阅读说明：本技术 脱除酰胺基团上的对甲氧基苯基保护基的方法 (Method for removing p-methoxyphenyl protecting group on amide group ) 是由 洪浩 肖毅 熊正常 金星 董长明 袁晓斌 田凯 徐聪聪 于 2021-09-22 设计创作，主要内容包括：本发明提供了一种脱除酰胺基团上的对甲氧基苯基保护基的方法。该方法包括：在有机溶剂的存在下,使底物和臭氧依次进行臭氧化反应和淬灭处理,得到氧化中间体,其中底物中的酰胺基团采用对甲氧基苯基进行保护；使氧化中间体与一氧化碳或含有一氧化碳的混合气进行还原反应,以脱除对甲氧基苯基。使底物和臭氧发生臭氧化反应后,对上述臭氧化反应的产物体系进行淬灭,然后再使淬灭后得到的氧化中间体与一氧化碳发生还原反应,以脱除对甲氧基苯基,得到所需的酰胺类有机物。本申请提供的脱除酰胺基团上的对甲氧基苯基保护基的方法中不需要使用硫脲,因而整个工艺不会产生含硫废水,且成本更低廉,更加绿色环保。(The invention provides a method for removing a p-methoxyphenyl protecting group on an amide group. The method comprises the following steps: in the presence of an organic solvent, sequentially carrying out ozonization reaction and quenching treatment on a substrate and ozone to obtain an oxidation intermediate, wherein an amide group in the substrate is protected by p-methoxyphenyl; and (3) carrying out reduction reaction on the oxidation intermediate and carbon monoxide or a mixed gas containing carbon monoxide to remove p-methoxyphenyl. After ozonization reaction is carried out on a substrate and ozone, a product system of the ozonization reaction is quenched, and then reduction reaction is carried out on an oxidation intermediate obtained after quenching and carbon monoxide to remove p-methoxyphenyl so as to obtain the required amide organic matter. The method for removing the p-methoxyphenyl protecting group on the amide group does not need thiourea, so that the whole process does not produce sulfur-containing wastewater, and the method is lower in cost and more environment-friendly.)

1. A method for removing a p-methoxyphenyl protecting group on an amide group, comprising:

in the presence of an organic solvent, sequentially carrying out ozonization reaction and quenching treatment on a substrate and ozone to obtain an oxidation intermediate, wherein an amide group in the substrate is protected by p-methoxyphenyl;

and (3) carrying out reduction reaction on the oxidation intermediate and carbon monoxide or a mixed gas containing carbon monoxide to remove the p-methoxyphenyl.

2. The method for removing a p-methoxyphenyl protective group on an amide group according to claim 1, wherein the partial pressure of carbon monoxide in the reduction reaction is 0.1 to 2MPa, the reaction temperature is 10 to 90 ℃, and the reaction time is 0.5 to 48 hours.

3. The method for deprotecting p-methoxyphenyl protecting group on an amide group according to claim 1 or 2, characterized in that the substrate has the following structure:

or，

Wherein R is¹，R²And R³Are each independently selected from hydrogen, C_1-5A straight-chain or branched alkyl group of (1), cyclopropyl, 2-hydroxypropyl, 1-hydroxyethyl, 1-tert-butyldimethylsilyloxyethyl, phenyl, p-methylphenyl, o-methylphenyl, p-chlorophenyl, o-chlorophenyl, p-bromophenyl, o-bromophenyl, C_2-6The heterocycle of (3), acetoxy, benzoyloxy or pivaloyloxy.

4. The method for removing a p-methoxyphenyl protecting group on an amide group according to claim 3, wherein the substrate is (3R, 4R) -3- [ (R) -1-tert-butyldimethylsilyloxyethyl ] -4-acetoxy-1- (4-ethoxyphenyl) -2-azetidinone.

5. The method for removing a p-methoxyphenyl protecting group on an amide group according to claim 1 or 2, wherein the temperature during the ozonization reaction is from-30 ℃ to-10 ℃, and the molar ratio of p-methoxyphenyl in the substrate to ozone is 1: (1.0-20.0).

