阅读说明：本技术 一种提高钯碳活性加氢脱除保护基的方法 (Method for improving palladium-carbon activity and removing protective group by hydrogenation ) 是由 杨祝红 路亚松 江雨桐 范吉雪 杨富柳 于 2021-10-12 设计创作，主要内容包括：本发明公开了一种提高钯碳活性加氢脱除保护基的方法,以需要脱除保护基的化合物为原料,加入醇类有机溶剂,催化剂Pd/C、提高钯碳活性的盐,在室温～60℃下,常压氢气环境下加氢,反应结束后,过滤、减压蒸馏后溶于萃取类溶剂,萃取、减压蒸馏后即可得到加氢后的产物。本发明通过加入提高钯碳活性的盐,增加钯碳的活性,加快反应速率,降低了反应对设备的要求、减少反应危险性和成本,具有良好的经济效益。(The invention discloses a method for removing a protecting group by improving palladium-carbon activity hydrogenation, which comprises the steps of taking a compound needing to remove the protecting group as a raw material, adding an alcohol organic solvent, a catalyst Pd/C and a salt for improving palladium-carbon activity, hydrogenating at room temperature to 60 ℃ under a normal pressure hydrogen environment, after the reaction is finished, filtering, distilling under reduced pressure, dissolving in an extraction solvent, extracting, distilling under reduced pressure to obtain a hydrogenated product. The invention adds salt for improving the activity of palladium carbon, increases the activity of palladium carbon, accelerates the reaction rate, reduces the requirement of the reaction on equipment, reduces the reaction danger and the cost, and has good economic benefit.)

1. A method for improving palladium carbon activity hydrogenation to remove protective group is characterized in that a salt for increasing palladium carbon activity is added into a reaction system for palladium carbon hydrogenation to remove protective group, and the structure of the salt is shown as formula (II):

wherein R is₇、R₈Are respectively selected from-H or C₁-C₁₀Alkyl, preferably-H, -CH₃or-C₂H₅；

R₉Selected from BF₄ ^-、SN^-、Cl^-、Br^-、I^-。

2. The method for removing the protecting group by improving the palladium-carbon activity through hydrogenation according to claim 1, wherein a catalyst Pd/C, an organic solvent, water and a salt for increasing the palladium-carbon activity are added into a raw material with the following structure (I), a hydrogen airbag is connected, air in the system is replaced by nitrogen and hydrogen for 3-4 times, the mixture is stirred, the temperature is controlled to be between room temperature and 60 ℃, and the reaction is carried out until the hydrogen amount is not reduced, so that the hydrogenated product is completely reacted;

wherein R is₁、R₂Each independently selected from-H or-C₁-C₁₀Alkyl, preferably-H, -CH₃or-C₂H₅；

R₃Is a functional group protecting group;

n is 1 to 1000, preferably 1 to 50;

R₄is an alcohol alkyl group or a polyoxyethylene ether group, and has a structure of-C_mH_2m+1OH or- (CH)₂CH₂O)_mH; wherein m is 1 to 1000, preferably 1 to 50;

R₅is a functional group protecting group;

R₆is selected from-H, C₁-C₁₀Alkyl or functional protecting groups, preferably-H, -CH₃、-C₂H₅Or a functional group protecting group.

3. The method for enhanced palladium on carbon active hydrogenation deprotection according to claim 2, characterised in that the functional protecting group is selected from benzyl, p-methoxybenzyl, trityl or benzyloxycarbonyl.

4. The method for removing the protecting group by improving the palladium-carbon activity through hydrogenation according to claim 2, wherein after the reaction is completed, the obtained product is filtered to remove the palladium-carbon; then carrying out reduced pressure distillation to remove water and organic solvent; dissolving in extraction solvent, stirring, filtering, and removing salt; and finally, carrying out reduced pressure distillation to remove the extraction solvent to obtain a hydrogenated product.

5. The method for removing the protecting group by improving the palladium-carbon activity through hydrogenation according to claim 4, wherein the extraction solvent is selected from diethyl ether, ethyl acetate, benzene, toluene, dichloromethane or chloroform.

6. The method for removing a protecting group by improving palladium on carbon through active hydrogenation according to claim 2, wherein the amount ratio of the salt to the raw material is (0.01-0.1): 1.

