyl acetate: cyclohexane 1: 1 plus 1% (volume fraction) of triethylamine to remove all small amounts of impurities of small polarity, followed by the use of (volume ratio) tetrahydrofuran: ethyl acetate ═ 5: 1 plus an eluent of 1% (volume fraction) triethylamine gave the target dimer, which after concentration gave 0.81g of a white solid, 81% yield, 99.0% purity.