6. The method of claim 5, wherein the ozonization reaction further comprises adding a basic reagent during the reaction,

wherein the alkaline agent is selected from one or more of the group consisting of sodium acetate, potassium acetate, sodium formate, potassium formate, sodium bicarbonate and potassium bicarbonate.

7. The method for removing a p-methoxyphenyl protecting group on an amide group according to claim 6, wherein the organic solvent is one or more selected from the group consisting of methanol, ethanol, isopropanol and dichloromethane.

8. The method for deprotecting p-methoxyphenyl protecting group on an amide group according to claim 6, characterized in that the molar ratio of p-methoxyphenyl in the substrate to the basic agent is 1: (0.5 to 8).

9. The method for removing a p-methoxyphenyl protecting group on an amide group according to claim 1, wherein the quenching treatment comprises: quenching the products of the ozonation reaction with a quenching agent, wherein the quenching agent is selected from one or more of the group consisting of sodium thiosulfate, sodium sulfite, and sodium bisulfite.

10. The method of removing a p-methoxyphenyl protecting group on an amide group according to claim 9, wherein the molar ratio of the p-methoxyphenyl in the substrate to the quencher is 1: (1-8).

Technical Field

The invention relates to the field of pharmaceutical chemicals, and particularly relates to a method for removing a p-methoxyphenyl protecting group on an amide group.

Background

In organic reactions, protecting groups for some functional groups which are not desired to participate in the reaction is a common means for adjusting reactivity. As for the protecting group of the amide group, p-methoxyphenyl (PMP) is an excellent protecting group which enables the amide to be effectively protected during the reaction, is stable under most reaction conditions such as acidic, basic and reducing conditions, and can be easily removed by an oxidation process after the reaction.

Currently, the removal of p-methoxyphenyl (PMP) is mainly performed by the following two methods:

one method is Cerium Ammonium Nitrate (CAN) removal. The method has the advantages of simple operation, high reaction speed and high yield, but the use amount of the ceric nitrate amine is large, so that the three wastes in the post-treatment process are high, and meanwhile, the cost of the ceric nitrate amine is high, so that the method is not suitable for industrial production.

Another method is a method suitable for ozone oxidation. Compared with ceric nitrate, ozone is a cheaper and green oxidant, and three wastes are not generated. However, in the post-treatment process of the reaction, the reaction intermediate needs to be quenched by sodium thiosulfate and thiourea to obtain a product, so that a large amount of sulfur-containing wastewater is generated, and the post-treatment cost is high and the environmental pollution is large.

In view of the above, it is desirable to provide an environmentally friendly method for post-treatment of p-methoxyphenyl with ozone with less wastewater generation and low cost.

Disclosure of Invention

The invention mainly aims to provide a method for removing a p-methoxyphenyl protecting group on an amide group, which aims to solve the problems of high wastewater yield, high cost and poor environmental protection in the existing post-treatment method for removing the p-methoxyphenyl by using ozone.

In order to achieve the above object, the present invention provides a method for removing a p-methoxyphenyl protecting group on an amide group, comprising: in the presence of an organic solvent, sequentially carrying out ozonization reaction and quenching treatment on a substrate and ozone to obtain an oxidation intermediate, wherein an amide group in the substrate is protected by p-methoxyphenyl; and (3) carrying out reduction reaction on the oxidation intermediate and carbon monoxide or a mixed gas containing carbon monoxide to remove p-methoxyphenyl.

Further, in the reduction reaction, the partial pressure of carbon monoxide is 0.1-2 MPa, the reaction temperature is 10-90 ℃, and the reaction time is 0.5-48 h.

Further, the substrate has the following structure:

or，

Wherein R is¹，R²And R³Are each independently selected from hydrogen, C_1-5A straight-chain or branched alkyl group of (1), cyclopropyl, 2-hydroxypropyl, 1-hydroxyethyl, 1-tert-butyldimethylsilyloxyethyl, phenyl, p-methylphenyl, o-methylphenyl, p-chlorophenyl, o-chlorophenyl, p-bromophenyl, o-bromophenyl, C_2-6The heterocycle of (3), acetoxy, benzoyloxy or pivaloyloxy.

Further, the substrate is (3R, 4R) -3- [ (R) -1-tert-butyldimethylsilyloxyethyl ] -4-acetoxy-1- (4-ethoxyphenyl) -2-azetidinone.

