Preparation method and intermediate of sulfonamide compound

Abstract

The invention discloses a preparation method and an intermediate of a sulfonamide compound, and belongs to the field of organic synthesis. The method comprises the following specific steps: in the presence of an alkali reagent and a second solvent, reacting a compound shown as a formula II with p-toluene sulfonamide to generate a compound shown as a formula III; the preparation method of the compound as shown in the formula II comprises the following step: in the presence of an acid-binding agent and a first solvent, reacting a compound as shown in the formula I with a sulfonylation reagent to generate the compound as shown in the formula II. Alcohol is adopted as an initial raw material, sulfonylation is performed firstly, and then the alcohol reacts with sulfonamide under the alkaline condition, so that the synthesis steps are effectively shortened, dangerous intermediates are not needed, and the whole production process is safer; and the total yield of the two steps is high. # imgabs0 #

Description

Technical Field

[0001] The invention relates to the field of organic synthesis, and in particular to a preparation method and intermediate of a sulfonamide compound. Background Art

[0003] Asymmetric Syntheses of (-)-Pentazocine and (-)-Eptazocine through an Aza-Prins Cyclization (Chem. Asian J. 2012, 7(11), 2543-2546) discloses two new routes for synthesizing (-)-Pentazocine and (-)-Eptazocine, respectively, wherein compounds 3a and 3b are important intermediates in the new routes.

[0004]

[0005] The document also reports a method for preparing compound 3a and compound 3b. According to the report in the document, the preparation methods of compound 3a and compound 3b are similar, both of which use alcohol as the starting material, prepare the azide intermediate through Mitsunobu reaction, and then use aluminum lithium hydrogen reduction and toluenesulfonyl protection to finally obtain compound 3a or 3b.

[0006] The above preparation method not only has a long synthetic route, but also needs to go through relatively dangerous azide intermediates. The use of lithium aluminum hydride is also quite limited in industry. Therefore, the above route is not suitable for industrial production. Summary of the invention

[0007] In view of the above problems existing in the prior art, the present invention provides a preparation method and intermediates of sulfonamide compounds. The synthesis route of the present invention is shorter, no dangerous intermediates are required, and the production process is simpler.

[0008] The technical solution of the present invention is as follows:

[0009] The first object of the present invention is to provide a method for preparing a sulfonamide compound, 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;

[0010]

[0011] Wherein, n=0 or 1, and R is H or methyl.

[0012] 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.

[0013] In one embodiment of the present invention, the molar ratio of the compound of formula II to the alkaline agent is 1:(1.0-5.0); for example, 1:3.

[0014] In one embodiment of the present invention, the second solvent is any one or more of dichloromethane, chloroform, ether, tetrahydrofuran, 2-methyltetrahydrofuran, DMF, and DMSO; for example, DMF.

[0015] In one embodiment of the present invention, the mass volume ratio of the compound of formula II to the second solvent is 1 g:(8-30) mL; for example, 1 g:15 mL.

[0016] 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.

[0017] In one embodiment of the present invention, the reaction temperature of the compound of formula II and p-toluenesulfonamide is 40-100°C; for example, 80°C.

[0018] In one embodiment of the present invention, the reaction time of the compound of formula II and p-toluenesulfonamide is 8-24 hours; for example, 20 hours.

[0019] In one embodiment of the present invention, after the reaction is completed, the following post-treatment steps are further included: adding water to the reaction solution for quenching, extracting with dichloromethane, taking the organic phase, concentrating to obtain a crude product, and recrystallizing the crude product with a mixture of water and ethanol.

[0020] Wherein, in the mixed solution of water and ethanol, the volume ratio of water to ethanol is 2:1.

[0021] In one embodiment of the present invention, the preparation method of the sulfonamide compound also includes the preparation method of the compound of formula II, comprising the following steps:

[0022] In the presence of an acid-binding agent and a first solvent, the compound of formula I reacts with a sulfonylating agent to generate a compound of formula II;

[0023]

[0024] Wherein, n=0 or 1, and R is H or methyl.

[0025] In one embodiment of the present invention, the sulfonylating agent is p-toluenesulfonyl chloride and / or p-toluenesulfonic anhydride.

