A method for preparing a cyclic sulfamide compound

Abstract

This invention relates to a method for preparing cyclic sulfonamide compounds. Specifically, the method involves: stirring a cyclic imine and a solvent at room temperature, then adding a nitrogen-containing heterocyclic carbene borane catalyst for reaction; after the reaction is complete, extraction is performed, and the residual crude product is purified to obtain the amine compound; the reaction equation is as follows: R in the cyclic imine and the amine compound... 1 Including hydrogen atoms, ester groups, C1-C4 alkyl or aryl groups, X 1 Including oxygen atoms or carbon and sulfur atoms directly connected at both ends, R 2 and X 2 Choose one of the connections, R 2 Including hydrogen atoms, methoxy groups, C1-C4 alkyl or aryl groups, X 2 It is a halogen; the molecular structure of the nitrogen-containing heterocyclic carbene borane is: R in the nitrogen-containing heterocyclic carbene borane 3 Including C1-C4 alkyl or aryl groups. Compared with the prior art, the cyclic imine compounds of the present invention exhibit rapid reduction under mild reaction conditions, a simple and efficient process, and a high overall yield.

Description

Technical Field

[0001] This invention belongs to the field of organic chemistry and pharmaceutical intermediates technology, and relates to a method for preparing cyclic sulfonamide compounds. Background Technology

[0002] Sulfonamides are important structural components of many drug molecules and are of great significance in many fields of chemistry, such as organic synthesis and biochemistry.

[0003] Currently, the main methods for preparing cyclic sulfonamide compounds are as follows:

[0004] (1)

[0005] (2)

[0006] The first method (Bioorg. Med. Chem. 2006, 14, 8386-8395) involved dissolving a cyclic imine in methanol under argon atmosphere, cooling to 0°C, adding 1.1 equivalents of sodium borohydride, and reacting for 30 min, yielding a 43% yield. This reaction was rapid and relatively simple, but the yield was low.

[0007] The second method (Eur. J. Org. Chem. 2019, 38, 6550-6556.) involves adding a cyclic imine and 0.05 mol% B(C6F5)3 under nitrogen atmosphere, followed by adding toluene via syringe and stirring for 5 min. Then, 4 equivalents of methylphenylsilane are added, and the reaction is carried out at 25 °C for 24 h, achieving a 99% yield. This reaction achieves a high yield and is widely applicable to cyclic imines. However, the reaction operation is relatively complex, requires a large equivalent of methylphenylsilane, and has a long reaction time.

[0008] It is evident that Method 2 has a relatively wide applicability and high yield. However, Method 1 is also practical when yield is not a primary concern. Both methods suffer from at least one drawback: long reaction time, complex operation, and low yield.

[0009] Patent CN101665470A discloses a method for stereospecifically synthesizing cyclic sulfonyl imines, sulfinamides, and sulfonamides. Under room temperature conditions, in an organic solvent and initiated by CsF, sulfinyl imines and a benzyne precursor react for 1-15 hours to generate cyclic sulfonyl imines. When the cyclic sulfonyl imine contains a sulfone group, the intramolecular sulfone group can be readily removed under Mg / HOAc / AcONaDMF / H2O conditions to obtain the cyclic sulfonyl imine. The cyclic sulfonyl imine can be readily converted into cyclic sulfinamides under HCl (Dioxane) conditions. The cyclic sulfinamides can be oxidized by mCPBA to obtain cyclic sulfonamides. However, this patent requires the use of a benzyne precursor, the preparation of an HCl (Dioxane) solution, and the reaction at -78°C, making the conditions relatively harsh.