Further, the temperature in the ozonization reaction process is-30 to-10 ℃, and the molar ratio of p-methoxyphenyl to ozone in the substrate is 1: (1.0-20.0).

Further, the ozonization reaction process further comprises adding an alkaline reagent during the reaction process, wherein the alkaline reagent is one or more selected from the group consisting of sodium acetate, potassium acetate, sodium formate, potassium formate, sodium bicarbonate and potassium bicarbonate.

Further, the organic solvent is one or more selected from the group consisting of methanol, ethanol, isopropanol, and dichloromethane.

Further, the ratio of the number of moles of p-methoxyphenyl group to the number of moles of the alkaline agent in the substrate is 1: (0.5 to 8).

Further, the quenching treatment process comprises the following steps: quenching the product of the ozonation reaction with a quenching agent, wherein the quenching agent is selected from one or more of the group consisting of sodium thiosulfate, sodium sulfite, and sodium bisulfite.

Further, the ratio of the number of moles of p-methoxyphenyl in the substrate to the number of moles of quencher in the substrate is 1: (1-8).

By applying the technical scheme of the invention, after ozonization reaction is carried out on a substrate and ozone, a product system of the ozonization reaction is quenched, and then an oxidation intermediate obtained after quenching and carbon monoxide are subjected to reduction reaction to remove p-methoxyphenyl so as to obtain the required amide organic matter. The method for removing the p-methoxyphenyl protecting group on the amide group does not need thiourea, so that the whole process does not produce sulfur-containing wastewater, and the method is lower in cost and more environment-friendly.

Detailed Description

It should be noted that the embodiments and features of the embodiments in the present application may be combined with each other without conflict. The present invention will be described in detail with reference to examples.

As described in the background art, the existing post-treatment method for removing p-methoxyphenyl by ozone has the problems of large wastewater yield, high cost and poor environmental protection. In order to solve the above technical problems, the present application provides a method for removing a p-methoxyphenyl protecting group on an amide group, comprising: in the presence of an organic solvent, sequentially carrying out ozonization reaction and quenching treatment on a substrate and ozone to obtain an oxidation intermediate, wherein an amide group in the substrate is protected by p-methoxyphenyl; and (3) carrying out reduction reaction on the oxidation intermediate and carbon monoxide or a mixed gas containing carbon monoxide to remove p-methoxyphenyl.

After ozonization reaction is carried out on a substrate and ozone, a product system of the ozonization reaction is quenched, and then reduction reaction is carried out on an oxidation intermediate obtained after quenching and carbon monoxide to remove p-methoxyphenyl so as to obtain the required amide organic matter. The method for removing the p-methoxyphenyl protecting group on the amide group does not need thiourea, so that the whole process does not produce sulfur-containing wastewater, and the method is lower in cost and more environment-friendly.

In the reduction reaction process, carbon monoxide can reduce the oxidation intermediate to obtain the required amide organic matter. In a preferred embodiment, the partial pressure of carbon monoxide in the reduction reaction is 0.1 to 2MPa, the reaction temperature is 10 to 90 ℃, and the reaction time is 0.5 to 48 hours. The partial pressure of carbon monoxide, the reaction temperature and the reaction time include but are not limited to the ranges, and limiting the three parameters in the ranges is beneficial to further improving the reaction degree of the reduction reaction, and further improving the deprotection rate of the amide organic substance.

Any organic compound that contains an amide group and in which the amide group is protected with a p-methoxyphenyl group is suitable for the deprotection method provided herein. In a preferred embodiment, the substrate has the following structure:

or，

Wherein R is¹，R²And R³Are each independently selected from hydrogen, C_1-5A straight-chain or branched alkyl group of (1), cyclopropyl, 2-hydroxypropyl, 1-hydroxyethyl, 1-tert-butyldimethylsilyloxyethyl, phenyl, p-methylphenyl, o-methylphenyl, p-chlorophenyl, o-chlorophenyl, p-bromophenyl, o-bromophenyl, C_2-6The heterocycle of (3), acetoxy, benzoyloxy or pivaloyloxy. Compared with substrates with other structures, the substrate with the structure has less side reactions and higher reaction activity in the process of deprotection. More preferably, the substrate is (3R, 4R) -3- [ (R) -1-tert-butyl)Dimethylsiloxyethyl radical]-4-acetoxy-1- (4-ethoxyphenyl) -2-azetidinone.