[0026] In one embodiment of the present invention, the molar ratio of the compound of formula I to the sulfonylating agent is 1:(0.9-2.0); for example, 1:1.2.

[0027] In one embodiment of the present invention, the acid binding agent is any one or more of pyridine, triethylamine, N,N-dimethylaniline, N,N-lutidine, diisopropylethylamine, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate; for example, triethylamine.

[0028] In one embodiment of the present invention, the molar ratio of the compound of formula I to the acid binding agent is 1:(1.0-5.0); preferably 1:(1-3), for example, 1:2.

[0029] In one embodiment of the present invention, the first solvent is any one or more of dichloromethane, chloroform, ether, tetrahydrofuran, 2-methyltetrahydrofuran, DMF, and DMSO; for example, DMF.

[0030] In one embodiment of the present invention, the mass volume ratio of the compound of formula I to the first solvent is 1 g:(5-7) mL; for example, 1 g:6 mL.

[0031] In one embodiment of the present invention, the reaction temperature of the reaction is 0-10°C; for example, 0-5°C.

[0032] In one embodiment of the present invention, the reaction time of the reaction is 2-10 h; for example, 3-4 h.

[0033] 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;

[0034] 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.

[0035] The second object of the present invention is to provide a method for preparing a compound of formula II, comprising the steps of:

[0036] In the presence of an acid-binding agent and a first solvent, the compound of formula I reacts with a sulfonylating agent to generate a compound of formula II;

[0037]

[0038] Wherein, n=0 or 1, and R is H or methyl.

[0039] In one embodiment of the present invention, the reaction conditions of the preparation method of the compound of formula II are as described above. The third object of the present invention is to provide a compound of formula II, the compound structure is shown below:

[0040]

[0041] Wherein, n=0 or 1, and R is H or methyl.

[0042] In one embodiment of the present invention, the compound of formula II is any one of the following structures:

[0043]

[0044] Preferably, the compound of formula II is any one of the following structures:

[0045]

[0046] In one embodiment of the present invention, the specific steps of the preparation method of sulfonamide compounds are:

[0047]

[0048] Wherein, n=0 or 1, R is H or methyl;

[0049] (1) reacting a compound of formula I with a sulfonylating agent in the presence of an acid binding agent and a first solvent to generate a compound of formula II;

[0050] (2) The 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.

[0051] In one embodiment of the present invention, when n=0 and R represents a methyl group, the compound of formula I is compound 1a, the compound of formula II is compound 2a, and the compound of formula III is 3a.

[0052] In one embodiment of the present invention, when n=1 and R represents H, the compound of formula I is compound 1b, the compound of formula II is compound 2b, and the compound of formula III is 3b.

[0053] In one embodiment of the present invention, when n=1 and R represents a methyl group, the compound of formula I is compound 1c, the compound of formula II is compound 2c, and the compound of formula III is 3c.

[0054] In one embodiment of the present invention, when n=0 and R is H, the compound of formula I is compound 1d, the compound of formula II is compound 2d, and the compound of formula III is 3d.

[0055]

[0056]

[0057] In one embodiment of the present invention, the reaction process of the compound of formula II is:

[0058] The compound of formula I is dissolved in the first solvent, an acid binding agent and N-methylimidazole are added, and then a sulfonylating agent is added, and the reaction is carried out for 2-4 hours. Water is added to quench the reaction, and the organic phase is extracted, washed, dried, filtered, and concentrated under reduced pressure to obtain a crude compound of formula II.

[0059] In one embodiment of the present invention, the reaction process of the compound of formula III is:

[0060] Add p-toluenesulfonamide to the second solvent, add an alkali reagent, raise the temperature to 40-60°C, add compound II, raise the temperature to 70-90°C, stir and react for 8-24 hours, add water to quench the reaction, extract with an organic solvent, take the organic phase, wash with saturated brine, dry, filter, take the filtrate, concentrate, recrystallize, filter, take the solid, and dry to obtain a compound of formula III.

[0061] The beneficial technical effects of the present invention are:

[0062] 1. Technical effects of the preparation method of sulfonamide compounds:

[0063] The method for preparing the compound of formula III by using the new raw material compound of formula II has high yield, and the prepared compound of formula III has an ee value of up to 95%, a purity of more than 99%, and is easy to operate, which is conducive to large-scale industrial application.

