A preparation method of trabectedin intermediate

Abstract

The present invention provides a method for preparing a trabectedin intermediate, specifically involving the generation of free radicals through electron transfer of a reaction substrate at the anode, and then the free radicals initiate an intramolecular cyclization reaction to prepare trabectedin intermediate A; in the method provided by the present invention, a series of reactions are carried out in the same system, without generating secondary pollution, and the reaction has high selectivity, short reaction steps, and significantly improved reaction yield.

Description

Technical Field

[0001] The present invention relates to the field of drug synthesis, and particularly to a preparation method of a trabectedin intermediate. Background Art

[0002] Trabectedin is a class of active natural products with a unique structure. In September 2007, it was approved by the European Union for the treatment of soft tissue sarcoma that has failed anthracycline and ifosfamide treatment, or those patients who are not suitable for receiving these two drugs; trabectedin is combined with liposomal azithromycin for the treatment of platinum-sensitive ovarian cancer; trabectedin is the first marine-derived anti-tumor drug derived from the tunicate Ecteinascidia turbinata, and is a semi-synthetic product of tetrahydroquinoline alkaloids extracted from sea squirts. In addition to blocking the differentiation of tumor cells in the G1 / G2 cycle, it can also inhibit the secretion of vascular endothelial growth factor (VEGF) and the expression of its receptor.

[0003] Currently, the main preparation methods of trabectedin include biological extraction methods. Among them, the highest yield of trabectedin is 0.0001% (ACS Chem. Biol. 2011, 6, 1244), and the preparation yield is very low, which cannot meet industrial use. The total synthesis method of trabectedin reported by Corey et al. involves 36-step reactions. This method has cumbersome steps, requires the use of expensive chiral ligands and precious metal ruthenium, and harsh reaction conditions such as reaction at -78°C; and the operation steps are cumbersome.

[0004] Compound NT028b04 is an important intermediate for the preparation of trabectedin.

[0005]

[0006] CN100475822C discloses a preparation method of the above compound NT028b04. This method includes using NT028b02 as the starting material, selectively removing the methyl group in the quinone system by reacting with a methanol solution of sodium hydroxide to convert it into compound NT028b03, and then reducing the benzoquinone by palladium-carbon hydrogenation reaction. Then, by reacting with bromochloromethane and cesium carbonate under hydrogen pressure, the hydroquinone intermediate is converted into compound NT028b04. This method requires 3 steps to prepare compound NT028b04 from compound NT028b02 as the starting material, and requires reaction under hydrogen pressure twice, which has a large potential safety hazard; the compound NT028b04 prepared by this method is a brown oil. The specific reaction route is as follows:

[0007]

[0008] CN103038240A discloses a reaction method similar to the hydrogenation reduction of quinone by palladium-carbon and then cyclization with methylene. The yield of this step of the reaction is only 36%. The reaction route is as follows:

[0009]

[0010] Regarding the preparation method of compound NT028b04 in the prior art, the reaction steps are long and the yield is low. The art still needs to develop a new preparation method of NT028b04 to improve the conversion efficiency of compound NT028b02, thereby increasing the preparation yield of NT028b04. SUMMARY OF THE INVENTION

[0011] The present invention provides a method for electrochemically preparing trabectedin intermediate A, and further provides a completely new preparation method for compound NT028b04.

[0012] Specifically, the present invention provides a method for electrochemically preparing trabectedin intermediate A, including a method for directly preparing compound A from compound B through a one-step reaction by using an electrochemical method for intramolecular cyclization reaction:

[0013]

[0014] Wherein, P1 is MOM or MEM, and P2 is Boc, Alloc, Troc or Cbz; further preferably, P1 is MOM or MEM, and P2 is Boc, and more preferably P1 is MOM and P2 is Boc;

[0015] In the above method, one of a Pt electrode, a graphite electrode and a glassy carbon electrode is used as the anode, and one of a Pt electrode, a Ni electrode and a graphite electrode is used as the cathode. The reactor uses a single-chamber cell reactor without a separator membrane. The electrochemical reactor adopts a constant voltage mode, and the voltage is 1.0 - 2.5V, preferably 2.0 - 2.5V.

