Bromination of a cyclopropanol compound

Abstract

The application provides a bromination reaction of a cyclopropanol compound and belongs to the field of organic synthesis. The bromination reaction of the cyclopropanol compound provided by the application can not only evade the use of high-risk chemical reagent bromine under the premise of ensuring high reaction yield, but also can make the whole reaction process under more mild conditions, so that the reaction can be more widely applied in industry.

Description

Technical Field

[0001] This invention relates to the field of organic chemistry, and more specifically to the bromination reaction of cyclopropanol compounds. Background Technology

[0002] PCT patent WO2022076626A1 discloses a regulator of transmembrane conductivity modulators in cystic fibrosis, and bromocyclopropane compounds are an important intermediate of one such compound.

[0003] In the prior art, such as PCT patent WO2022076626A1 and the paper A new general approach tobicyclopropylidenes (Journal of Organic Chemistry, 1993, 58(2):502-505), organophosphorus halides prepared by reacting triphenylphosphine with elemental bromine are commonly used to achieve the conversion of cyclopropanol compounds into brominated cyclopropane compounds.

[0004] However, on the one hand, bromine is not only highly toxic and corrosive, but it is also considered a "high environmental risk" product, which causes a certain degree of pollution to the environment. As a result, the industrial application of bromine is extremely limited and subject to strict regulation.

[0005] On the other hand, cyclopropyl groups are relatively unstable. Even at room temperature, bromine will undergo a ring-opening reaction with cyclopropyl groups. Therefore, in the prior art, cyclopropyl alcohol compounds and organophosphorus halides made from triphenylphosphine and elemental bromine must be carried out at a temperature of -15°C or lower. Summary of the Invention

[0006] The present invention was made to solve the above-mentioned problems, and aims to provide a low-hazard and environmentally friendly bromination reaction of cyclopropanol compounds that can be carried out at a milder temperature.

[0007] This invention provides a bromination reaction of cyclopropanol compounds, characterized by the following reaction formula:

[0008]

[0009] In the above formula, R is H, a C1-C6 alkyl group or a C3-C6 cycloalkyl group.

[0010] Includes the following steps:

[0011] Step 1: Prepare organophosphorus halides;

[0012] Step 2: Compound 1 and the acid-binding agent are added to the organophosphorus halide to carry out the reaction;

[0013] Step 3, post-processing, distillation, yielding compound 2.

[0014] The preparation method of organophosphorus halides includes the following steps:

[0015] Triphenylphosphine, a bromine source, and an organic solvent are mixed and reacted to obtain the product.

[0016] The bromine source is pyridinium tribromide.

[0017] In the bromination reaction of cyclopropanol compounds provided by the present invention, the following feature may also be present: wherein R is cyclopropyl.

[0018] In the bromination reaction of cyclopropanol compounds provided by the present invention, the following feature may also be present: wherein the acid-binding agent is selected from any one or more of pyridine, triethylamine or tert-butylmethylamine.

[0019] In the bromination reaction of cyclopropanol compounds provided by the present invention, the organic solvent is selected from any one of hexamethylphosphoric triamine, N,N-dimethylamide, dichloromethane or trichloromethane.

[0020] In the bromination reaction of cyclopropanol compounds provided by the present invention, the following feature may also be present: the molar ratio of compound 1 to the acid-binding agent is 1:(1-1.2). Preferably, the molar ratio of compound 1 to the acid-binding agent is 1:1.05.

[0021] In the bromination reaction of the cyclopropanol compounds provided by this invention, the following feature is also included: the molar ratio of compound 1 to the organophosphorus halide is 1:(1-1.2). Preferably, the molar ratio of compound 1 to the organophosphorus halide is 1:1.05.

[0022] The bromination reaction of cyclopropanol compounds provided by this invention may also have the following characteristic: in the method for preparing organophosphorus halides, the molar ratio of triphenylphosphine to the bromine source is 1:(0.8-1.2). Preferably, the molar ratio of triphenylphosphine to the bromine source is 1:1.

