Process for the preparation of sulfonamides and intermediates
By preparing sulfonamide compounds under alkaline conditions and avoiding dangerous intermediates, and by reacting compound II with p-toluenesulfonamide, the problem of long and dangerous preparation routes in existing technologies is solved, and high-yield and high-purity sulfonamide compounds are prepared, making them suitable for industrial applications.
Patent Information
- Application Number
- CN202411490036.2
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2024-10-24
- Publication Date
- 2025-11-18
- Estimated Expiration
- 2044-10-24
AI Technical Summary
The preparation methods of sulfonamide compounds in the existing technology are lengthy and require the use of hazardous intermediates, and the use of lithium aluminum hydride is limited, making them difficult to apply to industrial production.
Compound II is reacted with p-toluenesulfonamide in the presence of an alkaline reagent and a solvent to generate compound III. The reaction involves two steps: first, compound II is prepared in the presence of an acid-binding agent and a solvent, and then it is reacted with p-toluenesulfonamide under alkaline conditions to avoid dangerous intermediates.
The preparation of sulfonamide compounds with high yield and high purity was achieved, with an ee value as high as 95% and a purity of 99%. The operation is simple and suitable for industrial production.
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Figure CN119431199B_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of organic synthesis, and specifically to a method for preparing sulfonamide compounds and intermediates. Background Technology
[0002] The paper "Asymmetric Syntheses of (-)-Pentazocine and (-)-Eptazocine through anAza-Prins Cyclization" (Chem.Asian J. 2012, 7(11), 2543-2546) discloses two new routes for the synthesis of (-)-Pentazocine and (-)-Eptazocine, respectively. Compounds 3a and 3b are important intermediates in the new routes.
[0003]
[0004] The literature also reports methods for preparing compounds 3a and 3b. According to the literature, the preparation methods of compounds 3a and 3b are similar. Both start with alcohol as the starting material, prepare an azide intermediate through the Mitsunobu reaction, and then use lithium aluminum hydride reduction and p-toluenesulfonyl group protection to finally obtain compounds 3a or 3b.
[0005] The above preparation method not only has a long synthesis route, but also requires the use of a relatively dangerous azide intermediate. The use of aluminum lithium hydrogen is also quite limited in industry. Therefore, the above route is not suitable for industrial production. Summary of the Invention
[0006] To address the aforementioned problems in existing technologies, this invention provides a method for preparing sulfonamide compounds and intermediates. The synthetic route of this invention is shorter, eliminates the need for hazardous intermediates, and simplifies the production process.
[0007] The technical solution of the present invention is as follows:
[0008] The first objective of this invention is to provide a method for preparing sulfonamide compounds, wherein a compound of formula II reacts with p-toluenesulfonamide in the presence of an alkaline reagent and a second solvent to generate a compound of formula III;
[0009]
[0010] Where n = 0 or 1, and R is H or methyl.
[0011] In one embodiment of the present invention, the alkaline reagent is any one or more of potassium tert-butoxide, sodium tert-butoxide, sodium hydride, potassium hydroxide, and sodium hydroxide; for example, potassium tert-butoxide and / or sodium tert-butoxide.
[0012] In one embodiment of the present invention, the molar ratio of the compound of formula II to the base reagent is 1:(1.0-5.0); for example, 1:3.
[0013] In one embodiment of the present invention, the second solvent is any one or more of dichloromethane, chloroform, diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, DMF, and DMSO; for example, DMF.
[0014] In one embodiment of the present invention, the mass-to-volume ratio of the compound of formula II to the second solvent is 1 g:(8-30) mL; for example, 1 g:15 mL.
[0015] In one embodiment of the present invention, the molar ratio of the compound of formula II to p-toluenesulfonamide is 1:(1-5), for example, 1:3.
[0016] In one embodiment of the present invention, the reaction temperature of the compound of formula II with p-toluenesulfonamide is 40-100°C; for example, 80°C.