7. the method for removing protective groups by hydrogenation with improved palladium on carbon activity as claimed in claim 2, wherein the palladium on carbon is 10%.

8. The method for removing the protecting group by improving the palladium-carbon activity through hydrogenation according to claim 2, wherein the reaction temperature is 30-55 ℃, and preferably 45-50 ℃.

9. The method for improving palladium carbon activity hydrogenation protecting group removal according to claim 2, wherein the dry-basis dosage of palladium carbon in the method is not less than 5% of the raw material by mass, preferably 5-15%.

10. The method for removing a protecting group by improving palladium on carbon through active hydrogenation according to claim 2, wherein the organic solvent is selected from methanol, ethanol, propanol, n-butanol or ethyl acetate.

Technical Field

The invention relates to the technical field of organic synthesis, in particular to a method for removing a protecting group and improving palladium carbon activity by palladium carbon hydrogenation.

Background

Functional group protection is a common operation in organic synthesis, and protecting groups are often used to protect groups which are reactive and easy to react. Because of the activity of hydroxyl and amino, protecting groups are often needed for protection, wherein benzyl, p-methoxybenzyl, trityl, benzyloxycarbonyl and other groups are common protecting groups, and all the groups have a common removal mode, namely need to be removed by reduction reaction with hydrogen under the catalysis of palladium-carbon. Generally, under pressure, the protecting group can be effectively removed. However, experiments show that under the condition of pressurization, when the raw material contains a primary amine or secondary amine structure, the reaction rate of removing the protecting group by hydrogenation is obviously reduced. In Tetrahedron Letters,2004,45(6):1223-1226, it is clearly demonstrated that the activity of palladium on carbon is significantly reduced when the compound contains a primary or tertiary amine structure, but the document only discusses that the primary or tertiary amine in the raw material has an inhibitory effect on the activity of palladium on carbon, and does not describe a solution. The difficulty in removing the protecting group also indicates that the stability of the protecting group and the intermediate formed from the starting material is high, which is both a disadvantage and an advantage. The difficulty of removal is a disadvantage, and the high stability results in the selection of only the above-mentioned substituent groups under particular circumstances.

The existing method for removing the groups is to remove the groups by heating and pressurizing, which causes higher requirements on a reactor, has certain dangerousness under a certain pressure hydrogen environment, and has longer reaction time, which not only increases the dangerousness, but also increases the economic cost.

Disclosure of Invention

In order to solve the technical problems in the prior art, the invention finds a salt capable of increasing the activity of palladium carbon, can effectively increase the activity of palladium carbon in the hydrogenation process of palladium carbon, improves the reaction rate of hydrogenation, enables the reaction to be rapidly carried out in a normal pressure environment, reduces the requirements on equipment, reduces the danger, greatly reduces the reaction time and simultaneously reduces the economic cost.

The invention provides a method for improving palladium-carbon activity hydrogenation to remove a protecting group, which is characterized in that a salt for increasing palladium-carbon activity is added into a reaction system for palladium-carbon hydrogenation to remove the protecting group, wherein the salt has a structure shown in a formula (II):

wherein R is₇、R₈Are respectively selected from-H or C₁-C₁₀Alkyl, preferably-H, -CH₃or-C₂H₅；

R₉Selected from BF₄ ^-、SN^-、Cl^-、Br^-、I^-。

In a specific example, the method for removing the protecting group by hydrogenation for improving the activity of palladium on carbon, disclosed by the invention, specifically comprises the following steps: adding a catalyst Pd/C, an organic solvent, water and a salt for increasing palladium carbon activity into a raw material with a structure shown in the specification (I), connecting a hydrogen gas bag, replacing air in the system with nitrogen and hydrogen for 3-4 times, stirring, controlling the temperature to be between room temperature and 60 ℃, and reacting until the hydrogen amount is not reduced, thus obtaining a hydrogenated product which is completely reacted.

