A process for the preparation of cyclohexyl sulfamides

Abstract

The application discloses a preparation method of cyclohexyl sulfonamide and belongs to the technical field of pharmaceutical chemical synthesis. The method comprises the following steps: bromocyclohexane and potassium thioacetate are added into a solvent, and a thioesterification reaction is carried out under stirring and heating in nitrogen protection, then cooling and diluting with water, and then extracting with ethyl acetate, and drying and concentrating to obtain cyclohexyl thioacetate; the cyclohexyl thioacetate, water and KCl are added into a reactor, and Oxone is added in batches, and the mixture is uniformly stirred to carry out an oxidation reaction, and then extracted with dichloromethane, and then dried and distilled to obtain cyclohexyl sulfonyl chloride; the cyclohexyl sulfonyl chloride is subjected to an amination reaction in an ammonia / THF system, and then recrystallized in a solvent to obtain cyclohexyl sulfonamide. The process has the advantages of easy availability of starting materials, mild conditions, high selectivity, and product HPLC purity of greater than or equal to 99.5%, and is suitable for laboratory research and development. The cyclohexyl sulfonamide prepared by the method can be used as a key intermediate of KRAS G12C inhibitor, and is used for laboratory synthesis and structure-activity relationship research of an antitumor targeted drug.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemical synthesis technology, and specifically relates to a method for preparing cyclohexylsulfonamide. Background Technology

[0002] KRAS G12C mutation is a significant driving factor in malignant tumors such as non-small cell lung cancer and colorectal cancer, making covalent inhibitors targeting KRAS G12C a key focus in anti-tumor drug development. Cyclohexylsulfonamide is a crucial structural unit in the molecular construction of KRAS G12C inhibitors, providing hydrophobic binding, hydrogen bonding, and metabolic stability, directly influencing the inhibitor's activity, selectivity, and drug-likeness.

[0003] Currently, most synthetic routes for cyclohexylsulfonamides use cyclohexylsulfonyl chloride as a raw material for direct ammonolysis. However, this route has the following drawbacks: 1) Cyclohexylsulfonyl chloride is easily hydrolyzed and has poor stability, resulting in poor batch reproducibility in laboratory small-scale trials; 2) The source of raw materials is limited and the price is high, making it unsuitable for the early stages of drug development; 3) Traditional oxidation / ammoniation conditions are harsh, resulting in many byproducts and making it difficult to obtain high-purity intermediates with HPLC ≥ 99.5%; 4) The route has poor compatibility and cannot be matched with the modular laboratory synthesis of KRAS G12C inhibitors.

[0004] Using bromocyclohexane as a cheap and readily available starting material, the synthetic route via thioester → sulfonyl chloride → sulfonamide is stable in terms of raw materials, controllable in terms of route, and more suitable for laboratory research. However, the existing process still has problems such as poor oxidation selectivity, low yield of thioester, easy decomposition of sulfonyl chloride, and insufficient purity of amination. Furthermore, the lack of mild, efficient, and laboratory-friendly oxidants further limits the application of this route in drug development.

[0005] Therefore, developing a cyclohexylsulfonamide synthesis method that uses readily available starting materials, mild conditions, high selectivity, good reproducibility, and purity sufficient for drug development, and employs commonly used laboratory oxidants, is of great value for promoting the laboratory synthesis and structure-activity relationship studies of KRAS G12C inhibitors. Summary of the Invention

[0006] To overcome the above-mentioned shortcomings, this invention provides a method for preparing cyclohexylsulfonamide. Using bromocyclohexane as the starting material, the method involves thioesterification, oxidation, and amination reactions, with Oxone as the oxidant, to obtain cyclohexylsulfonamide. This invention solves the problems of unstable raw materials, poor oxidation selectivity, low product purity, and poor batch-to-batch reproducibility in existing routes, meeting the laboratory research and development needs for high-purity intermediates for KRAS G12C inhibitors.

[0007] To achieve the above objectives, the present invention is implemented using the following technical solution:

[0008] A method for preparing cyclohexylsulfonamide, characterized by comprising the following steps: adding bromocyclohexane and potassium thioacetate to a solvent, stirring and heating under nitrogen protection to carry out a thioesterification reaction, then cooling and diluting with water, extracting with ethyl acetate, drying and concentrating to obtain cyclohexylthioacetate; adding cyclohexylthioacetate, water and KCl to a reactor, adding Oxone in batches, stirring evenly to carry out an oxidation reaction, extracting with dichloromethane, drying and distilling to obtain cyclohexylsulfonyl chloride; carrying out an ammonification reaction of cyclohexylsulfonyl chloride in an ammonia / THF system, recrystallizing in a solvent to obtain cyclohexylsulfonamide.

