阅读说明：本技术 一种用于制备艾日布林的中间体(r)-2-甲基-1-溴-3-碘-3-丁烯的制备方法 (Preparation method of intermediate (R) -2-methyl-1-bromo-3-iodo-3-butene for preparing eribulin ) 是由 刘中华 程琳 简勇 葛敏 于 2020-08-17 设计创作，主要内容包括：本发明提供了一种用于制备艾日布林的中间体(R)-2-甲基-1-溴-3-碘-3-丁烯的制备方法,包括以下步骤：A)式Ⅰ所示化合物在碱性化合物的作用下,发生脱溴反应,制备得到式Ⅱ所示化合物；B)式Ⅱ所示化合物与碘化物进行碘代反应,制备得到式Ⅲ所示的(R)-2-甲基-1-溴-3-碘-3-丁烯。本发明采用溴烷基-1,1-二溴烯烃制备溴烷基炔烃,减少了溴取代离去基团的反应,一锅法即可制备得到产物,反应步骤短,三废少,原料易得,成本低,反应安全,只上一个碘原子,减少了碘试剂的使用量,具有很好的工业应用前景和商业价值。(The invention provides a preparation method of an intermediate (R) -2-methyl-1-bromo-3-iodo-3-butene for preparing eribulin, which comprises the following steps: A) carrying out debromination reaction on the compound shown in the formula I under the action of an alkaline compound to prepare a compound shown in a formula II; B) performing iodination reaction on the compound shown in the formula II and iodide to prepare the (R) -2-methyl-1-bromo-3-iodo-3-butene shown in the formula III. The invention adopts the bromoalkyl-1, 1-dibromoalkene to prepare the bromoalkyl alkyne, reduces the reaction of bromine for replacing leaving groups, can prepare the product by a one-pot method, has short reaction steps, less three wastes, easily obtained raw materials, low cost and safe reaction, only adds one iodine atom, reduces the using amount of an iodine reagent, and has good industrial application prospect and commercial value.)

1. A preparation method of intermediate (R) -2-methyl-1-bromo-3-iodo-3-butene for preparing eribulin, comprising the steps of:

A) carrying out elimination reaction on the compound shown in the formula I under the action of an alkaline compound to prepare a compound shown in a formula II;

B) performing iodine addition reaction on the compound shown in the formula II and iodide to prepare (R) -2-methyl-1-bromo-3-iodo-3-butene shown in the formula III;

2. the method according to claim 1, wherein the basic compound is one or more selected from the group consisting of n-butyllithium, lithium diisopropylamide, tetrabutylammonium fluoride, cesium carbonate, potassium carbonate and DBU.

3. The preparation method according to claim 1, wherein the molar ratio of the compound represented by the formula I to the basic compound is 1 (1.5-2.5).

4. The method according to claim 1, wherein the solvent for the elimination reaction is one or more selected from tetrahydrofuran, 2-methyltetrahydrofuran and dioxane.

5. The method according to claim 1, wherein the temperature of the elimination reaction is-110 to-45 ℃ and the reaction time is 1min to 3 hours.

6. The method according to claim 1, wherein the iodide is one or more selected from the group consisting of hydrogen iodide, lithium iodide, sodium iodide, potassium iodide, tetraethylammonium iodide, and tetrabutylammonium iodide.

7. The method according to claim 1, wherein the solvent for the iodine addition reaction is one or more selected from acetonitrile, ethyl acetate, acetone, dimethylformamide, toluene, tetrahydrofuran, 2-butanone, and 2-methyltetrahydrofuran.

8. The method according to claim 1, wherein the temperature of the iodine addition reaction is 0 to 100 ℃ and the reaction time is 1 to 60 hours.

9. The process according to claim 1, wherein the compound of formula I is prepared by the following process:

s1) reacting triphenylphosphine with carbon tetrabromide to prepare wittig reagent;

s2) mixing wittig reagent and (R) -2-methyl-3- [ (triphenylmethyl) oxy ] propionaldehyde, and reacting to obtain the compound (S) -3-methyl-1, 1, 4-tribromobutene.