Wherein R is₁、R₂Each independently selected from-H or-C₁-C₁₀Alkyl, preferably-H, -CH₃or-C₂H₅；

R₃As the functional group protecting group, there may be mentioned those commonly used in the art, including, for example, but not limited to, benzyl, p-methoxybenzyl, trityl or benzyloxycarbonyl;

n is 1 to 1000, preferably 1 to 50;

R₄is an alcohol alkyl group or a polyoxyethylene ether group, and has a structure of-C_mH_2m+1OH or- (CH)₂CH₂O)_mH; wherein m is 1 to 1000, preferably 1 to 50;

R₅for the functional group protecting group, there may be protecting groups commonly used in the art, for example, including, but not limited to, benzyl, p-methoxybenzyl, trityl, benzyloxycarbonyl;

R₆alternative-H, C₁-C₁₀Alkyl or functional protecting groups, preferably-H, -CH₃、-C₂H₅Or a functional protecting group which may be a protecting group commonly used in the art, for example including but not limited to benzyl, p-methoxybenzyl, trityl, benzyloxycarbonyl.

The characteristic framework of the salt for increasing palladium carbon activity is shown as the following (II):

wherein R is₇、R₈Can be respectively selected from-H or C₁-C₁₀Alkyl of (4), preferably-H, -CH₃or-C₂H₅；

R₉Can be selected from BF₄ ^-、SN^-、Cl^-、Br^-、I^-. The inventor finds that after the salt is added, the activity of palladium-carbon can be effectively increased, the reaction rate of hydrogenation is improved, the reaction can be rapidly carried out under the normal pressure environment, the requirement on equipment is reduced, and the danger is reduced.

After the reaction is completed, the obtained product can be filtered to remove palladium-carbon; then carrying out reduced pressure distillation to remove water and organic solvent; dissolving in extraction solvent, stirring, filtering, and removing salt;

and finally, carrying out reduced pressure distillation to remove the extraction solvent to obtain a hydrogenated product. The extraction solvent according to the present invention may be selected from conventional solvents in the art, such as diethyl ether, ethyl acetate, benzene, toluene, dichloromethane or chloroform.

In some embodiments, the amount ratio of salt to starting material in the process of the invention is (0.01-0.1): 1.

the water in the reaction system of the invention is only used for dissolving the salt and is dissolved in one phase with the organic solvent.

In some embodiments, the palladium on carbon in the process of the invention is preferably 10%.

In some embodiments, the reaction temperature of the method of the present invention is 30 ℃ to 55 ℃, and more preferably 45 ℃ to 50 ℃.

In some embodiments, the dry-based amount of palladium on carbon in the method of the present invention is not less than 5% by mass of the raw material, preferably 5 to 15% by mass of the raw material.

In some embodiments, the organic solvent in the method of the present invention may be selected from methanol, ethanol, propanol, n-butanol, ethyl acetate, or the like.

In some embodiments, the palladium carbon in the method of the present invention can be reused, and the quality of the palladium carbon should be ensured to be higher than 5% of the quality of the raw material in use.

The distillation of the invention can distill the byproducts of benzyl, p-methoxybenzyl and the like after hydrogenation besides water and organic solvent.

Compared with the prior art, the invention has the following advantages:

the compound difficult to hydrogenate is added with salt, so that the activity of palladium-carbon is effectively improved, the reaction has good reaction rate under normal pressure, the requirement of the reaction on equipment is reduced, the reaction time is greatly reduced, and the method has good economic benefit.

The activity of the palladium-carbon is improved by adding the salt, and after the reaction is finished, the salt can be well separated by extraction, so that the economic cost cannot be increased.

Detailed Description

The present invention will be described below by way of specific examples, but the present invention is not limited to these examples. The experimental procedures in the following examples are conventional unless otherwise specified. The test materials used in the following examples were purchased from a conventional biochemical reagent store unless otherwise specified.

The salt structures used in the examples are shown in table 1 below:

TABLE 1 Structure of salts

Example 1

1125g (4.7mol) of aminotriglycol monobenzyl ether, 5L of absolute ethyl alcohol, 0.5L of distilled water and 112g of salt I (0.187mol and 10% palladium on carbon (dry basis)) are added into a 10L reaction kettle, a hydrogen gas bag is connected for replacement for three times, stirring is carried out, the temperature is increased to 50 ℃, the reaction is carried out under normal pressure until hydrogen is not absorbed, the reaction time is 3h, sampling is carried out, and the mixture is dissolved in CH₂Cl₂After filtration and distillation under reduced pressure, the yield of aminotriglycol was analyzed to be 95.8%.