In the above-mentioned ozonization reaction, the ozonization reaction may be carried out by a procedure conventional in the art. In a preferred embodiment, the temperature during the ozonation reaction is between-30 and-10 ℃, and the ratio of the number of moles of p-methoxyphenyl and ozone in the substrate is 1: (1.0-20.0). The temperature of the ozonization reaction and the ratio of the raw materials include, but are not limited to, the above ranges, and it is advantageous to further improve the oxidation efficiency and the yield of the oxidation intermediate and the target product to be produced subsequently.

In a preferred embodiment, the ozonation reaction process further comprises adding an alkaline reagent during the reaction. The addition of the alkaline reagent is beneficial to improving the reaction rate of ozone and a substrate, improving the removal rate of p-methoxyphenyl and shortening the process period.

The alkaline agent may be of a kind commonly used in the art, wherein the alkaline agent includes, but is not limited to, one or more of the group consisting of sodium acetate, potassium acetate, sodium formate, potassium formate, sodium bicarbonate, and potassium bicarbonate.

The organic solvent used in the ozonization reaction can be selected from those commonly used in the art. Preferably, the organic solvent includes, but is not limited to, one or more of the group consisting of methanol, ethanol, isopropanol, and dichloromethane.

In a preferred embodiment, the ratio of moles of p-methoxyphenyl and alkaline agent in the substrate is 1: (0.5 to 8). The ratio of the number of moles of p-methoxyphenyl groups to the number of moles of the alkaline agent in the substrate includes, but is not limited to, the above range, and it is preferable to limit the ratio to the number of moles of the p-methoxyphenyl groups in the substrate to the number of moles of the alkaline agent in the above range to further improve the removal rate of the p-methoxyphenyl groups.

In a typical quenching process, the products of the ozonation reaction need to be quenched with a quenching agent. The above-mentioned quenching agent may be of a kind commonly used in the art, and preferably, the above-mentioned quenching agent includes, but is not limited to, one or more of the group consisting of sodium thiosulfate, sodium sulfite and sodium bisulfite.

To further increase the quenching efficiency, it is preferable that the ratio of the number of moles of p-methoxyphenyl in the substrate to the quencher is 1: (1-8).

The present application is described in further detail below with reference to specific examples, which should not be construed as limiting the scope of the invention as claimed.

The term "eq." means the amount of other reaction raw materials per mol of reaction substrate. For example, the reaction substrate is 1mol, and the amount of sodium acetate is 5eq, that is, the amount of sodium acetate is 5 mol.

Example 1

，

Wherein OTBS represents a 1-tert-butyldimethylsilyloxy group.

The process for removing the p-methoxyphenyl protecting group on the amide group comprises the following steps:

(1) ozonization reaction: 50g of the starting material, sodium acetate (50.8 g, 5.0 eq) was dissolved in methanol (300 mL), and ozone was introduced after cooling to-14 ℃. After the reaction is finished, oxygen blowing is continuously used for removing redundant ozone. Quenching treatment: the reaction was stopped, and 200 mL of an aqueous solution of sodium thiosulfate (40.2 g, 2.0 eq) was added thereto while maintaining the temperature at 35 ℃ and stirred for 30 min.

(2) Reduction reaction: transferring the quenched product system to an autoclave, replacing the product system with carbon monoxide for 5-6 times, introducing the solution to 0.5MPa, heating to 50 ℃, and stirring for 2 hours; discharging the system, and filtering to remove solids; concentrating the filtrate to remove methanol, cooling to 0 deg.C, precipitating solid, and stirring for 2 hr.

Filtration gave crude 4AA, which was then recrystallized from 200 mL of n-hexane to give 29.6 g of the desired compound (3R, 4R) -3- [ (R) -1-tert-butyldimethylsilyloxyethyl ] -4-acetoxy-2-azetidinone (4 AA), 81.20% yield, 99.30% HPLC purity.