[0017] In one embodiment of the present invention, the reaction time of the compound of formula II with p-toluenesulfonamide is 8-24 h; for example, 20 h.
[0018] In one embodiment of the present invention, the reaction is further comprising the following post-processing steps: adding water to quench the reaction solution, extracting with dichloromethane, taking the organic phase, concentrating it to obtain a crude product, and recrystallizing the crude product with a mixture of water and ethanol.
[0019] In the mixture of water and ethanol, the volume ratio of water to ethanol is 2:1.
[0020] In one embodiment of the present invention, the method for preparing the sulfonamide compound further includes a method for preparing the compound of formula II, comprising the following steps:
[0021] In the presence of an acid-binding agent and a first solvent, compound I reacts with a sulfonating agent to generate compound II.
[0022]
[0023] Where n = 0 or 1, and R is H or methyl.
[0024] In one embodiment of the present invention, the sulfonating agent is p-toluenesulfonyl chloride and / or p-toluenesulfonic anhydride.
[0025] In one embodiment of the present invention, the molar ratio of the compound of formula I to the sulfonating agent is 1:(0.9-2.0); for example, 1:1.2.
[0026] In one embodiment of the present invention, the acid-binding agent is any one or more of pyridine, triethylamine, N,N-dimethylaniline, N,N-dimethylpyridine, diisopropylethylamine, sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate; for example, triethylamine.
[0027] In one embodiment of the present invention, the molar ratio of the compound of formula I to the acid binder is 1:(1.0-5.0); preferably 1:(1-3), for example, 1:2.
[0028] In one embodiment of the present invention, the first solvent is any one or more of dichloromethane, trichloromethane, diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, DMF, and DMSO; for example, DMF.
[0029] In one embodiment of the present invention, the mass-to-volume ratio of the compound of formula I to the first solvent is 1 g:(5-7) mL; for example, 1 g:6 mL.
[0030] In one embodiment of the present invention, the reaction temperature is 0-10°C; for example, 0-5°C.
[0031] In one embodiment of the present invention, the reaction time is 2-10 hours; for example, 3-4 hours.
[0032] In one embodiment of the present invention, the compound of formula II can also be prepared in the presence of a catalyst, wherein the catalyst is 4-dimethylaminopyridine (DMAP) and / or N-methylimidazole;
[0033] In one embodiment of the present invention, the molar ratio of the compound of formula I to the catalyst is 1:(0.05-0.5); for example, 1:0.1.
[0034] A second object of the present invention is to provide a method for preparing a compound of formula II, comprising the following steps:
[0035] In the presence of an acid-binding agent and a first solvent, compound I reacts with a sulfonating agent to generate compound II.
[0036]
[0037] Where n = 0 or 1, and R is H or methyl.
[0038] In one embodiment of the present invention, the reaction conditions for preparing the compound of formula II are as described above. A third object of the present invention is to provide a compound of formula II, the structure of which is shown below:
[0039]
[0040] Where n = 0 or 1, and R is H or methyl.
[0041] In one embodiment of the present invention, the compound of formula II has any of the following structures:
[0042]
[0043] Preferably, the compound of formula II has any one of the following structures:
[0044]
[0045] In one embodiment of the present invention, the specific steps of the method for preparing sulfonamide compounds are as follows:
[0046]
[0047] Where n = 0 or 1, and R is H or methyl;
[0048] (1) Compound I reacts with a sulfonating agent in the presence of an acid-binding agent and a first solvent to generate compound II;
[0049] (2) Compound II reacts with p-toluenesulfonamide in the presence of a base reagent and a second solvent to produce compound III.
[0050] In one embodiment of the present invention, when n = 0 and R represents methyl, the compound of formula I is compound 1a, the compound of formula II is compound 2a, and the compound of formula III is 3a.
[0051] In one embodiment of the present invention, when n = 1 and R represents H, compound I is compound 1b, compound II is compound 2b, and compound III is compound 3b.