[0009] Furthermore, the molar ratio of potassium thioacetate to bromocyclohexane is 1.1-1.5:1.

[0010] Furthermore, the heating temperature for the thioesterification reaction is 30-60℃, and the reaction time is 6-10h.

[0011] Furthermore, the solvent in the heating reaction of the thioesterification reaction is one or more of DMF, DMAc, NMP, and DMSO.

[0012] Furthermore, the molar ratio of Oxone to cyclohexylthioacetate is 1.5-4.0:1.

[0013] Furthermore, the molar ratio of KCl to cyclohexylthioacetate is 0.5:1-2.0:1.

[0014] Furthermore, the oxidation reaction is carried out at a temperature of 0-40°C for 7-9 hours.

[0015] Furthermore, the molar ratio of ammonia to cyclohexylsulfonyl chloride is 2.5-4:1, and the mass ratio of THF to cyclohexylsulfonyl chloride is 5-10:1.

[0016] Furthermore, the solvent for recrystallization is isopropanol / water, isopropanol / n-heptane, acetone / water, methanol / water, or ethanol / water, and the volume-to-mass ratio of the recrystallization solvent to cyclohexylsulfonyl chloride is 5-10:1 mL / g.

[0017] Furthermore, the ammonolysis temperature of the ammoniation reaction is 0-25℃, and the ammoniation reaction time is 4-9h.

[0018] Beneficial effects

[0019] 1) Inexpensive and stable starting materials: Using bromocyclohexane as the starting material, it is widely available, easy to obtain in the laboratory, and inexpensive, which solves the problem of expensive and unstable starting materials in the traditional route.

[0020] 2) Oxidant suitable for laboratory research and development: Oxone (potassium persulfate compound salt) is used as the oxidant. It is mild, efficient and highly selective, and does not easily produce excessive oxidation byproducts. Oxone is also easy to obtain and safe to operate, and does not require special reaction conditions, which meets the needs of laboratory small-scale tests.

[0021] 3) Modular and controllable route: The three-step reaction of thioester-sulfonyl chloride-sulfonamide is smoothly connected, and the reaction conditions of each step are mild and easy to control, which is suitable for small-scale synthesis and batch scale-up in drug development, with good reproducibility.

[0022] 4) High product purity: Strong oxidation selectivity and mild amination conditions effectively inhibit the formation of by-products. After purification, the product has an HPLC purity of ≥99.5% and a single impurity of <0.1%, which fully meets the purity requirements of KRAS G12C inhibitor intermediates.

[0023] 5) Lab-friendly: Simple to operate, no special equipment required, all reagents are commonly used in laboratories, reaction conditions are mild and safe, suitable for the high-throughput and rapid synthesis needs of medicinal chemistry laboratories. Attached Figure Description

[0024] Figure 1 This is the synthetic route diagram of the present invention; wherein Formula 1 is bromocyclohexane, Formula 2 is thiocarboxylic acid cyclohexyl ester, Formula 3 is cyclohexylsulfonyl chloride, and Formula 4 is cyclohexylsulfonamide. Detailed Implementation

[0025] The present invention will be further described below with reference to the accompanying drawings. The following embodiments are only used to more clearly illustrate the technical solution of the present invention, and should not be used to limit the scope of protection of the present invention.

[0026] One synthetic route is as follows Figure 1 :

[0027] In this formula, Formula 1 is bromocyclohexane, Formula 2 is cyclohexylthioacetate, Formula 3 is cyclohexylsulfonyl chloride, and Formula 4 is cyclohexylsulfonamide.

[0028] In practical applications, those skilled in the art can use the cyclohexylsulfonamide prepared by the above preparation method as a key intermediate for KRAS G12C inhibitors, for laboratory synthesis and structure-activity relationship studies of antitumor targeted drugs.

