A kind of synthetic method of methyl bromide pyrrolidine carboxylate

Abstract

The invention discloses a synthetic method for methyl brominated pyrrolecarboxylates. The synthetic method of the present invention uses 3-methyl pyrrolecarboxylates or 2-methyl pyrrolecarboxylates as raw materials, uses dibromocyanoacetamide as brominating agent, carries out bromination reaction, and obtains methyl brominated pyrrolecarboxylates. The present invention uses dibromocyanoacetamide as brominating agent, avoids the use of N-bromosuccinimide, improves reaction selectivity, avoids the generation of by-products, and product yield is significantly improved. Post-processing and purification are simple, greatly reduce reaction cost and time cost, and are suitable for industrial amplification production.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and in particular relates to a method for synthesizing methyl bromide-pyrrolecarboxylate. Background Art

[0002] Halopyrrolidine carboxylic acid methyl ester compounds are an important class of organic compounds with wide applications in many fields such as synthesis, pesticides, and medicine. For example, 4-bromopyrrole-2-carboxylic acid methyl ester is used as a key intermediate in the synthesis of an azole triazone melanin concentrating hormone receptor 1 (MCHR1) antagonist in patent WO2010 / 042682, which can treat diabetes, obesity, and related diseases; in CN103848835, it is used in the synthesis of a dipeptidyl peptidase-IV inhibitor (DPP-IV), which can be used to treat or prevent DPP-IV-related diseases such as diabetes; in WO2022 / 007966, it is used in the synthesis of an azaindole derivative, which is a type of influenza virus R NA polymerase basic protein 2 inhibitors (PB2 inhibitors) have the advantages of good efficacy, high bioavailability and few side effects; 5-bromo-1H-pyrrole-2-carboxylic acid methyl ester is also used as a key intermediate in EP3626718 for the synthesis of compounds capable of degrading Ras proteins. These compounds can be used to prevent or treat diseases related to Ras activity, such as tumor growth and metastasis; in WO2022 / 087422, it is used for the synthesis of pyrrolidine-3-carboxamide derivatives, which can be used to treat viral infections (e.g., hepatitis B virus or Flaviviridae virus). Halopyrrolidine carboxylic acid methyl ester compounds have great application potential in drug development.

[0003] Among these compounds, methyl bromopyrrolyl carboxylate serves as an important molecular building block. For example, in WO2023 / 154519, methyl 5-bromo-3-pyrrolyl carboxylate is used to synthesize inhibitors of the RNA helicase DHX9, which can be used to inhibit DHX9 and treat various DHX9-mediated diseases, such as cancer. In EP2336107, it is used to synthesize pyrrole compounds with proton pump inhibitory activity. In WO2022 / 207404, it is used to synthesize substituted pyrrole carboxamide derivatives, which can be used as kinase inhibitors to treat diseases associated with kinase activity disorders, such as cancer, cell proliferative diseases, viral infections, immune diseases, neurodegenerative diseases, cardiovascular diseases, and bone-related diseases. Therefore, studying the synthesis method of methyl bromopyrrolyl carboxylate is of certain significance.

[0004] In the prior art, compound bromo-3-pyrrole carboxylic acid methyl ester, such as 5-bromo-3-pyrrole carboxylic acid methyl ester, its conventional synthesis method is to use 3-pyrrole carboxylic acid methyl ester as starting raw material, and synthesize 5-bromo-3-pyrrole carboxylic acid methyl ester under the effect of N-bromosuccinimide (NBS). The reaction selectivity of this synthetic method is poor, and the target product yield is not high. There is the generation of by-products, and it needs to be purified through column chromatography, which is not suitable for process amplification. Therefore, based on current process status, it is necessary to develop a synthetic method for bromo-3-pyrrole carboxylic acid methyl ester with mild reaction conditions, high selectivity and high yield. Summary of the Invention

[0005] In response to the shortcomings of the prior art, the present invention provides a method for synthesizing methyl brominated pyrrolecarboxylates. The method uses a compound represented by the general formula (I), such as methyl 3-pyrrolecarboxylates or methyl 2-pyrrolecarboxylates, as a raw material and dibromocyanoacetamide as a brominating reagent to synthesize compound 2, i.e., methyl brominated pyrrolecarboxylates, including methyl 5-bromo-3-pyrrolecarboxylates or methyl 5-bromo-2-pyrrolecarboxylates. The entire synthetic process is low-cost, has mild reaction conditions, is easy to operate, produces no by-products, and has simple post-processing. The yield is ideal and the process is suitable for industrial scale-up production.