[0016] Further, preferably in the above method, the specific steps are as follows: First, add compound B, a reaction solvent and an electrolyte into a four-necked flask with one of a Pt electrode, a graphite electrode and a glassy carbon electrode as the anode and one of a Pt electrode, a Ni electrode and a graphite electrode as the cathode, then control the temperature at 20°C to 30°C, react at a constant voltage of 1.0 - 2.5V, and finally concentrate, crystallize or purify by silica gel column to obtain compound A;

[0017] The reaction solvent is CH2Cl2, DMF, acetonitrile, methanol or THF, and the electrolyte is LiClO4, Bu4NBF4, Bu4NClO4 or Bu4NPF6; further preferably, the reaction solvent is acetonitrile, and the electrolyte is LiClO4 or Bu4NClO4; the anode is a Pt electrode, and the cathode is a Pt electrode or a graphite electrode.

[0018] In the above method, compound B reaches the electrode surface by diffusion, undergoes a single electron transfer in the anodic oxidation reaction, and then loses H + , forming a methylene radical, which then initiates an intramolecular cyclization reaction, and finally obtains an H from the reaction solution + to generate compound A, the reaction annihilates, and the product diffuses into the solution. The reaction process is as follows:

[0019]

[0020] In the above method, after the reaction, compound A is obtained by crystallization, which means that after the reaction is completed, it is concentrated, cooled, and crystallized; the silica gel column purification means that the concentrated product is separated and purified by a silica gel column, and the eluent is ethyl acetate / petroleum ether: 1:4 (v / v).

[0021] On the other hand, the present invention also provides a method for preparing trabectedin, including the step of electrochemically preparing the intermediate A of trabectedin according to the present invention.

[0022] Abbreviations: "MOM" refers to methoxymethyl ether; "MEM" refers to methoxyethoxymethyl; Boc refers to tert-butoxycarbonyl; Alloc refers to allyloxycarbonyl; Cbz refers to benzyloxycarbonyl; Troc refers to 2,2,2-trichloroethoxycarbonyl.

[0023] The above method provided by the present invention has the following advantages:

[0024] 1. The reaction steps are greatly shortened. In the prior art, usually three reaction steps are required to convert compound B into compound A, while the present invention can complete the conversion through only one reaction step, which not only significantly shortens the reaction route, but also simplifies the post-treatment and shortens the reaction cycle;

[0025] 2. The reaction yield is significantly improved: for the preparation method of compound NT028b04 disclosed in CN100475822C, the yield of the first reaction step is only 68%, and the target product obtained after the following two reaction steps is a brown oil, and the total yield of the three reaction steps is less than 30%; while for the similar hydrogenation reducing agent cyclization reaction disclosed in CN103038240A, the yield is only 36%; the yield of the method provided by the present invention can reach more than 80%.

[0026] 3. By adopting an electrochemical reaction, the present invention initiates electron transfer of the starting material compound B under an anodic oxidation reaction to generate free radicals, and the free radicals initiate an intramolecular cyclization reaction to form compound A. A series of reactions are carried out in the same system without generating secondary pollution. Compared with the prior art, it can shorten the process steps, shorten the reaction time, and make full use of the rare raw material compound B.

[0027] 4. By controlling the oxidation-reduction potential, the present invention can significantly improve the selectivity of the reaction, with fewer side reactions and by-products, high yield and easy separation and purification. Specific embodiments

[0028] The technical solutions and preferred implementation schemes of the present invention are further explained below in combination with specific embodiments.

[0029] Example 1: Preparation method of compound NT028b04

[0030]

[0031] Dissolve 1.00 g of NT028b02 in 20 mL of acetonitrile, and then add 0.53 g of LiClO4. Use a Pt electrode (1 cm × 1 cm) as the anode and a Pt electrode (1 cm × 1 cm) as the cathode, with a voltage of 2.1 V, and react at room temperature for 2 hours. Dilute the reaction solution with 50 mL of water, concentrate and remove acetonitrile under reduced pressure, extract the residue with 20 mL of ethyl acetate twice, combine the organic phases and evaporate to dryness under reduced pressure. The obtained crude product is purified by a silica gel column (the eluent is ethyl acetate / petroleum ether = 1 / 4, volume ratio) to obtain 0.85 g of pure product, and the yield is 85.2%.

[0032] Example 2: Preparation method of compound NT028e03

[0033]

[0034] Dissolve 1.00 g of NT028e02 in 20 mL of THF, and then add 1.70 g of Bu4NClO4. Use a Pt electrode (1 cm × 1 cm) as the anode and a graphite electrode (1 cm × 1 cm) as the cathode, with a voltage of 2.3 V, and react at room temperature for 1.5 hours. Concentrate the reaction solution to dryness under reduced pressure. The obtained crude product is purified by a silica gel column (the eluent is ethyl acetate / petroleum ether = 1 / 4, volume ratio) to obtain 0.80 g of pure product, and the yield is 80.2%.

