CN113582947B - A method for removing the sulfonyl protection of amines - Google Patents

Abstract

The invention discloses a method for removing sulfonyl protection of amine. The method comprises the following steps: dissolving N-sulfonyl protected amine and alkali into a reaction solvent, adding diphenylphosphine, uniformly mixing and keeping the temperature at 90 ℃; and when the TCL detection reaction is complete, obtaining a target product by adopting a recrystallization method or an extraction separation method. The method adopts diphenyl phosphine as a stripping reagent, utilizes nucleophilic substitution of sulfonyl under alkaline heating condition, has good reaction activity and high selectivity, can replace hazardous reagents, is environment-friendly, accords with the concept of green chemistry, is simple and easy to operate and wide in application range, can effectively reduce the deprotection cost, has no metal participation, has low and high-efficiency reaction, and has important significance for total synthesis, drug research and development and industrial production.

Description

A method for removing the sulfonyl protection of amine

technical field

The invention belongs to the fields of biomedical technology and chemical engineering, and specifically relates to a method for removing sulfonyl protection of amines.

Background technique

Due to the high reactivity of the amino group itself, the protection and deprotection strategies of the amino group play a crucial role in organic synthesis. So far, there has been good progress in the protection strategy of amino groups, some protecting groups (-Boc, -Fmoc, etc.) and their effective removal schemes have been developed, but there are still disadvantages, such as poor stability and cannot The next reaction was carried out under vigorous conditions. In recent years, the N-Ts group has received increasing attention in the field of nitrogen-containing chemistry. The N-Ts group is readily available, and the resulting compounds are usually stable and easy to purify due to their high crystallinity. However, the lack of an effective method to remove the sulfonyl protection greatly limits the use of N-Ts as a protecting group.

The currently developed methods for removing the sulfonyl protection of amines mainly include the following points:

First, the N-Ts group can be removed by hydrolysis promoted by strong acid, such as HBr, CF ₃ CO ₂ H, CF ₃ SO ₃ H or HClO ₄ ; the T s group can also be removed under strong basic conditions , but usually the above-mentioned conditions in practice require high concentration, high temperature or long reaction time, thus causing many substrates to be unable to tolerate these extremely harsh conditions and limit the use.

Second, a reductive cleavage process (ET) via one-electron transfer was also found to be useful for this reaction. The above methods are usually mediated by alkali metals, Mg/MeOH, SmI ₂ , AIBN, low-valent titanium, etc. Recently, photoactivated reduction via photoactivation in the presence of various photocatalysts (PC) has also emerged as a new approach for N-Ts cleavage. However, most of the above methods are still limited for industrial applications due to the impact of the use of some toxic and dangerous chemicals or expensive catalysts.

Therefore, there is still a need to develop practical and simple methods to deprotect N-Ts involved in chemical processes.

Contents of the invention

In order to solve the above problems, the present invention proposes a novel method for removing the sulfonyl protection of amines, which is simple and easy to operate and has a wide range of applications, without metal participation, and the reaction is cheap and efficient. Significance.

In order to achieve the above object, technical solution of the present invention is achieved in that way:

A method for removing the sulfonyl protection of amine, comprising the following steps:

Step 1. Dissolving the N-sulfonyl-protected amine and base in the reaction solvent, then adding diphenylphosphine to mix and keep at 90°C;

Step 2. When the TCL detection reaction is complete, the target product is obtained by recrystallization or extraction separation;

The extraction and separation method includes the following steps: washing the product with water, then extracting with ethyl acetate, separating and retaining the organic layer, removing the solvent after drying, and separating by column chromatography to obtain the target product;

The molar ratio of N-sulfonyl protected amine, base and diphenylphosphine is 1:(3-5):(1.1-1.4); the reaction solvent is DMSO, DMF, DMA, NMP, 1,4-Dioxane and one of THF.

Wherein, the base in the above method is one of KOH, t-BuOK, Cs ₂ CO ₃ , K ₂ CO ₃ , NaOH, t-BuONa, and Na ₂ CO ₃ ; the optimum is KOH.

