阅读说明：本技术 一种那布卡辛的合成方法 (Synthetic method of nabacacine ) 是由 曾鹏 林涛峰 吴会荣 王进 于 2019-12-11 设计创作，主要内容包括：本发明公开了一种那布卡辛的合成方法,属于化合物制备技术领域,包括以下步骤：(1)在有机溶剂和催化剂存在的条件下,化合物1与草酰氯反应生成化合物2；(2)在有机溶剂和碱存在的条件下,化合物2与N,O-二甲羟胺盐酸盐反应生成化合物3；(3)化合物3与格氏试剂反应生成那布卡辛。本发明以化合物1为原料,通过先合成韦伯酰胺,然后将韦伯酰胺与格氏试剂反应即可制备得到那布卡辛,路线短,收率高,成本低,操作简单,适宜工业化生产。<Image he="110" wi="700" file="DDA0002313071370000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention discloses a synthetic method of nabacacine, belonging to the technical field of compound preparation, and comprising the following steps: (1) reacting the compound 1 with oxalyl chloride in the presence of an organic solvent and a catalyst to generate a compound 2; (2) in the presence of an organic solvent and alkali, reacting the compound 2 with N, O-dimethylhydroxylamine hydrochloride to generate a compound 3; (3) reaction of compound 3 with grignard reagent produces nabacacine. The invention takes the compound 1 as a raw material, prepares the nabacacine by firstly synthesizing the webamide and then reacting the webamide with the Grignard reagent, has short route, high yield, low cost and simple operation, and is suitable for industrial production.)

1. A synthetic method of nabacacine is characterized by comprising the following steps:

(1) reacting the compound 1 with oxalyl chloride in the presence of an organic solvent and a catalyst to generate a compound 2;

(2) in the presence of an organic solvent and alkali, reacting the compound 2 with N, O-dimethylhydroxylamine hydrochloride to generate a compound 3;

(3) reaction of compound 3 with grignard reagent produces nabacacine.

2. The method of synthesis according to claim 1, characterized in that: in the step (1), the molar ratio of the compound 1 to oxalyl chloride is 1.80-2.00: 1.00; preferably, the molar ratio of compound 1 to oxalyl chloride is 1.80: 1.00.

3. the synthesis method according to claim 1, wherein step (1) satisfies at least one of the following:

the organic solvent is dichloromethane;

the catalyst is N, N-dimethylformamide;

the reaction temperature is 20-35 ℃.

4. The synthesis method according to any one of claims 1 to 3, wherein the step (1) is specifically: adding the compound 1 into an organic solvent, stirring and cooling to-5-0 ℃ under the protection of inert gas, then dropwise adding oxalyl chloride, adding a catalyst after dropwise adding, and reacting at room temperature to obtain a compound 2.

5. The method of synthesis according to claim 4, characterized in that: in the step (2), the molar ratio of the compound 2 to the N, O-dimethylhydroxylamine hydrochloride is 1.00: 1.05-2.00; preferably, the molar ratio of compound 2 to N, O-dimethylhydroxylamine hydrochloride is 1.00: 1.20.

6. the method of synthesis according to claim 4, characterized in that: in the step (2), the organic solvent is dichloromethane; the base is organic amine, and preferably, the organic amine is triethylamine.

7. The synthesis method according to claim 5 or 6, wherein the step (2) is specifically: adding N, O-dimethylhydroxylamine hydrochloride into an organic solvent, cooling to below 0 ℃ under the protection of inert gas, adding alkali, uniformly mixing, dropwise adding the compound 2, and reacting at 20-35 ℃ to obtain a compound 3.

8. The method of synthesis according to claim 7, characterized in that: in step (3), the molar ratio of compound 3 to grignard reagent is 1.00: 1.00.

9. the synthesis method according to claim 7, wherein the step (3) satisfies at least one of the following conditions:

the Grignard reagent is methyl magnesium bromide;

the Grignard reagent was added to methylene chloride before use to prepare a solution having a concentration of 1 mol/L.

10. The synthesis method according to claim 8 or 9, wherein the step (3) is specifically: adding a compound 3 into tetrahydrofuran, cooling to-20 +/-3 ℃ under the protection of inert gas, adding a dichloromethane solution of a Grignard reagent, reacting for 1h, and heating to 20-35 ℃ to react completely to obtain the compound 3.

Technical Field

The invention belongs to the technical field of compound preparation, and particularly relates to a synthetic method of nabacacine.

Background

Nabucacasin (Napabucasin), the chemical name of which is 2-acetyl-4H, 9H-naphtho [2,3-b ] furan-4, 9-dione, is an international pioneering cancer cell dryness inhibitor developed by Boston Biomecal (BBI), which is purchased by Japanese Sumitomo pharmaceutical (Dainippon Sumitomo Pharma) at $ 26.3 million, can simultaneously inhibit multiple key cancer cell "stem cell" pathways, directly acts on malignant tumor stem cells and mature cancer cells, and belongs to STAT3 inhibitors, which are currently undergoing clinical phase III studies on treatment of colon cancer and rectal cancer.