[0052] In one embodiment of the present invention, when n=1 and R represents methyl, compound I is compound 1c, compound II is compound 2c, and compound III is compound 3c.
[0053] In one embodiment of the present invention, when n = 0 and R represents H, compound I is compound 1d, compound II is compound 2d, and compound III is compound 3d.
[0054]
[0055]
[0056] In one embodiment of the present invention, the reaction process of the compound of formula II is as follows:
[0057] The compound of formula I is dissolved in the first solvent, and an acid-binding agent and N-methylimidazole are added. Then, a sulfonating agent is added, and the reaction is carried out for 2-4 hours. The reaction is quenched with water, extracted, and the organic phase is collected, washed, dried, filtered, and concentrated under reduced pressure to obtain the crude product of compound II.
[0058] In one embodiment of the present invention, the reaction process of the compound of formula III is as follows:
[0059] p-Toluenesulfonamide was added to the second solvent, followed by the addition of an alkaline reagent. The temperature was raised to 40-60°C, and then compound II was added. The temperature was raised to 70-90°C, and the mixture was stirred for 8-24 hours. The reaction was quenched with water, and the mixture was extracted with an organic solvent. The organic phase was collected, washed with saturated brine, dried, filtered, and the filtrate was collected. The filtrate was concentrated, recrystallized, filtered, and the solid was collected and dried to obtain compound III.
[0060] The beneficial technical effects of this invention are as follows:
[0061] 1. Technical advantages of the preparation method for sulfonamide compounds:
[0062] The new method for preparing compound III from compound II as a raw material has a high yield, and the obtained compound III has an ee value as high as 95% and a purity of over 99%. The method is easy to operate and is conducive to large-scale industrial application.
[0063] 2. Technical advantages of the compound of formula II and its preparation method:
[0064] Using compounds of formula II can shorten the preparation process of compounds of formula III, eliminate the need for hazardous intermediates, and improve the overall yield.
[0065] 3. This invention uses alcohol as the starting material, first sulfonates it, and then reacts it with sulfonamide under alkaline conditions. This not only effectively shortens the synthesis steps and eliminates the need for dangerous intermediates, but also makes the entire production process safer; moreover, the overall yield of the two steps is high. Attached Figure Description
[0066] Figure 1 This is the proton NMR spectrum of the crude compound 2b in Example 1 of this invention;
[0067] Figure 2 This is the HPLC spectrum of the crude compound 2b from Example 1 of the present invention;
[0068] Figure 3 This is the proton spectrum of compound 3b in Example 1 of the present invention;
[0069] Figure 4 This is the chiral HPLC spectrum of compound 3b in Example 1 of the present invention;
[0070] Figure 5 This is the HPLC chromatogram of compound 3b in Example 1 of the present invention to show its purity. Detailed Implementation
[0071] The present invention will now be described in detail with reference to the accompanying drawings and embodiments.
[0072] In the following embodiments, unless otherwise stated, all raw materials are commercially available products.
[0073] Example 1
[0074] A method for preparing a sulfonamide compound, the reaction formula is as follows:
[0075]
[0076] The reaction steps are as follows:
[0077] Step 1: 675 g of compound 1b (3.06 mol, 1.0 eq) was dissolved in 4 L of dichloromethane. 618 g of triethylamine (6.12 mol, 2.0 eq) and 25.1 g of N-methylimidazole (306 mmol, 0.1 eq) were added. The mixture was cooled to 0-5 °C, and 699.7 g of p-toluenesulfonyl chloride (3.67 mol, 1.2 eq) was slowly added. The mixture was stirred at 0-5 °C for 3.5 h. The reaction was quenched with 6 L of water, extracted, and the organic phase was collected. The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 1.11 kg of crude compound 2b with a purity of 96.3% and a yield of 93.3%.
[0078] The proton NMR spectrum of the crude compound 2b is as follows: Figure 1 As shown, the HPLC spectrum of the crude compound 2b is as follows. Figure 2 As shown.