[0023] The bromination reaction of cyclopropanol compounds provided by this invention may also have the following characteristic: in the method for preparing organophosphorus halides, the reaction temperature is 0-40°C. Preferably, the reaction temperature is 0-5°C.

[0024] The bromination reaction of cyclopropanol compounds provided by the present invention may also have the following characteristics: in step 2, compound 1 and an acid-binding agent are added to the organophosphorus halide at 0-40°C.

[0025] The bromination reaction of cyclopropanol compounds provided by the present invention may also have the following characteristics: wherein, in step 2, the reaction temperature is 0-40℃.

[0026] The bromination reaction of cyclopropanol compounds provided by this invention may also have the following characteristic: in the method for preparing organophosphorus halides, the mass-to-volume ratio of triphenylphosphine to solvent is (1.5-5) g:10 mL. Preferably, the mass-to-volume ratio of triphenylphosphine to solvent is (2-3) g:10 mL.

[0027] In the bromination reaction of cyclopropanol compounds provided by the present invention, the following features may also be included: the post-processing in step 3 includes the following steps: filtering the reaction solution obtained in step 2, taking the filtrate, concentrating it, and adding a solvent with a boiling point higher than that of the target product.

[0028] The bromination reaction of cyclopropanol compounds provided by this invention may also have the following characteristics, including the following steps:

[0029] Step 1: At 0-5℃, triphenylphosphine, bromine source and organic solvent are mixed to obtain an organophosphorus halide solution;

[0030] Step 2: Mix compound 1 with an acid-binding agent to obtain a raw material solution. At 0-5°C, mix the raw material solution with an organophosphorus halide solution and react.

[0031] Step 3: Post-processing, distillation, to obtain compound 2.

[0032] The role and effect of invention

[0033] The bromination reaction of cyclopropanol compounds according to the present invention uses an organophosphorus halide prepared from pyridinium tribromide as the brominating agent. Therefore, the present invention can not only avoid the use of high-risk chemical reagent bromine while ensuring high reaction yield, but also allow the reaction to be carried out under milder conditions, thereby enabling the reaction to be more widely used in industry. Detailed Implementation

[0034] To make the technical means, creative features, objectives and effects of this invention easy to understand, the invention will be specifically described below in conjunction with embodiments.

[0035] In the following examples, unless otherwise stated, all compounds are commercially available products.

[0036] <Example 1>

[0037] Preparation of compound 2a

[0038] This embodiment provides a method for preparing compound 2a, and the reaction formula is as follows:

[0039]

[0040] Includes the following steps:

[0041] Step 1: Add 10.5 L of dichloromethane to the reaction vessel, cool to 0-5 °C, and then add 3593 g of pyridinium tribromide (11.23 mol, 1.05 eq) and 2947 g of triphenylphosphine (11.23 mol, 1.05 eq) sequentially. Stir at 0-5 °C until dissolved to obtain an organophosphorus halide solution.

[0042] Step 2: Mix 1050g of compound 1a (10.69mol, 1.0eq) and 889g of pyridine (11.23mol, 1.05eq) to obtain a raw material solution. Add the raw material solution to the organophosphorus halide compound solution at 0-5℃. After the addition is complete, allow it to return to room temperature naturally and stir the reaction for 20h. Monitor the reaction to ensure it is basically complete.

[0043] Step 3: Filter the reaction solution obtained in Step 2, take the filtrate, concentrate it, add 2L of DMAc, and distill to obtain 1380.6g of compound 2a, a colorless liquid, with a yield of 80.2% and a purity of 99.0%.

[0044] <Comparison with Example 1>

[0045] Preparation of compound 2a

[0046] This embodiment provides a method for preparing compound 2a, and the reaction formula is as follows:

[0047]

[0048] Includes the following steps:

[0049] Step 1: Add 10.5 L of dichloromethane to the reaction vessel, cool to 0-5 °C, and then add 1794 g of bromine (11.23 mol, 1.05 eq) and 2947 g of triphenylphosphine (11.23 mol, 1.05 eq) sequentially. Stir and dissolve the solution at -20 °C to -15 °C to obtain an organophosphorus halide solution.