[0029] Example 1

[0030] (1) Synthesis of cyclohexylthioacetic acid ester by thioesterification

[0031] 2.10 kg of bromocyclohexane, 1.80 kg of potassium thioacetate, and 12.60 kg of DMF were added to a dry three-necked flask. The mixture was stirred and heated to 45 °C, and reacted for 6 h. The reaction was monitored by TLC until completion. After cooling, the mixture was diluted with water, extracted with ethyl acetate, dried, and concentrated to give 1.83 kg of cyclohexyl thioacetate, with a yield of 90%.

[0032] (2) Oxidation to prepare cyclohexylsulfonyl chloride

[0033] Take 1.00 kg of the above product, add 10 kg of water and 471 g of KCl, and add 7.8 kg of Oxone in portions at 20°C. Stir the reaction for 8 h. Extract with dichloromethane, dry, and distill to obtain 1.07 kg of cyclohexylsulfonyl chloride, with a yield of 93%.

[0034] (3) Preparation of cyclohexylsulfonamide by amination

[0035] Dissolve 1.00 kg of sulfonyl chloride in 6.6 kg of THF, pass 279 g of ammonia gas at 0°C, and stir for 4 h. Concentrate to remove the solvent, add 10 L of a mixed solution of isopropanol / n-heptane, wherein the volume ratio of isopropanol to n-heptane is 0.5:1, and recrystallize to obtain 804 g of white solid cyclohexylsulfonamide, with a yield of 90%.

[0036] Experimental results:

[0037] Product appearance: White needle-like solid;

[0038] Overall yield: 75% (based on bromocyclohexane);

[0039] HPLC purity: 99.81%;

[0040] Single impurity content: <0.1%.

[0041] Example 2-3

[0042] In Examples 2 and 3, the molar ratios of potassium thioacetate and bromocyclohexane in the thioesterification reaction were 1.1:1 and 1.5:1, respectively, and the other parameters were the same as in Example 1.

[0043] The experimental results are as follows: the total yields of Examples 2 and 3 were 48.2% and 72.8%, respectively, and the HPLC purities were 99.89% and 99.32%, respectively.

[0044] Based on the results of Example 1, the optimal molar ratio of potassium thioacetate to bromocyclohexane in the thioesterification reaction is 1.2:1.

[0045] Examples 4-5

[0046] The heating temperatures for the thioesterification reactions in Examples 4 and 5 were 30-35°C and 55-60°C, respectively, with the remaining parameters being the same as in Example 1.

[0047] The experimental results are as follows: the overall yields of Examples 4 and 5 were 58.5% and 70.3%, respectively, and the HPLC purities were 99.54% and 99.58%, respectively.

[0048] Based on the results of Example 1, the optimal heating temperature for the thioesterification reaction is 40-45℃.

[0049] Examples 6-8

[0050] The solvents used in the thioesterification reactions of Examples 6, 7, and 8 were DMAc, NMP, and DMSO, respectively, and the other parameters were the same as in Example 1.

[0051] The experimental results are as follows: the total yields of Examples 6, 7 and 8 were 69.5%, 54.3% and 62.1%, respectively, and the HPLC purities were 99.65%, 99.78% and 99.88%, respectively.

[0052] Based on the results of Example 1, the optimal reaction solvent for step 1 is DMF.

[0053] Examples 9-10

[0054] In the oxidation reactions of Examples 9 and 10, the molar ratios of Oxone to cyclohexylthioacetate were 1.5:1 and 4.0:1, respectively, and the remaining parameters were the same as in Example 1.

[0055] The experimental results are as follows: the overall yields of Examples 9 and 10 were 62.7% and 70.6%, respectively, and the HPLC purities were 99.68% and 99.50%, respectively.

[0056] Based on the results of Example 1, the optimal molar ratio of oxidant Oxone to cyclohexylthioacetate in the oxidation reaction is 2.0:1.

[0057] Examples 11-12

[0058] In the oxidation reactions of Examples 11 and 12, the molar ratios of KCl to cyclohexylthioacetate were 0.5:1 and 2.0:1, respectively, and the other parameters were the same as in Example 1.

[0059] The experimental results are as follows: the overall yields of Examples 11 and 12 were 45.6% and 71.2%, respectively, and the HPLC purities were 99.05% and 99.16%, respectively.

[0060] Based on the results of Example 1, the optimal molar ratio of the oxidation reaction auxiliary agent KCl to cyclohexylthioacetate is 1.0:1.