The sulfonyl group mentioned in the above method is an aromatic sulfonyl group, an alicyclic sulfonyl group or a straight chain aliphatic sulfonyl group.

The specific process of step 1 is: dissolving the N-sulfonyl-protected amine and the base in the reaction solvent and sealing it under an inert gas atmosphere, then adding diphenylphosphine to mix and maintaining at 90°C. The inert gas is nitrogen or argon.

In the extraction separation method, a neutral alumina column or a silica gel column is used for column chromatography separation.

The beneficial effects of the present invention are:

(1) It is easy to operate and has a wide range of applications, without metal participation, and the reaction is cheap and efficient, which is of great significance to total synthesis, drug research and development, and industrial production;

(2) The present invention adopts diphenylphosphine as the stripping reagent, utilizes the nucleophilic substitution of the sulfonyl group under its alkaline heating condition, has good reactivity, high selectivity, can replace the use of dangerous reagents, is environmentally friendly, and will not It is harmful to human health, can efficiently realize the construction of target compounds, and produces less waste, and the utilization rate of atoms is higher, which is in line with the concept of green chemistry, and can effectively reduce the cost of deprotection. In the industrialization of increasingly stringent environmental protection requirements In production, it will occupy a leading position in technology.

Detailed ways

The conception of the present invention and the technical effects produced will be clearly and completely described below in conjunction with the embodiments, so as to fully understand the purpose, scheme and effect of the present invention.

The inventors used N-Ts-N'-phenylpiperazine as a substrate and adopted the t-BuOK conditions used in the previous literature (Desulfonylation and Dehalogenation Reactions: Hantzsch Ester Anion as Electron and Hydrogen Atom Donor, J.Org.Chem.2020 , 85, 13481-13494. Specifically referring to experiments 1-2 in Table 1), it was found that the C-S bond could not be cleaved to synthesize the desired target product.

However, the inventors have found that the use of diphenylphosphine can significantly promote the removal of the sulfonyl group under alkaline conditions, without the presence of a base (as in experiment 14 in table 1) or in the absence of diphenylphosphine (as in experiments 1, 2 in table 1, 2, 12), or use Ph ₂ P(O)H to replace diphenylphosphine (as in the case of experiment 13 in table 1), the removal reaction cannot be started; in addition, the reaction solvent is DMSO, and the alkali uses KOH to achieve the best effect Good, specifically as shown in Table 1 (a small amount is expressed as 1%).

Table 1

Example 1:

The preparation of 1-phenylpiperazine, concrete process is as follows:

In a solution of N-tosyl-1-phenylpiperazine (1.00 g, 3.16 mmol) in DMSO (8 mL), add potassium hydroxide (531 mg, 9.48 mmol) and seal under argon atmosphere; then add HPPh ₂ (647mg, 3.48mmol), stirred at 90°C for 1h until the reaction was complete; quenched the reaction with water (20mL), removed the precipitate, then extracted with ethyl acetate (20mL), combined the organic phases with anhydrous sulfuric acid It was dried over sodium and concentrated under reduced pressure; the residue was separated and purified by neutral alumina column (DCM:MeOH=15:1) to obtain 1-phenylpiperazine (510 mg, yield 99%).

Example 2:

The preparation of 1-phenylpiperazine, concrete process is as follows:

To a solution of 1-(pyridine-3-sulfonyl)-4-phenylpiperazine (303 mg, 1.0 mmol) in DMSO (5 mL) was added potassium hydroxide (224 mg, 4.0 mmol) and sealed under argon atmosphere ; Then add HPPh ₂ (261mg, 1.4mmol), stir at 90°C for 6h until the reaction is complete; quench the reaction with water (10mL), and remove the precipitate, then extract with ethyl acetate (10mL), combine the organic phases with It was dried over anhydrous sodium sulfate and concentrated under reduced pressure; the residue was separated and purified by neutral alumina column (DCM:MeOH=15:1) to obtain 1-phenylpiperazine (131 mg, yield 81%).

