阅读说明：本技术 一种2-丁炔酸的制备方法 (Preparation method of 2-butynoic acid ) 是由 颜国和 刘汉燕 于 2019-10-16 设计创作，主要内容包括：本发明涉及2-丁炔酸的制备技术领域,尤其涉及一种2-丁炔酸的制备方法。本发明提供的制备方法,包括以下步骤：将2-丁炔-1-醇、催化剂、次氯酸盐、碱性物质和水混合,进行氧化反应后,加酸,得到2-丁炔酸。本发明在不使用相转移催化剂的基础上,保证了2-丁炔酸具有较高的收率和纯度。根据实施例的记载,本发明所述的制备方法制备得到的2-丁炔酸的HPLC纯度≥99.6％,收率≥52.7％。(The invention relates to the technical field of preparation of 2-butynoic acid, in particular to a preparation method of 2-butynoic acid. The preparation method provided by the invention comprises the following steps: mixing 2-butyne-1-ol, a catalyst, hypochlorite, an alkaline substance and water, carrying out oxidation reaction, and adding acid to obtain the 2-butynoic acid. The invention ensures that the 2-butynic acid has higher yield and purity on the basis of not using a phase transfer catalyst. According to the description of the embodiment, the HPLC purity of the 2-butynoic acid prepared by the preparation method is more than or equal to 99.6%, and the yield is more than or equal to 52.7%.)

1. The preparation method of 2-butynoic acid is characterized by comprising the following steps:

mixing 2-butyne-1-ol, a catalyst, hypochlorite, an alkaline substance and water, carrying out oxidation reaction, and adding acid to obtain the 2-butynoic acid.

2. The method of claim 1, wherein after the acid addition, the method further comprises post-treating the resulting product system;

the post-treatment comprises the following steps:

extracting the product system by using an organic solvent, removing the organic solvent, adding toluene for reflux, and removing the toluene to obtain a crude product of the 2-butynoic acid;

sublimating the crude product of the 2-butynic acid to obtain the 2-butynic acid.

3. The method according to claim 2, wherein the organic solvent is one or more selected from the group consisting of toluene, xylene, ethylbenzene, ethyl acetate, methyl acetate, isopropyl acetate, dichloromethane, chloroform, and 1, 2-dichloroethane.

4. The method of claim 2, wherein the sublimation is carried out under vacuum conditions;

the sublimation temperature is 45-75 ℃, and the sublimation time is 1-50 h.

5. The method of claim 1, wherein the catalyst is 2,2,6, 6-tetramethyl-4-hydroxypiperidinyl nitroxide radical;

the mass ratio of the catalyst to the 2-butyne-1-ol is (5-20): 100.

6. the preparation method according to claim 1, wherein the mass ratio of the water to the 2-butyn-1-ol is (6-15): 1.

7. the method of claim 1, wherein the equivalent molar ratio of hypochlorite to 2-butyn-1-ol is (2.2-4): 1;

the hypochlorite is measured as hypochlorite ions of hypochlorite in an aqueous solution;

the molar ratio of the alkaline substance to the 2-butyne-1-ol is (1-2): 1.

8. the method of claim 1, wherein the mixing is performed by: mixing 2-butyne-1-ol, a catalyst and water, and respectively adding solid hypochlorite and a solid alkaline substance.

9. The production method according to claim 1, wherein the oxidation reaction is carried out under an alkaline condition;

the pH value under the alkaline condition is 8-11.

10. The method according to claim 1 or 9, wherein the temperature of the oxidation reaction is-5 to 15 ℃; the time of the oxidation reaction is 0.5-2 hours;

the starting time of the oxidation reaction is measured as the time after the addition of hypochlorite and the alkaline substance is completed.

Technical Field

The invention relates to the technical field of preparation of 2-butynoic acid, in particular to a preparation method of 2-butynoic acid.

Background

2-butynoic acid is one of important raw materials of a novel targeted anticancer drug Acalabrutinib, and various methods have been reported in the literature for preparing the 2-butynoic acid, wherein the common method is to oxidize 2-butyn-1-ol into 2-alkynylbutyric acid, which is also a method suitable for industrial scale production.

International patent publication No. WO99/52849 discloses a process for oxidizing primary alcohols to acids in the presence of TEMPO, which consists essentially of using acetonitrile and a buffer solution of sodium phosphate as solvent, TEMPO as catalyst, sodium chlorite NaClO₂Then sodium hypochlorite NaClO is added for oxidationStirring primary alcohol at 35 ℃ until the reaction is complete, adjusting the pH value to 8.0 by using a sodium hydroxide solution, quenching the reaction by using sodium sulfite, extracting the reaction solution by using methyl tert-butyl ether, and acidifying the extraction solution by using hydrochloric acid until the pH value is 3-4 to obtain a methyl tert-butyl ether solution of the corresponding acid. However, the method of WO99/52849 not only uses acetonitrile as a solvent and is expensive, but also it is difficult to recycle the recovered acetonitrile, and further, the method of WO99/52849 finally gives a methyl t-butyl ether solution of 2-butynoic acid, and does not provide a method for obtaining a pure solid acid. And the above method is not suitable for the preparation of 2-butynoic acid using 2-butyn-1-ol, according to which explosion is liable to occur in a condensation tube connected to a reaction flask in practical operation. Therefore, it is difficult to realize industrial-scale production by this method.