[0006] The technical solutions of the present invention are as follows:

[0007] The present invention firstly protects the synthesis of methyl bromide pyrrolidine carboxylate, wherein the synthesis method is to react compound 1 with a bromination reagent to obtain the methyl bromide pyrrolidine carboxylate;

[0008] The general structural formula of the compound 1 is shown in formula (I):

[0009]

[0010] Wherein R1, R2 are selected from hydrogen atoms or Moreover, R1 and R2 are different; the bromination reagent is dibromocyanoacetamide.

[0011] Preferably, the synthetic route is as follows:

[0012]

[0013] The synthetic method is specifically:

[0014] S1: dissolve compound 1 in organic solvent I, add bromination reagent, and stir to react;

[0015] S2: The reaction solution is concentrated, and water is added and stirred. After solids are precipitated, they are filtered. The obtained solids are dissolved in organic solvent II, dried, and concentrated to obtain a crude product. After purification, compound 2, i.e., methyl bromopyrrolidone, is obtained.

[0016] Preferably, in step S1, the organic solvent I is selected from one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, dichloromethane, chloroform, and tetrachloromethane.

[0017] Preferably, in step S1, the mass volume ratio of the compound 1 to the organic solvent I is 1:(5-40) in g / mL.

[0018] Preferably, in step S1, the molar ratio of compound 1 to the bromination reagent is 1.0:(1.0-3.0).

[0019] Preferably, in step S1, the molar ratio of compound 1 to the bromination reagent is 1.0:1.0.

[0020] Preferably, in step S1, the stirring reaction is carried out at a temperature of 10-70° C. and for a time of 8-40 h.

[0021] Preferably, in step S2, the organic solvent II is selected from one or more of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane, and dichloroethane.

[0022] Preferably, in step S2, the time for adding water and stirring is 0.5-5 hours.

[0023] Preferably, in step S2, the mass volume ratio of the compound 1 to the amount of water added each time is 1:(10-20) in g / mL.

[0024] Preferably, in step S2, the purification includes one or more of beating, column chromatography, recrystallization, and distillation.

[0025] The beneficial technical effects of the present invention are:

[0026] The present invention uses a compound with a structure represented by general formula (I), such as 3-pyrrolidine carboxylic acid methyl ester or 2-pyrrolidine carboxylic acid methyl ester, as a raw material and dibromocyanoacetamide as a brominating reagent, thereby avoiding the use of N-bromosuccinimide (NBS) as a brominating reagent, thereby decisively improving the reaction selectivity, avoiding the generation of dibrominated by-products, significantly improving the yield of the target product, simplifying post-processing and purification, greatly reducing the reaction cost and time cost, and realizing process scale-up. In addition, the reaction conditions are mild, the operation is simple, no by-products are generated, and the yield is high.

[0027] The synthesis method of the present invention not only provides a potential route for the process synthesis of 5-bromo-3-pyrrolidine carboxylic acid methyl ester or 5-bromo-2-pyrrolidine carboxylic acid methyl ester, but also contributes to the development and utilization of halogenated pyrrolidine carboxylic acid methyl ester compounds. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1This is the H NMR spectrum of the target compound 5-bromo-3-pyrrolidine carboxylic acid methyl ester in Example 1 of the present invention.

[0029] Figure 2 This is the H NMR spectrum of the target compound 5-bromopyrrole-2-carboxylic acid methyl ester in Example 7 of the present invention. DETAILED DESCRIPTION

[0030] The present invention will be described in detail below with reference to the accompanying drawings and embodiments.

[0031] Unless otherwise specified in the following examples, all reagents and materials used were commercially available.