Example 2

The differences from example 1 are: in the step (2), the pressure of carbon monoxide is 0.8 MPa, and the reaction temperature of the carbon monoxide reduction reaction is 30 ℃.

The target compound 4AA was 29.4 g, yield 80.40%, HPLC purity 99.30%.

Example 3

The differences from example 1 are: in the step (2), the pressure of the carbon monoxide is 0.8 MPa, and the reaction time of the carbon monoxide reduction reaction is 12 h.

The target compound 4AA was 30.3g, yield 83.10%, HPLC purity 99.10%.

Example 4

The differences from example 1 are: in the step (2), the pressure of the carbon monoxide is 0.1 MPa, the reaction temperature of the carbon monoxide reduction reaction is 90 ℃, and the reaction time of the carbon monoxide reduction reaction is 2 hours.

The target compound 4AA was 29.8g, yield 81.50%, HPLC purity 99.40%.

Example 5

The differences from example 1 are: in the step (2), the pressure of the carbon monoxide is 2MPa, the reaction temperature of the carbon monoxide reduction reaction is 10 ℃, and the reaction time of the carbon monoxide reduction reaction is 6 hours.

The target compound 4AA was 30.9g, yield 84.50%, HPLC purity 99.40%.

Example 6

The differences from example 1 are: in the step (2), the pressure of carbon monoxide is 1.5MPa, and the reaction temperature of the carbon monoxide reduction reaction is 30 ℃.

The target compound 4AA was 31.1g, the yield was 85.20%, and the HPLC purity was 99.10%.

Example 7

The differences from example 1 are: in the step (2), the pressure of carbon monoxide is 1MPa, and the reaction temperature of the carbon monoxide reduction reaction is 70 ℃.

The target compound 4AA was 29.0g, yield 79.40%, HPLC purity 99.0%.

Example 8

The differences from example 1 are: in the step (2), the pressure of carbon monoxide is 0.5MPa, and the reaction temperature of the carbon monoxide reduction reaction is 50 ℃.

The target compound 4AA was 29.7g, yield 81.20%, HPLC purity 99.40%.

Example 9

The differences from example 1 are: in the step (2), the pressure of carbon monoxide is 3MPa, and the reaction temperature of the carbon monoxide reduction reaction is 5 ℃.

The target compound 4AA was 26.0g, yield 71.20%, HPLC purity 97.40%.

Example 10

The differences from example 2 are: during the ozonization reaction, sodium ethoxide was not added.

The target compound 4AA was 27.2g, yield 74.40%, HPLC purity 98.80%.

Comparative example 1

The process for removing the p-methoxyphenyl protecting group on the amide group comprises the following steps:

(1) ozonization reaction: 50g of the starting material was dissolved in methanol (300 mL) and the temperature was reduced to-14 ℃ and ozone was introduced. After the reaction is finished, oxygen blowing is continuously used for removing redundant ozone.

(2) Quenching reaction: the reaction was stopped, and 200 mL of an aqueous solution of sodium thiosulfate (40.2 g, 2 eq) was added thereto while maintaining the temperature at 35 ℃ and stirred for 30 min.

(3) Keeping the temperature at 35 ℃, dropwise adding thiourea (46.4 g, 4.8 eq) dissolved in methanol (600 mL) into the system, and stirring for 4h after dropwise adding; then concentrating, cooling to 0 ℃, and stirring for 2 h.

Filtration gave a crude product of 4AA, which was then recrystallized from 200 mL of n-hexane to give 23.3 g of the target compound (3R, 4R) -3- [ (R) -1-tert-butyldimethylsilyloxyethyl ] -4-acetoxy-2-azetidinone (4 AA), 75.20% yield, 99.40% HPLC purity.

TABLE 1

Compared with the prior art which uses thiourea for treatment, the method for deprotection provided by the application has the advantages that the yield of the obtained target product is higher and stable, and the purity of the obtained product is as high as 99.4%.

It is noted that the terms first, second and the like in the description and in the claims of the present application are used for distinguishing between similar elements and not necessarily for describing a particular sequential or chronological order. It is to be understood that the terms so used are interchangeable under appropriate circumstances such that the embodiments of the application described herein are, for example, capable of operation in sequences other than those described or illustrated herein.

The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.