Synthesis method of bromo-pyrrole methyl formate

Abstract

The invention discloses a synthetic method of bromo-pyrrole methyl formate. According to the synthetic method disclosed by the invention, 3-pyrrole methyl formate or 2-pyrrole methyl formate is taken as a raw material, dibromo cyanoacetamide is taken as a bromination reagent, and bromo-pyrrole methyl formate is obtained through bromination reaction. According to the present invention, the dibromo cyanoacetamide is adopted as the bromination reagent, such that the use of the N-bromosuccinimide is avoided, the reaction selectivity is improved, the generation of the by-product is avoided, the product yield is significantly improved, the post-treatment and the purification are simple, the reaction cost and the time cost are substantially reduced, and the method is suitable for the 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 pyrrolyl carboxylate. Background Art

[0002] Halopyrrol carboxylic acid methyl ester compounds are an important class of organic compounds, which are widely used in many fields such as synthesis, pesticides, and medicine. For example, methyl 4-bromopyrrole-2-carboxylate is used as a key intermediate in the patent WO2010 / 042682 for the synthesis of azole triazone melanin concentrating hormone receptor 1 (MCHR1) antagonists, which can treat diabetes, obesity and related diseases; in CN103848835, it is used for the synthesis of dipeptidyl peptidase-IV inhibitors (DPP-IV), which can be used to treat or prevent DPP-IV related diseases such as diabetes; in WO2022 / 007966, it is used for the synthesis of azaindole derivatives, which are used as 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, which can be used to prevent or treat diseases associated with 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] In this class of compounds, the compound methyl bromide pyrrol carboxylate is used as an important molecular building block. For example, in WO2023 / 154519, methyl 5-bromo-3-pyrrol carboxylate is used to synthesize an inhibitor of 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 related to kinase activity disorders, such as cancer, cell proliferative diseases, viral infections, immune diseases, neurodegenerative diseases, cardiovascular diseases and bone-related diseases. Therefore, it is of certain significance to study the synthesis method of methyl bromide pyrrol carboxylate.

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

[0005] In view of the shortcomings of the prior art, the present invention provides a method for synthesizing methyl brominated pyrrole carboxylate. The present invention uses a compound having a structure shown in general formula (I), such as methyl 3-pyrrole carboxylate or methyl 2-pyrrole carboxylate, as a raw material, and dibromocyanoacetamide as a brominating agent to synthesize compound 2, i.e., methyl brominated pyrrole carboxylate substances, including methyl 5-bromo-3-pyrrole carboxylate or methyl 5-bromo-2-pyrrole carboxylate. The entire synthesis process has low cost, mild reaction conditions, simple operation, no by-products, simple post-treatment, ideal yield, and is suitable for industrial scale-up production.

[0006] The technical solution of the present invention is as follows:

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

[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; and the bromination reagent is dibromocyanoacetamide.

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

[0012]

[0013] The synthetic method is specifically:

[0014] S1: dissolving compound 1 in organic solvent I, adding bromination reagent, and stirring for reaction;

[0015] S2: After the reaction solution is concentrated, water is added and stirred. After the solid is precipitated, it is filtered. The obtained solid is dissolved by adding organic solvent II, dried and concentrated to obtain a crude product. After purification, compound 2, i.e., methyl bromopyrrolidine carboxylate, 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 hours.

[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 0.5-5h.

[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) g / mL.

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

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

[0026] The invention uses a compound with a structure shown in the general formula (I), such as 3-pyrrole carboxylic acid methyl ester or 2-pyrrole carboxylic acid methyl ester, as a raw material and dibromocyanoacetamide as a brominating agent, thereby avoiding the use of N-bromosuccinimide (NBS) as a brominating agent, so that the reaction selectivity is decisively improved, the generation of dibromo by-products is avoided, the yield of the target product is significantly improved, the post-treatment and purification are simple, the reaction cost and time cost are greatly reduced, and the process can be enlarged; at the same time, 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 invention not only provides a potential route for the process synthesis of 5-bromo-3-pyrrolcarboxylic acid methyl ester or 5-bromo-2-pyrrolcarboxylic acid methyl ester, but also contributes to the development and utilization of halogenated pyrrolcarboxylic acid methyl ester compounds. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1This is the H NMR spectrum of the target compound 5-bromo-3-pyrrolcarboxylic 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 is described in detail below in conjunction with the accompanying drawings and embodiments.