Example 3:

The preparation of 1-phenylpiperazine, concrete process is as follows:

To a solution of 1-(cyclohexylsulfonyl)-4-phenylpiperazine (339 mg, 1.1 mmol) in DMSO (5 mL) was added potassium hydroxide (309 mg, 5.5 mmol), and sealed under argon atmosphere; then Add HPPh ₂ (246mg, 1.32mmol), stir at 90°C for 10h until the reaction is complete; quench the reaction with water (10mL), and remove the precipitate; then extract with ethyl acetate (10mL), combine the organic phases with anhydrous Dry over sodium sulfate and concentrate under reduced pressure; the residue is separated and purified by neutral alumina column (DCM:MeOH=15:1) to obtain 1-phenylpiperazine (30 mg, yield 17%).

Example 4:

The preparation of 1-phenylpiperazine, concrete process is as follows:

To a solution of 1-(propylsulfonyl)-4-phenylpiperazine (268 mg, 1.0 mmol) in DMSO (5 mL) was added potassium hydroxide (280 mg, 5.0 mmol), and sealed under argon atmosphere; then Add HPPh ₂ (242mg, 1.3mmol), stir at 90°C for 10h until the reaction is complete; quench the reaction with water (10mL), and remove the precipitate; then extract with ethyl acetate (10mL), combine the organic phases with anhydrous Dry over sodium sulfate and concentrate under reduced pressure; the residue is separated and purified by neutral alumina column (DCM:MeOH=15:1) to obtain 1-phenylpiperazine (83 mg, yield 51%).

Example 5:

The preparation of diphenylamine, concrete process is as follows:

In a solution of N-toluenesulfonyldianiline (647mg, 2.0mmol) in DMSO (5mL), potassium hydroxide (449mg, 8.0mmol) was added and sealed under argon atmosphere; then HPPh ₂ (484mg, 2.6 mmol), stirred at 90°C for 2.5h until the reaction was complete; the reaction was quenched with water (15mL), extracted with ethyl acetate (15mL), the combined organic phases were dried over anhydrous sodium sulfate, and concentrated under reduced pressure; the residue was washed with silica gel Separation and purification by column (PE:EA=6:1) gave diphenylamine (274mg, yield 81%) with a melting point of 52.8-53.4°C.

Embodiment 6:

The preparation of 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, the specific process is as follows:

In a solution of N,N'-di-p-toluenesulfonyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (481 mg, 1.0 mmol) in DMSO (4 mL), Add potassium hydroxide (225mg, 4.0mmol), and seal under argon atmosphere; then add HPPh ₂ (242mg, 1.3mmol), stir at 90°C for 2h until the reaction is complete; quench the reaction with water (10mL), then use Extracted with ethyl acetate (10 mL), combined the organic phases, dried over anhydrous sodium sulfate, and concentrated under reduced pressure; the residue was separated and purified by neutral alumina column (DCM:MeOH=15:1) to obtain 2,3,4, 5-Tetrahydro-1H-pyrido[4,3-b]indole (153 mg, 89% yield).

Embodiment 7:

The preparation of N-methylaniline, concrete process is as follows:

To a solution of N-p-toluenesulfonyl-N-methylaniline (340 mg, 1.3 mmol) in DMSO (6 mL) was added potassium hydroxide (292 mg, 5.2 mmol) and sealed under argon atmosphere; then _HPPh was added (315mg, 1.7mmol), stirred at 90°C for 1.5h until the reaction was complete; the reaction was quenched with water (15mL), then extracted with ethyl acetate (15mL), the combined organic phases were dried over anhydrous sodium sulfate, and concentrated under reduced pressure ; The residue was separated and purified with a silica gel column (PE:EA=10:1) to obtain N-methylaniline (134 mg, yield 96%).

Embodiment 8:

The preparation of imidazole, concrete process is as follows:

In a solution of N-toluenesulfonyl imidazole (267mg, 1.2mmol) in DMSO (5mL), potassium hydroxide (303mg, 5.4mmol) was added and sealed under argon atmosphere; then HPPh ₂ (268mg, 1.44mmol) was added ), stirred at 90°C for 1.5h until the reaction was complete; the reaction was quenched with water (10mL), then extracted with ethyl acetate (10mL), the combined organic phases were dried over anhydrous sodium sulfate, and concentrated under reduced pressure; the residue was used in Separation and purification on a permanent alumina column (DCM:MeOH=20:1) gave imidazole (77mg, yield 94%) with a melting point of 90.2-91.8°C.