[0010] Patent CN101260085A discloses a method for the catalytic asymmetric hydrogenation synthesis of chiral γ-sulfonamides, using a chiral diphosphorus complex of palladium as the catalytic system. The reaction can be carried out under the following conditions: temperature: 25-75℃; solvent: 2,2,2-trifluoroethanol; pressure: 35-40 atm; time: 10-12 h. The substrate-to-catalyst ratio is 50:1; the metal precursor of the catalyst is palladium trifluoroacetate; the chiral ligand is a chiral diphosphorus ligand; the catalyst is prepared by stirring the palladium metal precursor and the chiral diphosphorus ligand in acetone at room temperature, followed by vacuum concentration to obtain the catalyst. Hydrogenation of cyclic sulfonylimides can yield the corresponding chiral three-substituted γ-sulfonamides. However, this patent requires pressurization and specialized equipment; the system requires the use of noble metals and chiral ligands, increasing costs. Summary of the Invention

[0011] The purpose of this invention is to overcome at least one defect of the prior art and provide a method for preparing cyclic sulfonamide compounds. This invention uses a nitrogen-containing heterocyclic carbene borane as a reducing agent, and under specific solvent conditions, cyclic imine compounds are rapidly reduced. The reaction conditions are mild, the process is simple and efficient, and it is environmentally friendly, non-irritating, and free of allergens, with a high overall yield.

[0012] The objective of this invention can be achieved through the following technical solutions:

[0013] One of the technical solutions of the present invention is to provide a method for preparing cyclic sulfonamide compounds, the method comprising the following steps:

[0014] (1) At room temperature, cyclic imine (compound I) and solvent (Solvent) were added to the reactor and stirred. Then, the catalyst NHC-boranes was added to react, with NHC-boranes serving as a hydrogen source.

[0015] (2) After the reaction is complete, the product is extracted and the remaining crude product is purified to obtain amine compounds (compound II);

[0016] The reaction equation is as follows:

[0017]

[0018] R in the cyclic imines and amine compounds 1 Including hydrogen atoms, ester groups, C1-C4 alkyl or aryl groups, X 1 This includes oxygen atoms or carbon atoms and sulfur atoms directly connected at both ends (i.e., X). 1 (Does not exist), R 2 and X 2 Choose one of the connections, R 2 Including hydrogen atoms, methoxy groups, C1-C4 alkyl or aryl groups, X 2 It is a halogen;

[0019] The molecular structure of the aforementioned nitrogen-containing heterocyclic carbene borane is as follows:

[0020]

[0021] R in the nitrogen-containing heterocyclic carbene borane 3 Including C1 to C4 alkyl or aryl groups.

[0022] Furthermore, R in the cyclic imines and amine compounds 1 Including hydrogen atoms, methyl, ethyl ester groups, phenyl or substituted phenyl groups, R 2 Including hydrogen atoms, methyl, methoxy, or benzyl groups, X 2 Including chlorine or bromine.

[0023] As a preferred technical solution, R in the cyclic imine and amine compounds 1 Including hydrogen atoms or ethyl ester groups, R 2 Including hydrogen atoms, methyl or methoxy groups, X 2 It is bromine.

[0024] Furthermore, R in the nitrogen-containing heterocyclic carbene borane 3 Including methyl, ethyl, propyl or isopropyl.

[0025] As a preferred technical solution, R in the nitrogen-containing heterocyclic carbene borane 3 It is a methyl group.

[0026] Furthermore, the molar ratio of the cyclic imine to the nitrogen-heterocyclic carbene borane is 1:(0.3-1.0), and the ratio of the cyclic imine to the solvent is 1 mol:(1-4 L).

[0027] Furthermore, the reaction time is 0.5-2.0 h.

[0028] Furthermore, the solvent in step (1) is an alcohol.

[0029] Furthermore, the solvent in step (1) includes methanol, ethanol, isopropanol or aminoindanol.

[0030] As a preferred technical solution, the solvent in step (1) is methanol.

[0031] Furthermore, the extractant in step (2) includes ethyl acetate or dichloromethane.

[0032] Further, step (2) specifically involves: after the reaction is complete, the reaction solution is concentrated, extracted, washed with water, dried, and then the remaining crude product is purified by silica gel column chromatography.