Example 2

1077g (4.5mol) of aminotriglycol monobenzyl ether, 5L of absolute ethyl alcohol, 0.5L of distilled water, 0.412mol of salt I and 108g of 10% palladium-carbon (dry basis) are added into a 10L reaction kettle, a hydrogen gas bag is connected for replacement for three times, stirring is carried out, the temperature is raised to 50 ℃, the reaction is carried out under normal pressure until no hydrogen is absorbed, and the reaction time is 4 hours. Sampling, dissolving in CH₂Cl₂After filtration and distillation under reduced pressure, the yield of aminotriglycol was analyzed to be 88.2%.

Example 3

Adding 1190g (3.8mol) of dibenzylaminotriglycol, 5L of absolute ethyl alcohol, 0.5L of distilled water, 0.078mol of salt I and 119g of 10% palladium-carbon (dry basis) into a 10L reaction kettle, introducing a hydrogen gas bag, replacing for three times, stirring, heating to 50 ℃, reacting at normal pressure until hydrogen is not absorbed, and reacting for 8 hours. Sampling, dissolving in CH₂Cl₂After filtration and distillation under reduced pressure, the yield of monobenzylamino triethylene glycol was 5.6% and the yield of amino triethylene glycol was 78.2%.

Example 4

Adding 1124g (4.7mol) of aminotriglycol monobenzyl ether, 5L of absolute ethyl alcohol, 0.5L of distilled water, 0.152mol of salt II and 112g of 10% palladium-carbon (dry basis) into a 10L reaction kettle, introducing a hydrogen gas bag, replacing for three times, stirring, heating to 50 ℃, reacting at normal pressure until hydrogen is not absorbed, and reacting for 4 hours. Sampling, dissolving in CH₂Cl₂After filtration and distillation under reduced pressure, the yield of aminotriglycol was analyzed to be 96.6%.

Example 5

Adding 982g (4.1mol) of aminotriglycol monobenzyl ether, 5L of absolute ethyl alcohol, 0.5L of distilled water, 0.142mol of salt III and 99g of 10% palladium-carbon (dry basis) into a 10L reaction kettle, adding a hydrogen gas bag, replacing for three times, stirring, heating to 50 ℃, reacting at normal pressure until hydrogen is not absorbed, and reacting for 3 hours. Sampling, dissolving in CH₂Cl₂After filtration and distillation under reduced pressure, the yield of aminotriglycol was analyzed to be 93.6%.

Example 6

10L reactionAdding 1096g (2.8mol) of trityl triethylene glycol amine, 5L of absolute ethyl alcohol, 0.5L of distilled water, 0.103mol of salt I and 110g of 10% palladium-carbon (dry basis) into a kettle, introducing a hydrogen gas bag, replacing for three times, stirring, heating to 50 ℃, reacting at normal pressure until hydrogen is not absorbed, and reacting for 5 hours. Sampling, dissolving in CH₂Cl₂After filtration and distillation under reduced pressure, the yield of aminotriglycol was analyzed to be 94.9%.

Example 7

977g (3.5mol) of N- (8-hydroxyoctyl) carbamic acid phenyl methyl ester, 5L of absolute ethyl alcohol, 0.5L of distilled water, 0.134mol of salt I and 98g of 10% palladium carbon (dry basis) are added into a 10L reaction kettle, and then the mixture is added into a hydrogen gas bag to be replaced for three times, stirred, heated to 50 ℃, reacted under normal pressure until hydrogen is not absorbed, and reacted for 6 hours. Sampling, dissolving in CH₂Cl₂After filtration and distillation under reduced pressure, the yield of aminotriglycol was analyzed to be 93.7%.

Example 8

1171g (1.0mol) of the raw materials, 5L of absolute ethyl alcohol, 0.5L of distilled water, 0.021mol of salt I and 118g of 10% palladium carbon (dry basis) are added into a 10L reaction kettle, and then the mixture is put into a hydrogen gas bag for replacement for three times, stirred, heated to 50 ℃, reacted under normal pressure until no hydrogen is absorbed, and reacted for 6 hours. Sampling, dissolving in CH₂Cl₂After filtration and distillation under reduced pressure, the analytical yield was 94.5%.