Embodiment 9:

The preparation of isoindoline-1-ketone, concrete process is as follows:

In a solution of N-tosylisoindolin-1-one (430 mg, 1.5 mmol) in DMSO (6 mL), add potassium hydroxide (337 mg, 6.0 mmol), and seal under argon atmosphere; then add HPPh ₂ (391mg, 2.1mmol), stirred at 90°C for 1.5h until the reaction was complete; the reaction was quenched with water (15mL), then extracted with ethyl acetate (15mL), the combined organic phases were dried with anhydrous sodium sulfate, and reduced Concentrate under reduced pressure; the residue was separated and purified with a neutral alumina column (DCM:MeOH=30:1) to obtain isoindolin-1-one (188 mg, yield 94%), melting point 149.8-151.7°C.

Example 10:

The preparation of tetrahydropyrrole, concrete process is as follows:

To a solution of N-p-toluenesulfonyltetrahydropyrrole (248 mg, 1.1 mmol) in DMSO (5 mL), add potassium hydroxide (278 mg, 4.95 mmol), and seal under argon atmosphere; then add HPPh ₂ (266 mg, 1.43mmol), stirred at 90°C for 1.5h until the reaction was complete; the reaction was quenched with water (15mL), then extracted with ethyl acetate (15mL), the combined organic phases were dried over anhydrous sodium sulfate, and concentrated under reduced pressure; the residue Separation and purification with a neutral alumina column (DCM:MeOH=10:1) gave tetrahydropyrrole (62 mg, yield 79%).

Detection experiment:

(1) The chemical formula of the de-Ts protected amine that embodiment 1-4 makes is:

对实施例1制得的1-苯基哌嗪进行检测，其结果如下：

The 1-phenylpiperazine that embodiment 1 is made detects, and its result is as follows:

¹ H NMR (400MHz, Chloroform-d) δ7.20–7.20(m,2H),6.91–6.73(m,3H),3.10–3.02(m,4H),3.01–2.87(m,4H),1.69( s, 1H). ¹³ C NMR (101 MHz, Chloroform-d) δ 151.9, 129.1, 119.6, 116.1, 50.4, 46.2.

(2) The chemical formula of the de-Ts protected amine that embodiment 5 makes is:

对实施例5制得的二苯胺进行检测，其结果如下：

The diphenylamine that embodiment 5 is made detects, and its result is as follows:

¹ H NMR (400MHz, Chloroform-d) δ7.26–7.21(m, 4H), 7.06(d, J=7.9Hz, 4H), 6.92(t, J=7.4Hz, 2H), 5.66(s, 1H ). ¹³ C NMR (101 MHz, Chloroform-d) δ 143.2, 129.4, 121.0, 117.9.

(3) The chemical formula of the de-Ts protected amine that embodiment 6 makes is:

对实施例6制得的2,3,4,5-四氢-1H-吡啶并[4,3-b]吲哚进行检测，其结果如下：

The 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole prepared in Example 6 was detected, and the results were as follows:

¹ H NMR (400MHz, Chloroform-d) δ10.80(s, 1H), 7.35(d, J=7.7Hz, 1H), 7.28(d, J=8.0Hz, 1H), 7.00(ddd, J=8.1 ,7.0,1.3Hz,1H),6.94(td,J=7.4,1.1Hz,1H),4.92(d,J=7.8Hz,1H),3.97(s,2H),3.08(t,J=5.7Hz , 2H), 2.66 (t, J=5.5Hz, 2H). ¹³ C NMR (101 MHz, Chloroform-d) δ 136.1, 132.2, 127.3, 121.0, 118.8, 117.8, 111.4, 106.9, 43.2, 42.3, 21.3.