[0035] Example 3: Preparation method of compound NT028c03

[0036]

[0037] Dissolve 1.00 g of NT028c02 in 20 mL of DMF, and then add 1.90 g of Bu4NPF6. Use a Pt electrode (1 cm × 1 cm) as the anode and a Pt electrode (1 cm × 1 cm) as the cathode, with a voltage of 2.5 V. React for 1.5 hours at room temperature. Concentrate the reaction solution under reduced pressure to dryness. Purify the obtained crude product through a silica gel column (the eluent is ethyl acetate / petroleum ether = 1 / 4, volume ratio) to obtain 0.81 g of the pure product, with a yield of 81%.

[0038] Example 4: Preparation method of compound NT028f04

[0039]

[0040] Dissolve 1.00 g of NT028f02 in 20 mL of CH2Cl2, and then add 1.64 g of Bu4NBF4. Use a Pt electrode (1 cm × 1 cm) as the anode and a graphite electrode (1 cm × 1 cm) as the cathode, with a voltage of 2.2 V. React for 1.5 hours at room temperature. Concentrate the reaction solution under reduced pressure to dryness. Purify the obtained crude product through a silica gel column (the eluent is ethyl acetate / petroleum ether = 1 / 4, volume ratio) to obtain 0.84 g of the pure product, with a yield of 84%.

[0041] Example 5: Preparation method of compound NT028b04

[0042]

[0043] Dissolve 1.00 g of NT028b02 in 20 mL of acetonitrile, and then add 0.53 g of LiClO4. Use a Pt electrode (1 cm × 1 cm) as the anode and a graphite electrode (1 cm × 1 cm) as the cathode, with a voltage of 1.0 V. React for 2 hours at room temperature. Dilute the reaction solution with 50 mL of water, and then concentrate and remove acetonitrile under reduced pressure. Extract the residue with 20 mL of ethyl acetate twice. Combine the organic phases and concentrate under reduced pressure to a volume of about 10 mL, and then let it stand in an ice bath at 0 °C for 10 h to obtain 0.81 g of the pure product of NT028b04, with a yield of 81%.

Claims

1. An electrochemical method for preparing trabectedin intermediate A, characterized in that, A method for directly preparing compound A from compound B in one step by using an electrochemical method for intramolecular cyclization reaction: Wherein, P1 is MOM or MEM, and P2 is Boc, Alloc, Troc or Cbz; The method includes using one of a Pt electrode, a graphite electrode and a glassy carbon electrode as the anode, and using one of a Pt electrode, a Ni electrode and a graphite electrode as the cathode. The reactor uses a single-chamber cell reactor without a separator membrane. The electrochemical reactor adopts a constant voltage mode with a voltage of 1.0 - 2.5 V. The reaction solvent is CH2Cl2, DMF, acetonitrile, methanol or THF, and the electrolyte is LiClO4, Bu4NBF4, Bu4NClO4 or Bu4NPF6.

2. The method according to claim 1, wherein The specific steps are as follows: First, add compound B, the reaction solvent and the electrolyte into a four-necked flask containing one of a Pt electrode, a graphite electrode and a glassy carbon electrode as the anode, and one of a Pt electrode, a Ni electrode and a graphite electrode as the cathode. Then control the temperature at 20°C to 30°C and carry out the reaction at a constant voltage of 1.0 - 2.5 V. Finally, concentrate, crystallize or purify by silica gel column to obtain compound A.

3. The method according to claim 1, wherein The reaction solvent is acetonitrile, the electrolyte is LiClO4 or Bu4NClO4, the anode is a Pt electrode, and the cathode is a Pt electrode or a graphite electrode.

4. The method according to claim 1, wherein Compound B undergoes single electron transfer in the anodic oxidation reaction and then loses H + , forming a methylene radical, which subsequently initiates an intramolecular cyclization reaction, and finally obtains an H from the reaction solution + to produce Compound A and the reaction annihilates.

5. The method according to claim 2, wherein The crystallization to obtain compound A means that after the reaction is completed, concentrate, cool down, and crystallize.

6. The method according to claim 2, wherein The silica gel column purification means separating and purifying the concentrated product through a silica gel column, and the eluent is ethyl acetate / petroleum ether: 1:4 (v / v).

7. According to the method according to any one of claims 1 to 6, characterized in that P1 is MOM or MEM, and P2 is Boc.

8. A preparation method of trabectedin, characterized in that, It includes the method described in any one of the above claims 1 to 7.

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