[0050] Step 2: Mix 1050g of compound 1a (10.69mol, 1.0eq) and 889g of pyridine (11.23mol, 1.05eq) to obtain a raw material solution. Add the raw material solution to the organophosphorus halide compound solution at -20℃ to -15℃. After the addition is complete, allow it to return to room temperature naturally and stir the reaction for 20h. Monitor the reaction to ensure it is basically complete.

[0051] Step 3: Filter the reaction solution obtained in Step 2, take the filtrate, concentrate it, add 2L of DMAc, and distill to obtain 1279.0g of compound 2a, a colorless liquid, with a yield of 74.3% and a purity of 99.0%.

[0052] <Example 2>

[0053] Screening of bromine sources

[0054] This embodiment, based on Example 1, further screens the bromine source.

[0055] The screening experimental steps are as follows:

[0056] Add 100 mL of dichloromethane to a flask, cool to 0-5 °C, and then add bromine source (1.07 mol, 1.05 eq) and 280.7 g of triphenylphosphine (1.07 mol, 1.05 eq) in sequence. Stir at 0-5 °C until dissolved to obtain an organophosphorus halide solution.

[0057] 100g of compound 1a (1.02mol, 1.0eq) and 84.6g of pyridine (1.07mol, 1.05eq) were added to obtain a starting solution. The starting solution was added to an organophosphorus halide compound solution at 0-5℃. After the addition was complete, the mixture was allowed to return to room temperature and stirred for 20h.

[0058] Step 3: Filter the reaction solution obtained in Step 2, take the filtrate, concentrate it, add 20 mL of DMAc, and distill to obtain compound 2a.

[0059] The screening results are shown in Table 1.

[0060]

[0061] As shown in Table 1, pyridinium tribromide exhibits the best reaction performance as a bromine source, with a yield of up to 80%, while other bromine sources generally range from 30% to 60%. Further analysis of Examples 1 and Comparative Example 1 reveals that when liquid bromine is used as a bromine source, the corresponding organophosphorus halide solution must be prepared and used at temperatures below -15°C, otherwise the reaction yield will be significantly reduced. However, when pyridinium tribromide is used as a bromine source, the preparation and use of the organophosphorus halide solution at 0-5°C does not significantly affect the reaction yield.

[0062] <Example 3>

[0063] Stability study of organophosphorus halide solutions

[0064] Prepare organophosphorus halide solutions A, B, and C separately, and then react them using the following method:

[0065] 100g of compound 1a (i.e., [1,1'-bis(cyclopropane)]-1-ol, 1.02mol, 1.0eq) and 84.6g of pyridine (1.07mol, 1.05eq) were added to obtain a starting solution. The starting solution was added to an organophosphorus halide compound solution at 0-5℃. After the addition was complete, the mixture was allowed to return to room temperature and stirred for 20h. The resulting reaction solution was filtered, the filtrate was collected, concentrated, and 20mL of DMAc was added. The mixture was then distilled to obtain compound 2a (i.e., 1-bromo-1,1'-bis(cyclopropane)).

[0066] The preparation methods for each organophosphorus halide solution are as follows:

[0067] Organophosphorus halide solution A: Add 100 mL of dichloromethane to a flask, cool to -20℃ to -15℃, then add 171.0 g of bromine (1.07 mol, 1.05 eq) and 280.7 g of triphenylphosphine (1.07 mol, 1.05 eq) sequentially. Stir until dissolved at -20℃ to -15℃, and store at -20℃ to -15℃ for 20 h to obtain organophosphorus halide solution A.

[0068] Organophosphorus halide solution B: Add 100 mL of dichloromethane to a flask, cool to -20℃ to -15℃, then add 171.0 g of bromine (1.07 mol, 1.05 eq) and 280.7 g of triphenylphosphine (1.07 mol, 1.05 eq) sequentially. Stir until dissolved at -20℃ to -15℃, and store at 0-5℃ for 8 h to obtain organophosphorus halide solution B.