[0064] 2. Technical effects of the compound of formula II and the method for preparing the compound of formula II:

[0065] The use of the compound of formula II can not only shorten the preparation process of the compound of formula III without going through dangerous intermediates, but also improve the overall yield.

[0066] 3. The present invention uses alcohol as the starting material, which is first sulfonylated and then reacted with sulfonamide under alkaline conditions, which not only effectively shortens the synthesis steps and eliminates the need for dangerous intermediates, but also makes the entire production process safer; and the total yield of the two steps is high. BRIEF DESCRIPTION OF THE DRAWINGS

[0067] Figure 1 is the hydrogen spectrum of the crude compound 2b in Example 1 of the present invention;

[0068] Figure 2 is the HPLC spectrum of the crude compound 2b in Example 1 of the present invention;

[0069] Figure 3is the hydrogen spectrum of compound 3b in Example 1 of the present invention;

[0070] Figure 4 is the chiral HPLC spectrum of compound 3b in Example 1 of the present invention;

[0071] Figure 5 It is the purity HPLC spectrum of compound 3b in Example 1 of the present invention. DETAILED DESCRIPTION

[0072] The present invention is described in detail below in conjunction with the accompanying drawings and embodiments.

[0073] In the following examples, unless otherwise specified, all raw materials are commercially available products.

[0074] Example 1

[0075] A method for preparing a sulfonamide compound, the reaction formula is as follows:

[0076]

[0077] The reaction steps are as follows:

[0078] Step 1, 675g of compound 1b (3.06mol, 1.0eq) was dissolved in 4L of dichloromethane, 618g of triethylamine (6.12mol, 2.0eq) and 25.1g of N-methylimidazole (306mmol, 0.1eq) were added, the temperature was lowered to 0-5°C, 699.7g of p-toluenesulfonyl chloride (3.67mol, 1.2eq) was slowly added, the temperature was controlled at 0-5°C and stirred for 3.5h, 6L of water was added to quench the reaction, extracted, the organic phase was taken, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered to take the filtrate, and concentrated under reduced pressure to obtain 1.11kg of crude compound 2b with a purity of 96.3% and a yield of 93.3%.

[0079] The hydrogen spectrum of crude compound 2b is as follows Figure 1 As shown, the HPLC spectrum of the crude compound 2b is as follows Figure 2 shown.

[0080] Step 2, add 785.9g of p-toluenesulfonamide (4.59mol, 3.0eq) to 9L DMF, then add 515.0g of potassium tert-butoxide (4.59mol, 3.0eq), heat to 50°C, add 595g of crude compound 2b (purity 96.3%, 1.53mol, 1.0eq), heat to 80°C, stir and react for 20h, add 9L of water to quench the reaction, extract with dichloromethane, take the organic phase, wash with saturated brine, dry with anhydrous sodium sulfate, filter, take the filtrate, concentrate under reduced pressure, add 3L of ethanol / water mixed solution (volume ratio ethanol / water = 1:2) for recrystallization, filter, take the solid, and dry to obtain 516.6g of compound 3b as a white solid with a purity of 99.2%, an ee value of 96.2%, and a yield of 90.4%.

[0081] The hydrogen 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 purity HPLC spectrum of compound 3b is as follows Figure 5 shown.

[0082] Example 2

[0083] A method for preparing a sulfonamide compound, the reaction steps are as follows:

[0084] Step 1, dissolve 69g of compound 1b (313.2mmol, 1.0eq) in 400mL of dichloromethane, add 63.3g of triethylamine (626.4mol, 2.0eq), cool to 0-5°C, slowly add 71.6g of p-toluenesulfonyl chloride (375.8mol, 1.2eq), control the temperature at 0-5°C and stir to react for 8h, add 600mL of water to quench the reaction, extract, take the organic phase, wash once with saturated brine, dry over anhydrous sodium sulfate, filter and take the filtrate, and concentrate under reduced pressure to obtain 93.7g of crude compound 2b with a purity of 95.5% and a yield of 76.3%.