On the basis of the above, U.S. Pat. No. US2004/0059154 discloses a process for the oxidation of butyn-2-ol to 2-butynoic acid by oxidation of butyn-2-ol to 2-butynoic acid in the presence of a catalyst 4-OH-TEMPO and a phase transfer catalyst. In this process, a phase transfer catalyst is used to increase the yield of the product. In addition, this process also does not provide a process for obtaining pure solid 2-butynoic acid.

Disclosure of Invention

The invention aims to provide a preparation method of 2-butynoic acid, which can be used for reaction in a single phase of an aqueous solution and has high yield and purity.

In order to achieve the above object, the present invention provides the following technical solutions:

the invention provides a preparation method of 2-butynoic acid, which comprises the following steps:

mixing 2-butyne-1-ol, a catalyst, hypochlorite, an alkaline substance and water, carrying out oxidation reaction, and adding acid to obtain the 2-butynoic acid.

Preferably, after the acid is added, the method further comprises the step of carrying out post-treatment on the obtained product system;

the post-treatment comprises the following steps:

extracting the product system by using an organic solvent, removing the organic solvent, adding toluene for reflux, and removing the toluene to obtain a crude product of the 2-butynoic acid;

sublimating the crude product of the 2-butynic acid to obtain the 2-butynic acid.

Preferably, the organic solvent is one or more of toluene, xylene, ethylbenzene, ethyl acetate, methyl acetate, isopropyl acetate, dichloromethane, trichloromethane and 1, 2-dichloroethane.

Preferably, the sublimation is carried out under vacuum conditions;

the sublimation temperature is 45-75 ℃, and the sublimation time is 1-50 h.

Preferably, the catalyst is 2,2,6, 6-tetramethyl-4-hydroxypiperidine nitroxide radical;

the mass ratio of the catalyst to the 2-butyne-1-ol is (5-20): 100.

preferably, the mass ratio of the water to the 2-butyn-1-ol is (6-15): 1.

preferably, the equivalent molar ratio of the hypochlorite to the 2-butyn-1-ol is (2.2-4): 1;

the hypochlorite is measured as hypochlorite ions of hypochlorite in an aqueous solution;

the molar ratio of the alkaline substance to the 2-butyne-1-ol is (1-2): 1.

preferably, the mixing process is as follows: mixing 2-butyne-1-ol, a catalyst and water, and respectively adding solid hypochlorite and a solid alkaline substance in batches.

Preferably, the oxidation reaction is carried out under alkaline conditions;

the pH value under the alkaline condition is 8-11.

Preferably, the temperature of the oxidation reaction is-5 to 15 ℃; the time of the oxidation reaction is 0.5-2 hours;

the starting time of the oxidation reaction is measured as the time after the addition of hypochlorite and the alkaline substance is completed.

The invention provides a preparation method of 2-butynoic acid, which comprises the following steps: mixing 2-butyne-1-ol, a catalyst, hypochlorite, an alkaline substance and water, carrying out oxidation reaction, and adding acid to obtain the 2-butynoic acid. The invention ensures that the 2-butynic acid has higher yield and purity on the basis of not using a phase transfer catalyst. According to the description of the embodiment, the HPLC purity of the 2-butynoic acid prepared by the preparation method is more than or equal to 99.6%, and the yield is more than or equal to 52.7%.

Drawings

FIG. 1 is a hydrogen nuclear magnetic spectrum of 2-butynoic acid prepared in example 1.

Detailed Description

The invention provides a preparation method of 2-butynoic acid, which comprises the following steps:

mixing 2-butyne-1-ol, a catalyst, hypochlorite, an alkaline substance and water, carrying out oxidation reaction, and adding acid to obtain the 2-butynoic acid.

In the present invention, all the raw materials are commercially available products well known to those skilled in the art unless otherwise specified.

In the invention, the catalyst is preferably 2,2,6, 6-tetramethyl-4-hydroxypiperidine nitroxide free radical (TMHPO), and the mass ratio of the catalyst to the 2-butyn-1-ol is preferably (5-20): 100, more preferably (8-15): 100, most preferably (10-12): 100.

in the invention, the hypochlorite is preferably one or more of sodium hypochlorite, potassium hypochlorite and calcium hypochlorite; when the hypochlorite is more than two of the specific choices, the proportion of the specific substances is not limited in any way, and the specific substances are mixed according to any proportion; in the present invention, the equivalent molar ratio of the hypochlorite to the 2-butyn-1-ol is preferably (2.2-4): 1, more preferably (2.5 to 3.5): 1, most preferably (2.8-3.2): 1.

in the invention, the alkaline substance is preferably one or more of sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate; when the alkaline substances are more than two of the specific choices, the proportion of the specific substances is not limited in any way, and the specific substances are mixed according to any proportion; in the present invention, the molar ratio of the basic substance to the 2-butyn-1-ol is preferably (1-2): 1, more preferably (1.2 to 1.8): 1, most preferably (1.4-1.6): 1. in the invention, the mass ratio of the water to the 2-butyn-1-ol is preferably (6-15): 1, more preferably (8-12): 1, most preferably 10: 1.