[0033] Furthermore, the washing agent is saturated brine, the drying agent is anhydrous sodium sulfate or anhydrous magnesium sulfate, and the silica gel column chromatography eluent is a mixture of ethyl acetate and petroleum ether, wherein the volume ratio of ethyl acetate to petroleum ether is 1:(2-4).

[0034] Compared with the prior art, the present invention has the following advantages:

[0035] This invention employs a method for preparing sulfonamide compounds by reducing imines. It uses a nitrogen-containing heterocyclic carbene borane as a hydrogen source to reduce imines in an alcohol solvent. The reaction conditions are mild, the reaction is rapid, the yield is high, it does not require complex reagents, the amount of nitrogen-containing heterocyclic carbene borane used is small, it is green and economical, conducive to industrial production, and can create significant economic benefits. Detailed Implementation

[0036] The present invention will now be described in detail with reference to specific embodiments. These embodiments are based on the technical solution of the present invention and provide detailed implementation methods and specific operating procedures. However, the scope of protection of the present invention is not limited to the following embodiments.

[0037] Unless otherwise specified, the equipment used in the following embodiments is conventional equipment in the art; unless otherwise specified, the reagents used are commercially available products or prepared by conventional methods in the art. In the following embodiments, unless otherwise described in detail, conventional experimental methods in the art can be used.

[0038] The solvents, extractants, washing agents and desiccants used in the examples were all purchased from the exploration platform. The cyclic imine was prepared according to the literature method (Org. Lett. 2016, 18(4): 692-695), and the nitrogen heterocyclic carbene borane was prepared according to the literature method (J. Am. Chem. Soc. 2010, 132(7): 2350-2358).

[0039] Example 1:

[0040] A cyclic sulfonamide compound and its preparation method are described below, with the reaction equation as follows:

[0041]

[0042] The specific steps are as follows:

[0043] At room temperature, cyclic imine I-a (45.75 mg, 0.25 mmol) was dissolved in anhydrous methanol (1.0 mL), and R was added with stirring. 3 The methyl-substituted nitrogen-containing heterocyclic carbene borane catalyst (9.625 mg, 0.0875 mmol) was stirred at room temperature for 30 min. The reaction solution was concentrated by rotary evaporation, extracted with dichloromethane (10 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, and the crude product was purified by silica gel column chromatography to obtain a white solid product, amine compound II-a (42.5 mg, yield 92%).

[0044] The NMR characterization data are as follows:

[0045] 1 H NMR (400MHz, Chloroform-d) δ7.29(t,J=7.9Hz,1H),7.20–7.08(m,2H),6.94(d,J=8.3Hz,1H),4.91(s,1H),4.62(s,2H). 13 C NMR (101MHz, Chloroform-d) δ151.60,129.23,126.58,125.26,118.55,118.21,46.36.

[0046] Examples 2 to 4:

[0047] A method for preparing a cyclic sulfonamide compound is basically the same as in Example 1, except that different R is used. 3 The reaction results of the nitrogen-containing heterocyclic carbene borane catalyst are shown in Table 1.

[0048] Table 1. Reaction results of I-a with different catalysts

[0049] Example <![CDATA[Substituent R 3 > <![CDATA[Yield a (%)]]> 2 Ethyl 85 3 propyl 80 4 Isopropyl 75

[0050] In Table 1, the superscript 'a' indicates the separation yield.

[0051] Examples 5 to 7:

[0052] A method for preparing a cyclic sulfonamide compound is basically the same as that in Example 1, except that a different solvent is used. The reaction results are shown in Table 2.

[0053] Table 2 shows the reaction results of I-a in different solvents.

[0054] Example solvent <![CDATA[Yield a (%)]]> 5 ethanol 86 6 Isopropanol 80 7 aminoindole 76

[0055] In Table 2, the superscript 'a' indicates the separation yield.