[0085] Step 2, add 52.4g of p-toluenesulfonamide (306mmol, 3.0eq) to 600mL of DMF, then add 12.2g of sodium hydride (purity 60%, 306mmol, 3.0eq), heat to 50°C, add 40g of crude compound 2b (purity 95.5%, 102mmol, 1.0eq), heat to 80°C, stir and react for 20h, add 600mL of water to quench the reaction, extract with dichloromethane, take the organic phase, wash with saturated brine, dry with anhydrous sodium sulfate, filter, take the filtrate, concentrate under reduced pressure, column chromatography, and dry to obtain 33.8g of compound 3b as a yellow oil with a purity of 99.7%, an ee value of 94.5%, and a yield of 88.6%.

[0086] In summary, the addition of a catalytic amount of N-methylimidazole in step 1 of the above embodiment can greatly accelerate the reaction rate of the reaction in step 1. The reaction originally required 6-8 hours to complete the reaction, but after adding the catalytic amount of N-methylimidazole, the reaction can be completed in only 3.5 hours;

[0087] In the post-treatment process of step 2 in the above embodiment, 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 embodiment, if column chromatography is used for purification, only an oily product can be obtained, which is not conducive to industrial production.

[0088] The embodiments provided above are not intended to limit the scope of the present invention, and the steps described are not intended to limit the execution order thereof. Those skilled in the art may make obvious improvements to the present invention in combination with existing common knowledge, which also fall within the scope of protection defined by the claims of the present invention.

Claims

1. A method for preparing a sulfonamide compound, characterized in that: In the presence of a base reagent and a second solvent, the compound of formula II reacts with p-toluenesulfonamide to generate a compound of formula III; Wherein, n=0 or 1, and R is H or methyl.

2. The method for preparing a sulfonamide compound according to claim 1, characterized in that: The preparation method of the sulfonamide compound meets one or more of the following conditions: (1) The alkaline reagent is any one or more of potassium tert-butoxide, sodium tert-butoxide, sodium hydride, potassium hydroxide, and sodium hydroxide; (2) The molar ratio of the compound of formula II to the alkaline reagent is 1:(1.0-5.0); (3) the second solvent is any one or more of dichloromethane, chloroform, ether, tetrahydrofuran, 2-methyltetrahydrofuran, DMF, and DMSO; (4) The mass volume ratio of the compound of formula II to the second solvent is 1 g: (8-30) mL; (5) Reaction conditions: reaction temperature is 40-100°C; (6) Reaction conditions: The reaction time is 8-24h.

3. The method for preparing a sulfonamide compound according to claim 1, characterized in that: The preparation method of the sulfonamide compound also includes the preparation method of the compound of formula II, comprising the following steps: In the presence of an acid-binding agent and a first solvent, the compound of formula I reacts with a sulfonylating agent to generate a compound of formula II; Wherein, n=0 or 1, and R is H or methyl.

4. The method for preparing a sulfonamide compound according to claim 3, characterized in that: The preparation method of the compound of formula II satisfies one or more of the following conditions: (1) The sulfonylating agent is p-toluenesulfonyl chloride and / or p-toluenesulfonic anhydride; (2) The molar ratio of the compound of formula I to the sulfonylating 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, ether, tetrahydrofuran, 2-methyltetrahydrofuran, DMF, and DMSO; (6) The mass volume ratio of the compound of formula I to the first solvent is 1 g: (5-7) mL; (7) Reaction conditions: reaction temperature is 0-10°C; (8) Reaction conditions: The reaction time is 2-10h.

5. The method for preparing a sulfonamide compound 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; And / or, the molar ratio of the compound of formula I to the catalyst is 1:(0.05-0.5).

6. A method for preparing a compound of formula II, characterized in that: The steps include: In the presence of an acid-binding agent and a first solvent, the compound of formula I reacts with a sulfonylating agent to generate a compound of formula II; Wherein, n=0 or 1, and R is H or methyl.

7. The method for preparing the compound of formula II according to claim 6, characterized in that: The reaction conditions of the method for preparing the compound of formula II are as described in claim 4 or 5.

8. A compound of formula II, characterized in that The compound structure is shown below: Wherein, n=0 or 1, and R is H or methyl.

9. The compound of formula II according to claim 8, characterized in that The compound of formula II is any one of the following structures:

10. The compound of formula II according to claim 8, characterized in that The compound of formula II is any one of the following structures:

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