[0061] Examples 13-14

[0062] In Examples 13 and 14, the reaction temperatures were 0-10℃ and 30-40℃, respectively, and the other parameters were the same as in Example 1.

[0063] The experimental results are as follows: the overall yields of Examples 13 and 14 were 65.7% and 68.1%, respectively, and the HPLC purities were 99.85% and 99.21%, respectively.

[0064] Based on the results of Example 1, the optimal reaction temperature for the oxidation reaction is 15-25℃.

[0065] Examples 15-16

[0066] In Examples 15 and 16, the molar ratios of ammonia to cyclohexylsulfonyl chloride in the amination reactions were 2.5:1 and 4.0:1, respectively, with the remaining parameters being the same as in Example 1.

[0067] The experimental results are as follows: the overall yields of Examples 15 and 16 were 65.1% and 73.2%, respectively, and the HPLC purities were 99.61% and 99.73%, respectively.

[0068] Based on the results of Example 1, the optimal molar ratio of ammonia to cyclohexylsulfonyl chloride for the ammoniation reaction is 3.0:1.

[0069] Examples 17-20

[0070] The recrystallization solvents for the amination reactions in Examples 17, 18, 19, and 20 were isopropanol / water, acetone / water, methanol / water, and ethanol / water, respectively, and the other parameters were the same as in Example 1.

[0071] The experimental results are as follows: the total yields of Examples 17, 18, 19 and 20 were 62.3%, 46.3%, 65.5% and 68.1%, respectively, and the HPLC purities were 97.82%, 93.65%, 99.43% and 99.36%, respectively.

[0072] Based on the results of Example 1, the optimal solvent for recrystallization of the amination reaction is isopropanol / n-heptane.

Claims

1. A method for preparing cyclohexylsulfonamide, characterized in that, Includes the following steps: Bromocyclohexane and potassium thioacetate were added to a solvent and stirred and heated under nitrogen protection to carry out a thioesterification reaction. The mixture was then cooled, diluted with water, extracted with ethyl acetate, dried, and concentrated to obtain cyclohexyl thioacetate. Cyclohexyl thioacetate, water, and KCl were added to a reactor, and Oxone was added in batches. The mixture was stirred until homogeneous to carry out an oxidation reaction. The mixture was extracted with dichloromethane, dried, and distilled to obtain cyclohexylsulfonyl chloride. Cyclohexylsulfonyl chloride was subjected to an ammoniation reaction in an ammonia / THF system, and recrystallized in a solvent to obtain cyclohexylsulfonamide.

2. The method for preparing cyclohexylsulfonamide according to claim 1, characterized in that, The molar ratio of potassium thioacetate to bromocyclohexane is 1.1-1.5:

1.

3. The method for preparing cyclohexylsulfonamide according to claim 1, characterized in that, The heating temperature for the thioesterification reaction is 30-60℃, and the reaction time is 6-10h.

4. The method for preparing cyclohexylsulfonamide according to claim 1, characterized in that, The solvent used in the heated thioesterification reaction is one or more of DMF, DMAc, NMP, and DMSO.

5. The method for preparing cyclohexylsulfonamide according to claim 1, characterized in that, The molar ratio of Oxone to cyclohexylthioacetate is 1.5-4.0:

1.

6. The method for preparing cyclohexylsulfonamide according to claim 1, characterized in that, The molar ratio of KCl to cyclohexylthioacetate is 0.5:1-2.0:

1.

7. The method for preparing cyclohexylsulfonamide according to claim 1, characterized in that, The oxidation reaction is carried out at a temperature of 0-40℃ for 7-9 hours.

8. The method for preparing cyclohexylsulfonamide according to claim 1, characterized in that, The molar ratio of ammonia to cyclohexylsulfonyl chloride is 2.5-4:1, and the mass ratio of THF to cyclohexylsulfonyl chloride is 5-10:

1.

9. The method for preparing cyclohexylsulfonamide according to claim 1, characterized in that, The solvent for recrystallization is isopropanol / water, isopropanol / n-heptane, acetone / water, methanol / water, or ethanol / water, and the volume-to-mass ratio of the recrystallization solvent to cyclohexylsulfonyl chloride is 5-10:1 mL / g.

10. The method for preparing cyclohexylsulfonamide according to claim 1, characterized in that, The ammoniation reaction is carried out at a temperature of 0-25℃ and for a time of 4-9 hours.

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