[0079] Step 2: 785.9 g of p-toluenesulfonamide (4.59 mol, 3.0 eq) was added to 9 L of DMF, followed by 515.0 g of potassium tert-butoxide (4.59 mol, 3.0 eq). The mixture was heated to 50 °C, and then 595 g of crude compound 2b (purity 96.3%, 1.53 mol, 1.0 eq) was added. The mixture was heated to 80 °C and stirred for 20 h. The reaction was quenched with 9 L of water, extracted with dichloromethane, and the organic phase was collected. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was collected. The filtrate was concentrated under reduced pressure, and recrystallized by adding 3 L of a mixed solution of ethanol / water (volume ratio ethanol / water = 1:2). The mixture was filtered, and the solid was collected and dried to obtain 516.6 g of compound 3b, a white solid with a purity of 99.2%, an ee value of 96.2%, and a yield of 90.4%.
[0080] The proton spectrum of compound 3b is as follows: Figure 3 As shown, the chiral HPLC spectrum of compound 3b is as follows: Figure 4 As shown, the HPLC chromatogram of compound 3b with purity is as follows. Figure 5 As shown.
[0081] Example 2
[0082] A method for preparing a sulfonamide compound, comprising the following reaction steps:
[0083] Step 1: 69 g of compound 1b (313.2 mmol, 1.0 eq) was dissolved in 400 mL of dichloromethane, and 63.3 g of triethylamine (626.4 mol, 2.0 eq) was added. The mixture was cooled to 0-5 °C, and 71.6 g of p-toluenesulfonyl chloride (375.8 mol, 1.2 eq) was slowly added. The mixture was stirred at 0-5 °C for 8 h. The reaction was quenched with 600 mL of water, extracted, and the organic phase was collected. The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 93.7 g of crude compound 2b with a purity of 95.5% and a yield of 76.3%.
[0084] Step 2: 52.4 g of p-toluenesulfonamide (306 mmol, 3.0 eq) was added to 600 mL of DMF, followed by 12.2 g of sodium hydride (60% purity, 306 mmol, 3.0 eq). The mixture was heated to 50 °C, and 40 g of crude compound 2b (95.5% purity, 102 mmol, 1.0 eq) was added. The mixture was heated to 80 °C and stirred for 20 h. The reaction was quenched with 600 mL of water, extracted with dichloromethane, and the organic phase was collected. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was then subjected to column chromatography and dried to obtain 33.8 g of compound 3b, a yellow oily substance with a purity of 99.7%, an ee value of 94.5%, and a yield of 88.6%.
[0085] In summary, the addition of a catalytic amount of N-methylimidazole in step 1 of the above embodiments can greatly accelerate the reaction rate in step 1. The reaction that originally required 6-8 hours to complete can be completed in only 3.5 hours after the addition of a catalytic amount of N-methylimidazole.
[0086] In the post-processing step 2 of the above embodiments, a mixed solution of ethanol / water was used to recrystallize the product, which not only effectively purified the product but also successfully obtained a solid product. Compared with the above embodiments, if column chromatography is used for purification, only an oily product can be obtained, which is not conducive to industrial production.
[0087] The embodiments provided above are not intended to limit the scope of the invention, nor are the described steps intended to limit the order of execution. Any obvious modifications made to the invention by those skilled in the art based on existing common knowledge also fall within the scope of protection defined by the claims.
Claims
1. A method for preparing a sulfonamide compound, characterized in that, In the presence of a base reagent and a second solvent, compound II reacts with p-toluenesulfonamide to produce compound III. Where n = 0 or 1, and R is H or methyl; The alkaline reagent is any one or more of potassium tert-butoxide, sodium tert-butoxide, sodium hydride, potassium hydroxide, and sodium hydroxide. The second solvent is any one or more of dichloromethane, chloroform, diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, DMF, and DMSO.