10. A preparation method of eribulin comprises the following steps:

A) carrying out elimination reaction on the compound shown in the formula I under the action of an alkaline compound to prepare a compound shown in a formula II;

B) performing iodine addition reaction on the compound shown in the formula II and iodide to prepare (R) -2-methyl-1-bromo-3-iodo-3-butene shown in the formula III;

C) taking (R) -2-methyl-1-bromo-3-iodo-3-butene as a raw material to prepare eribulin.

Technical Field

The invention relates to the technical field of drug synthesis, in particular to a preparation method of an intermediate (R) -2-methyl-1-bromo-3-iodo-3-butene for preparing eribulin.

Background

Kishi et al at Harvard university have systematically studied the total synthesis of halichondrin B (J Am Chem Soc, 1992, 114: 3162-3164), and invented eribulin (formula 1), a derivative thereof. Formula 1 can be synthesized by formula 2, wherein the chiral compound represented by formula 2 is a key intermediate for synthesizing eribulin. The key intermediate for preparing formula 2 is compound formula 3.

The literature for the synthesis of formula 3 is mainly:

1) kishi, published in J Am Chem Soc, 2009, 131: 15636-15641 reports that the compound of formula 3 is prepared by two routes, the synthesis route is long, the raw material 1, 4-dihydroxy-2-butyne is expensive, and the dangerous reagents dimethyl zinc and trimethyl aluminum are respectively adopted, so that the method is not suitable for industrial production.

2) A process for preparing compound formula 3 is disclosed in 2011 patent WO2013078559 by argla canada (Alphora Research Inc). TBDPS is adopted to protect hydroxyl, TBDPS protecting group is removed by hydroxyl, Ts protecting hydroxyl is changed, and TsO is replaced by iodine; expensive 9-iodo-9-borabicyclo [3.3.1] nonane reagent is used in the iodine addition process. The method has long synthesis route, complex method and more three wastes, and the prepared product has low atom economy, is not suitable for industrialization and has no optimistic commercial prospect.

Disclosure of Invention

In view of this, the technical problem to be solved by the present invention is to provide a method for preparing (R) -2-methyl-1-bromo-3-iodo-3-butene, which is an intermediate for preparing eribulin, wherein (R) -2-methyl-1-bromo-3-iodo-3-butene is used as the intermediate, and the method has a short reaction route and low cost, and is suitable for industrial production.

In order to solve the above technical problems, the present invention provides a method for preparing an eribulin intermediate (R) -2-methyl-1-bromo-3-iodo-3-butene, comprising the steps of:

A) carrying out elimination reaction on the compound shown in the formula I under the action of an alkaline compound to prepare a compound shown in a formula II;

B) performing iodine addition reaction on the compound shown in the formula II and iodide to prepare (R) -2-methyl-1-bromo-3-iodo-3-butene shown in the formula III;

in the present invention, the basic compound is preferably one or more of n-butyllithium, lithium diisopropylamide, tetrabutylammonium fluoride, cesium carbonate, potassium carbonate and DBU. More preferably n-butyllithium.

The solvent for the elimination reaction is preferably one or more of tetrahydrofuran, 2-methyltetrahydrofuran and dioxane. More preferably tetrahydrofuran.

The molar ratio of the compound shown in the formula I to the alkaline compound is 1: (1.5-2.5), preferably 1: (1.7-2.3), more preferably 1 (1.90-2.10), and still more preferably 1 (1.98-2.02). In some embodiments of the invention, the molar ratio of the compound of formula I to the basic compound is 1: 2.0.

The temperature of the elimination reaction is-110 to-45 ℃, and more preferably-90 to-70 ℃; more preferably from-90 to-80 ℃.

The reaction time of the elimination reaction is preferably 1min to 3h, and more preferably 1min to 40 min.

The iodide is preferably one or more of hydrogen iodide, lithium iodide, sodium iodide, potassium iodide, tetraethylammonium iodide and tetrabutylammonium iodide. More preferably lithium iodide.