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

[0032] The invention provides a method for synthesizing a bromopyrrole carboxylic acid methyl ester compound. The method uses a compound with a structure represented by general formula (I), such as 3-pyrrole carboxylic acid methyl ester or 2-pyrrole carboxylic acid methyl ester, as a raw material and dibromocyanoacetamide as a bromination reagent to carry out a bromination reaction to obtain a target compound, such as 5-bromo-3-pyrrole carboxylic acid methyl ester or 5-bromopyrrole-2-carboxylic acid methyl ester.

[0033] In the present invention, raw materials used, such as 3-pyrrole carboxylic acid methyl ester or 2-pyrrole carboxylic acid methyl ester 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, the target product yield is not high, and it is necessary to purify by column chromatography at the same time, and the purification difficulty cost is large, which is not suitable for process amplification. Compared with other brominating agents, the brominating agent used in the present invention improves reaction selectivity, avoids the generation of dibromo by-products, and the product yield is significantly improved, and the corresponding post-processing and purification are simple, which greatly reduces the reaction cost and time cost, and the amplification of process property can be achieved.

[0034] It is understandable that the relative amounts of the raw materials and the brominating agent will affect the yield of the reaction. 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 can be 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 (5-bromo-3-pyrrolylcarboxylic acid methyl ester) 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 the mixture was stirred at room temperature for 12 hours.

[0042] (2) After the reaction is completed, the reaction solution is concentrated and most of the solvent is removed until a small amount of solid is precipitated. Then water (6.0 L) is added and stirred for 1 hour. Solid is precipitated and filtered. The obtained solid is added with water (6.0 L) again and stirred for 1 hour. The obtained solid is filtered and dissolved in dichloromethane (7.0 L). The obtained solid is 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., 5-bromo-3-pyrrolcarboxylic acid methyl ester (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] Embodiment 2-6

[0046] Examples 2-6 are basically the same as Example 1, except that the relative amounts of the raw material 1a and the bromination reagent, the organic solvent I, the 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 the mixture was stirred at room temperature for 12 hours.

[0052] (2) After the reaction is completed, the reaction solution is concentrated and most of the solvent is removed until a small amount of solid is precipitated. Then water (6.0 L) is added and stirred for 1 hour. Solid is precipitated and filtered. The obtained solid is added with water (6.0 L) again and stirred for 1 hour. The obtained solid is filtered and dissolved in dichloromethane (7.0 L). The obtained solid is 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, i.e., 5-bromopyrrole-2-carboxylic acid methyl ester (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) is 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-pyrrolcarboxylic 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 dibromocyanoacetamide is used as the brominating agent in Example 1 and Comparative Example 1, the reaction selectivity is decisively improved, the formation of by-products is avoided, and the product yield is significantly improved. In Comparative Example 1-2, when the molar ratio of raw material 1 to the brominating agent is 1:1, the reaction effect is better. When the amount of the brominating agent is increased, by-products are generated and the product yield decreases. In Comparative Examples 1, 3-4, the reaction can be carried out in solvents such as tetrahydrofuran (THF), N,N-dimethylformamide (DMF), and dichloromethane (DCM), among which tetrahydrofuran is more effective as a solvent. In Comparative 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, which provides a new idea for preparing brominated pyrrolyl ester substances.

[0063] The above is only a preferred embodiment of the present invention, and the present invention is not limited to the above embodiments. It is understood that other improvements and changes directly derived or associated 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 protection scope of the present invention.

Claims

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

2. The synthesis method according to claim 1, characterized in that The route of the synthetic method is as follows: The synthetic method comprises the following steps: S1: dissolving compound 1 in organic solvent I, adding bromination reagent, and stirring for reaction; S2: After the reaction solution is concentrated, water is added and stirred. After the solid is precipitated, it is filtered. The obtained solid is dissolved by adding organic solvent II, dried and concentrated to obtain a crude product, which is purified to obtain methyl bromopyrrolidine carboxylate.

3. The synthesis method according to claim 1, 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 1, 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 1, 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 1, 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 1, characterized in that In step S1, the stirring reaction is carried out at a temperature of 10-70°C and for a time of 8-40 hours.

8. The synthesis method according to claim 1, characterized in that In step S2, the organic solvent II is selected from one or more of ethyl acetate, butyl acetate, chloroform, toluene, methyl chloride, and ethylene dichloride.

9. The synthesis method according to claim 1, characterized in that In step S2, the time of adding water and stirring is 0.5-5h.

10. The synthesis method according to claim 1, characterized in that In step S2, the purification includes one or more of beating, column chromatography, recrystallization, and distillation.

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