(4) The chemical formula of the de-Ts protected amine that embodiment 7 makes is:

对实施例7制得的N-甲基苯胺进行检测，其结果如下：

The N-methylaniline that embodiment 7 is made detects, and its result is as follows:

¹ H NMR (400MHz, Chloroform-d) δ7.56–7.43(m,2H),7.03(tt,J＝7.3,1.2Hz,1H),6.92–6.75(m,2H),3.80(s,1H) ,3.01(s,3H). ¹³ C NMR (101 MHz, Chloroform-d) δ 149.8, 129.5, 117.4, 112.7, 30.9.

(5) The chemical formula of the de-Ts protected amine that embodiment 8 makes is:

对实施例8制得的咪唑进行检测，其结果如下：

The imidazole that embodiment 8 is made detects, and its result is as follows:

¹ H NMR (400 MHz, Chloroform-d) δ 12.16 (s, 1H), 7.68 (t, J=1.1 Hz, 1H), 7.05 (d, J=0.9 Hz, 2H). ¹³ C NMR (101 MHz, Chloroform-d) δ 135.6, 122.2.

(6) The chemical formula of the de-Ts protected amine that embodiment 9 makes is:

对实施例9制得的异吲哚啉-1-酮进行检测，其结果如下：

The isoindoline-1-ketone that embodiment 9 is made detects, and its result is as follows:

¹ H NMR (400 MHz, Chloroform-d) δ 13.34 (s, 1H), 12.31 (s, 2H), 12.23 (s, 1H), 9.13 (s, 2H). ¹³ C NMR (101 MHz, Chloroform-d) δ 175.2, 149.3, 137.8, 136.4, 132.8, 128.9, 128.0, 50.1.

(7) The chemical formula of the de-Ts protected amine that embodiment 10 makes is:

对实施例10制得的四氢吡咯进行检测，其结果如下：

The tetrahydropyrrole that embodiment 10 is made detects, and its result is as follows:

¹ H NMR (400 MHz, Chloroform-d) δ 2.88–2.46 (m, 4H), 2.09 (s, 1H), 1.74–1.36 (m, 4H). ¹³ C NMR (101 MHz, Chloroform-d) δ 47.0, 25.7.

The above descriptions are only preferred embodiments of the present invention, and the present invention is not limited to the above-mentioned embodiments, as long as they achieve the technical effects of the present invention by the same means, they should all belong to the protection scope of the present invention. Various modifications and changes may be made to the technical solutions and/or implementations within the protection scope of the present invention.

Claims (6)

1. a method for removing the sulfonyl protection of amine, is characterized in that, comprises the following steps: Step 1. Dissolve the N-sulfonyl protected amine and base in the reaction solvent, then add diphenylphosphine to mix and keep at 90°C; Step 2. When the TCL detection reaction is complete, the target product is obtained by recrystallization or extraction separation; The extraction and separation method includes the following steps: washing the product with water, then extracting with ethyl acetate, separating and retaining the organic layer, removing the solvent after drying, and separating by column chromatography to obtain the target product; The molar ratio of N-sulfonyl protected amine, base and diphenylphosphine is 1:(3-5):(1.1-1.4); the reaction solvent is DMSO, DMF, DMA, NMP, 1,4-Dioxane and one of THF; the base is one of KOH, t-BuOK, Cs ₂ CO ₃ , K ₂ CO ₃ , NaOH, t-BuONa and Na ₂ CO ₃ . 2. The method according to claim 1, characterized in that the alkali is KOH. 3. The method according to claim 1, wherein the sulfonyl group is an aromatic sulfonyl group, an alicyclic sulfonyl group or a straight-chain aliphatic sulfonyl group. 4. The method according to claim 1, characterized in that, the specific process of step 1 is: the amine and alkali of N-sulfonyl protection are dissolved in the reaction solvent, and sealed under an inert gas atmosphere, then add diphenyl Mix the base phosphine and keep it at 90°C. 5. The method according to claim 4, wherein the inert gas is nitrogen or argon. 6. The method according to claim 1, characterized in that, adopting a neutral alumina column or a silica gel column to carry out column chromatography separation.