[0032] The present invention provides a method for synthesizing methyl brominated pyrrole carboxylate compounds. The method comprises the following steps: using a compound having a structure represented by general formula (I), such as methyl 3-pyrrole carboxylate or methyl 2-pyrrole carboxylate, as a raw material, and using dibromocyanoacetamide as a bromination reagent to carry out a bromination reaction to obtain a target compound, such as methyl 5-bromo-3-pyrrole carboxylate or methyl 5-bromopyrrole-2-carboxylate.

[0033] In the present invention, raw materials used, such as 3-pyrrolecarboxylic acid methyl esters or 2-pyrrolecarboxylic acid methyl esters have the advantage of low price. When using N-bromosuccinimide as brominating agent for prior art, due to poor reaction selectivity, there is the generation of dibromo by-products, and the target product yield is not high, and it is necessary to purify through column chromatography simultaneously, and the purification difficulty cost is large, and it is not suitable for process amplification. The brominating agent used in the present invention is compared with other brominating agents, improves reaction selectivity, avoids the generation of dibromo by-products, and product yield has significantly improved, and corresponding aftertreatment and purification are simple, greatly reduce reaction cost and time cost, and can realize the amplification of processability.

[0034] It is understandable that the relative amounts of the raw materials and the brominating agent will affect the reaction yield. In the present invention, if the brominating agent is too much, other by-products will be generated; if the brominating agent is too little, the reaction will be incomplete.

[0035] It is understood that the solvent used in the present invention can provide good solubility and stability for the reaction, and the solvent used is preferably THF.

[0036] The present invention will be further described below by way of examples and the like.

[0037] Example 1

[0038] The synthetic route of compound 2a (methyl 5-bromo-3-pyrrolidone) is as follows:

[0039]

[0040] The specific synthesis steps are:

[0041] (1) Compound 1a, methyl 3-pyrrolidine carboxylate (500.00 g, 4.00 mol, 1.0 eq) was dissolved in tetrahydrofuran (5.0 L), and dibromocyanoacetamide (966.50 g, 4.00 mol, 1.0 eq) was slowly added and stirred at room temperature for 12 hours.

[0042] (2) After the reaction is complete, the reaction solution is concentrated and most of the solvent is removed until a small amount of solid precipitates. Water (6.0 L) is then added and stirred for 1 hour. Solid precipitates and is filtered. The resulting solid is again added with water (6.0 L) and stirred for 1 hour. The solid is filtered and dissolved in dichloromethane (7.0 L), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product is slurried with petroleum ether (1.0 L) and filtered to obtain the target compound 2a, i.e., methyl 5-bromo-3-pyrrolidone (yellow solid, weight 801.30 g, purity 98%, yield 96%).

[0043] The H NMR spectrum of the obtained compound 2a is as follows Figure 1 The obtained characterization data are as follows:

[0044] 1 H NMR (400MHz, cdcl3) δ8.79(s,1H),7.36(dd,J=3.0,1.7Hz,1H),6.59(dd,J=2.6,1.8Hz,1H),3.81(s,3H).

[0045] Examples 2-6

[0046] Examples 2-6 are basically the same as Example 1, except that the relative amounts of raw material 1a and bromination reagent, organic solvent I, reaction time, etc. used in the reaction are adjusted, as shown in Table 1.

[0047] Example 7

[0048] The synthetic route of compound 2b (methyl 5-bromopyrrole-2-carboxylate) is as follows:

[0049]

[0050] The specific synthesis steps are:

[0051] (1) Compound 1b, methyl 2-pyrrolidinecarboxylate (500.00 g, 4.00 mol, 1.0 eq), was dissolved in tetrahydrofuran (5.0 L), and dibromocyanoacetamide (966.50 g, 4.00 mol, 1.0 eq) was slowly added and stirred at room temperature for 12 hours.

[0052] (2) After the reaction is complete, the reaction solution is concentrated and most of the solvent is removed until a small amount of solid precipitates. Water (6.0 L) is then added and stirred for 1 hour. Solid precipitates and is filtered. The resulting solid is again added with water (6.0 L) and stirred for 1 hour. The solid is filtered and dissolved in dichloromethane (7.0 L), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product is slurried with petroleum ether (1.0 L) and filtered to obtain the target compound 2b, methyl 5-bromopyrrole-2-carboxylate (off-white solid, weight 793.90 g, purity 98%, yield 95%).

