CN108069889B

CN108069889B - Synthesis method of azetidine-3-formic acid

Info

Publication number: CN108069889B
Application number: CN201611010633.6A
Authority: CN
Inventors: 秦勇; 陈悦
Original assignee: Shanghai Xipu Medicine Technology Co ltd
Current assignee: Gansu Boxi Biotechnology Co.,Ltd.
Priority date: 2016-11-10
Filing date: 2016-11-10
Publication date: 2021-10-01
Anticipated expiration: 2036-11-10
Also published as: CN108069889A

Abstract

The invention relates to the field of organic synthesis, in particular to a method for synthesizing azetidine-3-formic acid, which comprises the steps of reacting 2, 2-dihydroxymethylmalonic acid-1, 3-diethyl ester with benzhydrylamine after the protection of methanesulfonyl chloride, and then decarboxylating and removing the protection of benzhydryl to obtain the final product azetidine-3-formic acid. The synthesis method takes 2, 2-dimethylolmalonic acid-1, 3-diethyl ester as a raw material, is cheap and easy to obtain, reduces the cost of the whole synthesis line by more than 30 percent compared with the cost of the original synthesis line, does not adopt a highly toxic substance sodium cyanide, and has great industrial production prospect.

Description

Synthesis method of azetidine-3-formic acid

Technical Field

The invention relates to the field of organic synthesis, in particular to a synthetic method of azetidine-3-formic acid.

Background

Azetidine-3-carboxylic acid is an important intermediate, and downstream products thereof are useful in the synthesis of a variety of immunosuppressive agents, particularly in the treatment or prevention of diseases or conditions mediated by lymphocyte interactions, e.g., chinese patent No. CN101679235A discloses an azetidine derivative and its use as a prostaglandin E2 antagonist.

At present, the synthetic route of azetidine-3-carboxylic acid is as follows US 20100249399:

in the synthesis process, a large amount of highly toxic substance sodium cyanide is needed, the harmful effects such as poisoning and the like are caused to operators, and the generated wastewater has potential risk of polluting the environment. In addition, the initial raw material used in the route is benzhydryl-3-hydroxyazetidine, which has a high market price, so that the price of downstream products is high.

Disclosure of Invention

Aiming at the defects of the prior art, the invention provides a method for synthesizing azetidine-3-formic acid, which reduces the production cost and does not use sodium cyanide.

In order to achieve the purpose, the invention is realized by the following technical scheme:

a synthetic method of azetidine-3-formic acid comprises the following synthetic route:

the method comprises the following steps:

(1) reacting 2, 2-dimethylolmalonic acid-1, 3-diethyl ester (A) serving as a raw material with methanesulfonyl chloride to generate an intermediate product (B);

(2) reacting the intermediate product (B) with benzhydrylamine to generate an intermediate product (C);

(3) carrying out decarboxylation reaction on the intermediate product (C) to obtain an intermediate product (D);

(4) and (3) reacting the intermediate product (D) with hydrogen under the action of a catalyst to remove benzhydryl protection, and adjusting the pH value by using alkali to obtain a target product (E), namely azetidine-3-formic acid.

Preferably, the reaction temperature in the step (1) is-15-10 ℃, and the reaction time is 12-36 h.

Preferably, the reaction temperature in the step (2) is 100-120 ℃, and the reaction time is 12-36 h.

Preferably, the reaction temperature in the step (3) is 70-100 ℃, and the reaction time is 12-36 h.

Preferably, the reaction temperature in the step (4) is 10-60 ℃, and the reaction time is 3-10 h.

Preferably, the catalyst in the step (4) is palladium hydroxide carbon.

Preferably, the pH value is adjusted in the step (4) by using a base, wherein the base is one selected from potassium carbonate, sodium carbonate and sodium bicarbonate, and the pH value is adjusted to be 6-7.

Compared with the prior art, the invention has the following advantages: the synthetic method does not adopt highly toxic substance sodium cyanide, avoids the human harm and the environmental pollution caused by the highly toxic substance sodium cyanide, takes the 2, 2-dihydroxymethylmalonic acid-1, 3-diethyl ester as the raw material, is cheap and easy to obtain, and reduces the cost of the whole synthetic line by more than 30 percent compared with the cost of the original synthetic line, thereby being beneficial to the cost adjustment of the downstream bulk drugs and having great industrial production prospect.