The solvent of the iodine addition reaction is preferably one or more of acetonitrile, ethyl acetate, acetone, dimethylformamide, toluene, tetrahydrofuran, 2-butanone and 2-methyltetrahydrofuran. More preferably acetone.

The temperature of the iodine addition reaction is preferably 0-100 ℃, and more preferably 45-65 ℃.

The time for the iodine addition reaction is preferably 1-60 hours, and more preferably 20-24 hours.

In a preferred embodiment of the invention, the compound of formula I is prepared by the following method:

s1) reacting triphenylphosphine with carbon tetrabromide to prepare wittig reagent;

s2) mixing wittig reagent and (R) -2-methyl-3- [ (triphenylmethyl) oxy ] propionaldehyde, and reacting to obtain the compound (S) -3-methyl-1, 1, 4-tribromobutene.

Preferably, after the reaction in step S2) is finished, the method further includes a post-treatment step, specifically:

after the reaction is completed, quenching the reaction, filtering, extracting the filtrate by toluene, concentrating the extract, and purifying to obtain the compound (S) -3-methyl-1, 1, 4-tribromobutene.

The method adopts specific reaction temperature and the dosage of alkaline compounds, so that bromine atoms of bromoalkyl in the compound shown in the formula I are not easy to generate debromination reaction, two bromine atoms of olefin are easy to generate elimination reaction, the reaction has better selectivity, and the yield and the purity of the final product (R) -2-methyl-1-bromo-3-iodo-3-butene are higher.

The by-products of the above reaction, including the remaining raw materials, alkyl alkynes, bromoalkyl monobromoalkenes, can be removed by means of rectification under reduced pressure.

The invention provides a preparation method of eribulin, which comprises the following steps:

A) carrying out elimination reaction on the compound shown in the formula I under the action of an alkaline compound to prepare a compound shown in a formula II;

B) performing iodine addition reaction on the compound shown in the formula II and iodide to prepare (R) -2-methyl-1-bromo-3-iodo-3-butene shown in the formula III;

C) taking (R) -2-methyl-1-bromo-3-iodo-3-butene as a raw material to prepare eribulin.

The specific method for preparing eribulin from (R) -2-methyl-1-bromo-3-iodo-3-butene as a raw material is not particularly limited in the present invention, and may be a method known to those skilled in the art.

Compared with the prior art, the invention provides a preparation method of an intermediate (R) -2-methyl-1-bromo-3-iodo-3-butene for preparing eribulin, which comprises the following steps: A) carrying out debromination reaction on the compound shown in the formula I under the action of an alkaline compound to prepare a compound shown in a formula II; B) performing iodination reaction on the compound shown in the formula II and iodide to prepare the (R) -2-methyl-1-bromo-3-iodo-3-butene shown in the formula III. The invention adopts the bromoalkyl-1, 1-dibromoalkene to prepare the bromoalkyl alkyne, reduces the reaction of bromine for replacing leaving groups, can prepare the product by a one-pot method, has short reaction steps, less three wastes, easily obtained raw materials, low cost and safe reaction, only adds one iodine atom, reduces the using amount of an iodine reagent, and has good industrial application prospect and commercial value.

Detailed Description

To further illustrate the present invention, the preparation method of the intermediate (R) -2-methyl-1-bromo-3-iodo-3-butene for the preparation of eribulin provided by the present invention is described in detail below with reference to examples.

Preparing raw materials: preparation of the Compounds of formula I

A dry flask was charged with 200mL of acetonitrile and 62.4g of triphenylphosphine, and then purged with nitrogen, a mixture of 39.5g of carbon tetrabromide and 100mL of acetonitrile was added at once, the mixture was cooled to-30 ℃ and 26.2g (79.4mmol, prepared according to Organic Letters,10(13), 2821-propanal 2824; 2008) of (R) -2-methyl-3- [ (triphenylmethyl) oxy ] propanal was added, followed by stirring at-12 ℃ for 20min, 180mL of acetone was added, stirring for 40min and completion of the reaction was detected by TLC. Adding water for quenching, filtering, adding toluene for extraction, concentrating and purifying to obtain 17.6g of compound (S) -3-methyl-1, 1, 4-tribromobutene.