[0053] The H NMR spectrum of the obtained compound 2b is as follows Figure 2 The obtained characterization data are as follows:

[0054] 1 H NMR (400MHz, cdcl3) δ9.21 (s, 1H), 6.89–6.72 (m, 1H), 6.30–6.09 (m, 1H), 3.86 (d, J = 4.5Hz, 3H).

[0055] Comparative Example 1

[0056] Comparative Example 1 is the same as Example 1, except that the bromination reagent used in reaction step (1) was adjusted, as shown in Table 1.

[0057] Test example:

[0058] Through Examples 1-6 and Comparative Example 1, the effects of various reaction conditions on the reaction yield in the synthesis of 5-bromo-3-pyrrolidine carboxylic acid methyl ester were explored, and the results obtained by the reaction are shown in Table 1.

[0059] Table 1 Synthesis conditions and results of Examples and Comparative Examples

[0060]

[0061] As shown in Table 1, when comparing Example 1 and Comparative Example 1, dibromocyanoacetamide is used as the brominating agent, the reaction selectivity is decisively improved, the formation of by-products is avoided, and the product yield is significantly improved. Comparing Examples 1-2, when the molar ratio of raw material 1 to the brominating agent is 1:1, the reaction effect is better. Increasing the amount of the brominating agent will result in the formation of by-products and a decrease in the product yield. Comparing Examples 1, 3-4, the reaction can be carried out in the solvents tetrahydrofuran (THF), N,N-dimethylformamide (DMF), and dichloromethane (DCM), among which tetrahydrofuran is more effective as a solvent. Comparing Examples 1 and 5, the reaction time is extended to 12 hours, and the reaction effect is better.

[0062] The present invention can also prepare compound 2b by changing the raw materials, and has good purity and yield, providing a new idea for the preparation of brominated pyrrolidone ester substances.

[0063] The above description is merely a preferred embodiment of the present invention, and the present invention is not limited to the above embodiment. It is understood that other improvements and variations directly derived or imagined by those skilled in the art without departing from the spirit and concept of the present invention should be considered to be included in the scope of protection of the present invention.

Claims

1. A method for synthesizing methyl brominated pyrrolidone, characterized in that: The synthesis method is to react compound 1 with a bromination reagent to obtain the compound; The general structural formula of the compound 1 is shown in formula (I): (Ⅰ) Wherein R1 and R2 are independently selected from hydrogen atom or structural formula (II); (Ⅱ) Moreover, R1 and R2 are different; The brominating agent is dibromocyanoacetamide.

2. The synthesis method according to claim 1, wherein The route of the synthetic method is as follows: The synthetic method comprises the steps of: S1: dissolve compound 1 in organic solvent I, add bromination reagent, and stir to react; S2: After the reaction solution is concentrated, water is added and stirred. After the solid precipitates, it is filtered. The obtained solid is dissolved in organic solvent II, dried, and concentrated to obtain a crude product, which is purified to obtain methyl bromopyrrolidone.

3. The synthesis method according to claim 2, characterized in that In step S1, the organic solvent I is selected from one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, dichloromethane, chloroform, and tetrachloromethane.

4. The synthesis method according to claim 2, characterized in that In step S1, the mass volume ratio of the compound 1 to the organic solvent I is 1:(5-40) in g / mL.

5. The synthesis method according to claim 2, characterized in that In step S1, the molar ratio of compound 1 to the bromination reagent is 1.0:(1.0-3.0).

6. The synthesis method according to claim 2, characterized in that In step S1, the molar ratio of compound 1 to the bromination reagent is 1.0:1.

0.

7. The synthesis method according to claim 2, characterized in that In step S1, the stirring reaction temperature is 10-70° C. and the time is 8-40 hours.

8. The synthesis method according to claim 2, characterized in that In step S2, the organic solvent II is selected from one or more of ethyl acetate, butyl acetate, chloroform, toluene, chloromethane, and dichloroethane.

9. The synthesis method according to claim 2, characterized in that In step S2, the time of adding water and stirring is 0.5-5h.

10. The synthesis method according to claim 2, characterized in that In step S2, the purification is selected from one or more of beating, column chromatography, recrystallization, and distillation.

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