[0056] Examples 8 to 10:

[0057] A method for preparing a cyclic sulfonamide compound is basically the same as that in Example 1, except that different amounts of nitrogen-containing heterocyclic carbene borane catalysts are used. The reaction results are shown in Table 3.

[0058] Table 3 shows the reaction results of I-a with different amounts of catalyst.

[0059] Example Amount of substance (mmol) <![CDATA[Yield a (%)]]> 8 0.125 93 9 0.25 93 10 0.075 85

[0060] In Table 3, the superscript 'a' indicates the separation yield.

[0061] As shown in Tables 1 to 3, the optimal reaction conditions for a 0.25 mmol Ia reaction were 0.0875 mmol of methyl-substituted nitrogen-heterocyclic carbene borane catalyst and 1.0 mL of methanol solvent (Example 1), under which the product yield reached 92%. Although Examples 8 and 9 achieved slightly higher yields, the amount of nitrogen-heterocyclic carbene borane used was greater (incomplete reaction), and Example 1 represented the optimal reaction conditions.

[0062] Example 11:

[0063] A cyclic sulfonamide compound and its preparation method are basically the same as in Example 1, except that a different cyclic imine I-b (53.80 mg, 0.25 mmol) is used. The reaction equation is as follows:

[0064]

[0065] A white solid product, amine compound II-b (48.9 mg, 91%), was obtained.

[0066] The NMR characterization data are as follows:

[0067] 1 H NMR (400MHz, Chloroform-d) δ7.10(t,J=8.0Hz,1H),6.89(d,J=8.1Hz,1H),6.69(d,J=7.8Hz,1H),4.80–4.71(m,1H),4.66(d,J=7.9Hz,2H),3.87(s,3H). 13C NMR (101MHz, Chloroform-d) δ144.03,137.27,132.78,130.10,125.01,120.99,45.58,21.66.

[0068] Example 12:

[0069] A cyclic sulfonamide compound and its preparation method are basically the same as in Example 1, except that a different cyclic imine I-c (49.70 mg, 0.25 mmol) is used. The reaction equation is as follows:

[0070]

[0071] A white solid product, amine compound II-c (45.8 mg, 92%), was obtained.

[0072] The NMR characterization data are as follows:

[0073] 1 H NMR (400MHz, Chloroform-d) δ7.04–6.90(m,2H),6.80(s,1H),4.75(s,1H),4.61(s,2H),2.34(s,3H). 13 C NMR (101MHz, Chloroform-d) δ151.55,139.80,126.14,126.06,118.89,115.04,46.31,21.00.

[0074] Example 13:

[0075] A cyclic sulfonamide compound and its preparation method are basically the same as in Example 1, except that a different cyclic imine I-d (53.80 mg, 0.25 mmol) is used. The reaction equation is as follows:

[0076]

[0077] A white solid product, amine compound II-d (49.7 mg, 92.5%), was obtained.

[0078] The NMR characterization data are as follows:

[0079] 1 H NMR (400MHz, Chloroform-d) δ7.01(d,J=8.6Hz,1H),6.73(dd,J=8.6,2.5Hz,1H),6.51(d,J=2.5Hz,1H),4.85(s,1H),4.58(s,2H),3.78(s,3H). 13C NMR (101MHz, Chloroform-d) δ160.27,152.43,127.06,109.93,103.57,46.03.

[0080] Example 14:

[0081] A cyclic sulfonamide compound and its preparation method are basically the same as in Example 1, except that a different cyclic imine I-e (49.70 mg, 0.25 mmol) is used. The reaction equation is as follows:

[0082]

[0083] A white solid product, amine compound II-e (45.8 mg, 92%), was obtained.