2. The method for preparing sulfonamide compounds according to claim 1, characterized in that, The preparation method of the sulfonamide compound satisfies any one of the following conditions: (1) The molar ratio of the compound of formula II to the base reagent is 1:(1.0-5.0). (2) The mass-to-volume ratio of compound II to the second solvent is 1 g: (8-30) mL; (3) Reaction conditions: The reaction temperature is 40-100℃; (4) Reaction conditions: The reaction time is 8-24h.
3. The method for preparing sulfonamide compounds according to claim 1, characterized in that, The method for preparing the sulfonamide compound also includes a method for preparing the compound of formula II, comprising the following steps: In the presence of an acid-binding agent and a first solvent, compound I reacts with a sulfonating agent to generate compound II. Where n = 0 or 1, and R is H or methyl.
4. The method for preparing sulfonamide compounds according to claim 3, characterized in that, The preparation method of the compound of formula II satisfies any one of the following conditions: (1) The sulfonating agent is p-toluenesulfonyl chloride and / or p-toluenesulfonic anhydride; (2) The molar ratio of the compound of formula I to the sulfonating agent is 1:(0.9-2.0); (3) The acid-binding agent is any one or more of pyridine, triethylamine, N,N-dimethylaniline, N,N-dimethylpyridine, diisopropylethylamine, sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate; (4) The molar ratio of the compound of formula I to the acid-binding agent is 1:(1.0-5.0). (5) The first solvent is any one or more of dichloromethane, chloroform, diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, DMF, and DMSO; (6) The mass-to-volume ratio of compound I to the first solvent is 1 g: (5-7) mL; (7) Reaction conditions: The reaction temperature is 0-10℃; (8) Reaction conditions: The reaction time is 2-10h.
5. The method for preparing sulfonamide compounds according to claim 3, characterized in that, The compound of formula II is prepared in the presence of a catalyst, wherein the catalyst is 4-dimethylaminopyridine and / or N-methylimidazole.
6. The method for preparing sulfonamide compounds according to claim 5, characterized in that, The molar ratio of the compound of Formula I to the catalyst is 1:(0.05-0.5).
7. A method for preparing a compound of formula II, characterized in that, Includes the following steps: In the presence of an acid-binding agent and a first solvent, compound I reacts with a sulfonating agent to generate compound II. Where n = 0 or 1, and R is H or methyl.
8. The method for preparing the compound of formula II according to claim 7, characterized in that, The reaction conditions for preparing the compound of formula II satisfy any one of the following conditions: (1) The sulfonating agent is p-toluenesulfonyl chloride and / or p-toluenesulfonic anhydride; (2) The molar ratio of the compound of formula I to the sulfonating agent is 1:(0.9-2.0); (3) The acid-binding agent is any one or more of pyridine, triethylamine, N,N-dimethylaniline, N,N-dimethylpyridine, diisopropylethylamine, sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate; (4) The molar ratio of the compound of formula I to the acid-binding agent is 1:(1.0-5.0). (5) The first solvent is any one or more of dichloromethane, chloroform, diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, DMF, and DMSO; (6) The mass-to-volume ratio of compound I to the first solvent is 1 g: (5-7) mL; (7) Reaction conditions: The reaction temperature is 0-10℃; (8) Reaction conditions: The reaction time is 2-10h.
9. The method for preparing the compound of formula II according to claim 7, characterized in that, The compound of formula II is prepared in the presence of a catalyst, wherein the catalyst is 4-dimethylaminopyridine and / or N-methylimidazole.
10. The method for preparing the compound of formula II according to claim 9, characterized in that, The molar ratio of the compound of Formula I to the catalyst is 1:(0.05-0.5).
11. A compound of formula II, characterized in that, The structure of the compound is shown below: Where n = 0 or 1, and R is H or methyl.
12. The compound of formula II according to claim 11, characterized in that, Compound II has any of the following structures: , , or .
13. The compound of formula II according to claim 11, characterized in that, Compound II has any of the following structures: 。
Citation Information
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