[0069] Organophosphorus halide solution C: Add 100 mL of dichloromethane to a flask, cool to 0℃~5℃, then add 342.2 g of pyridinium tribromide (1.07 mol, 1.05 eq) and 280.7 g of triphenylphosphine (1.07 mol, 1.05 eq) sequentially. Stir until dissolved at 0-5℃, and store at 0-5℃ for 20 h to obtain organophosphorus halide solution C.

[0070] The results of the investigation are shown in Table 2.

[0071]

[0072] As shown in Table 2, the organophosphorus halide solutions prepared with bromine exhibit poor stability. Even when stored at -20℃ to -15℃, the reaction yield decreases significantly after 20 hours. If stored at 0-5℃, the reaction yield drops drastically after only 8 hours. Therefore, organophosphorus halide solutions prepared with bromine generally need to be prepared and used immediately at low temperatures, thus limiting their industrial applications. In contrast, organophosphorus halide solutions prepared with pyridinium tribromide demonstrate excellent stability. Even when stored at 0-5℃ for up to 20 hours, the reaction yield hardly decreases and remains at a satisfactory level.

[0073] The role and effect of the embodiments

[0074] According to the bromination reaction of cyclopropanol compounds involved in the above embodiments, since organophosphorus halides prepared from pyridinium tribromide are used as brominating reagents, the present invention can not only avoid the use of high-risk chemical reagent bromine while ensuring high reaction yield, but also the preparation and use temperatures of the corresponding organophosphorus halides can be carried out at 0-5°C, which is milder than the preparation and use temperatures of organophosphorus halides prepared from bromine, thereby enabling the reaction to be more widely used in industry.

[0075] Furthermore, the organophosphorus halides prepared from pyridinium tribromide exhibit better stability, and the reaction yield does not decrease significantly even after storage at 0-5°C for at least 20 hours.

[0076] The above embodiments are preferred embodiments of the present invention and are not intended to limit the scope of protection of the present invention.

Claims

1. A bromination reaction of a cyclopropanol compound, characterized in that, The reaction formula is as follows: In the above formula, R is H, a C1-C6 alkyl group or a C3-C6 cycloalkyl group. Includes the following steps: Step 1: Prepare organophosphorus halides; Step 2: Compound 1 and the acid-binding agent are added to the organophosphorus halide to carry out the reaction; Step 3, post-processing, distillation, yielding compound 2. The preparation method of organophosphorus halides includes the following steps: Triphenylphosphine, a bromine source, and an organic solvent are mixed and reacted to obtain the product. The bromine source is pyridinium tribromide.

2. The bromination reaction of cyclopropanol compounds according to claim 1, characterized in that: in, R stands for cyclopropyl.

3. The bromination reaction of cyclopropanol compounds according to claim 1, characterized in that: in, The acid-binding agent is selected from any one or more of pyridine, triethylamine, or tert-butylmethylamine.

4. The bromination reaction of cyclopropanol compounds according to claim 1, characterized in that: in, The organic solvent is selected from any one of hexamethylphosphoric triamine, N,N-dimethylamide, dichloromethane, or trichloromethane.

5. The bromination reaction of cyclopropanol compounds according to claim 1, characterized in that: in, The molar ratio of compound 1 to the acid-binding agent is 1:(1-1.2).

6. The bromination reaction of cyclopropanol compounds according to claim 1, characterized in that, in, The molar ratio of compound 1 to organophosphorus halide is 1:(1-1.2).

7. The bromination reaction of cyclopropanol compounds according to claim 1, characterized in that, in, In the preparation method for organophosphorus halides, the molar ratio of triphenylphosphine to bromine source is 1:(0.8-1.2).

8. The bromination reaction of cyclopropanol compounds according to claim 1, characterized in that, in, In the preparation of organophosphorus halides, the reaction temperature is 0-40℃.

9. The bromination reaction of cyclopropanol compounds according to claim 1, characterized in that, in, In step 2, compound 1 and the acid-binding agent are added to the organophosphorus halide at 0-40°C.

10. The bromination reaction of cyclopropanol compounds according to claim 1, characterized in that, in, In the preparation method of organophosphorus halides, the mass-volume ratio of triphenylphosphine to solvent is (1.5-5) g: 10 mL.

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