[0084] The NMR characterization data are as follows:

[0085] 1 H NMR (400MHz, Chloroform-d) δ7.09(dd,J=8.4,2.1Hz,1H),6.92(s,1H),6.87(d,J=8.4Hz,1H),4.81(t,J=8.2Hz,1H),4.59(d,J=7.9Hz,2H),2.32(s,3H). 13 C NMR (101MHz, Chloroform-d) δ149.62,135.04,129.84,126.66,118.36,117.73,46.48,20.64.

[0086] Example 15:

[0087] A cyclic sulfonamide compound and its preparation method are basically the same as in Example 1, except that a different cyclic imine I-f (53.80 mg, 0.25 mmol) is used. The reaction equation is as follows:

[0088]

[0089] A white solid product, amine compound II-f (49.5 mg, 92%), was obtained.

[0090] The NMR characterization data are as follows:

[0091] 1H NMR(400MHz,Chloroform-d)δ6.91(d,J=9.1Hz,1H),6.82(dd,J=9.1,3.0Hz,1H), 6.61(d,J=2.9Hz,1H), 4.85(d,J=7.8Hz,1H), 4.59(d,J=6.0Hz,2H), 3.78(s,3H). 13 CNMR(101MHz,Chloroform-d)δ156.68,145.44,119.54,118.94,114.89,110.95,55.77,46.58.

[0092] Example 16:

[0093] A cyclic sulfonamide compound and its preparation method are basically the same as in Example 1, except that a different cyclic imine I-g (66.00 mg, 0.25 mmol) is used. The reaction equation is as follows:

[0094]

[0095] A white solid product, amine compound II-g (60.1 mg, 93%), was obtained.

[0096] The NMR characterization data are as follows:

[0097] 1 H NMR (400MHz, DMSO-d6) δ8.63(d,J=6.5Hz,1H),7.60–7.51(m,2H),7.08(d,J=8.7Hz,1H),4.59(d,J=5.2Hz,2H). 13 C NMR (101MHz, DMSO-d6) δ151.02,132.18,130.32,121.89,120.61,117.00,45.26.

[0098] Example 17:

[0099] A cyclic sulfonamide compound and its preparation method are basically the same as in Example 1, except that a different cyclic imine I-h (63.57 mg, 0.25 mmol) is used. The reaction equation is as follows:

[0100]

[0101] A white solid product, amine compound II-h (58.5 mg, 91%), was obtained.

[0102] The NMR characterization data are as follows:

[0103] 1 H NMR(400MHz,Chloroform-d)δ7.50(d,J=7.9Hz,1H),7.37(t,J=7.8Hz,1H),7.21(t,J=7.6Hz,1H),7.05(d,J= 8.3Hz,1H),5.55(d,J=8.5Hz,1H),5.46(d,J=8.3Hz,1H),4.41(q,J=7.1Hz,2H),1.40(td,J=7.2,1.5Hz,3H). 13 C NMR (101MHz, Chloroform-d) δ167.40,151.23,130.46,126.34,125.63,119.56,116.20,63.68,58.73,14.08.

[0104] Example 18:

[0105] A cyclic sulfonamide compound and its preparation method are basically the same as in Example 1, except that a different cyclic imine I-i (83.59 mg, 0.5 mmol) is used, the amount of substance is doubled, and the amount of reagents used in other reactions is also twice that in Example 1. The reaction equation is as follows:

[0106]

[0107] A white solid product, amine compound II-i (78.68 mg, 93%), was obtained.

[0108] The NMR characterization data are as follows:

[0109] 1 H NMR (400MHz, Chloroform-d) δ7.74(d,J=7.8Hz,1H),7.58(t,J=7.5Hz,1H),7.48(t,J=7.6Hz,1H),7.36(d,J=7.7Hz,1H),5.05(s,1H),4.50(s,2H). 13 C NMR(101MHz,Chloroform-d)δ136.91,135.49,132.98,129.11,124.81,121.24,45.69.