Comparative example 1

Adding 1147g (4.8mol) of aminotriglycol monobenzyl ether, 5L of absolute ethyl alcohol, 0.5L of distilled water and 115g of 10% palladium-carbon (dry basis) into a 10L reaction kettle, introducing into a hydrogen gas bag, replacing for three times, stirringAnd the temperature is increased to 50 ℃, and the reaction is carried out under normal pressure until no hydrogen is absorbed for 48 hours. Sampling, dissolving in CH₂Cl₂After filtration and distillation under reduced pressure, the yield of aminotriglycol was analyzed to be 7.4%.

Comparative example 2

1162g (4.8mol) of aminotriglycol monobenzyl ether, 5.5L of absolute ethyl alcohol and 116g of 10% palladium-carbon (dry basis) are added into a 10L reaction kettle, hydrogen gas bags are connected for replacement for three times, stirring is carried out, the temperature is raised to 50 ℃, the reaction is carried out until no hydrogen is absorbed, and the reaction time is 48 hours under normal pressure. Sampling, dissolving in CH₂Cl₂After filtration and distillation under reduced pressure, the yield of aminotriglycol was analyzed to be 11.3%.

Comparative example 3

Adding 1053g (4.4mol) of aminotriglycol monobenzyl ether, 5.5L of absolute ethyl alcohol and 106g of 10% palladium carbon (dry basis) into a 10L hydrogenation kettle, introducing into nitrogen and hydrogen cylinders, respectively replacing for three times, stirring, heating to 50 ℃, controlling the hydrogenation pressure to be 2MPa, and reacting for 48 hours until hydrogen is not absorbed. Sampling, dissolving in CH₂Cl₂After filtration and distillation under reduced pressure, the yield of aminotriglycol was analyzed to be 63.8%.

Comparative example 4

Adding 1252g (4mol) of dibenzylamino triethylene glycol, 5.5L of absolute ethyl alcohol and 125g of 10% palladium carbon (dry basis) into a 10L hydrogenation kettle, introducing into nitrogen and hydrogen cylinders, respectively replacing for three times, stirring, heating to 50 ℃, controlling the hydrogenation pressure to be 2MPa, and reacting for 48 hours until hydrogen is not absorbed. Sampling, dissolving in CH₂Cl₂Filtering, vacuum distilling, analyzing mono-benzylaminoThe yield of triethylene glycol was 45.2% and the yield of aminotriglycol was 5.8%.

Comparative example 5

Trityl triethylene glycol amine 1096(2.8mol), anhydrous ethanol 5.5L and 10% palladium-carbon (dry basis) 110g are added into a 10L reaction kettle, a hydrogen gas bag is connected for replacement for three times, stirring is carried out, the temperature is increased to 50 ℃, reaction is carried out under normal pressure until hydrogen is not absorbed, and the reaction time is 48 hours. Sampling, dissolving in CH₂Cl₂After filtration and distillation under reduced pressure, the yield of aminotriglycol was analyzed to be 13.2%.

Comparative example 6

977g (3.5mol) of N- (8-hydroxyoctyl) carbamic acid phenyl methyl ester, 5.5L of absolute ethyl alcohol and 98g of 10% palladium carbon (dry basis) are added into a 10L reaction kettle, and then the mixture is put into a hydrogen gas bag for replacement for three times, stirred, heated to 50 ℃, reacted under normal pressure until hydrogen is not absorbed, and reacted for 48 hours. Sampling, dissolving in CH₂Cl₂After filtration and distillation under reduced pressure, the yield of aminotriglycol was analyzed to be 11.3%.

Comparative example 7

Adding 982g (4.1mol) of aminotriglycol monobenzyl ether, 5.5L of absolute ethyl alcohol and 99g of 10% palladium-carbon (dry basis) into a 10L reaction kettle, adding a hydrogen gas bag, replacing for three times, stirring, heating to 50 ℃, reacting under normal pressure until no hydrogen is absorbed, and reacting for 48 h. Sampling, dissolving in CH₂Cl₂After filtration and distillation under reduced pressure, the yield of aminotriglycol was analyzed to be 10.3%.

The results of the embodiment and the comparative example of the invention show that the activity and the catalytic efficiency of palladium-carbon can be obviously improved after the salt is added, the reaction can be carried out under normal pressure, and the effect is even obviously better than the efficiency of the comparative example 4 or the comparative example 5 after pressurization.