In the present invention, the mixing of the 2-butyn-1-ol, the catalyst, the hypochlorite, the alkaline substance and the water is preferably: mixing 2-butyne-1-ol, a catalyst and water, and sequentially adding hypochlorite and an alkaline substance in batches, namely, marking the first addition of hypochlorite and the alkaline substance as a first batch; the second addition of hypochlorite and alkaline material is noted as the second batch and so on. In the present invention, the hypochlorite is preferably a solid hypochlorite, and the alkaline substance is preferably a solid alkaline substance.

In the invention, when hypochlorite and alkaline substances are added, the temperature of the mixture of the 2-butyn-1-ol, the catalyst and water is preferably 5-40 ℃; in the invention, the number of times of dividing the batches is preferably 10-20 times, but the condition that the number of times of dividing the batches is within the range of the batches is not necessarily understood, and the times of dividing the batches can be adjusted according to the actual production scale and the temperature control condition; the batch addition has the function of ensuring that the temperature and the pH value of the reaction are maintained within the range of-5-15 ℃ and 8-11, so that the reaction is prevented from being too violent, and the occurrence of side reactions is reduced.

In the invention, the alkaline substance provides alkaline conditions for the oxidation reaction, and neutralizes the acid generated in the reaction, so that the oxidation reaction can be carried out under the condition that the pH value is 8-11.

In the present invention, the temperature of the oxidation reaction is preferably-5 to 15 ℃, more preferably-5 to 10 ℃; the time of the oxidation reaction is preferably 0.5-2 hours; the start time of the oxidation reaction is measured as the time after the addition of hypochlorite and base is completed.

In the present invention, the oxidation reaction proceeds as shown in the following formula:

after the oxidation reaction is completed, the invention preferably filters and drains the obtained product system, leaches the filter cake with water to obtain filtrate, and adds 20g of sodium sulfite and acid into the filtrate. In the invention, the acid in the acid is preferably hydrochloric acid with the mass concentration of 30%, and the invention has no special requirement on the addition amount of the hydrochloric acid and can ensure that the pH value of a system after oxidation reaction is adjusted to 1-3.

In the invention, after the acid is added, the method also comprises the step of carrying out post-treatment on the obtained product system;

the post-treatment preferably comprises the steps of:

extracting the product system by using an organic solvent, removing the organic solvent, adding toluene for reflux, and removing the toluene to obtain a crude product of the 2-butynoic acid;

sublimating the crude product of the 2-butynic acid to obtain the 2-butynic acid.

In the invention, the organic solvent is preferably one or more of toluene, xylene, ethylbenzene, ethyl acetate, methyl acetate, isopropyl acetate, dichloromethane, trichloromethane and 1, 2-dichloroethane; when the organic solvent is more than two of the above specific choices, the invention has no special limitation on the proportion of the specific substances, and the specific substances can be mixed according to any proportion. In the invention, the mass ratio of the volume of the organic solvent to the 2-butyn-1-ol is preferably (1-10) L: 1Kg, preferably (3-4) L: 1 Kg; in the present invention, the number of the extractions is preferably 3; after the extraction is completed, the organic solvent layers obtained after the 3 times of extraction are preferably combined in the present invention.

In the invention, the organic solvent removal is the organic solvent layer after the combination is removed; the manner of removing the organic solvent is preferably distillation under reduced pressure, and the distillation under reduced pressure is not particularly limited in the present invention and may be performed by a process well known to those skilled in the art. In the invention, the mass ratio of the volume of the toluene to the 2-butyn-1-ol is preferably (2-4) L: 1 Kg; the reflux is not particularly limited in the present invention and may be carried out by a process known to those skilled in the art. In the present invention, the toluene removal is preferably performed by distillation, and the distillation is performed by a process known to those skilled in the art without any particular limitation. After the toluene removal is completed, the present invention preferably cools the resulting product system to room temperature to obtain crude 2-butynoic acid.

In the present invention, the sublimation is preferably carried out under vacuum conditions, the pressure of the vacuum is preferably ≦ -0.08 MPa; the sublimation temperature is preferably 45-75 ℃, more preferably 50-70 ℃, and most preferably 55-65 ℃; the sublimation time is preferably 1 to 50 hours, more preferably 10 to 40 hours, and most preferably 20 to 30 hours.

The process for the preparation of 2-butynoic acid according to the present invention is illustrated in detail below with reference to the examples, but they should not be construed as limiting the scope of the present invention.