[0110] Example 19:

[0111] A cyclic sulfonamide compound and its preparation method are basically the same as in Example 18, except that a different cyclic imine I-j (83.59 mg, 0.5 mmol) is used. The reaction equation is as follows:

[0112]

[0113] A white solid product, amine compound II-j (84.3 mg, 92%), was obtained.

[0114] The NMR characterization data are as follows:

[0115] 1 H NMR (400MHz, Chloroform-d) δ7.74(d,J=8.1Hz,1H),7.39(d,J=9.4Hz,1H),5.24(s,1H),4.56(s,2H),2.54(s,3H). 13 C NMR (101MHz, Chloroform-d) δ144.03,137.27,132.78,130.10,125.01,120.99,45.58,21.66.

[0116] The above description of the embodiments is provided to enable those skilled in the art to understand and use the invention. It will be apparent to those skilled in the art that various modifications can be made to these embodiments, and the general principles described herein can be applied to other embodiments without inventive effort. Therefore, the present invention is not limited to the above embodiments, and any improvements and modifications made by those skilled in the art based on the disclosure of the present invention without departing from the scope of the invention should be within the protection scope of the present invention.

Claims

1. A method for preparing a cyclic sulfonamide compound, characterized in that, The method includes the following steps: (1) At room temperature, the cyclic imine and solvent are stirred, and then the catalyst nitrogen-containing heterocyclic carbene borane is added to react; (2) After the reaction is complete, the product is extracted, and the remaining crude product is purified to obtain amine compounds; The equation for the reaction is as follows: ； R in the cyclic imines and amine compounds 1 It is a hydrogen atom, an ester group, a C1-C4 alkyl or aryl group, X 1 For oxygen atoms or carbon and sulfur atoms directly connected at both ends, R 2 and X 2 Choose one of the connections, R 2 It is a hydrogen atom, a methoxy group, a C1-C4 alkyl group or an aryl group, X 2 It is a halogen; The molecular structural formula of the nitrogen-containing heterocyclic carbene borane is: ； R in the nitrogen-containing heterocyclic carbene borane 3 It is an alkyl group from C1 to C4; The molar ratio of the cyclic imine to the nitrogen-containing carbene borane is 1:(0.3-1.0), and the molar ratio of the cyclic imine to the solvent is 1 mol:(1-4 L).

2. The method for preparing a cyclic sulfonamide compound according to claim 1, characterized in that, R in the cyclic imines and amine compounds 1 It is methyl, ethyl ester or phenyl, R 2 It is methyl, methoxy, or benzyl, X 2 It is chlorine or bromine.

3. The method for preparing a cyclic sulfonamide compound according to claim 1, characterized in that, R in the nitrogen-containing heterocyclic carbene borane 3 It can be methyl, ethyl, propyl or isopropyl.

4. The method for preparing a cyclic sulfonamide compound according to claim 1, characterized in that, The reaction time is 0.5-2.0 h.

5. The method for preparing a cyclic sulfonamide compound according to claim 1, characterized in that, The solvent in step (1) is an alcohol.

6. The method for preparing a cyclic sulfonamide compound according to claim 5, characterized in that, In step (1), the solvent is methanol, ethanol, isopropanol or aminoindanol.

7. The method for preparing a cyclic sulfonamide compound according to claim 1, characterized in that, In step (2), the extractant is ethyl acetate or dichloromethane.

8. The method for preparing a cyclic sulfonamide compound according to claim 1, characterized in that, Step (2) specifically involves: after the reaction is complete, the reaction solution is concentrated, extracted, washed with water, dried, and then the remaining crude product is purified by silica gel column chromatography.

9. The method for preparing a cyclic sulfonamide compound according to claim 8, characterized in that, The washing agent is saturated saline solution, the drying agent is anhydrous sodium sulfate or anhydrous magnesium sulfate, and the eluent for silica gel column chromatography is a mixture of ethyl acetate and petroleum ether with a volume ratio of 1:(2-4).

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