Detailed Description

In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are some embodiments of the present invention, but not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

Example 1: synthesis of intermediate (B)

Adding 110g of 2, 2-dimethylolmalonic acid-1, 3-diethyl ester, 1.5L of dichloromethane and 150g of triethylamine into a clean 3L three-necked bottle, mechanically stirring for 10min, cooling to 0 ℃, slowly dropwise adding 115g of methanesulfonyl chloride into the three-necked bottle, controlling the temperature to be 0-5 ℃, generating a large amount of solid salt, reacting at room temperature overnight, adding 1L of water for washing the next day, layering, drying an organic layer, concentrating and drying to obtain 180g of an intermediate product (B), wherein the yield is 95.7%, and purification is not needed.

Example 2: synthesis of intermediate (C)

Adding 1.5L of toluene into a clean 3L three-necked bottle, adding 180g of the intermediate product (B) prepared in example 1, continuously adding 87g of benzhydrylamine and 150g of triethylamine, heating to 110 ℃, carrying out reflux reaction, allowing solids to be generated, refluxing overnight, stopping the reaction, filtering to remove salt, washing an organic layer, drying and concentrating to obtain 120g of the intermediate product (C), and purifying is not required.

Example 3: synthesis of intermediate (D)

120g of the intermediate (C) obtained in example 2 was added to 1L of 6N hydrochloric acid, heated to 80 ℃ and allowed to react overnight with heat preservation, with generation of gas, followed by evaporation of water the next day while taking care to prevent washing, to give a brown oily substance, and added with 300mL of acetone and heated to recrystallize, to give 78g of the intermediate (D) as a pale yellow solid. 1H-NMR Spectrum (CDCl3), delta (ppm): 3.00-3.90(5H, m), 4.95(1H, s), 7.25-7.28(2H, m), 7.33(4H, m), 7.53(4H, m).

Example 4: synthesis of target product (E)

78g of the intermediate product (D) obtained in example 3 was added to a mixture of 500mL of methanol and 100mL of water, 7g of palladium hydroxide carbon (10%) was added, hydrogen was introduced into the mixture to make the pressure of the reaction vessel reach 3 MPa, the reaction was carried out for 6 hours, the reaction was completed, the catalyst was removed by filtration, 500mL of water was added, methanol was evaporated, diphenylmethane was extracted twice with ethyl acetate, the aqueous layer was concentrated to dryness, 300mL of water was added again to the obtained solid, pH 6.7 was adjusted with potassium carbonate solid to have a turbidity phenomenon, ethyl acetate was used for extraction, the organic layer was dried, and 25g of azetidine-3-carboxylic acid, which is a solid product, was obtained by concentration to dryness, with a yield of 85%.

In summary, the embodiment of the invention has the following beneficial effects: the raw materials used in the whole synthesis line are cheap and easily available, and the cost is reduced by more than 30% compared with the cost of the original synthesis line.

It is noted that, herein, relational terms such as first and second, and the like may be used solely to distinguish one entity or action from another entity or action without necessarily requiring or implying any actual such relationship or order between such entities or actions. Also, the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus. Without further limitation, an element defined by the phrase "comprising an … …" does not exclude the presence of other identical elements in a process, method, article, or apparatus that comprises the element.

The above examples are only intended to illustrate the technical solution of the present invention, but not to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some technical features may be equivalently replaced; and such modifications or substitutions do not depart from the spirit and scope of the corresponding technical solutions of the embodiments of the present invention.

Claims

1. A synthetic method of azetidine-3-formic acid is characterized in that the synthetic route is as follows:

the method comprises the following steps:

(1) reacting 2, 2-dimethylolmalonic acid-1, 3-diethyl ester (A) serving as a raw material with methanesulfonyl chloride to generate an intermediate product (B), wherein the reaction temperature in the step is-15-10 ℃, and the reaction time is 12-36 hours;

(2) reacting the intermediate product (B) with benzhydrylamine to generate an intermediate product (C), wherein the reaction temperature in the step is 100-120 ℃, and the reaction time is 12-36 hours;

(3) carrying out decarboxylation reaction on the intermediate product (C) under the action of hydrochloric acid to obtain an intermediate product (D), wherein the reaction temperature in the step is 70-100 ℃, and the reaction time is 12-36 h;

(4) and (3) reacting the intermediate product (D) with hydrogen under the action of a catalyst palladium hydroxide carbon to remove benzhydryl protection, and adjusting the pH value to 6-7 by using potassium carbonate to obtain a target product (E), namely azetidine-3-formic acid, wherein the reaction temperature in the step is 10-60 ℃, and the reaction time is 3-10 hours.