The existing synthesis methods of nabacacine mainly comprise the following 5 methods: 1) phthalic anhydride is used as an initial raw material, coupled with 2-lithium furan, reduced, further coupled and acetylated to form a naphtho [2,3-b ] furan ring, and oxidized to obtain a target compound, wherein reagents used in the synthetic route are expensive; 2) lapachol is used as a starting material; obtaining the nabacacine through ozone oxidation in one step, and has the defects that the nabacacine is not a main product of the reaction, and the route is mainly used for generating derivatives of the nabacacine; 3) 2-hydroxy-1, 4-naphthoquinone is used as a starting material, and after the 2, 3-dimethoxy-1, 3-butadiene is subjected to oxidative addition by ammonium cerium nitrate, the mixture is oxidized by DBU to obtain nabacacine, the reagent of the method is expensive, and the ammonium cerium nitrate has certain toxicity; 4) 2-hydroxy-1, 4-naphthoquinone is taken as a starting material, and is cyclized with 3, 4-dibromobutanone under the action of DBU, and then the cyclized product is further oxidized to obtain nabacacine; 5) 1, 4-naphthoquinone is used as a starting material, the starting material reacts with Thiele-Winter, then hydrolysis and oxidation are carried out to obtain 2-hydroxy-1, 4-naphthoquinone, 2-hydroxy-1, 4-naphthoquinone reacts with 3, 4-dibromo butanone in a cyclization mode, then oxidation is carried out to obtain the nabacacine, and the total yield of the whole synthesis route is only 18.99%.

Disclosure of Invention

The invention aims to provide a synthetic method of nabacacine, which has the advantages of short synthetic route, high yield and low cost.

A synthetic method of nabacacine comprises the following steps:

(1) reacting the compound 1 with oxalyl chloride in the presence of an organic solvent and a catalyst to generate a compound 2;

(2) in the presence of an organic solvent and alkali, reacting the compound 2 with N, O-dimethylhydroxylamine hydrochloride to generate a compound 3;

(3) reaction of compound 3 with grignard reagent produces nabacacine.

In the synthesis method, in the step (1), the molar ratio of the compound 1 to oxalyl chloride is 1.80-2.00: 1.00; preferably, the molar ratio of compound 1 to oxalyl chloride is 1.80: 1.00.

wherein, in the synthesis method, the step (1) meets at least one of the following conditions:

the organic solvent is dichloromethane;

the catalyst is N, N-dimethylformamide;

the reaction temperature is 20-35 ℃.

The synthesis method is characterized in that the step (1) is specifically as follows: adding the compound 1 into an organic solvent, stirring and cooling to-5-0 ℃ under the protection of inert gas, then dropwise adding oxalyl chloride, adding a catalyst after dropwise adding, and reacting at room temperature to obtain a compound 2.

In the above synthesis method, in the step (2), the molar ratio of the compound 2 to the N, O-dimethylhydroxylamine hydrochloride is 1.00: 1.05-2.00; preferably, the molar ratio of compound 2 to N, O-dimethylhydroxylamine hydrochloride is 1.00: 1.20.

in the above synthesis method, in the step (2), the organic solvent is dichloromethane; the base is organic amine, and preferably, the organic amine is triethylamine.

Wherein, the synthesis method comprises the following specific steps of (2): adding N, O-dimethylhydroxylamine hydrochloride into an organic solvent, cooling to below 0 ℃ under the protection of inert gas, adding alkali, uniformly mixing, dropwise adding the compound 2, and reacting at 20-35 ℃ to obtain a compound 3.

In the above synthesis method, in the step (3), the molar ratio of the compound 3 to the grignard reagent is 1.00: 1.00.

wherein, in the synthesis method, the step (3) satisfies at least one of the following conditions:

the Grignard reagent is methyl magnesium bromide;

the Grignard reagent was added to methylene chloride before use to prepare a solution having a concentration of 1 mol/L.

Wherein, the synthesis method comprises the following specific steps in step (3): adding a compound 3 into tetrahydrofuran, cooling to-20 +/-3 ℃ under the protection of inert gas, adding a dichloromethane solution of a Grignard reagent, reacting for 1h, and heating to 20-35 ℃ to react completely to obtain the compound 3.

The terms referred to in the present invention explain:

DMF: n, N-dimethylformamide.

A Grignard reagent: the general formula is RMgX, wherein R is aliphatic hydrocarbon group or aromatic hydrocarbon group, and X is halogen (Cl, Br or I). It is usually prepared from halohydrocarbon and magnesium metal in anhydrous ether or tetrahydrofuran.

Inert gas: means a gas which does not react with the raw material or the solvent in the chemical reaction, such as argon gas, nitrogen gas.

The invention has the beneficial effects that:

the invention takes the compound 1 as a raw material, prepares the nabacacine by firstly synthesizing the webamide and then reacting the webamide with the Grignard reagent, has short route, high yield, low cost and simple operation, and is suitable for industrial production.

Detailed Description

The following examples are provided to further illustrate the embodiments of the present invention and are not intended to limit the scope of the present invention.

The starting materials used in the following examples are all commercially available.